Sample records for adrenoceptor agonist dexmedetomidine

  1. Dexmedetomidine: a novel sedative-analgesic agent

    PubMed Central

    2001-01-01

    Since the first report of clonidine, an α2-adrenoceptor agonist, the indications for this class of drugs have continued to expand. In December 1999, dexmedetomidine was approved as the most recent agent in this group and was introduced into clinical practice as a short-term sedative (<24 hours). α2-Adrenoceptor agonists have several beneficial actions during the perioperative period. They decrease sympathetic tone, with attenuation of the neuroendocrine and hemodynamic responses to anesthesia and surgery; reduce anesthetic and opioid requirements; and cause sedation and analgesia. They allow psychomotoric function to be preserved while letting the patient rest comfortably. With this combination of effects, α2-adrenoceptor agonists may offer benefits in the prophylaxis and adjuvant treatment of perioperative myocardial ischemia. Furthermore, their role in pain management and regional anesthesia is expanding. Side effects consist of mild to moderate cardiovascular depression, with slight decreases in blood pressure and heart rate. The development of new, more selective α2-adrenoceptor agonists with improved side effect profiles may provide a new concept for the administration of perioperative anesthesia and analgesia. This review aims to give background information to improve understanding of the properties and applications of the novel α2-adrenoceptor agonist, dexmedetomidine. PMID:16369581

  2. Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene.

    PubMed

    Tanila, H; Mustonen, K; Sallinen, J; Scheinin, M; Riekkinen, P

    1999-02-01

    The role of the alpha2C-adrenoceptor subtype in mediating the beneficial effect of alpha2-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the alpha2C-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype nonselective alpha2-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 microg/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of alpha2C-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with alpha2-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the alpha2C-adrenoceptor subtype.

  3. Depression of NMDA receptor-mediated synaptic transmission by four α2 adrenoceptor agonists on the in vitro rat spinal cord preparation

    PubMed Central

    Faber, E S L; Chambers, J P; Evans, R H

    1998-01-01

    α2-Adrenoceptor agonists have a spinal site of analgesic action. In the current study the synaptic depressant actions of xylazine, detomidine, romifidine and dexmedetomidine have been compared on segmental reflexes containing NMDA receptor-mediated components in the neonatal rat hemisected spinal cord preparation in vitro.Reflexes were evoked in the ventral root following either supramaximal electrical stimulation of the corresponding ipsilateral lumbar dorsal root to evoke the high intensity excitatory postsynaptic potential (e.p.s.p.) involving all primary afferent fibres, or low intensity stimulation to evoke the solely A fibre-mediated low intensity e.p.s.p. The high intensity e.p.s.p. contains a greater NMDA receptor-mediated component.Xylazine, romifidine, detomidine and dexmedetomidine all depressed both the high intensity e.p.s.p. and the low intensity e.p.s.p. giving respective EC50 values of 0.91±0.2 μM (n=12), 23.4±3 nM (n=12), 37.7±7 nM (n=8) and 0.84±0.1 nM (n=4) for depression of the high intensity e.p.s.p. and 0.76±0.1 μM (n=12), 22.0±3 nM (n=12), 24.9±6 nM (n=4) and 2.7±0.6 nM (n=4) for depression of the low intensity e.p.s.p., respectively. Unlike the other three drugs, the two values for dexmedetomidine, showing a greater selectivity for the high intensity e.p.s.p., are significantly different.Each of these depressant actions was reversed by the selective α2-adrenoceptor antagonist atipamezole (1 μM).In contrast to previous reports of the actions of α2-adrenoceptor agonists on the in vitro spinal cord preparation, at concentrations ten fold higher than the above EC50 values xylazine, romifidine, detomidine and dexmedetomidine depressed the initial population spike of motoneurons (MSR). This depression was not reversed by atipamezole.Comparison of the rank order of the present EC50 values for depression of the high intensity e.p.s.p. with potency ratios from in vivo analgesic tests in previous studies show a close

  4. Importance of agonists in alpha-adrenoceptor classification and localisation of alpha1-adrenoceptors in human prostate.

    PubMed

    McGrath, J C; Naghadeh, M A; Pediani, J D; Mackenzie, J F; Daly, C J

    1999-01-01

    alpha-Adrenoceptor blocker drugs are commonly used in the clinical (non-surgical) treatment of BPH. alpha1-adrenoceptors were originally sub-divided using agonists but, subsequently, were sub-divided using only antagonists in ligand-ligand interactions, which did not require agonists at all. Ultimately, proof that adrenoceptors are functional receptors for the natural ligands, noradrenaline and adrenaline, requires that agonists be used. The earlier excitement engendered by finding varying agonist potency series in different tissues has not been revisited to place it in the context of current concepts of alpha1-adrenoceptor subtypes. This review will consider the advantages and limitations of different agonists for the study of alpha1-adrenoceptor subtypes including 'extreme' examples where the archetypal alpha1-adrenoceptor agonist phenylephrine activates alpha2-adrenoceptors and others where UK14304, often the alpha2-adrenoceptor agonist of choice, activates alpha1-adrenoceptors. New work will also be presented showing the interaction between agonists and the fluorescent alpha1-adrenoceptor antagonist QAPB. This introduces the novel point of view of studying the displacement of antagonists by agonists. Possible errors in antagonist classification arising from complexity in the actions of agonists and the recently developed method of fluorescent ligand binding on isolated living human prostatic smooth muscle cells will be discussed.

  5. Treating agitation with dexmedetomidine in the ICU.

    PubMed

    Boyer, Jeanne

    2009-01-01

    Patients in the intensive care unit frequently experience delirium, anxiety, and agitation, with a variety of treatments used. This article discusses the role of an alpha-adrenoceptor agonist, dexmedetomidine, and its clinical relevance and advantages for the agitated patient.

  6. beta-Adrenoceptor agonists enhance 5-hydroxytryptamine-mediated behavioural responses.

    PubMed Central

    Cowen, P. J.; Grahame-Smith, D. G.; Green, A. R.; Heal, D. J.

    1982-01-01

    The beta-adrenoceptor agonists, salbutamol, terbutaline and clenbuterol, were investigated for their effect on 5-hydroxytryptamine-mediated (5-HT) hyperactivity. 2 The lipophilic beta-adrenoceptor agonist, clenbuterol (5 mg/kg) enhanced the behaviours induced by quipazine (25 mg/kg), including headweaving, forepaw treading and hind-limb abduction and thus increased automated activity recording. Clenbuterol (5 mg/kg) also enhanced the hyperactivity syndrome produced by the 5-HT agonist, 5-methoxy N,N-dimethyltryptamine (2 mg/kg) and the combination of tranylcypromine (10 mg/kg) and L-tryptophan (50 mg/kg). Salbutamol and terbutaline potentiated quipazine-induced hyperactivity only when given at the higher dose of 20 mg/kg. 3 The effect of clenbuterol in enhancing quipazine hyperactivity was blocked by the centrally acting beta 1-adrenoceptor antagonist, metoprolol (5 mg/kg), but not by the beta 2-adrenoceptor antagonist, butoxamine (5 mg/kg) or the peripherally acting beta 1-adrenoceptor antagonist, atenolol (5 mg/kg). 4 Clenbuterol (5 mg/kg) did not enhance the circling responses produced by methamphetamine (0.5 mg/kg) in unilateral nigrostriatal-lesioned rats. 5 The results suggest that beta-adrenoceptor agonists in common with some established antidepressant treatments produce enhancement of 5-HT-mediated behavioural responses. PMID:6124294

  7. Actions of alpha2 adrenoceptor ligands at alpha2A and 5-HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for alpha2A adrenoceptors.

    PubMed

    Newman-Tancredi, A; Nicolas, J P; Audinot, V; Gavaudan, S; Verrièle, L; Touzard, M; Chaput, C; Richard, N; Millan, M J

    1998-08-01

    This study examined the activity of chemically diverse alpha2 adrenoceptor ligands at recombinant human (h) and native rat (r) alpha2A adrenoceptors compared with 5-HT1A receptors. First, in competition binding experiments at h alpha2A and h5-HT1A receptors expressed in CHO cells, several compounds, including the antagonists 1-(2-pyrimidinyl)piperazine (1-PP), (+/-)-idazoxan, benalfocin (SKF 86466), yohimbine and RX 821,002, displayed preference for h alpha2A versus h5-HT1A receptors of only 1.4-, 3.6-, 4-, 10- and 11-fold, respectively (based on differences in pKi values). Clonidine, brimonidine (UK 14304), the benzopyrrolidine fluparoxan and the guanidines guanfacine and guanabenz exhibited intermediate selectivity (22- to 31-fold) for h alpha2A receptors. Only the antagonist atipamezole and the agonist dexmedetomidine (DMT) displayed high preference for alpha2 adrenoceptors (1290- and 91-fold, respectively). Second, the compounds were tested for their ability to induce h5-HT1A receptor-mediated G-protein activation, as indicated by the stimulation of [35S]GTPgammaS binding. All except atipamezole and RX 821,002 exhibited agonist activity, with potencies which correlated with their affinity for h5-HT1A receptors. Relative efficacies (Emax values) were 25-35% for guanabenz, guanfacine, WB 4101 and benalfocin, 50-65% for 1-PP, (+/-)-idazoxan and clonidine, and over 70% for fluparoxan, oxymetazoline and yohimbine (relative to 5-HT = 100%). Yohimbine-induced [35S]GTPgammaS binding was inhibited by the selective 5-HT1A receptor antagonist WAY 100,635. In contrast, RX 821,002 was the only ligand which exhibited antagonist activity at h5-HT1A receptors, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Atipamezole, which exhibited negligeable affinity for 5-HT1A receptors, was inactive. Third, the affinities for r alpha2A differed considerably from the affinities for h alpha2A receptors whereas the affinities for r5-HT1A differed much less from the affinities for h5-HT

  8. Evaluation of partial beta-adrenoceptor agonist activity.

    PubMed

    Lipworth, B J; Grove, A

    1997-01-01

    A partial beta-adrenoceptor (beta-AR) agonist will exhibit opposite agonist and antagonist activity depending on the prevailing degree of adrenergic tone or the presence of a beta-AR agonist with higher intrinsic activity. In vivo partial beta-AR agonist activity will be evident at rest with low endogenous adrenergic tone, as for example with chronotropicity (beta 1/beta 2), inotropicity (beta 1) or peripheral vasodilatation and finger tremor (beta 2). beta-AR blocking drugs which have partial agonist activity may exhibit a better therapeutic profile when used for hypertension because of maintained cardiac output without increased systemic vascular resistance, along with an improved lipid profile. In the presence of raised endogenous adrenergic tone such as exercise or an exogenous full agonist, beta-AR subtype antagonist activity will become evident in terms of effects on exercise induced heart rate (beta 1) and potassium (beta 2) responses. Reduction of exercise heart rate will occur to a lesser degree in the case of a beta-adrenoceptor blocker with partial beta 1-AR agonist activity compared with a beta-adrenoceptor blocker devoid of partial agonist activity. This may result in reduced therapeutic efficacy in the treatment of angina on effort when using beta-AR blocking drugs with partial beta 1-AR agonist activity. Effects on exercise hyperkalaemia are determined by the balance between beta 2-AR partial agonist activity and endogenous adrenergic activity. For predominantly beta 2-AR agonist such as salmeterol and salbutamol, potentiation of exercise hyperkalaemia occurs. For predominantly beta 2-AR antagonists such as carteolol, either potentiation or attenuation of exercise hyperkalaemia occurs at low and high doses respectively. beta 2-AR partial agonist activity may also be expressed as antagonism in the presence of an exogenous full agonist, as for example attenuation of fenoterol induced responses by salmeterol. Studies are required to investigate whether

  9. Functional assessment of recombinant human alpha(2)-adrenoceptor subtypes with cytosensor microphysiometry.

    PubMed

    Pihlavisto, M; Scheinin, M

    1999-12-03

    We applied the Cytosensor Microphysiometry system to study the three human alpha(2)-adrenoceptor subtypes, alpha(2A), alpha(2B) and alpha(2C), expressed in Chinese hamster ovary (CHO) cells, and assessed its potential in the quantitative monitoring of agonist activity. The natural full agonist, (-)-noradrenaline, was used to define agonist efficacy. The imidazole derivative dexmedetomidine was a potent full agonist of all three receptor subtypes. The imidazolines clonidine and UK 14,304 (5-bromo-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine) appeared to be partial agonists at alpha(2B)-adrenoceptors (E(max) approximately 60% of (-)-noradrenaline) but full agonists at alpha(2A)- and alpha(2C)-adrenoceptors. The responses mediated by all three alpha(2)-adrenoceptor subtypes were partly inhibited by the sodium-hydrogen (Na(+)/H(+)) exchange inhibitor, MIA (5-(N-methyl-N-isobutyl)-amiloride). The agonist responses were totally abolished by pretreatment with pertussis toxin in cells with alpha(2A)- and alpha(2C)-adrenoceptors, and partly abolished in cells with alpha(2B)-adrenoceptors. The residual signal in alpha(2B)-cells was sensitive to the intracellular Ca(2+)chelator, BAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid acetoxymethyl ester). Cholera toxin (which acts on G(s)-proteins) had no effect on the agonist responses. The results suggest that the extracellular acidification responses mediated by all three human alpha(2)-adrenoceptor subtypes are dependent on Na(+)/H(+)exchange and G(i/o) pathways, and that alpha(2B)-adrenoceptors are capable of coupling to another, G(i/o)-independent and Ca(2+)-dependent signaling pathway.

  10. Bioavailability of dexmedetomidine after extravascular doses in healthy subjects

    PubMed Central

    Anttila, Markku; Penttilä, Jani; Helminen, Antti; Vuorilehto, Lauri; Scheinin, Harry

    2003-01-01

    Aim To determine the absolute bioavailability of extravascularly administered dexmedetomidine, a novel a2-adrenoceptor agonist, in healthy subjects. Methods Single 2 µg kg−1 doses of dexmedetomidine were given intravenously, intramuscularly, perorally and buccally (where the solution is not swallowed) to 12 healthy male subjects. The drug concentration-time data were analysed using linear one-compartment (buccal and peroral data), or two-compartment modelling (intravenous data), or noncompartmental methods (intramuscular data). Results Mean (95% CI) absolute bioavailability after peroral, buccal and intramuscular administration was 16% (12–20%), 82% (73–92%) and 104% (96–112%), respectively. Conclusion Dexmedetomidine is well absorbed systemically through the oral mucosa, and therefore buccal dosing may provide an effective, noninvasive route to administer the drug. PMID:14616431

  11. Beta2-adrenoceptor agonists for dysmenorrhoea.

    PubMed

    Fedorowicz, Zbys; Nasser, Mona; Jagannath, Vanitha A; Beaman, Jessica H; Ejaz, Kiran; van Zuuren, Esther J

    2012-05-16

    Dysmenorrhoea is a common gynaecological complaint that can affect as many as 50% of premenopausal women, 10% of whom suffer severely enough to be rendered incapacitated for one to three days during each menstrual cycle. Primary dysmenorrhoea is where women suffer from menstrual pain but lack any pathology in their pelvic anatomy. Beta2-adrenoceptor agonists have been used in the treatment of women with primary dysmenorrhoea but their effects are unclear. To determine the effectiveness and safety of beta2-adrenoceptor agonists in the treatment of primary dysmenorrhoea. We searched the Cochrane Menstrual Disorders and Subfertility Group Specialised Register; CENTRAL (The Cochrane Library 2011, Issue 8); MEDLINE; EMBASE; PsycINFO and the EBM Reviews databases. The last search was on 22 August 2011. Randomised controlled trials comparing beta2-adrenoceptor agonists with placebo or no treatment, each other or any other conventional treatment in women of reproductive age with primary dysmenorrhoea. Two review authors independently assessed trial quality and extracted the data. Five trials involving 187 women with an age range of 15 to 40 years were included. Oral isoxsuprine was compared with placebo in two trials; terbutaline oral spray, ritodrine chloride and oral hydroxyphenyl-orciprenalin were compared with placebo in a further three trials. Clinical diversity in the studies in terms of the interventions being evaluated, assessments at different time points and the use of different assessment tools mitigated against pooling of outcome data across studies in order to provide a summary estimate of effect for any of the comparisons. Only one study, with unclear risk of bias, reported pain relief with a combination of isoxsuprine, acetaminophen and caffeine. None of the other studies reported any significant clinical difference in effectiveness between the intervention and placebo. Adverse effects were reported with all of these medications in up to a quarter of the

  12. The protective effects of dexmedetomidine on ischemic brain injury: A meta-analysis.

    PubMed

    Jiang, Lianxiang; Hu, Meizhu; Lu, Yan; Cao, Ya; Chang, Yan; Dai, Zeping

    2017-08-01

    Intracranial lesions, trauma or surgery-related damage activate immune inflammation and neuroendocrine responses, causing ischemic brain injury. Studies have shown that inflammatory cascade mediated by neuroendocrine hormones and proinflammatory mediators is implicated in the pathophysiology of ischemic brain injury. Alpha2-adrenoceptor agonists, dexmedetomidine, is widely used as neuroprotectants in anesthesia practice. However, it is still lack of a comprehensive meta-analysis to evaluate the neuroprotection of dexmedetomidine against ischemic brain injury via suppressing these two physiological responses. Searched the Cochrane Library, Pub-Med, EMBASE, EBSCO, Ovid, Chinese biological and medical database (CBM). Related literatures published in English or Chinese before January 2017 were enrolled. We assessed the quality of eligible studies and synthesized predefined outcomes with a random-effects model or fixed-effects model. Nineteen Randomized Controlled Trials including 879 patients were included. Findings for meta-analysis of various outcomes were summarised. Primary results shown that compared with placebo, dexmedetomidine reduced a surge of TNF-α [SMD=-2.34, 95%CI (-3.25, -1.44)], IL-6 [SMD=-2.44, 95%CI (-3.40, -1.47)], S100-β [SMD=-2.73, 95%CI (-3.65, -1.82)], NSE [SMD=-1.69, 95%CI (-2.77, -0.61)], cortisol [SMD=-2.48, 95%CI (-3.38, -1.58)] and glucose [SMD=-1.44, 95%CI (-1.85, -1.04)]; maintained the level of SOD [SMD=1.36, 95%CI (0.62, 2.10)]; decreased the rise in CRP level at postoperative one day. In response to stress reaction, dexmedetomidine attenuated the stress-related increasing of MAP, HR and intracranial pressure without significant effects on cerebral oxygen metabolism. Alpha2-adrenoceptor agonists, dexmedetomidine, could reduce the release of inflammatory mediators and neuroendocrine hormones as well as maintain intracranial homoeostasis, alleviating ischemic brain injury and exerting an effect on brain protection. Copyright © 2017

  13. Genetic variations in the α(2A)-adrenoreceptor are associated with blood pressure response to the agonist dexmedetomidine.

    PubMed

    Kurnik, Daniel; Muszkat, Mordechai; Li, Chun; Sofowora, Gbenga G; Friedman, Eitan A; Scheinin, Mika; Wood, Alastair J J; Stein, C Michael

    2011-04-01

    α(2A)-Adrenoceptors (α(2A)-ARs) have important roles in sympathetic cardiovascular regulation. Variants of ADRA2A affect gene transcription and expression and are associated with insulin release and risk for type 2 diabetes. We examined whether ADRA2A variants are also associated with cardiovascular responses to the selective α(2)-AR-agonist dexmedetomidine. Seventy-three healthy subjects participated in a placebo-controlled, single-blind study. After 3 infusions of placebo, subjects received 3 incremental infusions of dexmedetomidine (cumulative dose, 0.4 μg/kg). Primary outcomes were changes in systolic blood pressure (SBP) and plasma norepinephrine concentrations, measured as difference of the area-under-the-curve during placebo and dexmedetomidine infusions (ΔAUC). We used multiple linear regression analysis to examine the associations between 9 ADRA2A tagging variants and 5 inferred haplotypes and ΔAUC after adjustment for covariates. Homozygous carriers of rs553668 and the corresponding haplotype 4, previously associated with increased α(2A)-AR expression, had a 2.2-fold greater decrease in AUC(SBP) after dexmedetomidine (adjusted P=0.006); similarly, the maximum decrease in SBP was 24.7±8.1 mm Hg compared with 13.6±5.9 mm Hg in carriers of the wild-type allele (P=0.007). Carriers of haplotype 3, previously associated with reduced α(2A)-AR expression, had a 44% smaller decrease in AUC(SBP) (P=0.013). Haplotype information significantly improved the model predicting the decrease in SBP (P<0.001). There were similar but nonsignificant trends for diastolic blood pressure and heart rate. Genotypes were not significantly associated with norepinephrine responses. Common ADRA2A variants are associated with the hypotensive response to dexmedetomidine. Effects of specific variants/haplotypes in vivo are compatible with their known effects on gene expression in vitro.

  14. Cell type-specific regulation of beta2-adrenoceptor mRNA by agonists.

    PubMed

    Danner, S; Lohse, M J

    1997-07-16

    Prolonged agonist stimulation of beta2-adrenoceptors results in receptor down-regulation which is often paralleled by a reduction of the corresponding mRNA. In this study, we investigated the agonist-dependent regulation of beta2-adrenoceptor mRNA in DDT1-MF2 smooth muscle cells and C6 glioma cells. In DDT1-MF2 cells the half-life of the mRNA was 12 h in monolayer compared to 2 h in suspension cultures. Under both conditions, the agonist isoproterenol reduced this half-life by a factor of 2. In contrast, in C6 glioma cells isoproterenol had no effect on the mRNA stability, even though it reduced mRNA levels by approximately 50%. Isoproterenol-induced downregulation of beta2-adrenoceptor mRNA was completely blocked in C6 cells by the presence of a protein synthesis inhibitor, while this was not so in DDT1-MF2-cells. These data show that beta2-adrenoceptor downregulation occurs via cell-type specific mechanisms.

  15. The effects of dexmedetomidine alone and in combination with tramadol or amitriptyline in a neuropathic pain model.

    PubMed

    Farghaly, Hanan Sm; Abd-Ellatief, Rasha B; Moftah, Marie Z; Mostafa, Mostafa G; Khedr, Eman M; Kotb, Hassan I

    2014-01-01

    Interactions between the sympathetic and somatic nervous system play an essential role in the pathophysiologic mechanisms of neuropathic pain. The α2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Multidrug therapy is potentially valuable to decrease side effects. The aim of the present study was to investigate the possible antinociceptive effect of dexmedetomidine, an α2-adrenoceptor agonist, and its combination with front-line treatment of neuropathic pain, i.e., amitriptyline or tramadol, in a chronic constriction injury (CCI) model of the sciatic nerve in rats. Controlled animal study. Following unilateral ligation of the left sciatic nerve, the effect of intraperitoneal (i.p.) dexmedetomidine (5 ug/kg), tramadol (5 mg/kg), and amitriptyline (30 mg/kg) on mechanical allodynia (measured by electrical von Frey apparatus) and hyperalgesia (measured by Randall and Selitto test) was studied. The sham-operated rats and un-operated hind paw (right paw) press normally on the floor reproduced by a weighted pain score of 0. Behavioral and mechanical tests confirmed the development of neuropathic pain after CCI. All individual drugs and dexmedetomidine combination with either tramadol or amitriptyline were effective in reducing mechanical allodynia and hyperalgesia. Dexmedetomidine, amitriptyline, tramadol, amitriptyline+dexmedetomidine, and tramadol+dexmedetomidine combination did not produce any sedation/motor impairment (P > 0.05). Although the combination of these drugs improved the CCI model of neuropathic pain in this study, an additional interpretation of the underlying mechanism(s) will be needed to confirm these findings. The combination of these drugs appears to be more effective in increasing the pain threshold after peripheral nerve injury, when compared with the administration of either of amitriptyline or tramadol alone and should be considered as a possible alternative to decrease side effects of

  16. Cardiac implications for the use of β2-adrenoceptor agonists for the management of muscle wasting

    PubMed Central

    Molenaar, Peter; Chen, Lu; Parsonage, William A

    2006-01-01

    There are proposals for the implementation of β2-adrenoceptor agonists for the management of muscle wasting diseases. The idea has been initiated by studies in animal models which show that β2-adrenoceptor agonists cause hypertrophy of skeletal muscle. Their use in clinical practice will also need an understanding of possible effects of activation of human heart β2-adrenoceptors. Consequences could include an increased probability of arrhythmias in susceptible patients. PMID:16432500

  17. Electroencephalogram spindle activity during dexmedetomidine sedation and physiological sleep.

    PubMed

    Huupponen, E; Maksimow, A; Lapinlampi, P; Särkelä, M; Saastamoinen, A; Snapir, A; Scheinin, H; Scheinin, M; Meriläinen, P; Himanen, S-L; Jääskeläinen, S

    2008-02-01

    Dexmedetomidine, a selective alpha(2)-adrenoceptor agonist, induces a unique, sleep-like state of sedation. The objective of the present work was to study human electroencephalogram (EEG) sleep spindles during dexmedetomidine sedation and compare them with spindles during normal physiological sleep, to test the hypothesis that dexmedetomidine exerts its effects via normal sleep-promoting pathways. EEG was continuously recorded from a bipolar frontopolar-laterofrontal derivation with Entropy Module (GE Healthcare) during light and deep dexmedetomidine sedation (target-controlled infusions set at 0.5 and 3.2 ng/ml) in 11 healthy subjects, and during physiological sleep in 10 healthy control subjects. Sleep spindles were visually scored and quantitatively analyzed for density, duration, amplitude (band-pass filtering) and frequency content (matching pursuit approach), and compared between the two groups. In visual analysis, EEG activity during dexmedetomidine sedation was similar to physiological stage 2 (S2) sleep with slight to moderate amount of slow-wave activity and abundant sleep spindle activity. In quantitative EEG analyses, sleep spindles were similar during dexmedetomidine sedation and normal sleep. No statistically significant differences were found in spindle density, amplitude or frequency content, but the spindles during dexmedetomidine sedation had longer duration (mean 1.11 s, SD 0.14 s) than spindles in normal sleep (mean 0.88 s, SD 0.14 s; P=0.0014). Analysis of sleep spindles shows that dexmedetomidine produces a state closely resembling physiological S2 sleep in humans, which gives further support to earlier experimental evidence for activation of normal non-rapid eye movement sleep-promoting pathways by this sedative agent.

  18. Distribution and types of adrenoceptors in the guinea-pig ileum: the action of α-and β-adrenoceptor agonists

    PubMed Central

    Bauer, V.

    1981-01-01

    1 Segments of guinea-pig ileum and the myenteric plexus-longitudinal smooth muscle preparation were used for a study of the actions of adrenaline, noradrenaline, isoprenaline, ephedrine and phenylephrine on the responses of coaxially stimulated ileum at different distances from the ileocaecal valve. 2 The responses of the ileum to electrical stimulation were suppressed by adrenaline, nonadrenaline and ephedrine, while phenylephrine and isoprenaline inhibited them only partially. 3 The twitch inhibition elicited by these adrenoceptor agonists was the same at all distances from the ileocaecal valve. There was no significant difference between their cumulative and non-cumulative concentration-response curves. 4 Smooth muscle relaxation was induced only by isoprenaline and contraction only by phenylephrine at all distances from the ileocaecal junction. Adrenaline and noradrenaline evoked smooth muscle contraction in the terminal (0 to 20 cm), a concentration-dependent, biphasic response in the intermediate part (21 to 50 cm) and a relaxation in the proximal ileum (> 50 cm from the ilecocaecal valve). Ephedrine did not change significantly the smooth muscle tension in the terminal and the intermediate segments and induced smooth muscle relaxation in the proximal ones. 5 Ouabain and a potassium-free solution did not appear to influence the prejunctional action of noradrenaline nor the amplitude of smooth muscle relaxation in the proximal ileum, whereas the concentration-contractor response curves were significantly depressed and shifted to the right by ouabain and in a potassium-free solution. 6 The brief initial (phasic) contraction induced by acetylcholine was not influenced during the sustained increase or decrease in tension induced by catecholamines. On the contrary, the stimulatory catecholamine actions disappeared or were changed to smooth muscle relaxation by acetylcholine pretreatment. Potassium chloride pretreatment did not change the character of the

  19. Synthesis, biological evaluation and molecular modeling of 2-amino-2-phenylethanol derivatives as novel β2-adrenoceptor agonists.

    PubMed

    Ge, Xinyue; Mo, Yongmei; Xing, Gang; Ji, Lei; Zhao, Haiyan; Chen, Jianfang; He, Bin; Chen, Xuyao; Xing, Ruijuan; Li, Xiaoqiang; Zhao, Ying; Li, Jinyan; Yan, Haining; Woo, Anthony Yiu-Ho; Zhang, Yuyang; Lin, Bin; Pan, Li; Cheng, Maosheng

    2018-04-26

    A novel series of 2-amino-2-phenylethanol derivatives were developed as β 2 -adrenoceptor agonists. Among them, 2-amino-3-fluoro-5-(2-hydroxy-1-(isopropylamino)ethyl)benzonitrile (compound 2f) exhibited the highest activity (EC 50 = 0.25 nM) in stimulating β 2 -adrenoceptor-mediated cellular cAMP production with a 763.6-fold selectivity over the β 1 -adrenoceptor. The (S)-isomer of 2f was subsequently found to be 8.5-fold more active than the (R)-isomer. Molecular docking was performed to determine the putative binding modes of this new class of β 2 -adrenoceptor agonists. Taken together, these data show that compound 2f is a promising lead compound worthy of further study for the development of β 2 -adrenoceptor agonists. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Dexmedetomidine's inhibitory effects on acetylcholine release from cholinergic nerves in guinea pig trachea: a mechanism that accounts for its clinical benefit during airway irritation.

    PubMed

    Mikami, Maya; Zhang, Yi; Kim, Benjamin; Worgall, Tilla S; Groeben, Harald; Emala, Charles W

    2017-03-29

    Airway instrumentation can evoke upper airway reflexes including bronchoconstriction and cough which can cause serious complications including airway trauma, laryngospasm or bronchospasm which may in turn lead to difficulty with ventilation and hypoxemia. These airway events are mediated in part by irritant-induced neuronal modulation of airway tone and cough responses. We investigated whether the commonly used anesthetic agents dexmedetomidine, lidocaine or remifentanil attenuated neuronal and airway smooth muscle responses in the upper airways of guinea pigs. The ability of dexmedetomidine, lidocaine or remifentanil to attenuate direct cholinergic nerve stimulation, C-fiber stimulation or direct smooth muscle contraction were studied using isolated tracheal rings from male guinea pigs under four paradigms; (1) the magnitude of contractile force elicited by cholinergic electrical field stimulation (EFS); (2) the amount of acetylcholine released during cholinergic EFS; (3) the direct airway smooth muscle relaxation of a sustained acetylcholine-induced contraction and (4) the magnitude of C-fiber mediated contraction. Dexmedetomidine (1-100 μM) and lidocaine (1 mM) attenuated cholinergic 30Hz EFS-induced tracheal ring contraction while remifentanil (10 μM) had no effect. Dexmedetomidine at 10 μM (p = 0.0047) and 100 μM (p = 0.01) reduced cholinergic EFS-induced acetylcholine release while lidocaine (10 μM-1 mM) and remifentanil (0.1-10 μM) did not. Tracheal ring muscle force induced by the exogenous addition of the contractile agonist acetylcholine or by a prototypical C-fiber analogue of capsaicin were also attenuated by 100 μM dexmedetomidine (p = 0.0061 and p = 0.01, respectively). The actual tracheal tissue concentrations of dexmedetomidine achieved (0.54-26 nM) following buffer application of 1-100 μM of dexmedetomidine were within the range of clinically achieved plasma concentrations (12 nM). The α2 adrenoceptor agonist

  1. The alpha2-adrenoreceptor agonist dexmedetomidine protects against lipopolysaccharide-induced apoptosis via inhibition of gap junctions in lung fibroblasts.

    PubMed

    Zhang, Yuan; Tan, Xiaoming; Xue, Lianfang

    2018-01-01

    The α2-adrenoceptor inducer dexmedetomidine protects against acute lung injury (ALI), but the mechanism of this effect is largely unknown. The present study investigated the effect of dexmedetomidine on apoptosis induced by lipopolysaccharide (LPS) and the relationship between this effect and gap junction intercellular communication in human lung fibroblast cell line. Flow cytometry was used to detect apoptosis induced by LPS. Parachute dye coupling assay was used to measure gap junction function, and western blot analysis was used to determine the expression levels of connexin43 (Cx43). The results revealed that exposure of human lung fibroblast cell line to LPS for 24 h increased the apoptosis, and pretreatment of dexmedetomidine and 18α-GA significantly reduced LPS-induced apoptosis. Dexmedetomidine exposure for 1 h inhibited gap junction function mainly via a decrease in Cx43 protein levels in human lung fibroblast cell line. These results demonstrated that the inhibition of gap junction intercellular communication by dexmedetomidine affected the LPS-induced apoptosis through inhibition of gap junction function by reducing Cx43 protein levels. The present study provides evidence of a novel mechanism underlying the effects of analgesics in counteracting ALI. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Interruption of spinal cord microglial signaling by alpha-2 agonist dexmedetomidine in a murine model of delayed paraplegia.

    PubMed

    Bell, Marshall T; Agoston, Viktor A; Freeman, Kirsten A; Puskas, Ferenc; Herson, Paco S; Mares, Joshua; Fullerton, David A; Reece, T Brett

    2014-04-01

    Despite investigation into preventable pharmacologic adjuncts, paraplegia continues to complicate thoracoabdominal aortic interventions. The alpha 2a adrenergic receptor agonist, dexmedetomidine, has been shown to preserve neurologic function and neuronal viability in a murine model of spinal cord ischemia reperfusion, although the mechanism remains elusive. We hypothesize that dexmedetomidine will blunt postischemic inflammation in vivo following thoracic aortic occlusion with in vitro demonstration of microglial inhibition following lipopolysaccharide (LPS) stimulation. Adult male C57BL/6 mice underwent 4 minutes of aortic occlusion. Mice received 25 μg/kg intraperitoneal dexmedetomidine (n = 8) or 0.9% normal saline (n = 7) at reperfusion and 12-hour intervals postoperatively until 48 hours. Additionally, sham mice (n = 3), which had aortic arch exposed with no occlusion, were included for comparison. Functional scoring was done at 6 hours following surgery and 12-hour intervals until 60 hours when spinal cords were removed and examined for neuronal viability and cytokine production. Additional analysis of microglia activation was done in 12 hours following surgery. Age- and sex-matched mice had spinal cord removed for microglial isolation culture. Cells were grown to confluence and stimulated with toll-like receptor-4 agonist LPS 100 ng/mL in presence of dexmedetomidine or vehicle control for 24 hours. Microglia and media were then removed for analysis of protein expression. Dexmedetomidine treatment at reperfusion significantly preserved neurologic function with mice in treatment group having a Basso Score of 6.3 in comparison to 2.3 in ischemic control group. Treatment was associated with a significant reduction in microglia activation and in interleukin-6 production. Microglial cells in isolation when stimulated with LPS had an increased production of proinflammatory cytokines and markers of activation. Treatment with dexmedetomidine significantly

  3. Neuroprotection and neurotoxicity in the developing brain: an update on the effects of dexmedetomidine and xenon.

    PubMed

    Alam, Azeem; Suen, Ka Chun; Hana, Zac; Sanders, Robert D; Maze, Mervyn; Ma, Daqing

    Growing and consistent preclinical evidence, combined with early clinical epidemiological observations, suggest potentially neurotoxic effects of commonly used anesthetic agents in the developing brain. This has prompted the FDA to issue a safety warning for all sedatives and anesthetics approved for use in children under three years of age. Recent studies have identified dexmedetomidine, the potent α2-adrenoceptor agonist, and xenon, the noble gas, as effective anesthetic adjuvants that are both less neurotoxic to the developing brain, and also possess neuroprotective properties in neonatal and other settings of acute ongoing neurologic injury. Dexmedetomidine and xenon are effective anesthetic adjuvants that appear to be less neurotoxic than other existing agents and have the potential to be neuroprotective in the neonatal and pediatric settings. Although results from recent clinical trials and case reports have indicated the neuroprotective potential of xenon and dexmedetomidine, additional randomized clinical trials corroborating these studies are necessary. By reviewing both the existing preclinical and clinical evidence on the neuroprotective effects of dexmedetomidine and xenon, we hope to provide insight into the potential clinical efficacy of these agents in the management of pediatric surgical patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. The pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor agonists in the treatment of airway and bladder disease☆

    PubMed Central

    Dale, Philippa R; Cernecka, Hana; Schmidt, Martina; Dowling, Mark R; Charlton, Steven J; Pieper, Michael P; Michel, Martin C

    2014-01-01

    Muscarinic receptor antagonists and β-adrenoceptor agonists are used in the treatment of obstructive airway disease and overactive bladder syndrome. Here we review the pharmacological rationale for their combination. Muscarinic receptors and β-adrenoceptors are physiological antagonists for smooth muscle tone in airways and bladder. Muscarinic agonism may attenuate β-adrenoceptor-mediated relaxation more than other contractile stimuli. Chronic treatment with one drug class may regulate expression of the target receptor but also that of the opposing receptor. Prejunctional β2-adrenoceptors can enhance neuronal acetylcholine release. Moreover, at least in the airways, muscarinic receptors and β-adrenoceptors are expressed in different locations, indicating that only a combined modulation of both systems may cause dilatation along the entire bronchial tree. While all of these factors contribute to a rationale for a combination of muscarinic receptor antagonists and β-adrenoceptor agonists, the full value of such combination as compared to monotherapy can only be determined in clinical studies. PMID:24682092

  5. Dexmedetomidine alleviates anxiety-like behaviors and cognitive impairments in a rat model of post-traumatic stress disorder.

    PubMed

    Ji, Mu-Huo; Jia, Min; Zhang, Ming-Qiang; Liu, Wen-Xue; Xie, Zhong-Cong; Wang, Zhong-Yun; Yang, Jian-Jun

    2014-10-03

    Post-traumatic stress disorder (PTSD) is a psychiatric disease that has substantial health implications, including high rates of health morbidity and mortality, as well as increased health-related costs. Although many pharmacological agents have proven the effects on the development of PTSD, current pharmacotherapies typically only produce partial improvement of PTSD symptoms. Dexmedetomidine is a selective, short-acting α2-adrenoceptor agonist, which has anxiolytic, sedative, and analgesic effects. We therefore hypothesized that dexmedetomidine possesses the ability to prevent the development of PTSD and alleviate its symptoms. By using the rat model of PTSD induced by five electric foot shocks followed by three weekly exposures to situational reminders, we showed that the stressed rats displayed pronounced anxiety-like behaviors and cognitive impairments compared to the controls. Notably, repeated administration of 20μg/kg dexmedetomidine showed impaired fear conditioning memory, decreased anxiety-like behaviors, and improved spatial cognitive impairments compared to the vehicle-treated stressed rats. These data suggest that dexmedetomidine may exert preventive and protective effects against anxiety-like behaviors and cognitive impairments in the rats with PTSD after repeated administration. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Influenza A virus infection and cigarette smoke impair bronchodilator responsiveness to β-adrenoceptor agonists in mouse lung.

    PubMed

    Donovan, Chantal; Seow, Huei Jiunn; Bourke, Jane E; Vlahos, Ross

    2016-05-01

    β2-adrenoceptor agonists are the mainstay therapy for patients with asthma but their effectiveness in cigarette smoke (CS)-induced lung disease such as chronic obstructive pulmonary disease (COPD) is limited. In addition, bronchodilator efficacy of β2-adrenoceptor agonists is decreased during acute exacerbations of COPD (AECOPD), caused by respiratory viruses including influenza A. Therefore, the aim of the present study was to assess the effects of the β2-adrenoceptor agonist salbutamol (SALB) on small airway reactivity using mouse precision cut lung slices (PCLS) prepared from CS-exposed mice and from CS-exposed mice treated with influenza A virus (Mem71, H3N1). CS exposure alone reduced SALB potency and efficacy associated with decreased β2-adrenoceptor mRNA expression, and increased tumour necrosis factor α (TNFα) and interleukin-1β (IL-1β) expression. This impaired relaxation was restored by day 12 in the absence of further CS exposure. In PCLS prepared after Mem71 infection alone, responses to SALB were transient and were not well maintained. CS exposure prior to Mem71 infection almost completely abolished relaxation, although β2-adrenoceptor and TNFα and IL-1β expression were unaltered. The present study has shown decreased sensitivity to SALB after CS or a combination of CS and Mem71 occurs by different mechanisms. In addition, the PCLS technique and our models of CS and influenza infection provide a novel setting for assessment of alternative bronchodilators. © 2016 The Author(s).

  7. The β3 -adrenoceptor agonist mirabegron increases human atrial force through β1 -adrenoceptors: an indirect mechanism?

    PubMed

    Mo, Weilan; Michel, Martin C; Lee, Xiang Wen; Kaumann, Alberto J; Molenaar, Peter

    2017-08-01

    Mirabegron has been classified as a β 3 -adrenoceptor agonist approved for overactive bladder syndrome. We investigated possible cardiac effects of mirabegron in the absence or presence of β-adrenoceptor subtype antagonists. In view of its phenylethanolamine structure, we investigated whether mirabegron has indirect sympathomimetic activity by using neuronal uptake blockers. Right atrial trabeculae, from non-failing hearts, were paced and contractile force measured at 37°C. Single concentrations of mirabegron were added in the absence or presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), β 3 (L-748,337), β 1 (CGP 20712A), β 2 (ICI 118,551) -adrenoceptor antagonists, neuronal uptake inhibitors desipramine or phenoxybenzamine. Mirabegron significantly increased contractile force in human right atrium (1 μM, 7.6 ± 2.6%, n = 7; 10 μM, 10.2 ± 1.5%, n = 22 compared with (-)-isoprenaline P < 0.05). In the presence of IBMX, mirabegron (10 μM) caused a greater contraction. L-748,337 (100 nM) had no effect on the increase in contractile force caused by mirabegron (10 μM). In contrast, mirabegron (10 μM) reduced contractile force in the presence of CGP 20712A, which was not affected by L-748,337 (100 nM) or ICI 118,551 (50 nM). Mirabegron (10 μM) also reduced contractile force in the presence of desipramine or phenoxybenzamine. Mirabegron increases human atrial force through β 1 - but not β 3 -adrenoceptors. Desipramine and phenoxybenzamine block neuronal uptake and conceivably prevent mirabegron from releasing noradrenaline. A non-specific cardiodepressant effect is not mediated through β 3 (or β 2 )-adrenoceptors, consistent with lack of β 3 -adrenoceptor function on human atrial contractility. © 2017 The British Pharmacological Society.

  8. Locomotor activity of rats with SCI is improved by dexmedetomidine by targeting the expression of inflammatory factors.

    PubMed

    Wang, Wei-Guo; Wang, Lin; Jiao, Zhen-Hua; Xue, Bin; Xu, Zhan-Wang

    2018-04-26

    Dexmedetomidine, a well‑known selective α‑2 adrenoceptor agonist, inhibits the apoptosis of neurons and protects other organs from oxidative damage. In the present study, the effect of dexmedetomidine on spinal cord injury (SCI) in a rat model was investigated. The SCI rat model was prepared using the weight‑drop method, and the effect of dexmedetomidine on locomotor activity was analyzed using the Basso, Beattie and Bresnahan (BBB) rating scale. Western blot analysis was used to observe changes in the expression of apoptosis‑related proteins, including B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein (Bax). The results revealed that treatment of the SCI rats with dexmedetomidine at a dose of 50 mg/kg significantly prevented the formation of edema in the tissues of the spinal cord. Dexmedetomidine also inhibited the SCI‑induced accumulation of neutrophils in the spinal cord. The BBB scores were significantly increased (P<0.05) in the rats with SCI treated with dexmedetomidine after 10 days. The results of grid walking test revealed a marked decrease in the number of missteps following 10 days of dexmedetomidine treatment. The expression levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑1β were significantly reduced (P<0.05) in the spinal cord tissues of the dexmedetomidine group, compared with those in the control group of rats. Dexmedetomidine treatment following SCI exerted an inhibitory effect on the SCI‑induced increase in the expression of Bax. The expression of Bcl‑2 was increased in the dexmedetomidine treated rats, compared with that in the control group. Taken together, dexmedetomidine improved the locomotor activity of the rats through the inhibition of edema, reduction in the expression levels of TNF‑α and IL‑1β, and inhibition of the induction of apoptosis. Therefore, dexmedetomidine may be of therapeutic importance for patients with SCI.

  9. A cell-based assay to assess the persistence of action of agonists acting at recombinant human beta(2) adrenoceptors.

    PubMed

    Summerhill, Susan; Stroud, Timothy; Nagendra, Roshini; Perros-Huguet, Christelle; Trevethick, Michael

    2008-01-01

    The aim was to establish a robust, 96-well, cell-based assay to assess the potency and persistence of action of agonists acting at human recombinant beta(2) adrenoceptors expressed in CHO (Chinese Hamster Ovary) cells and to compare this with published duration of action data in guinea pig isolated trachea and human bronchus. Cells were treated with either: (i) beta-adrenoceptor agonist for 30 min, washed and cyclicAMP (cAMP) measured 30 min later-termed 'washed' cells or, (ii) treated with solvent for 30 min, washed, and then treated with beta-adrenoceptor agonist for 30 min and cAMP measured-termed 'unwashed' cells. The 'washed' EC(50) was divided by the 'unwashed' EC(50) to determine a rightward shift concentration ratio, which was indicative of the persistence of action at the receptor. At the beta(2) adrenoceptor salmeterol, carmoterol and indacaterol were resistant to washing with a concentration ratio of <5, indicating a long persistence of action, whereas formoterol, isoprenaline and salbutamol were washed out with a ratio of 32, >294 and >800 respectively, suggesting a shorter persistence of action. At beta(1) and beta(3) adrenoceptors all compounds washed out. The persistent effects of salmeterol at beta(2) following washing could be reversed by the selective beta(2) antagonist ICI 118551, suggesting continued receptor activation. The data presented agree well with published data assessing duration of action of beta(2) agonists in human isolated bronchus and guinea pig isolated trachea. Key features are: (a) it is a 96-well format which can be used to assess many compounds in a single experiment, (b) both potency and persistence of agonist action are assessed in the same assay, (c) any effects of concentration on the persistence of action can be highlighted, and (d) it allows triage of compounds prior to tissue bath studies thus reducing the use of animal tissue.

  10. In vitro desensitization of beta-adrenoceptors in guinea pig trachea: interactions between beta-adrenoceptor agonists and influence of adenosine and other drugs.

    PubMed

    Matran, R; Naline, E; Advenier, C; Duroux, P

    1989-01-01

    The aim of this study was to investigate quantitatively the action of and the interaction between beta-adrenergic receptor agonists in desensitizing guinea pig isolated trachea. It was also to evaluate the influence of substances whose effects on desensitization are either disputed (theophylline, indomethacin, ketotifen, hydrocortisone) or unknown (nicardipine, Bay K 8644, fenspiride, adenosine). Tracheal strips were contracted with histamine (5 x 10(-5) M) or acetylcholine (5.10(-5) M) and concentration-response (C/R) curves for various beta-adrenoceptor agonists were determined before and after incubation (20 min to 4 h) with the same beta-adrenoceptor agonist (autodesensitization), with other beta-adrenoceptor agonists (cross-desensitization), or with a beta-adrenoceptor agonist and another substance. Our results show that the autodesensitization induced by isoprenaline is concentration dependent and that concentration dependence is more pronounced with salbutamol and fenoterol than with isoprenaline and adrenaline with respect to autodesensitization: shifts (log unit) of the C/R curves were 0.59 +/- 0.06 (N = 5) for salbutamol (10(-5) M), 0.78 +/- 0.09 (N = 5) for fenoterol (10(-6) M), 0.30 +/- 0.04 (N = 9) for isoprenaline (10(-5) M), and 0.33 +/- 0.05 (N = 5) for adrenaline (10(-5) M). Our studies of cross-desensitization (desensitization to isoprenaline, adrenaline, salbutamol, and fenoterol induced by incubation with isoprenaline 10(-5) M) showed a significantly greater shift in the C/R curves for fenoterol (0.56 +/- 0.08, N = 5) and salbutamol (0.62 +/- 0.05, N = 5) than for adrenaline (0.35 +/- 0.07, N = 5) and isoprenaline itself (0.30 +/- 0.05, N = 9). Of the substances we studied, none modified the desensitization induced by isoprenaline except hydrocortisone and adenosine. Hydrocortisone (10(-8) M) reduced it significantly, although to a negligible extent. Adenosine (3 x 10(-4) M) did not shift the C/R curve to isoprenaline by itself, but incubation

  11. Effects of muscarinic receptor agonists and antagonists on alpha 2-adrenoceptors in rat brain.

    PubMed

    Hollingsworth, P J; Smith, C B

    1989-09-13

    The specific binding of [3H]clonidine to alpha 2-adrenoceptors on neural membranes isolated from six brain areas was determined with rats treated for various periods of time with the muscarinic agonists, oxotremorine or pilocarpine, or with the muscarinic antagonists atropine, atropine methyl nitrate, scopolamine and scopolamine methyl bromide. Administration of pilocarpine, 10 mg/kg, twice daily i.p. for 1 and 14 days increased markedly the number of alpha 2-adrenoceptors on neural membranes from all six brain areas. In contrast, oxotremorine, 0.3 mg/kg, twice daily i.p., for 7 days decreased the number of alpha 2-adrenoceptors on membranes from all brain areas except the brainstem and caudate nucleus. Both atropine and scopolamine increased the density of alpha 2-adrenoceptors in specific brain areas. Neither atropine methyl nitrate nor scopolamine methyl bromide had an appreciable effect upon the specific binding of [3H]clonidine to neural membranes from most brain areas.

  12. In vivo microdialysis of noradrenaline overflow: effects of alpha-adrenoceptor agonists and antagonists measured by cumulative concentration-response curves.

    PubMed Central

    van Veldhuizen, M. J.; Feenstra, M. G.; Heinsbroek, R. P.; Boer, G. J.

    1993-01-01

    1. The purpose of the present study was to compare the effects of several alpha-adrenoceptor agonists and antagonists on cerebral cortical overflow of endogenous noradrenaline (NA) in freely moving rats. One or two days after the implantation of transcerebral dialysis tubes in the frontoparietal cortex, extracellular NA levels were monitored on-line with high performance liquid chromatography and electrochemical detection. The drugs were applied locally via the dialysis membrane, and effects on NA overflow were determined in cumulative concentration-response curves. 2. The average basal cortical NA overflow of all experiments was 0.25 pg min-1. The alpha 2-adrenoceptor agonists caused a concentration-dependent decrease in NA levels. UK-14,304 was the most potent and B-HT 933 the least potent agonist. The maximal decrease in NA overflow was to 10-15% of control levels after UK-14,304 or moxonidine, to 30% after clonidine and to 50% after B-HT 933 administration. Continuous activation of the presynaptic alpha 2-adrenoceptor with 10(-6) M UK-14,304 caused a decrease in NA levels to 40-50% of basal levels. This decrease was reached within 1 h and remained stable for the entire 3 h measurement period. The alpha 1-adrenoceptor agonists, phenylephrine and methoxamine, induced an increase in NA levels to 225% and 300%, respectively, at a concentration of 10(-3) M. 3. Local application of alpha 2-adrenoceptor antagonists caused an increase in NA levels, with idazoxan being more potent than piperoxan. Yohimbine did not cause any significant change. 4. All drugs used in these in vivo experiments had in vitro recoveries across the dialysis membrane between 10 and 20%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8102934

  13. Effect of alpha 2-adrenoceptor agonists on gastric pepsin and acid secretion in the rat.

    PubMed Central

    Tazi-Saad, K.; Chariot, J.; Del Tacca, M.; Rozé, C.

    1992-01-01

    1. The purpose of the present study was to analyze the effects of the alpha 2-adrenoceptor agonists clonidine, guanabenz, detomidine and medetomidine on pepsin secretion in conscious rats provided with gastric chronic fistula and to compare this with acid secretion. 2. Basal interdigestive gastric secretion, which is mainly neurally driven in the rat, and the secretion directly stimulated by the two main stimulants of chief cells, cholecystokinin octapeptide (CCK8) and methacholine, were studied. 3. Basal secretion of pepsin and acid was inhibited by all four drugs with comparable EC50S. 4. CCK-stimulated pepsin and acid secretion was less sensitive than basal pepsin and acid secretion to alpha 2-adrenoceptor inhibition. 5. Methacholine-stimulated pepsin and acid secretion was not changed by clonidine and guanabenz; methacholine-stimulated acid was even marginally increased by clonidine. 6. These results do not favour the presence of alpha 2-receptors on chief cells in the rat stomach. They rather suggest that pepsin inhibition by alpha 2-adrenoceptor agonists is indirect and due to central or peripheral inhibition of the discharge of nerve fibres activating pepsin secretion. PMID:1356566

  14. Activation of alpha2 adrenergic receptors suppresses fear conditioning: expression of c-Fos and phosphorylated CREB in mouse amygdala.

    PubMed

    Davies, M Frances; Tsui, Janet; Flannery, Judy A; Li, Xiangqi; DeLorey, Timothy M; Hoffman, Brian B

    2004-02-01

    alpha(2) adrenergic agonists such as dexmedetomidine generally suppress noradrenergic transmission and have sedative, analgesic, and antihypertensive properties. Considering the importance of the neurotransmitter norepinephrine in forming memories for fearful events, we have investigated the acute and chronic effects of dexmedetomidine on discrete cue and contextual fear conditioning in mice. When administered before training, dexmedetomidine (10-20 microg/kg, i.p.) selectively suppressed discrete cue fear conditioning without affecting contextual memory. This behavioral change was associated with a decrease in memory retrieval-induced expression of c-Fos and P-CREB in the lateral, basolateral, and central nuclei of the amygdala. Dexmedetomidine's action on discrete cue memory did not occur in alpha(2A) adrenoceptor knockout (KO) mice. When dexmedetomidine was administered after training, it suppressed contextual memory, an effect that did not occur in alpha(2A) adrenoceptor KO mice. We conclude that dexmedetomidine, acting at alpha(2A) adrenoceptors, must be present during the encoding process to decrease discrete cue fear memory; however, its ability to suppress contextual memory is likely the result of blocking the consolidation process. The ability of alpha(2) agonists to suppress fear memory may be a valuable property clinically in order to suppress the formation of memories during stressful situations.

  15. Adverse reactions of α2-adrenoceptor agonists in cats reported in 2003-2013 in Finland.

    PubMed

    Raekallio, Marja R; Virtanen, Marika; Happonen, Irmeli; Vainio, Outi M

    2017-07-01

    To describe suspected adverse drug reactions in cats associated with use of α 2 -adrenoceptor agonists. Retrospective study. A total of 90 cats. Data were collected from reports on adverse reactions to veterinary medicines sent to the Finnish Medicines Agency during 2003-2013. All reports of suspected adverse reactions associated with use of α 2 -adrenoceptor agonists in cats were included. Probable pulmonary oedema was diagnosed based on post mortem or radiological examination, or presence of frothy or excess fluid from the nostrils or trachea. If only dyspnoea and crackles on auscultation were reported, possible pulmonary oedema was presumed. Pulmonary oedema was suspected in 61 cases. Of these cats, 37 were categorised as probable and 24 as possible pulmonary oedema. The first clinical signs had been noted between 1 minute and 2 days (median, 15 minutes) after α 2 -adrenoceptor agonist administration. Many cats probably had no intravenous overhydration when the first clinical signs were detected, as either they presumably had no intravenous cannula or the signs appeared before, during or immediately after cannulation. Of the 61 cats, 43 survived, 14 died and for four the outcome was not clearly stated. Pulmonary oedema is a perilous condition that may appear within minutes of an intramuscular administration of sedative or anaesthetic agent in cats. The symptoms were not caused by intravenous overhydration, at least in cats having no venous cannula when the first clinical signs were detected. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

  16. Effect of beta2-adrenoceptor agonists and other cAMP-elevating agents on inflammatory gene expression in human ASM cells: a role for protein kinase A.

    PubMed

    Kaur, Manminder; Holden, Neil S; Wilson, Sylvia M; Sukkar, Maria B; Chung, Kian Fan; Barnes, Peter J; Newton, Robert; Giembycz, Mark A

    2008-09-01

    In diseases such as asthma, airway smooth muscle (ASM) cells play a synthetic role by secreting inflammatory mediators such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, or IL-8 and by expressing surface adhesion molecules, including ICAM-1. In the present study, PGE(2), forskolin, and short-acting (salbutamol) and long-acting (salmeterol and formoterol) beta(2)-adrenoceptor agonists reduced the expression of ICAM-1 and the release of GM-CSF evoked by IL-1beta in ASM cells. IL-1beta-induced IL-8 release was also repressed by PGE(2) and forskolin, whereas the beta(2)-adrenoceptor agonists were ineffective. In each case, repression of these inflammatory indexes was prevented by adenoviral overexpression of PKIalpha, a highly selective PKA inhibitor. These data indicate a PKA-dependent mechanism of repression and suggest that agents that elevate intracellular cAMP, and thereby activate PKA, may have a widespread anti-inflammatory effect in ASM cells. Since ICAM-1 and GM-CSF are highly NF-kappaB-dependent genes, we used an adenoviral-delivered NF-kappaB-dependent luciferase reporter to examine the effects of forskolin and the beta(2)-adrenoceptor agonists on NF-kappaB activation. There was no effect on luciferase activity measured in the presence of forskolin or beta(2)-adrenoceptor agonists. This finding is consistent with the observation that IL-1beta-induced expression of IL-6, a known NF-kappaB-dependent gene in ASM, was also unaffected by beta(2)-adrenoceptor agonists, forskolin, PGE(2), 8-bromo-cAMP, or rolipram. Collectively, these results indicate that repression of IL-1beta-induced ICAM-1 expression and GM-CSF release by cAMP-elevating agents, including beta(2)-adrenoceptor agonists, may not occur through a generic effect on NF-kappaB.

  17. Stereochemistry of an agonist determines coupling preference of beta2-adrenoceptor to different G proteins in cardiomyocytes.

    PubMed

    Woo, Anthony Yiu-Ho; Wang, Tian-Bing; Zeng, Xiaokun; Zhu, Weizhong; Abernethy, Darrell R; Wainer, Irving W; Xiao, Rui-Ping

    2009-01-01

    A fundamental question regarding receptor-G protein interaction is whether different agonists can lead a receptor to different intracellular signaling pathways. Our previous studies have demonstrated that although most beta(2)-adrenoceptor agonists activate both G(s) and G(i) proteins, fenoterol, a full agonist of beta(2)-adrenoceptor, selectively activates G(s) protein. Fenoterol contains two chiral centers and may exist as four stereoisomers. We have synthesized a series of stereoisomers of fenoterol and its derivatives and characterized their receptor binding and pharmacological properties. We tested the hypothesis that the stereochemistry of an agonist determines selectivity of receptor coupling to different G protein(s). We found that the R,R isomers of fenoterol and methoxyfenoterol exhibited more potent effects to increase cardiomyocyte contraction than their S,R isomers. It is noteworthy that although (R,R)-fenoterol and (R,R)-methoxyfenoterol preferentially activate G(s) signaling, their S,R isomers were able to activate both G(s) and G(i) proteins as evidenced by the robust pertussis toxin sensitivities of their effects on cardiomyocyte contraction and on phosphorylation of extracellular signal-regulated kinase 1/2. The differential G protein selectivities of the fenoterol stereoisomers were further confirmed by photoaffinity labeling studies on G(s),G(i2), and G(i3) proteins. The inefficient G(i) signaling with the R,R isomers is not caused by the inability of the R,R isomers to trigger the protein kinase A (PKA)-mediated phosphorylation of the beta(2)-adrenoceptor, because the R,R isomers also markedly increased phosphorylation of the receptor at serine 262 by PKA. We conclude that in addition to receptor subtype and phosphorylation status, the stereochemistry of a given agonist plays an important role in determining receptor-G protein selectivity and downstream signaling events.

  18. ICI D7114 a novel selective beta-adrenoceptor agonist selectively stimulates brown fat and increases whole-body oxygen consumption.

    PubMed Central

    Holloway, B. R.; Howe, R.; Rao, B. S.; Stribling, D.; Mayers, R. M.; Briscoe, M. G.; Jackson, J. M.

    1991-01-01

    1. ICI D7114 is a novel, beta-adrenoceptor agonist which stimulates whole body oxygen consumption in conscious rats, cats and dogs and brown adipose tissue (BAT) activity in conscious rats. Treatment of rats with ICI D7114 stimulated oxygen consumption (ED50, 0.04 mg kg-1, p.o.) and BAT mitochondrial guanosine diphosphate (GDP)-binding (ED50, 0.15 mg kg-1, p.o.) with no chronotropic effects on the heart at these doses. 2. Reference beta-adrenoceptor agonists, isoprenaline and clenbuterol, also stimulated oxygen consumption and BAT activity but were less selective because they also produced effects on heart rate at these doses. 3. Treatment of conscious rats with ICI D7114 did not attenuate the chronotropic effects on the heart of a subsequent isoprenaline challenge. 4. Administration of ICI D7114 or of its acid metabolite had no effect in a cat soleus muscle model of tremor or on blood potassium levels in the conscious dog, indicating lack of effects at beta 2-adrenoceptors. 5. The results indicate that ICI D7114 may have activity at atypical beta-adrenoceptors in brown adipose tissue leading to increased whole body oxygen consumption. PMID:1686210

  19. Alpha 2-adrenoceptor blockade, pituitary-adrenal hormones, and agonistic interactions in rats.

    PubMed

    Haller, J; Barna, I; Kovács, J L

    1994-08-01

    The effects of adrenergic activation on aggressiveness and the aggression induced endocrine changes were tested in rats. Alpha 2 adrenoceptor blockers were used for enhancing activation of the adrenergic system, and changes in aggressiveness were tested in resident-intruder contests. Three experiments were conducted. In experiment 1, saline injected rats responded to the presence of an opponent by aggression and the increase in plasma ACTH and corticosterone. Intraperitoneal administration of 1 mg/kg CH-38083 (an alpha 2 adrenoceptor antagonist) produced a several fold increase in clinch fighting and mutual upright scores, and also further enhanced the plasma ACTH and corticosterone response. In experiment 2, the effect of three doses (0.5, 1 and 2 mg/kg) of three different alpha 2 adrenoceptor blockers CH-38083, idazoxan and yohimbine were tested. All the substances increased aggression at 0.5 and 1 mg/kg; at 2 mg/kg the effect of idazoxan and yohimbine disappeared, while with CH-38083 an additional increase was obtained. In yohimbine treated animals the enhancement of aggression was reduced already at 1 mg/kg. In experiment 3, indomethacin, a potent inhibitor of the catecholamine-induced ACTH release completely abolished the effects of the alpha 2 adrenoceptor antagonist CH-38083: the intensity of agonistic interactions, as well as ACTH and corticosterone plasma concentrations, returned to control levels. The possible role of catecholamines and the stress hormones in the activation of aggression is discussed.

  20. Evidence for alpha 2-adrenoceptor agonist activity of minoxidil.

    PubMed

    Sharma, N; Mehta, A A; Santani, D D; Goyal, R K

    1997-09-01

    The present investigation was undertaken to study the mechanism of action of minoxidil using various smooth muscle preparations. Minoxidil (4.7 x 10(-6) M to 4.7 x 10(-4) M) produced a concentration-dependent inhibition of field stimulation-evoked responses in rat anococcygeus muscle and vas deferens. The inhibition produced by minoxidil was antagonized by yohimbine (2.5 x 10(-7) M). Minoxidil (1.4 x 10(-5) M to 4.7 x 10(-4) M) also produced a concentration-dependent relaxation in oestrogen-primed potassium chloride-depolarized rat uterus. These responses were blocked not only by yohimbine but also by glibenclamide (2.02 x 10(-8) M). Our results suggest that minoxidil possesses alpha 2-adrenoceptor agonist activity in addition to potassium-channel-opening activity.

  1. Effect of dexmedetomidine injected into the oral mucosa in combination with lidocaine on local anesthetic potency in humans: a crossover double-blind study.

    PubMed

    Yamane, Ayaka; Higuchi, Hitoshi; Tomoyasu, Yumiko; Ishii-Maruhama, Minako; Maeda, Shigeru; Miyawaki, Takuya

    2015-04-01

    Recently, attention has been paid to dexmedetomidine, a selective α-2 adrenoceptor agonist, as a possible additive for local anesthesia. However, the effect of locally injected dexmedetomidine on the anesthetic action in humans has not fully been clarified. Thus, the purpose of the present study was to evaluate the effect of dexmedetomidine injected into the oral mucosa in combination with lidocaine on local anesthetic potency in humans. Twenty healthy volunteers were included in the present crossover double-blinded study. Lidocaine solution or lidocaine plus dexmedetomidine solution was submucosally injected into the alveolar mucosa in a crossover and double-blinded manner. The local anesthetic effect of the solutions was evaluated by measuring the current perception threshold (CPT) in the oral mucosa for 120 minutes after injection. Furthermore, the sedation level, blood pressure, and heart rate of the volunteers were evaluated. For statistical analysis, the Wilcoxon signed rank test and 2-way repeated measures analysis of variation were used. The CPT was increased with the 2 solutions and peaked 10 minutes after injection. CPT values 10 and 20 minutes after injection of lidocaine plus dexmedetomidine solution were considerably higher than those with lidocaine solution. The duration of an important increase in the CPT after injection with lidocaine plus dexmedetomidine solution was longer than that with lidocaine. Furthermore, the area under the time curve of CPT was considerably higher with lidocaine plus dexmedetomidine solution than with lidocaine solution. No volunteer showed a change in sedation level, blood pressure, or heart rate after injection with either test solution throughout the experiment. The present study showed that a combination of dexmedetomidine plus lidocaine considerably enhances the local anesthetic potency of lidocaine without any major influences on the cardiovascular system when locally injected into the oral mucosa. Copyright © 2015

  2. Review of adjunctive dexmedetomidine in the management of severe acute alcohol withdrawal syndrome.

    PubMed

    Wong, Adrian; Smithburger, Pamela L; Kane-Gill, Sandra L

    2015-01-01

    The primary management of alcohol withdrawal involves the administration of a γ-aminobutyric acid agonist, such as benzodiazepines, for management of symptoms and to prevent further progression to seizure or delirium tremens. Despite escalating doses of benzodiazepines, published literature indicates that some patient's alcohol withdrawal syndrome symptoms do not respond, and that the use of adjunctive agents may be beneficial in these patients. Dexmedetomidine, an α2-agonist, serves as a potential adjunctive agent through management of associated autonomic symptoms. Understanding of recent literature evaluating its use is necessary for appropriate selection. To review available literature supporting the use of adjunctive dexmedetomidine for management of severe alcohol withdrawal syndrome. A total of 13 published articles evaluating the efficacy and safety of dexmedetomidine as an adjunctive agent for the treatment of alcohol withdrawal in adult patients were identified from a MEDLINE search using the key words alcohol withdrawal, delirium tremens and dexmedetomidine. Evaluation of the literature indicates that dexmedetomidine is associated with a decrease in short-term benzodiazepine requirements after initiation, and improvement in hemodynamic parameters in relation to the adrenergic drive present in alcohol withdrawal. The use of dexmedetomidine in the management of severe alcohol withdrawal should be considered as an adjunctive agent. Dexmedetomidine appears to be well tolerated, with an expected decrease in blood pressure and heart rate. Seizures have occurred in patients with alcohol withdrawal despite the use of dexmedetomidine, with and without benzodiazepines, due to lack of γ-aminobutyric acid agonist administration.

  3. Comparative 3D QSAR study on β1-, β2-, and β3-adrenoceptor agonists

    PubMed Central

    Senthil Kumar, P.

    2009-01-01

    A quantitative structure–activity relationship study of tryptamine-based derivatives of β1-, β2-, and β3-adrenoceptor agonists was conducted using comparative molecular field analysis (CoMFA). Correlation coefficients (cross-validated r2) of 0.578, 0.595, and 0.558 were obtained for the three subtypes, respectively, in three different CoMFA models. All three CoMFA models have different steric and electrostatic contributions, implying different requirements inside the binding cavity. The CoMFA coefficient contour plots of the three models and comparisons among these plots provide clues regarding the main chemical features responsible for the biological activity variations and also result in predictions which correlate very well with the observed biological activity. Based on the analysis, a summary regeospecific description of the requirements for improving β-adrenoceptor subtype selectivity is given. PMID:21170122

  4. The β2 agonist terbutaline specifically decreases pulmonary arterial pressure under normoxia and hypoxia via α adrenoceptor antagonism.

    PubMed

    Neumann, Vanessa; Knies, Ralf; Seidinger, Alexander; Simon, Annika; Lorenz, Kristina; Matthey, Michaela; Breuer, Johannes; Wenzel, Daniela

    2018-05-01

    Pulmonary hypertension is a severe, incurable disease with a poor prognosis. Although treatment regimens have improved during the last 2 decades, current pharmacologic strategies are limited and focus on the modulation of only a few pathways related to endothelin, NO, and prostacyclin signaling. Therefore, the identification of novel molecular targets is urgently needed. We found that the β 2 adrenoceptor (AR) agonists terbutaline (TER) and salbutamol induced a dose-dependent vasorelaxation in large pulmonary arteries but not aortas of mouse. This effect was found to be independent of β ARs and the endothelium but was determined by the type of the preconstrictor. Vasodilation by β 2 AR agonists occurred after pretreatment of pulmonary arteries with phenylephrine and serotonin, both agonists of α 1 ARs, but was absent after preconstriction with the thromboxane analog U46619. These data indicated α-adrenolytic activity of β 2 AR agonists, which was confirmed by a right shift of the phenylephrine dose-response curve by TER. This effect was physiologically relevant because TER also relaxed small intrapulmonary arteries in lung slices and diminished pulmonary arterial pressure in an isolated perfused lung model under normoxia and hypoxia. Finally, TER applied as an aerosol also selectively decreased pulmonary arterial pressure without effects on systemic blood pressure and heart rate in mouse in vivo. Thus, β 2 AR agonists display α-adrenolytic activity in pulmonary arteries ex vivo and in vivo, and may provide a novel option to reduce pulmonary arterial pressure in pulmonary hypertension.-Neumann, V., Knies, R., Seidinger, A., Simon, A., Lorenz, K., Matthey, M., Breuer, J., Wenzel, D. The β 2 agonist terbutaline specifically decreases pulmonary arterial pressure under normoxia and hypoxia via α adrenoceptor antagonism.

  5. β2-Adrenoceptors and non-β-adrenoceptors mediate effects of BRL37344 and clenbuterol on glucose uptake in soleus muscle: studies using knockout mice

    PubMed Central

    Ngala, Robert A; O'Dowd, Jacqueline; Wang, Steven J; Stocker, Claire; Cawthorne, Michael A; Arch, Jonathan RS

    2009-01-01

    Background and purpose: In previous work, 10 pM BRL37344 and 10 pM clenbuterol stimulated glucose uptake in mouse soleus muscle. Ten nM BRL37344 also stimulated uptake but 100 nM clenbuterol inhibited uptake. Antagonist studies suggested that the opposite effects of 10 nM BRL37344 and 100 nM clenbuterol are mediated by the β2-adrenoceptor. BRL37344 and clenbuterol have been studied in muscles that lack β3-, β2- or all three β-adrenoceptors. Effects of β-adrenoceptor antagonists on responses to the agonists have been studied further using muscles from wild-type mice. Experimental approach: Soleus muscles of wild-type or β-adrenoceptor knockout mice were incubated with 2-deoxy[1-14C]-glucose, and β-adrenoceptor ligands. Formation of 2-deoxy[1-14C]-glucose-6-phosphate was measured. Key results: Concentration–response relationships were similar for BRL37344 and clenbuterol in normal muscle and muscle lacking β3-adrenoceptors. Ten pM BRL37344 and clenbuterol stimulated glucose uptake in muscle lacking β2-adrenoceptors or all three β-adrenoceptors, but 10 nM BRL37344 did not stimulate uptake in either case, and 100 nM clenbuterol stimulated, rather than inhibited, uptake in muscle lacking β2-adrenoceptors. One hundred nM clenbuterol also stimulated glucose uptake in normal muscle when β2-adrenoceptors were blocked with ICI118551, and this was not prevented by antagonism of β1- or β3-adrenoceptors. Conclusions and implications: Ten nM BRL37344 and 100 nM clenbuterol have opposite effects on glucose uptake but both effects are mediated by the β2-adrenoceptor – apparently an example of agonist-directed signalling. Ten pM BRL37344, 10 pM clenbuterol and 100 nM clenbuterol in the presence of ICI118551 stimulate glucose uptake via β-adrenoceptor-independent mechanisms, demonstrating unknown properties for the agonists. PMID:19912225

  6. Beta2-adrenoceptor agonist fenoterol enhances functional repair of regenerating rat skeletal muscle after injury.

    PubMed

    Beitzel, Felice; Gregorevic, Paul; Ryall, James G; Plant, David R; Sillence, Martin N; Lynch, Gordon S

    2004-04-01

    Beta(2)-adrenoceptor agonists such as fenoterol are anabolic in skeletal muscle, and because they promote hypertrophy and improve force-producing capacity, they have potential application for enhancing muscle repair after injury. No previous studies have measured the beta(2)-adrenoceptor population in regenerating skeletal muscle or determined whether fenoterol can improve functional recovery in regenerating muscle after myotoxic injury. In the present study, the extensor digitorum longus (EDL) muscle of the right hindlimb of deeply anesthetized rats was injected with bupivacaine hydrochloride, which caused complete degeneration of all muscle fibers. The EDL muscle of the left hindlimb served as the uninjured control. Rats received either fenoterol (1.4 mg x kg(-1) x day(-1)) or an equal volume of saline for 2, 7, 14, or 21 days. Radioligand binding assays identified a approximately 3.5-fold increase in beta(2)-adrenoceptor density in regenerating muscle at 2 days postinjury. Isometric contractile properties of rat EDL muscles were measured in vitro. At 14 and 21 days postinjury, maximum force production (P(o)) of injured muscles from fenoterol-treated rats was 19 and 18% greater than from saline-treated rats, respectively, indicating more rapid restoration of function after injury. The increase in P(o) in fenoterol-treated rats was due to increases in muscle mass, fiber cross-sectional area, and protein content. These findings suggest a physiological role for beta(2)-adrenoceptor-mediated mechanisms in muscle regeneration and show clearly that fenoterol hastens recovery after injury, indicating its potential therapeutic application.

  7. Portal hypertension and liver cirrhosis in rats: effect of the β3-adrenoceptor agonist SR58611A

    PubMed Central

    Vasina, Valentina; Giannone, Ferdinando; Domenicali, Marco; Latorre, Rocco; Berzigotti, Annalisa; Caraceni, Paolo; Zoli, Marco; De Ponti, Fabrizio; Bernardi, Mauro

    2012-01-01

    BACKGROUND AND PURPOSE β3-Adrenoceptors participate in the regulation of vascular tone in physiological and pathological conditions. We aimed to assess the effect of pharmacological modulation of β3-adrenoceptors on portal pressure (PP) and systemic haemodynamics and their expression in the liver and mesenteric vessels of cirrhotic rats. EXPERIMENTAL APPROACH PP, central venous pressure (CVP) and systemic haemodynamics were invasively assessed in control and CCl4-treated cirrhotic rats before and during infusion of the selective β3-adrenoceptor agonist, SR58611A. Tissue samples were also collected from liver, heart, portal vein and mesenteric artery for immunohistochemistry and molecular biology analysis. The effect of SR58611A on isolated portal vein was assessed. KEY RESULTS At baseline, cirrhotic rats showed portal hypertension, reduced CVP and hyperdynamic circulation. SR58611A induced a significant, dose-dependent decrease in PP in cirrhotic rats, but not in controls. Although both groups manifested a dose-dependent reduction in mean arterial pressure, this effect was associated with decreased cardiac index (CI) and unchanged indicized peripheral vascular resistance (PVRI) in cirrhotic rats and increased CI and decreased PVRI in control animals. Pretreatment with the selective β3-adrenoceptor antagonist SR59230 prevented all SR58611A-induced changes in cirrhotic rats. SR58611A concentration-dependently relaxed portal vein in cirrhotic rats to a significantly greater extent than in healthy rats; pretreatment with SR59230A completely prevented SR58611A-induced cirrhotic portal vein relaxation. Finally, β3-adrenoceptors were identified in the liver, heart and portal vein of cirrhotic and control animals; their expression was increased in cirrhotic rats. CONCLUSIONS AND IMPLICATIONS β3-Adrenoceptors are altered in portal hypertension of experimental cirrhosis and may represent a novel therapeutic target. PMID:22708587

  8. The costo-uterine muscle of the rat contains a homogeneous population of beta-adrenoceptors.

    PubMed Central

    Hartley, M. L.; Pennefather, J. N.

    1985-01-01

    The effects of two selective beta-adrenoceptor antagonists on the inhibitory responses to some sympathomimetic amines of electrically-stimulated preparations of costo-uterine muscle, taken from virgin rats, have been examined quantitatively. pA2 values for the antagonist, atenolol (beta 1-selective) and ICI 118,551 (beta 2-selective) were obtained using as agonists, fenoterol (beta 2-selective agonist) and noradrenaline (alpha- and beta-adrenoceptor agonist, beta 1-selective); and in addition, with ICI 118,551 only, isoprenaline (beta-agonist, non-selective) and adrenaline (alpha- and beta-adrenoceptor agonist, beta 2-selective). Catecholamine uptake mechanisms and alpha-adrenoceptors were not blocked in any of these experiments. Atenolol competitively antagonized the effects of fenoterol and noradrenaline to a similar extent, the pA2 values being 5.4 and 5.7, respectively. ICI 118,551 competitively antagonized the effects of fenoterol, isoprenaline, adrenaline and noradrenaline to a similar extent; pA2 values ranged from 8.7 with noradrenaline to 9.1 with isoprenaline. These results extend our previous observations which indicated that the adrenoceptors mediating inhibition of electrically-evoked contractions of costo-uterine muscle of the virgin rat are homogeneous and of the beta 2-subtype. The potency of the beta 1-selective agonist RO 363 in producing inhibition of electrically-evoked contractions of this tissue was also examined. RO 363 was 200 times less potent than isoprenaline but was a full agonist. This indicates that there is efficient coupling between beta 2-adrenoceptor activation and tissue response in this non-innervated preparation. PMID:2858239

  9. Modulation of fear/anxiety responses, but not food intake, following α-adrenoceptor agonist microinjections in the nucleus accumbens shell of free-feeding rats.

    PubMed

    Kochenborger, Larissa; Zanatta, Débora; Berretta, Luigi Marins; Lopes, Ana Paula Fraga; Wunderlich, Bruna Luiza; Januário, Ana Cláudia; Neto, José Marino; Terenzi, Mariana Graciela; Paschoalini, Marta Aparecida; Faria, Moacir Serralvo

    2012-01-01

    This study investigated the effect of α-adrenoceptor agonists microinjected into the shell region of the accumbens nucleus (AcbSh) on feeding and anxiety-related behaviors in free-feeding rats. Male Wistar rats with a chronically implanted cannula into the AcbSh were unilaterally microinjected with either clonidine (CLON, α(2)-adrenoceptor agonist) or phenylephrine (PHEN, α(1)-adrenoceptor agonist) at the doses of 6 and 20 nmol and submitted to the elevated plus-maze (EPM), a pre-clinical test of anxiety. Immediately after the EPM test, the animals underwent food intake evaluation for 30 min. The data showed that rats microinjected with CLON (20 nmol/0.2 μl) into the AcbSh exhibited increased %Open arm time, which is compatible with an anxiolytic-like effect. The CLON-induced anxiolysis was corroborated by increased head-dipping and decreased stretched-attend posture, two ethologically derived behaviors which are fear/anxiety-motivated. The animal's locomotor activity was not changed by 20 nmol CLON microinjection into the AcbSh. However, neither dose of PHEN microinjected into the AcbSh was able to alter either the spatial-temporal or ethological variables representative of fear/anxiety and locomotion. Food intake was not altered by any dose of CLON and PHEN microinjected into the AcbSh, but the 20 nmol CLON microinjection induced increased motor activity in the feeding test. The data suggests that noradrenergic projections to the AcbSh may underlie fear/anxiety modulation through α(2)-adrenoceptor in the AcbSh, while feeding behavior was unaffected by noradrenergic modulation in the AcbSh of free-feeding rats. This article is part of a Special Issue entitled 'Anxiety and Depression'. Copyright © 2011 Elsevier Ltd. All rights reserved.

  10. The changes in beta-adrenoceptor-mediated cardiac function in experimental hypothyroidism: the possible contribution of cardiac beta3-adrenoceptors.

    PubMed

    Arioglu, E; Guner, S; Ozakca, I; Altan, V M; Ozcelikay, A T

    2010-02-01

    Thyroid hormone deficiency has been reported to decrease expression and function of both beta(1)- and beta(2)-adrenoceptor in different tissues including heart. The purpose of this study was to examine the possible contribution of beta(3)-adrenoceptors to cardiac dysfunction in hypothyroidism. In addition, effect of this pathology on beta(1)- and beta(2)-adrenoceptor was investigated. Hypothyroidism was induced by adding methimazole (300 mg/l) to drinking water of rats for 8 weeks. Cardiac hemodynamic parameters were measured in anesthetised rats in vivo. Responses to beta-adrenoceptor agonists were examined in rat papillary muscle in vitro. We also studied the effect of hypotyroidism on mRNA expression of beta-adrenoceptors, Gialpha, GRK, and eNOS in rat heart. All of the hemodynamic parameters (systolic, diastolic and mean arterial pressure, left ventricular pressure, heart rate, +dp/dt, and -dp/dt) were significantly reduced by the methimazole treatment. The negative inotropic effect elicited by BRL 37344 (a beta(3)-adrenoceptor preferential agonist) and positive inotropic effects produced by isoprenaline and noradrenaline, respectively, were significantly decreased in papillary muscle of hypothyroid rats as compared to those of controls. On the other hand, hypothyroidism resulted in increased cardiac beta(2)- and beta(3)-adrenoceptor, Gialpha(2), Gialpha(3), GRK3, and eNOS mRNA expressions. However, beta(1)-adrenoceptor and GRK2 mRNA expressions were not changed significantly in this pathology. These results show that mRNA expression of beta(3)-adrenoceptors as well as the signalling pathway components mediated through beta(3)-adrenoceptors are significantly increased in hypothyroid rat heart. Since we could not correlate these alternates with the decreased negative inotropic response mediated by this receptor subtype, it is not clear whether these changes are important for hypothyroid induced reduction in cardiac function.

  11. Attenuation of spinal cord ischemia-reperfusion injury by specific α-2a receptor activation with dexmedetomidine.

    PubMed

    Bell, Marshall T; Puskas, Ferenc; Smith, Phillip D; Agoston, Viktor A; Fullerton, David A; Meng, Xianzhong; Weyant, Michael J; Reece, T Brett

    2012-11-01

    Despite surgical adjuncts, paralysis remains a devastating complication after thoracoabdominal aortic interventions. Dexmedetomidine, a selective α-2a agonist commonly used for sedation in the critical care setting, has been shown to have protective effects against ischemia-reperfusion injuries in multiple organ systems. We hypothesized that treatment with dexmedetomidine would attenuate spinal cord ischemia-reperfusion injury via α-2a receptor activation. Adult C57BL/6 mice underwent sternotomy, followed by occlusion of the aortic arch for 4 minutes. Eight experimental mice received pretreatment with intraperitoneal dexmedetomidine (25 μg/kg) and at 12-hour intervals after reperfusion. Eight control mice received an equivalent amount of 0.9% normal saline. Five mice underwent the same procedure with dexmedetomidine (25 μg/kg) and atipamezole (250 μg/kg), an α-2a receptor antagonist. Functional analysis of the mice was obtained at 12-hour intervals and scored using the Basso Mouse Scale for Locomotion until 60 hours. All mice were euthanized at 60 hours. Their spinal cords were removed en bloc and were stained with hematoxylin and eosin to assess cytoarchitecture and neuronal viability. Mice treated with the α-2a agonist demonstrated preserved motor function compared with ischemic controls and with mice treated with the α-2a antagonist in addition to the agonist. Functional differences in the dexmedetomidine group were statistically significant from 24 hours through the remainder of the experiment (P < .05). In addition, the treated mice had preserved cytoarchitecture, decreased vacuolization, and improved neuronal viability compared with ischemic control mice and mice concurrently treated with atipamezole, the dexmedetomidine α-2a antagonist. Treatment of mice with the α-2a agonist dexmedetomidine preserves motor function and neuronal viability after aortic cross-clamping. In addition, mice exhibited almost complete reversal of the protective effect with

  12. Thermodynamics and docking of agonists to the β(2)-adrenoceptor determined using [(3)H](R,R')-4-methoxyfenoterol as the marker ligand.

    PubMed

    Toll, Lawrence; Pajak, Karolina; Plazinska, Anita; Jozwiak, Krzysztof; Jimenez, Lucita; Kozocas, Joseph A; Tanga, Mary J; Bupp, James E; Wainer, Irving W

    2012-06-01

    G protein-coupled receptors (GPCRs) are integral membrane proteins that change conformation after ligand binding so that they can transduce signals from an extracellular ligand to a variety of intracellular components. The detailed interaction of a molecule with a G protein-coupled receptor is a complicated process that is influenced by the receptor conformation, thermodynamics, and ligand conformation and stereoisomeric configuration. To better understand the molecular interactions of fenoterol analogs with the β(2)-adrenergic receptor, we developed a new agonist radioligand for binding assays. [(3)H](R,R')-methoxyfenoterol was used to probe the binding affinity for a series of fenoterol stereoisomers and derivatives. The results suggest that the radioligand binds with high affinity to an agonist conformation of the receptor, which represents approximately 25% of the total β(2)-adrenoceptor (AR) population as determined with the antagonist [(3)H]CGP-12177. The β(2)-AR agonists tested in this study have considerably higher affinity for the agonist conformation of the receptor, and K(i) values determined for fenoterol analogs model much better the cAMP activity of the β(2)-AR elicited by these ligands. The thermodynamics of binding are also different when interacting with an agonist conformation, being purely entropy-driven for each fenoterol isomer, rather than a mixture of entropy and enthalpy when the fenoterol isomers binding was determined using [(3)H]CGP-12177. Finally, computational modeling identified the molecular interactions involved in agonist binding and allow for the prediction of additional novel β(2)-AR agonists. The study underlines the possibility of using defined radioligand structure to probe a specific conformation of such shape-shifting system as the β(2)-adrenoceptor.

  13. Thermodynamics and Docking of Agonists to the β2-Adrenoceptor Determined Using [3H](R,R′)-4-Methoxyfenoterol as the Marker Ligand

    PubMed Central

    Pajak, Karolina; Plazinska, Anita; Jozwiak, Krzysztof; Jimenez, Lucita; Kozocas, Joseph A.; Tanga, Mary J.; Bupp, James E.; Wainer, Irving W.

    2012-01-01

    G protein-coupled receptors (GPCRs) are integral membrane proteins that change conformation after ligand binding so that they can transduce signals from an extracellular ligand to a variety of intracellular components. The detailed interaction of a molecule with a G protein-coupled receptor is a complicated process that is influenced by the receptor conformation, thermodynamics, and ligand conformation and stereoisomeric configuration. To better understand the molecular interactions of fenoterol analogs with the β2-adrenergic receptor, we developed a new agonist radioligand for binding assays. [3H](R,R′)-methoxyfenoterol was used to probe the binding affinity for a series of fenoterol stereoisomers and derivatives. The results suggest that the radioligand binds with high affinity to an agonist conformation of the receptor, which represents approximately 25% of the total β2-adrenoceptor (AR) population as determined with the antagonist [3H]CGP-12177. The β2-AR agonists tested in this study have considerably higher affinity for the agonist conformation of the receptor, and Ki values determined for fenoterol analogs model much better the cAMP activity of the β2-AR elicited by these ligands. The thermodynamics of binding are also different when interacting with an agonist conformation, being purely entropy-driven for each fenoterol isomer, rather than a mixture of entropy and enthalpy when the fenoterol isomers binding was determined using [3H]CGP-12177. Finally, computational modeling identified the molecular interactions involved in agonist binding and allow for the prediction of additional novel β2-AR agonists. The study underlines the possibility of using defined radioligand structure to probe a specific conformation of such shape-shifting system as the β2-adrenoceptor. PMID:22434858

  14. Effect of dexmedetomidine and cold stress in a rat model of neuropathic pain: Role of interleukin-6 and tumor necrosis factor-α.

    PubMed

    Farghaly, Hanan Sayed M; Mahmoud, Ahmed Mostafa; Abdel-Sater, Khaled A

    2016-04-05

    Dexmedetomidine (Dex) is a novel Alpha 2-adrenoceptor agonist. It decreases sympathetic tone and attenuates the stress responses to anesthesia and surgery. People exposed to cold suffer unpleasant thermal pain, which is experienced as stress and causes the release of noradrenaline from the sympathetic terminals. The present study investigated the effects of cold stress and dexmedetomidine on chronic constriction injury (CCI) model of the sciatic nerve in rats. Sixty four male Wistar rats were divided into seven groups of eight rats each: repeated cold stress (RCS) group, sham RCS group, CCI group, sham CCI group, Dex-treated group received a single dose of Dex (5 μg/kg), CCI+Dex group, CCI+RCS group. Interleukin-6 (IL-6) and tumor necrosis factor- alpha (TNF-α) levels in the serum were measured by enzyme-linked immunosorbent assay. The mean body weight of CCI, RCS, CCI+RCS, CCI+Dex and RCS+Dex groups decreased significantly compared with pre-values. Dexmedetomidine and CCI caused significant changes of the systolic, diastolic and mean blood pressure. Both RCS and CCI groups showed significant decreased of reaction time in the hot plate test. The RCS and CCI groups demonstrated a significant mechanical hyperalgesia, while pain threshold was increased in the RCS+Dex group. A significant decrease of serum IL-6 and TNF-α was demonstrated in CCI+RCS and CCI+Dex groups. The therapeutic effectiveness of dexmedetomidine in neuropathic pain may be through inhibition of proinflammatory cytokines, primarily IL-6 and TNF-α. Moreover, cold stress may result in increased resistance to neuropathic pain. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Dexmedetomidine for Refractory Adrenergic Crisis in Familial Dysautonomia

    PubMed Central

    Dillon, Ryan C.; Palma, Jose-Alberto; Spalink, Christy L.; Altshuler, Diana; Norcliffe-Kaufmann, Lucy; Fridman, David; Papadopoulos, John; Kaufmann, Horacio

    2016-01-01

    Objective Adrenergic crises are a cardinal feature of familial dysautonomia (FD). Traditionally, adrenergic crisis have been treated with the sympatholytic agent clonidine or with benzodiazepines, which can cause excessive sedation and respiratory depression. Dexmedetomidine is an α2A-adrenergic agonist with greater selectivity and shorter half-life than clonidine. We aimed to evaluate the preliminary effectiveness and safety of intravenous dexmedetomidine in the treatment of refractory adrenergic crisis in patients with FD. Methods Retrospective chart review of patients with genetically confirmed FD who received intravenous dexmedetomidine for refractory adrenergic crises. The primary outcome was preliminary effectiveness of dexmedetomidine defined as change in blood pressure (BP) and heart rate (HR) 1-hour after the initiation of dexmedetomidine. Secondary outcomes included incidence of adverse events related to dexmedetomidine, hospital and intensive care unit (ICU) length of stay, and hemodynamic parameters 12-hours after dexmedetomidine cessation. Results Nine patients over 14 admissions were included in the final analysis. At 1-hour after the initiation of dexmedetomidine, systolic BP decreased from 160±7 to 122±7 mmHg (p=0.0005), diastolic BP decreased from 103±6 to 65±8 (p=0.0003), and HR decreased from 112±4 to 100±5 bpm (p=0.0047). The median total adverse events during dexmedetomidine infusion was 1 per admission. Median hospital length of stay was 9 days (IQR, 3 – 11 days) and median ICU length of stay was 7 days (IQR, 3 – 11 days). Conclusions Intravenous dexmedetomidine is safe in patients with FD and appears to be effective to treat refractory adrenergic crisis. Dexmedetomidine may be considered in FD patients who do not respond to conventional clonidine and benzodiazepine pharmacotherapy. PMID:27752785

  16. Dexmedetomidine ameliorates nocifensive behavior in humanized sickle cell mice

    PubMed Central

    Calhoun, Gabriela; Wang, Li; Almeida, Luis E.F.; Kenyon, Nicholas; Afsar, Nina; Nouraie, Mehdi; Finkel, Julia C.; Quezado, Zenaide M.N.

    2015-01-01

    Patients with sickle cell disease (SCD) can have recurrent episodes of vaso-occlusive crises, which are associated with severe pain. While opioids are the mainstay of analgesic therapy, in some patients, increasing opioid use results in continued and increasing pain. Many believe that this phenomenon results from opioid-induced tolerance or hyperalgesia or that SCD pain involves non-opioid-responsive mechanisms. Dexmedetomidine, a specific α2-adrenoreceptor agonist, which has sedative and analgesic properties, reduces opioid requirements, and can facilitate opioid withdrawal in clinical settings. We hypothesized that dexmedetomidine would ameliorate the nociception phenotype of SCD mice. Townes and BERK SCD mice, strains known to have altered nociception phenotypes, were used in a crossover preclinical trial that measured nocifensive behavior before and after treatment with dexmedetomidine or vehicle. In a linear dose-effect relationship, over 60-min, dexmedetomidine, compared with vehicle, significantly increased hot plate latency in Townes and BERK mice (P≤0.006). In sickling, but not control mice, dexmedetomidine improved grip force, an indicator of muscle pain (P=0.002). As expected, dexmedetomidine had a sedative effect in sickling and control mice as it decreased wakefulness scores compared with vehicle (all P<0.001). Interestingly, the effects of dexmedetomidine on hot plate latency and wakefulness scores were different in sickling and control mice, i.e., dexmedetomidine-related increases in hotplate latency and decreases in wakefulness scores were significantly smaller in Townes sickling compared to control mice. In conclusion, these findings of beneficial effects of dexmedetomidine on the nociception phenotype in SCD mice might support the conduct of studies of dexmedetomidine in SCD patients. PMID:25724786

  17. Dexmedetomidine-induced Contraction Involves Phosphorylation of Caldesmon by JNK in Endothelium-denuded Rat Aortas

    PubMed Central

    Baik, Jiseok; Ok, Seong-Ho; Cho, Hyunhoo; Yu, Jongsun; Kim, Woochan; Nam, In-Koo; Choi, Mun-Jeoung; Lee, Heon-Keun; Sohn, Ju-Tae

    2014-01-01

    Caldesmon, an inhibitory actin binding protein, binds to actin and inhibits actin-myosin interactions, whereas caldesmon phosphorylation reverses the inhibitory effect of caldesmon on actin-myosin interactions, potentially leading to enhanced contraction. The goal of this study was to investigate the cellular signaling pathway responsible for caldesmon phosphorylation, which is involved in the regulation of the contraction induced by dexmedetomidine (DMT), an alpha-2 adrenoceptor agonist, in endothelium-denuded rat aortas. SP600125 (a c-Jun NH2-terminal kinase [JNK] inhibitor) dose-response curves were generated in aortas that were pre-contracted with DMT or phorbol 12,13-dibutyrate (PDBu), a protein kinase C (PKC) activator. Dose-response curves to the PKC inhibitor chelerythrine were generated in rat aortas pre-contracted with DMT. The effects of SP600125 and rauwolscine (an alpha-2 adrenoceptor inhibitor) on DMT-induced caldesmon phosphorylation in rat aortic vascular smooth muscle cells (VSMCs) were investigated by western blot analysis. PDBu-induced caldesmon and DMT-induced PKC phosphorylation in rat aortic VSMCs was investigated by western blot analysis. The effects of GF109203X (a PKC inhibitor) on DMT- or PDBu-induced JNK phosphorylation in VSMCs were assessed. SP600125 resulted in the relaxation of aortas that were pre-contracted with DMT or PDBu, whereas rauwolscine attenuated DMT-induced contraction. Chelerythrine resulted in the vasodilation of aortas pre-contracted with DMT. SP600125 and rauwolscine inhibited DMT-induced caldesmon phosphorylation. Additionally, PDBu induced caldesmon phosphorylation, and GF109203X attenuated the JNK phosphorylation induced by DMT or PDBu. DMT induced PKC phosphorylation in rat aortic VSMCs. These results suggest that alpha-2 adrenoceptor-mediated, DMT-induced contraction involves caldesmon phosphorylation that is mediated by JNK phosphorylation by PKC. PMID:25332685

  18. Effects of chronic treatment with the new ultra-long-acting β2 -adrenoceptor agonist indacaterol alone or in combination with the β1 -adrenoceptor blocker metoprolol on cardiac remodelling.

    PubMed

    Rinaldi, Barbara; Donniacuo, Maria; Sodano, Loredana; Gritti, Giulia; Martuscelli, Eugenio; Orlandi, Augusto; Rafaniello, Concetta; Rossi, Francesco; Calzetta, Luigino; Capuano, Annalisa; Matera, Maria Gabriella

    2015-07-01

    The ability of a chronic treatment with indacaterol, a new ultra-long-acting β2 -adrenoceptor agonist, to reverse cardiac remodelling and its effects in combination with metoprolol, a selective β1 -adrenoceptor antagonist, were investigated on myocardial infarction in a rat model of heart failure (HF). We investigated the effects of indacaterol and metoprolol, administered alone or in combination, on myocardial histology, β-adrenoceptor-mediated pathways, markers of remodelling and haemodynamic parameters in a rat model of HF. Five groups of rats were assessed: sham-operated rats; HF rats; HF + indacaterol 0.3 mg·kg(-1) ·day(-1) ; HF + metoprolol 100 mg·kg(-1) ·day(-1) ; HF + metoprolol + indacaterol. All pharmacological treatments continued for 15 weeks. Treatment with either indacaterol or metoprolol significantly reduced the infarct size in HF rats. However, the combination of indacaterol and metoprolol reduced the infarct size even further, reduced both BP and heart rate, reversed the decrease in ejection fraction, normalized left ventricular systolic and diastolic internal diameters, normalized the decreased β1 adrenoceptor mRNA expression as well as cardiac cAMP levels and reduced cardiac GPCR kinase 2 expression, compared with the untreated HF group. The results of our study demonstrated an additive interaction between indacaterol and metoprolol in normalizing and reversing cardiac remodelling in our experimental model of HF. The translation of these findings to clinical practice might be of interest, as this combination of drugs could be safer and more effective in patients suffering from HF and COPD. © 2015 The British Pharmacological Society.

  19. Inhibition of basal and stimulated release of endothelin-1 from guinea pig tracheal epithelial cells in culture by beta 2-adrenoceptor agonists and cyclic AMP enhancers.

    PubMed

    Yang, Quan; Battistini, Bruno; Pelletier, Stéphane; Sirois, Pierre

    2007-10-01

    The effects of cyclic AMP-related compounds and beta adrenoceptor agonists on the basal and lipopolysaccharide (LPS)-stimulated release of endothelin-1 (ET-1) from guinea-pig tracheal epithelial cells (GPTEpCs) in culture were studied. Forskolin (a potent activator of adenylyl cyclase), 8-bromo-cyclic AMP (a cyclic AMP analogue), salbutamol and salmeterol (two beta 2-adrenoceptor agonists), were used to increase cyclic AMP levels. Cultured GPTEpCs released ET-1 continuously over a 24 h incubation period. The values reached 1,938 +/- 122 pg/mg of total cell proteins after 24 h. LPS (10 microg/ml) significantly stimulated the release of ET-1 by 1.6- to 1.8-fold, up to 1,262 +/- 56 pg/mg total cell proteins after an 8 h incubation period. Compound 8-bromo-cyclic AMP (10(-5), 10(-4) and 10(-3) M) reduced the basal release of ET-1 from GPTEpCs by up to 31% (P < 0.01) and the LPS stimulated release by up to 42% (P < 0.05), after an 8 h incubation period. Forskolin (10(-6), 10(-5) and 10(-4) M) also inhibited the basal release of ET-1 by up to 28% (P < 0.05) and LPS-stimulated release of ET-1 by up to 50% (P < 0.05), after an 8 h incubation period. At the concentration of 10(-5) M, forskolin increased cyclic AMP levels in GPTEpCs by 17-fold (P < 0.001) in the medium, 15 min after the beginning of the incubation. Salbutamol (10(-8) to 10(-6) M) had no effect on the basal production and release of ET-1 after 8 h. Conversely, this short acting beta 2-adrenoceptor agonist significantly reduced LPS-mediated increase of ET-1 production by up to 55% (P < 0.05) after an 8 h incubation period. Salmeterol (10(-9) M to 10(-5) M) inhibited basal and LPS-stimulated production and release of ET-1 after an 8 h incubation period (between 44 and 51%, P < 0.01). Both salbutamol and salmeterol (10(-6) M) increase cyclic AMP levels by five- and twofold, respectively (P < 0.05). In summary, these observations indicate that beta 2-adrenoceptor agonists or cyclic AMP enhancers can modulate both

  20. Alpha2-adrenoceptor modulation of long-term potentiation elicited in vivo in rat occipital cortex.

    PubMed

    Mondaca, Mauricio; Hernández, Alejandro; Pérez, Hernán; Valladares, Luis; Sierralta, Walter; Fernández, Victor; Soto-Moyano, Rubén

    2004-09-24

    Pretreatment with the alpha(2)-adrenoceptor agonist clonidine (31.25, 62.5, or 125 microg/kg, i.p.) dose-dependently reduced long-term potentiation (LTP) elicited in vivo in the occipital cortex of anesthetized rats, whereas pretreatment with the alpha(2)-adrenoceptor antagonist yohimbine (0.133, 0.4, or 1.2 mg/kg, i.p.) increased neocortical LTP in a dose-dependent fashion. These effects could be related to the reported disruptive and facilitatory actions induced on memory formation by pretreatment with alpha(2)-adrenoceptor agonists and antagonists, respectively.

  1. β1 -Adrenoceptor, but not β2 -adrenoceptor, subtype regulates heart rate in type 2 diabetic rats in vivo.

    PubMed

    Cook, Rosalind F; Bussey, Carol T; Mellor, Kimberley M; Cragg, Patricia A; Lamberts, Regis R

    2017-08-01

    What is the central question of the study? The sympathetic system regulates heart rate via β-adrenoceptors; this is impaired during diabetes. However, the specific β-adrenoceptor subtype contributions in heart rate regulation in diabetes in vivo are unknown. What is the main finding and its importance? Telemetric recordings in conscious non-diabetic and type 2 diabetic rats demonstrated that the β 1 -adrenoceptor subtype, and not the β 2 -adrenoceptor, regulated the lower resting heart rate and increased β-adrenoceptor responsiveness in diabetes in vivo. This provides new physiological insight into the dysregulation of heart rate in type 2 diabetes, which is important for improving therapeutic strategies targeting the diabetic chronotropic incompetence. β-Adrenoceptor blockers are widely used to reduce heart rate, the strongest predictor of mortality in cardiac patients, but are less effective in diabetic patients. This study aimed to determine the specific contributions of β 1 - and β 2 -adrenoceptor subtypes to chronotropic responses in type 2 diabetes in vivo, which are currently unknown. Type 2 diabetic and non-diabetic rats were implanted with radiotelemeters to measure arterial blood pressure and derive heart rate in conscious conditions. Vascular access ports were implanted to inject isoprenaline (β 1 - and β 2 -adrenoceptor agonist, 0.1-300 μg kg -1 ) in the presence of atenolol (β 1 -adrenoceptor antagonist, 2000 μg kg -1 ) or nadolol (β 1 - and β 2 -adrenoceptor agonist, 4000 μg kg -1 ) to determine the chronotropic contributions of the β-adrenoceptor subtypes. Resting heart rate was reduced in diabetic rats (388 ± 62 versus 290 ± 37 beats min -1 non-diabetic versus diabetic, P < 0.05, mean ± SD), which remained after atenolol or nadolol administration. Overall β-adrenoceptor chronotropic responsiveness was increased in diabetic rats (change in heart rate at highest dose of isoprenaline: 135 ± 66 versus 205 ± 28

  2. Impaired activation of adenylyl cyclase in lung of the Basenji-greyhound model of airway hyperresponsiveness: decreased numbers of high affinity beta-adrenoceptors.

    PubMed Central

    Emala, C. W.; Aryana, A.; Hirshman, C. A.

    1996-01-01

    1. To evaluate mechanisms involved in the impaired beta-adrenoceptor stimulation of adenylyl cyclase in tissues from the Basenji-greyhound (BG) dog model of airway hyperresponsiveness, we compared agonist and antagonist binding affinity of beta-adrenoceptors, beta-adrenoceptor subtypes, percentage of beta-adrenoceptors sequestered, and coupling of the beta-adrenoceptor to Gs alpha in lung membranes from BG and control mongrel dogs. We found that lung membranes from the BG dog had higher total numbers of beta-adrenoceptors with a greater percentage of receptors of the beta 2 subtype as compared to mongrel lung membranes. 2. Agonist and antagonist binding affinity and the percentage of beta-adrenoceptors sequestered were not different in BG and mongrel dog lung membranes. However, the percentage of beta-adrenoceptors in the high affinity state for agonist was decreased in BG lung membranes suggesting an uncoupling of the receptor from Gs alpha. 3. Impaired coupling between the beta-adrenoceptor and G protein documented by the decreased numbers of beta-adrenoceptors in the high affinity state in BG lung membranes, is a plausible explanation for the reduced stimulation of adenylyl cyclase and the resultant reduction in airway smooth muscle relaxation in this model. PMID:8864536

  3. Interpatient Variability in Dexmedetomidine Response: A Survey of the Literature

    PubMed Central

    Holliday, Samantha F.; Kane-Gill, Sandra L.; Empey, Philip E.; Buckley, Mitchell S.; Smithburger, Pamela L.

    2014-01-01

    Fifty-five thousand patients are cared for in the intensive care unit (ICU) daily with sedation utilized to reduce anxiety and agitation while optimizing comfort. The Society of Critical Care Medicine (SCCM) released updated guidelines for management of pain, agitation, and delirium in the ICU and recommended nonbenzodiazepines, such as dexmedetomidine and propofol, as first line sedation agents. Dexmedetomidine, an alpha-2 agonist, offers many benefits yet its use is mired by the inability to consistently achieve sedation goals. Three hypotheses including patient traits/characteristics, pharmacokinetics in critically ill patients, and clinically relevant genetic polymorphisms that could affect dexmedetomidine response are presented. Studies in patient traits have yielded conflicting results regarding the role of race yet suggest that dexmedetomidine may produce more consistent results in less critically ill patients and with home antidepressant use. Pharmacokinetics of critically ill patients are reported as similar to healthy individuals yet wide, unexplained interpatient variability in dexmedetomidine serum levels exist. Genetic polymorphisms in both metabolism and receptor response have been evaluated in few studies, and the results remain inconclusive. To fully understand the role of dexmedetomidine, it is vital to further evaluate what prompts such marked interpatient variability in critically ill patients. PMID:24558330

  4. Intranasal dexmedetomidine for adrenergic crisis in familial dysautonomia.

    PubMed

    Spalink, Christy L; Barnes, Erin; Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio

    2017-08-01

    To report the use of intranasal dexmedetomidine, an α 2 -adrenergic agonist for the acute treatment of refractory adrenergic crisis in patients with familial dysautonomia. Case series. Three patients with genetically confirmed familial dysautonomia (case 1: 20-year-old male; case 2: 43-year-old male; case 3: 26-year-old female) received intranasal dexmedetomidine 2 mcg/kg, half of the dose in each nostril, for the acute treatment of adrenergic crisis. Within 8-17 min of administering the intranasal dose, the adrenergic crisis symptoms abated, and blood pressure and heart rate returned to pre-crises values. Adrenergic crises eventually resumed, and all three patients required hospitalization for investigation of the cause of the crises. Intranasal dexmedetomidine is a feasible and safe acute treatment for adrenergic crisis in patients with familial dysautonomia. Further controlled studies are required to confirm the safety and efficacy in this population.

  5. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit.

    PubMed

    Venn, R M; Bradshaw, C J; Spencer, R; Brealey, D; Caudwell, E; Naughton, C; Vedio, A; Singer, M; Feneck, R; Treacher, D; Willatts, S M; Grounds, R M

    1999-12-01

    Dexmedetomidine, a highly selective and potent alpha2-adrenergic agonist, has a potentially useful role as a sedative agent in patients requiring intensive care. As part of a larger European multicentre trial, a total of 119 postoperative cardiac and general surgical patients requiring ventilation and sedation in an intensive care unit were enrolled in four centres in the United Kingdom. One hundred and five patients were randomly allocated to receive either dexmedetomidine or placebo with rescue sedation and analgesia provided by midazolam and morphine, respectively. Compared with the control group, intubated patients receiving dexmedetomidine required 80% less midazolam [mean 4.9 (5.8) microg.kg-1.h-1 vs. 23.7 (27.5) microg.kg-1.h-1, p < 0.0001], and 50% less morphine [11.2 (13.4) microg.kg-1.h-1 vs. 21.5 (19.4) microg.kg-1.h-1,p = 0.0006]. Cardiovascular effects and adverse events could be predicted from the known properties of alpha-2 agonists. In conclusion, dexmedetomidine is a useful agent for the provision of postoperative analgesia and sedation.

  6. The design, synthesis and pharmacological characterization of novel β2-adrenoceptor antagonists

    PubMed Central

    Hothersall, J Daniel; Black, James; Caddick, Stephen; Vinter, Jeremy G; Tinker, Andrew; Baker, James R

    2011-01-01

    BACKGROUND AND PURPOSE Selective and potent antagonists for the β2-adrenoceptor are potentially interesting as experimental and clinical tools, and we sought to identify novel ligands with this pharmacology. EXPERIMENTAL APPROACH A range of pharmacological assays was used to assess potency, affinity, selectivity (β2-adrenoceptor vs. β1-adrenoceptor) and efficacy. KEY RESULTS Ten novel compounds were identified but none had as high affinity as the prototypical β2-adrenoceptor blocker ICI-118,551, although one of the novel compounds was more selective for β2-adrenoceptors. Most of the ligands were inverse agonists for β2-adrenoceptor-cAMP signalling, although one (5217377) was a partial agonist and another a neutral antagonist (7929193). None of the ligands were efficacious with regard to β2-adrenoceptor-β-arrestin signalling. The (2S,3S) enantiomers were identified as the most active, although unusually the racemates were the most selective for the β2-adrenoceptors. This was taken as evidence for some unusual enantiospecific behaviour. CONCLUSIONS AND IMPLICATIONS In terms of improving on the pharmacology of the ligand ICI-118,551, one of the compounds was more selective (racemic JB-175), while one was a neutral antagonist (7929193), although none had as high an affinity. The results substantiate the notion that β-blockers do more than simply inhibit receptor activation, and differences between the ligands could provide useful tools to investigate receptor biology. PMID:21323900

  7. α2A- and α2C-Adrenoceptors as Potential Targets for Dopamine and Dopamine Receptor Ligands.

    PubMed

    Sánchez-Soto, Marta; Casadó-Anguera, Verònica; Yano, Hideaki; Bender, Brian Joseph; Cai, Ning-Sheng; Moreno, Estefanía; Canela, Enric I; Cortés, Antoni; Meiler, Jens; Casadó, Vicent; Ferré, Sergi

    2018-03-18

    The poor norepinephrine innervation and high density of Gi/o-coupled α 2A - and α 2C -adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D 2 -like receptor ligands, such as the D 3 receptor agonist 7-OH-PIPAT and the D 4 receptor agonist RO-105824, to α 2 -adrenoceptors in cortical and striatal tissue, which express α 2A -adrenoceptors and both α 2A - and α 2C -adrenoceptors, respectively. The affinity of dopamine for α 2 -adrenoceptors was found to be similar to that for D 1 -like and D 2 -like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α 2A - and α 2C -adrenoceptors. Their ability to activate Gi/o proteins through α 2A - and α 2C -adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α 2 -adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α 2A - and α 2C -adrenoceptors was nearly identical to its binding to the crystallized D 3 receptor. Therefore, we provide conclusive evidence that α 2A - and α 2C -adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D 2 -like receptor ligands, which calls for revisiting previous studies with those ligands.

  8. Epinephrine increases contextual learning through activation of peripheral β2-adrenoceptors.

    PubMed

    Alves, Ester; Lukoyanov, Nikolay; Serrão, Paula; Moura, Daniel; Moreira-Rodrigues, Mónica

    2016-06-01

    Phenylethanolamine-N-methyltransferase knockout (Pnmt-KO) mice are unable to synthesize epinephrine and display reduced contextual fear. However, the precise mechanism responsible for impaired contextual fear learning in these mice is unknown. Our aim was to study the mechanism of epinephrine-dependent contextual learning. Wild-type (WT) or Pnmt-KO (129x1/SvJ) mice were submitted to a fear conditioning test either in the absence or in the presence of epinephrine, isoprenaline (non-selective β-adrenoceptor agonist), fenoterol (selective β2-adrenoceptor agonist), epinephrine plus sotalol (non-selective β-adrenoceptor antagonist), and dobutamine (selective β1-adrenoceptor agonist). Catecholamines were separated by reverse-phase HPLC and quantified by electrochemical detection. Blood glucose was measured by coulometry. Re-exposure to shock context induced higher freezing in WT and Pnmt-KO mice treated with epinephrine and fenoterol than in mice treated with vehicle. In addition, freezing response in Pnmt-KO mice was much lower than in WT mice. Freezing induced by epinephrine was blocked by sotalol in Pnmt-KO mice. Epinephrine and fenoterol treatment restored glycemic response in Pnmt-KO mice. Re-exposure to shock context did not induce a significant difference in freezing in Pnmt-KO mice treated with dobutamine and vehicle. Aversive memories are best retained if moderately high plasma epinephrine concentrations occur at the same moment as the aversive stimulus. In addition, epinephrine increases context fear learning by acting on peripheral β2-adrenoceptors, which may induce high levels of blood glucose. Since glucose crosses the blood-brain barrier, it may enhance hippocampal-dependent contextual learning.

  9. Use of Intranasal Dexmedetomidine as a Solo Sedative for MRI of Infants.

    PubMed

    Olgun, Gokhan; Ali, Mir Hyder

    2018-01-23

    Dexmedetomidine, a selective α-2 receptor agonist, can be delivered via the intranasal (IN) route and be used for procedural sedation. The drug's favorable hemodynamic profile and relative ease of application make it a promising agent for sedation during radiologic procedures, although there are few studies on its efficacy for MRI studies. A retrospective chart review was performed between June 2014 and December 2016. Outpatients between 1 and 12 months of age who received 4 μg/kg of IN dexmedetomidine for MRI were included in the analysis. Our aim with this study was to determine the rate of successful completion of the sedation procedure without the need for a rescue drug (other than repeat IN dexmedetomidine). A total of 52 subjects were included in our study. Median (interquartile range) patient age was 7 (5-8) months. Median (interquartile range) procedure length was 40 (35-50) minutes. Overall success rate (including first dose and any rescue dose IN) of dexmedetomidine was 96.2%. None of the patients had significant adverse effects related to dexmedetomidine. IN dexmedetomidine is an effective solo sedative agent for MRI in infants. Copyright © 2018 by the American Academy of Pediatrics.

  10. Antinociceptive synergism of MD-354 and clonidine. Part II. The alpha-adrenoceptor component.

    PubMed

    Young, Shawquia; Vainio, Minna; Scheinin, Mika; Dukat, Małgorzata

    2010-08-01

    Previously, we reported that antinociceptive synergism of a 5-HT(3)/alpha(2)-adrenoceptor ligand MD-354 (m-chlorophenylguanidine) and clonidine combination occurs, in part, through a 5-HT(3) receptor antagonist mechanism. In the present investigation, a possible role for alpha(2)-adrenoceptors was examined. Mechanistic studies using yohimbine (a subtype non-selective alpha(2)-adrenoceptor antagonist), BRL 44408 (a preferential alpha(2A)-adrenoceptor antagonist) and imiloxan (a preferential alpha(2B/C)-adrenoceptor antagonist) on the antinociceptive actions of a MD-354/clonidine combination were conducted. Subcutaneous pre-treatment with all three antagonists inhibited the antinociceptive synergism of MD-354 and clonidine in the mouse tail-flick assay in a dose-dependent manner (AD(50) = 0.33, 2.1, and 0.17 mg/kg, respectively). Enhancement of clonidine antinociception by MD-354 did not potentiate clonidine's locomotor suppressant activity in a mouse locomotor assay. When [ethyl-3H]RS-79948-197 was used as radioligand, MD-354 displayed almost equal affinity to alpha(2A)- and alpha(2B)-adrenoceptors (K(i) = 110 and 220 nM) and showed lower affinity at alpha(2C)-adrenoceptors (K(i) = 4,700 nM). MD-354 had no subtype-selectivity for the alpha(2)-adrenoceptor subtypes as an antagonist in functional [35S]GTPgammaS binding assays. MD-354 was a weak partial agonist at alpha(2A)-adrenoceptors. Overall, in addition to the 5-HT(3) receptor component, the present investigation found MD-354 to be a weak partial alpha(2A)-adrenoceptor agonist that enhances clonidine's thermal antinociceptive actions through an alpha(2)-adrenoceptor-mediated mechanism without augmenting sedation.

  11. β2 Agonists.

    PubMed

    Billington, Charlotte K; Penn, Raymond B; Hall, Ian P

    2017-01-01

    History suggests β agonists, the cognate ligand of the β 2 adrenoceptor, have been used as bronchodilators for around 5,000 years, and β agonists remain today the frontline treatment for asthma and chronic obstructive pulmonary disease (COPD). The β agonists used clinically today are the products of significant expenditure and over 100 year's intensive research aimed at minimizing side effects and enhancing therapeutic usefulness. The respiratory physician now has a therapeutic toolbox of long acting β agonists to prophylactically manage bronchoconstriction, and short acting β agonists to relieve acute exacerbations. Despite constituting the cornerstone of asthma and COPD therapy, these drugs are not perfect; significant safety issues have led to a black box warning advising that long acting β agonists should not be used alone in patients with asthma. In addition there are a significant proportion of patients whose asthma remains uncontrolled. In this chapter we discuss the evolution of β agonist use and how the understanding of β agonist actions on their principal target tissue, airway smooth muscle, has led to greater understanding of how these drugs can be further modified and improved in the future. Research into the genetics of the β 2 adrenoceptor will also be discussed, as will the implications of individual DNA profiles on the clinical outcomes of β agonist use (pharmacogenetics). Finally we comment on what the future may hold for the use of β agonists in respiratory disease.

  12. Effect of fenoterol-induced constitutive beta(2)-adrenoceptor activity on contractile receptor function in airway smooth muscle.

    PubMed

    de Vries, B; Roffel, A F; Zaagsma, J; Meurs, H

    2001-11-23

    In the present study, we investigated the effect of fenoterol-induced constitutive beta(2)-adrenoceptor activity on muscarinic receptor agonist- and histamine-induced bovine tracheal smooth muscle contractions. Bovine tracheal smooth muscle strips were incubated with 10 microM fenoterol or vehicle for various periods of time (5, 30 min, 18 h) at 37 degrees C. After extensive washout (3 h, 37 degrees C), isometric contractions were measured to the full muscarinic receptor agonist methacholine, the partial muscarinic receptor agonist 4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium (McN-A-343) and histamine. Fenoterol treatment significantly reduced the sensitivity (pEC(50)) to methacholine in a time-dependent manner, without affecting maximal contraction (E(max)). Fenoterol treatment similarly reduced the pEC(50) of McN-A-343 and histamine; however, E(max) values were also reduced, to approximately 70% of control after 18-h treatment. The inverse agonist timolol, having no effect on control preparations, consistently restored the reduced pEC(50) and E(max) values of the contractile agonists. Remarkably, in the presence of timolol the pEC(50) values of McN-A-343 and histamine in fenoterol-treated airways were significantly enhanced compared to controls. In conclusion, fenoterol-induced constitutive beta(2)-adrenoceptor activity reduces muscarinic receptor agonist- and histamine-induced contractions of bovine tracheal smooth muscle, which can be reversed by the inverse agonist timolol. Moreover, after beta(2)-adrenoceptor agonist treatment, inverse agonism by beta-adrenoceptor antagonists may cause enhanced airway reactivity to contractile mediators.

  13. Dexmedetomidine use in the ED for control of methamphetamine-induced agitation.

    PubMed

    Lam, Rex Pui Kin; Yip, Wai Lam; Wan, Chi Keung; Tsui, Matthew Sik Hon

    2017-04-01

    Chemical restraint is often required to control agitation induced by methamphetamine. Dexmedetomidine is an α-2 adrenergic receptor agonist with sedative, analgesic, and sympatholytic properties. Its use in the emergency department (ED) to control methamphetamine-induced agitation has not been reported. To report two cases of methamphetamine-induced agitation successfully sedated with dexmedetomidine in the ED. The first case was a 42-year-old man with unstable emotion and violent behaviours after smoking methamphetamine. His agitation did not respond to a large cumulative dose of benzodiazepines (10mg of diazepam and 332mg of midazolam) administered over 48h and sedation was achieved with dexmedetomidine. The second case was a 38-year-old methamphetamine user with unstable emotion and recurrent episodes of agitation despite repeated doses of benzodiazepines, whose agitation was controlled with dexmedetomidine infusion. In both cases, dexmedetomidine apparently reduced the dose of benzodiazepines needed to achieve adequate sedation. Transient falls in blood pressure and slowing of the heart rate were noted, which resolved either spontaneously or after reducing the infusion rate without requiring drug treatment. Dexmedetomidine can be considered as an adjunct for chemical restraint when standard treatment fails to control the agitation induced by methamphetamine, but patient's hemodynamic state should be monitored closely during administration. Its efficacy and safety in the ED warrant further evaluation with prospective controlled trials. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Dexmedetomidine Prevents Excessive γ-Aminobutyric Acid Type A Receptor Function after Anesthesia.

    PubMed

    Wang, Dian-Shi; Kaneshwaran, Kirusanthy; Lei, Gang; Mostafa, Fariya; Wang, Junhui; Lecker, Irene; Avramescu, Sinziana; Xie, Yu-Feng; Chan, Nathan K; Fernandez-Escobar, Alejandro; Woo, Junsung; Chan, Darren; Ramsey, Amy J; Sivak, Jeremy M; Lee, C Justin; Bonin, Robert P; Orser, Beverley A

    2018-06-08

    Postoperative delirium is associated with poor long-term outcomes and increased mortality. General anesthetic drugs may contribute to delirium because they increase cell-surface expression and function of α5 subunit-containing γ-aminobutyric acid type A receptors, an effect that persists long after the drugs have been eliminated. Dexmedetomidine, an α2 adrenergic receptor agonist, prevents delirium in patients and reduces cognitive deficits in animals. Thus, it was postulated that dexmedetomidine prevents excessive function of α5 γ-aminobutyric acid type A receptors. Injectable (etomidate) and inhaled (sevoflurane) anesthetic drugs were studied using cultured murine hippocampal neurons, cultured murine and human cortical astrocytes, and ex vivo murine hippocampal slices. γ-Aminobutyric acid type A receptor function and cell-signaling pathways were studied using electrophysiologic and biochemical methods. Memory and problem-solving behaviors were also studied. The etomidate-induced sustained increase in α5 γ-aminobutyric acid type A receptor cell-surface expression was reduced by dexmedetomidine (mean ± SD, etomidate: 146.4 ± 51.6% vs. etomidate + dexmedetomidine: 118.4 ± 39.1% of control, n = 8 each). Dexmedetomidine also reduced the persistent increase in tonic inhibitory current in hippocampal neurons (etomidate: 1.44 ± 0.33 pA/pF, n = 10; etomidate + dexmedetomidine: 1.01 ± 0.45 pA/pF, n = 9). Similarly, dexmedetomidine prevented a sevoflurane-induced increase in the tonic current. Dexmedetomidine stimulated astrocytes to release brain-derived neurotrophic factor, which acted as a paracrine factor to reduce excessive α5 γ-aminobutyric acid type A receptor function in neurons. Finally, dexmedetomidine attenuated memory and problem-solving deficits after anesthesia. Dexmedetomidine prevented excessive α5 γ-aminobutyric acid type A receptor function after anesthesia. This novel α2 adrenergic receptor- and brain-derived neurotrophic factor

  15. Interaction of fenoterol stereoisomers with β2-adrenoceptor-G sα fusion proteins: antagonist and agonist competition binding.

    PubMed

    Reinartz, Michael T; Kälble, Solveig; Wainer, Irving W; Seifert, Roland

    2015-05-01

    The specific interaction between G-protein-coupled receptors and ligand is the starting point for downstream signaling. Fenoterol stereoisomers were successfully used to probe ligand-specific activation (functional selectivity) of the β2-adrenoceptor (β2AR) (Reinartz et al. 2015). In the present study, we extended the pharmacological profile of fenoterol stereoisomers using β2AR-Gsα fusion proteins in agonist and antagonist competition binding assays. Dissociations between binding affinities and effector potencies were found for (R,S')- and (S,S')-isomers of 4'-methoxy-1-naphthyl-fenoterol. Our data corroborate former studies on the importance of the aminoalkyl moiety of fenoterol derivatives for functional selectivity.

  16. Dexmedetomidine in addition to benzodiazepine-based sedation in patients with alcohol withdrawal delirium.

    PubMed

    Tolonen, Jukka; Rossinen, Juhani; Alho, Hannu; Harjola, Veli-Pekka

    2013-12-01

    Alcohol withdrawal delirium (AWD) is often refractory to conventional medication. We report a prospective series of patients treated with α2-agonist dexmedetomidine added to conventional sedation. Eighteen patients with AWD were diagnosed by Confusion assessment method for ICU score. Treatment, complications, length of stay (LOS) in ICU and hospital were recorded. In addition, hospital and 1-year mortality were assessed. Dexmedetomidine was given for 23.9 (18.4) h [mean (SD)]. All the patients also received benzodiazepines but three patients were given haloperidole. No patient was intubated. The maximum infusion rate of dexmedetomidine was 1.5 (1.2) µg/kg/h. Time to resolution of AWD was 3.8 (1.3) days. The ICU LOS was 7.1 (2.7) days and in-hospital LOS 12.1 (4.5) days. No adverse events were observed although one patient died from acute pancreatitis. The use of dexmedetomidine in AWD seems safe but warrants further studies.

  17. Inhibition by fenoterol of human eosinophil functions including beta2-adrenoceptor-independent actions.

    PubMed

    Tachibana, A; Kato, M; Kimura, H; Fujiu, T; Suzuki, M; Morikawa, A

    2002-12-01

    Agonists at beta2 adrenoceptors are used widely as bronchodilators in treating bronchial asthma. These agents also may have important anti-inflammatory effects on eosinophils in asthma. We examined whether widely prescribed beta2-adrenoceptor agonists differ in ability to suppress stimulus-induced eosinophil effector functions such as superoxide anion (O2-) generation and degranulation. To examine involvement of cellular adhesion in such responses, we also investigated effects of beta2 agonists on cellular adhesion and on CD11b expression by human eosinophils. O2- was measured using chemiluminescence. Eosinophil degranulation and adhesion were assessed by a radioimmunoassay for eosinophil protein X (EPX). CD11b expression was measured by flow cytometry. Fenoterol inhibited platelet-activating factor (PAF)-induced O2- generation by eosinophils significantly more than salbutamol or procaterol. Fenoterol partially inhibited PAF-induced degranulation by eosinophils similarly to salbutamol or procaterol. Fenoterol inhibited phorbol myristate acetate (PMA)-induced O2- generation and degranulation by eosinophils, while salbutamol or procaterol did not. Fenoterol inhibition of PMA-induced O2- generation was not reversed by ICI-118551, a selective beta2-adrenoceptor antagonist. Fenoterol, but not salbutamol or procaterol, significantly inhibited PAF-induced eosinophil adhesion. Fenoterol inhibited O2- generation and degranulation more effectively than salbutamol or procaterol; these effects may include a component involving cellular adhesion. Inhibition also might include a component not mediated via beta2 adrenoceptors.

  18. Dexmedetomidine Pharmacology in Neonates and Infants After Open Heart Surgery.

    PubMed

    Su, Felice; Gastonguay, Marc R; Nicolson, Susan C; DiLiberto, MaryAnn; Ocampo-Pelland, Alanna; Zuppa, Athena F

    2016-05-01

    Dexmedetomidine is a highly selective α2-agonist with hypnotic, analgesic, and anxiolytic properties. Despite off-label administration, dexmedetomidine has found a niche in critically ill neonates and infants with congenital heart disease because of its minimal effects on respiratory function at sedative doses, facilitating early extubation and fast-track postoperative care. There are little pharmacokinetic data regarding newborns who have immature drug metabolizing capacity and who are at risk for reduced dexmedetomidine clearance and drug toxicity. The aim of this study was to determine the pharmacokinetics of dexmedetomidine in neonates and infants after open heart surgery. This study included 23 evaluable neonates (age, 1 day-1 month) and 36 evaluable infants (age, 1 month-24 months) after open heart surgery. Full-term neonates and infants requiring mechanical ventilation after open heart surgery received dexmedetomidine in a dose-escalation study. Dexmedetomidine was administered as a loading dose over 10 minutes followed by a continuous IV infusion up to 24 hours. Cohorts of 12 infants were enrolled sequentially to receive 0.35, 0.7, or 1 μg/kg dexmedetomidine followed by 0.25, 0.5, or 0.75 μg/kg/h dexmedetomidine, respectively. Cohorts of 9 neonates received 0.25, 0.35, or 0.5 μg/kg dexmedetomidine followed by 0.2, 0.3, or 0.4 μg/kg/h dexmedetomidine, respectively. Plasma dexmedetomidine concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population nonlinear mixed effects modeling approach was used to characterize dexmedetomidine pharmacokinetics. Pharmacokinetic parameters of dexmedetomidine were estimated using a 2-compartment disposition model with weight allometrically scaled as a covariate on drug clearance, intercompartmental clearance, central and peripheral volume of distributions and age, total bypass time, and intracardiac shunting on clearance. Dexmedetomidine demonstrated

  19. Dexmedetomidine infusion as adjunctive therapy to benzodiazepines for acute alcohol withdrawal.

    PubMed

    Darrouj, Jamil; Puri, Nitin; Prince, Erin; Lomonaco, Anthony; Spevetz, Antoinette; Gerber, David R

    2008-11-01

    To report a case of alcohol withdrawal and delirium tremens successfully treated with adjunctive dexmedetomidine. A 30-year-old man with a history of alcohol abuse was admitted to the general medical unit because of altered mental status and agitation. He was initially treated for alcohol withdrawal with benzodiazepines; his condition then deteriorated and he was transferred to the intensive care unit. Because of the patient's poor response to benzodiazepines (oxazepam and lorazepam, with midazolam the last one used), intravenous dexmedetomidine was started at an initial dose of 0.2 microg/kg/h and titrated to 0.7 microg/kg/h to the patient's comfort. Midazolam was subsequently tapered to discontinuation due to excessive sedation. In the intensive care unit, the patient's symptoms remained controlled with use of dexmedetomidine alone. He remained in the intensive care unit for 40 hours; dexmedetomidine was then tapered to discontinuation and the patient was transferred back to the general medical unit on oral oxazepam and thiamine, which had been started in the emergency department. He was discharged after 5 days. A review of the PubMed database (1989-2007) failed to identify any other instances of dexmedetomidine having been used as the principal agent to treat alcohol withdrawal. The use of sedative to treat delirium tremens is well documented, with benzodiazepines being the agents of choice. The clinical utility of benzodiazepines is limited by their stimulation of the gamma-aminobutyric acid receptors, an effect not shared by dexmedetomidine, a central alpha(2)-receptor agonist that induces a state of cooperative sedation and does not suppress respiratory drive. In patients with delirium tremens, dexmedetomidine should be considered as an option for primary treatment. This case illustrates the need for further studies to investigate other potential uses for dexmedetomidine.

  20. Preliminary experience with dexmedetomidine for monitored anesthesia care during ENT surgical procedures.

    PubMed

    Busick, Tamra; Kussman, Mary; Scheidt, Troy; Tobias, Joseph D

    2008-01-01

    Dexmedetomidine is an alpha2-adrenergic agonist that produces anxiolysis, amnesia, sedation, potentiation of opioid analgesia, and sympatholysis. It is currently approved by the U.S. Food & Drug Administration for the sedation of adults in the intensive care setting for up to 24 hours during mechanical ventilation. Given its beneficial sedative and anxiolytic properties and limited adverse effect profile, it has been used in several other clinical scenarios. The authors present their experience using dexmedetomidine for monitored anesthesia care (MAC) during "awake" ENT procedures such as thyroplasty, a procedure requiring a patient to verbalize when requested but to otherwise remain immobile to allow for completion of the procedure, and in a patient with post-polio syndrome with poor pulmonary reserve requiring esophagoscopy with dilation and botulinum toxin injection for cricopharyngeal dysfunction. Our preliminary experience suggests that dexmedetomidine provides effective sedation as the primary agent for MAC during such procedures in adult patients. The end-organ effects of dexmedetomidine and previous reports of its use during MAC are reviewed.

  1. Eszopiclone and Dexmedetomidine Depress Ventilation in Obese Rats with Features of Metabolic Syndrome

    PubMed Central

    Filbey, William A.; Sanford, David T.; Baghdoyan, Helen A.; Koch, Lauren G.; Britton, Steven L.; Lydic, Ralph

    2014-01-01

    Study Objectives: Obesity alters the therapeutic window of sedative/hypnotic drugs and increases the probability of respiratory complications. The current experiments used an established rodent model of obesity to test the hypothesis that the sedative/hypnotic drugs eszopiclone and dexmedetomidine alter ventilation differentially in obese rats compared with lean/fit rats. Design: This study used a within-groups/between-groups experimental design. Setting: University of Michigan. Participants: Experiments were conducted using lean/fit rats (n = 21) and obese rats (n = 21) that have features of metabolic syndrome. Interventions: Breathing was measured with whole-body plethysmography after systemic administration of vehicle (control), the nonbenzodiazepine, benzodiazepine site agonist eszopiclone, or the alpha-2 adrenergic receptor agonist dexmedetomidine. Measurements and Results: Data were analyzed using two-way analysis of variance and appropriate post hoc comparisons. At baseline, the obese/metabolic syndrome rats had increased respiratory rates (21.6%), lower tidal volumes/body weight (-24.1%), and no differences in minute ventilation compared to lean/fit rats. In the obese rats, respiratory rate was decreased by dexmedetomidine (-29%), but not eszopiclone. In the lean and the obese rats, eszopiclone decreased tidal volume (-12%). Both sedative/hypnotic drugs caused a greater decrease in minute ventilation in the obese (-26.3%) than lean (-18%) rats. Inspiratory flow rate (VT / TI) of the obese rats was decreased by dexmedetomidine (-10.6%) and eszopiclone (-18%). Duty cycle (TI / TTOT) in both rat lines was decreased by dexmedetomidine (-16.5%) but not by eszopiclone. Conclusions: Dexmedetomidine, in contrast to eszopiclone, decreased minute ventilation in the obese/metabolic syndrome rats by depressing both duty cycle and inspiratory flow rate. The results show for the first time that the obese phenotype differentially modulates the respiratory effects of

  2. Contribution of β-adrenoceptor subtypes to relaxation of colon and oesophagus and pacemaker activity of ureter in wildtype and β3-adrenoceptor knockout mice

    PubMed Central

    Oostendorp, Jaap; Preitner, Frédéric; Moffatt, James; Jimenez, Maria; Giacobino, Jean Paul; Molenaar, Peter; Kaumann, Alberto Julio

    2000-01-01

    The smooth muscle relaxant responses to the mixed β3-, putative β4-adrenoceptor agonist, (−)-CGP 12177 in rat colon are partially resistant to blockade by the β3-adrenoceptor antagonist SR59230A suggesting involvement of β3- and putative β4-adrenoceptors. We now investigated the function of the putative β4-adrenoceptor and other β-adrenoceptor subtypes in the colon, oesophagus and ureter of wildtype (WT) and β3-adrenoceptor knockout (β3KO) mice.(−)-Noradrenaline and (−)-adrenaline relaxed KCl (30 mM)-precontracted colon mostly through β1-and β3-adrenoceptors to a similar extent and to a minor extent through β2-adrenoceptors. In colon from β3KO mice, (−)-noradrenaline was as potent as in WT mice but the effects were mediated entirely through β1-adrenoceptors. (−)-CGP 12177 relaxed colon from β3KO mice with 2 fold greater potency than in WT mice. The maintenance of potency for (−)-noradrenaline and increase for (−)-CGP 12177 indicate compensatory increases in β1- and putative β4-adrenoceptor function in β3KO mice.In oesophagi precontracted with 1 μM carbachol, (−)-noradrenaline caused relaxation mainly through β1-and β3-adrenoceptors. (−)-CGP 12177 (2 μM) relaxed oesophagi from WT by 61.4±5.1% and β3KO by 67.3±10.1% of the (−)-isoprenaline-evoked relaxation, consistent with mediation through putative β4-adrenoceptors.In ureter, (−)-CGP 12177 (2 μM) reduced pacemaker activity by 31.1±2.3% in WT and 31.3±7.5% in β3KO, consistent with mediation through putative β4-adrenoceptors.Relaxation of mouse colon and oesophagus by catecholamines are mediated through β1- and β3-adrenoceptors in WT. The putative β4-adrenoceptor, which presumably is an atypical state of the β1-adrenoceptor, mediates the effects of (−)-CGP 12177 in colon, oesophagus and ureter. PMID:10864880

  3. Autoradiographic localization of beta-adrenoceptors in asthmatic human lung

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Spina, D.; Rigby, P.J.; Paterson, J.W.

    1989-11-01

    The autoradiographic distribution and density of beta-adrenoceptors in human non-diseased and asthmatic bronchi were investigated using (125I)iodocyanopindolol (I-CYP). Analysis of the effects of the beta-adrenoceptor antagonists on I-CYP binding demonstrated that betaxolol (20 nM, beta 1-selective) had no significant effect on specific grain density in either nonasthmatic or asthmatic human bronchus, whereas ICI-118551 (20 nM, beta 2-selective) inhibited I-CYP binding by 85 +/- 9% and 89 +/- 3%, respectively. Thus, homogeneous populations of beta 2-adrenoceptors existed in bronchi from both sources. Large populations of beta-adrenoceptors were localized to the bronchial epithelium, submucosal glands, and airway smooth muscle. Asthmatic bronchial tissuemore » featured epithelial damage with exfoliated cells associated with luminal mucus plugs. A thickened basement membrane and airway smooth muscle hyperplasia were also evident. High levels of specific I-CYP binding were also detected over asthmatic bronchial smooth muscle, as assessed by autoradiography and quantitation of specific grain densities. Isoproterenol and fenoterol were 10- and 13-fold less potent, respectively, in bronchi from asthmatic lung than in those from nonasthmatic lung. However, this attenuated responsiveness to beta-adrenoceptor agonists was not caused by reduced beta-adrenoceptor density in asthmatic airways. A defect may exist in the coupling between beta-adrenoceptors and postreceptor mechanisms in severely asthmatic lung.« less

  4. Inhibition by fenoterol of human eosinophil functions including β2-adrenoceptor-independent actions

    PubMed Central

    TACHIBANA, A; KATO, M; KIMURA, H; FUJIU, T; SUZUKI, M; MORIKAWA, A

    2002-01-01

    Agonists at β2 adrenoceptors are used widely as bronchodilators in treating bronchial asthma. These agents also may have important anti-inflammatory effects on eosinophils in asthma. We examined whether widely prescribed β2-adrenoceptor agonists differ in ability to suppress stimulus-induced eosinophil effector functions such as superoxide anion (O2−) generation and degranulation. To examine involvement of cellular adhesion in such responses, we also investigated effects of β2 agonists on cellular adhesion and on CD11b expression by human eosinophils. O2− was measured using chemiluminescence. Eosinophil degranulation and adhesion were assessed by a radioimmunoassay for eosinophil protein X (EPX). CD11b expression was measured by flow cytometry. Fenoterol inhibited platelet-activating factor (PAF)-induced O2− generation by eosinophils significantly more than salbutamol or procaterol. Fenoterol partially inhibited PAF-induced degranulation by eosinophils similarly to salbutamol or procaterol. Fenoterol inhibited phorbol myristate acetate (PMA)-induced O2− generation and degranulation by eosinophils, while salbutamol or procaterol did not. Fenoterol inhibition of PMA-induced O2− generation was not reversed by ICI-118551, a selective β2-adrenoceptor antagonist. Fenoterol, but not salbutamol or procaterol, significantly inhibited PAF-induced eosinophil adhesion. Fenoterol inhibited O2− generation and degranulation more effectively than salbutamol or procaterol; these effects may include a component involving cellular adhesion. Inhibition also might include a component not mediated via β2 adrenoceptors. PMID:12452831

  5. Structure-activity relationship studies of (+/-)-terbutaline and (+/-)-fenoterol on beta3-adrenoceptors in the guinea pig gastric fundus.

    PubMed

    Horinouchi, T; Nakagawa, Y; Wakabayashi, M; Koike, K

    2001-08-01

    (+/-)-Terbutaline and (+/-)-fenoterol are both arylethanolamine analogs that have tertbutyl and aryliso-propyl substituents respectively at the a position on the nitrogen of the ethanolamine side chain. In the present study, we have investigated the structure-activity relationships of (+/-)-terbutaline and (+/-)-fenoterol as beta3-adrenoceptor agonists in the guinea pig gastric fundus. (+/-)-Terbutaline and (+/-)-fenoterol induced concentration-dependent relaxation of the precontracted gastric fundus with pD2 values of 4.45+/-0.10 and 5.90+/-0.09, and intrinsic activities of 1.00+/-0.03 and 0.99+/-0.01 respectively. The combination of the selective beta1-adrenoceptor antagonist (+/-)-atenolol (100 microM), and the selective beta2-adrenoceptor antagonist (+/-)-butoxamine (100 microM), produced a 2 and 6 fold rightward shift of the concentration-response curves for (+/-)-terbutaline and (+/-)-fenoterol respectively, without depressing the maximal responses. The order of potency of these agonists was (pD2 value): (+/-)-fenoterol (5.09+/-0.10) > (+/-)-terbutaline (4.13+/-0.08). In the presence of (+/-)-atenolol and (+/-)-butoxamine, however, the non-selective beta1, beta2- and beta3-adrenoceptor antagonist (+/-)-bupranolol caused a concentration-dependent rightward shift of the concentration-response curves for (+/-)-terbutaline and (+/-)-fenoterol. Schild plot analyses of the effects of (+/-)-bupranolol against these agonists gave pA2 values of 6.21+/-0.07 ((+/-)-terbutaline) and 6.37+/-0.06 ((+/-)-fenoterol) respectively, and the slopes of the Schild plot were not significantly different from unity (p>0.05). These results suggest that the relaxant responses to (+/-)-terbutaline and (+/-)-fenoterol are mainly mediated through beta3-adrenoceptors in the guinea pig gastric fundus. The beta3-adrenoceptor agonist potencies of arylethanolamine analogs depend on the size of the end of the alkylamine side chain.

  6. Icilin-evoked behavioral stimulation is attenuated by alpha2-adrenoceptor activation

    PubMed Central

    Kim, Jae; Cowan, Alan; Lisek, Renata; Raymondi, Natalie; Rosenthal, Aaron; Hirsch, Daniel D.; Rawls, Scott M.

    2011-01-01

    Icilin is a transient receptor potential cation channel subfamily M (TRPM8) agonist that produces behavioral activation in rats and mice. Its hallmark overt pharmacological effect is wet-dog shakes (WDS) in rats. The vigorous shaking associated with icilin is dependent on NMDA receptor activation and nitric oxide production, but little else is known about the biological systems that modulate the behavioral phenomenon. The present study investigated the hypothesis that alpha2-adrenoceptor activation inhibits icilin-induced WDS. Rats injected with icilin (0.5, 1, 2.5, 5 mg/kg, i.p.) displayed dose-related WDS that were inhibited by pretreatment with a fixed dose of clonidine (0.15 mg/kg, s.c.). Shaking behavior caused by a fixed dose (2.5 mg/kg) of icilin was also inhibited in a dose-related manner by clonidine pretreatment (0.03–0.15 mg/kg, s.c.) and reduced by clonidine posttreatment (0.15 mg/kg, s.c.). Pretreatment with a peripherally restricted alpha2-adrenoceptor agonist, ST91 (0.075, 0.15 mg/kg), also decreased the incidence of shaking elicited by 2.5 mg/kg of icilin. Pretreatment with yohimbine (2 mg/kg, i.p.) enhanced the shaking induced by a low dose of icilin (0.5 mg/kg). The imidazoline site agonists, agmatine (150 mg/kg, i.p.) and 2-BFI (7 mg/kg, i.p.), did not affect icilin-evoked shaking. These results suggest that alpha2-adrenoceptor activation inhibits shaking induced by icilin and that increases in peripheral, as well as central, alpha2-adrenoceptor signaling oppose the behavioral stimulant effect of icilin. PMID:21315691

  7. A Role for Presynaptic alpha(sub 2)-Adrenoceptors in Angiotensin 2-Induced Drinking in Rats

    NASA Technical Reports Server (NTRS)

    Fregly, Melvin J.; Rowland, Neil E.; Greenleaf, John E.

    1984-01-01

    Studies from this laboratory have shown that either central or peripheral administration of clonidine, the alpha(sub 2)-adrenoceptor agonist, can attenuate a variety of dipsogenic stimuli in rats. Further, yohimbine and tolazoline, alpha(sub 2)-adrenoceptor antagonists, augment the drinking response to both peripherally administered isoproterenol and angiotensin 2. Studies reported here establish a dose-inhibition relationship between the dose of clonidine administered (2 to 32 micrograms/kg) intracerebroventricularly (IVT) and inhibition of the drinking response to peripherally administered angiotensin 2 (200 micrograms/kg, SC). DI(sub 50) was approximately 4 micrograms/kg. Yohimbine (300 micrograms/kg, SC) reversed the antidipsogenic effect of centrally administered clonidine (32 micrograms/kg, IVT) on angiotensin 2-induced (200 micrograms/kg, SC) water intake. Phenylephrine, an alpha(sub 2)-adrenoceptor agonist, administered IVT (40 and 80 micrograms/kg) also inhibited angiotensin 2-induced drinking in a dose-related fashion. The antidipsogenic effect of phenylephfine (80 micrograms/kg) was blocked by administration of yohimbine (100 micrograms/kg, SC). Thus, this effect of phenylephrine most likely occurs by way of alpha(sub 2)- adrenoceptors. These results support a role for the pre-synaptic alpha(sub 2)-adrenoceptor in the mediation of drinking in rats. Activation of alpha(sub 2)-adrenoceptors is accompanied by reduced water intake while inhibition of these receptors enhances water intake.

  8. Characterization and autoradiographic localization of beta-adrenoceptor subtypes in human cardiac tissues.

    PubMed Central

    Buxton, B. F.; Jones, C. R.; Molenaar, P.; Summers, R. J.

    1987-01-01

    1 Receptor autoradiography using (-)-[125I]-cyanopindolol (CYP) was used to study the distribution of beta-adrenoceptor subtypes in human right atrial appendage, left atrial free wall, left ventricular papillary muscle and pericardium. 2 The binding of (-)-[125I]-CYP to slide-mounted tissue sections of human right atrial appendage was time-dependent (K1 = 4.11 +/- 1.01 X 10(8) M-1 min-1, K-1 = 1.47 +/- 0.25 X 10(-3) min-1, n = 3), saturable (42.02 +/- 2.96 pM, n = 4) and stereoselective with respect to the optical isomers of propranolol (pKD (-):8.97 +/- 0.02, (+):6.88 +/- 0.06, n = 3). 3 The proportions of beta-adrenoceptor subtypes were determined in slide-mounted tissue sections using the antagonists CGP 20712A (beta 1-selective) and ICI 118,551 (beta 2-selective). In right atrial appendage and left ventricular papillary muscle 40% (34-45%) of the beta-adrenoceptors were of the beta 2-subtype. 4 Images from X-ray film and nuclear emulsion coated coverslips exposed to (-)-[125I]-CYP-labelled sections showed an even distribution of beta-adrenoceptor subtypes over the myocardium of the right atrial appendage, left ventricular papillary muscle and left atrial free wall. Sections of pericardium exhibited predominantly beta 2-adrenoceptors. beta 2-Adrenoceptors were localized to the intimal surface of coronary arteries. 5 The selective beta 1-adrenoceptor agonist RO363 and beta 2-selective agonist procaterol produced concentration-dependent inotropic responses in right atrial appendage strips. Responses to RO363 were antagonized by CGP 20712A (pKB = 9.29) suggesting an interaction with beta 1-adrenoceptors. Responses to procaterol were antagonized by ICI 118,551 (pKB = 9.06) suggesting an interaction at beta 2-adrenoceptors. 6 The finding that a significant proportion of human myocardial adrenoceptors are of the beta 2-subtype has important clinical implications for the involvement of these receptors in the control of heart rate and force, and the autoradiographic

  9. Fenoterol inhibits superoxide anion generation by human polymorphonuclear leukocytes via beta-adrenoceptor-dependent and -independent mechanisms.

    PubMed

    Mirza, Zafar Nazir; Kato, Masahiko; Kimura, Hirokazu; Tachibana, Atsushi; Fujiu, Toru; Suzuki, Masato; Mochizuki, Hiroyuki; Tokuyama, Kenichi; Morikawa, Akihiro

    2002-05-01

    Beta2-adrenoceptor agonists, used widely as bronchodilator in treating bronchial asthma, may have anti-inflammatory activity. We examined whether various widely prescribed beta2-adrenoceptor agonists differ in anti-inflammatory mechanisms. We investigated effects of these drugs on superoxide anion generation by stimulated human polymorphonuclear leukocytes in vitro using chemiluminescence. At high concentrations, fenoterol significantly inhibited both N-formylmethionyl-leucyl-phenylalanine- and phorbol myristate acetate-induced superoxide generation by neutrophils. In contrast, salbutamol or procaterol partially inhibited generation with the former stimulus but not the latter. Inhibition by salbutamol or procaterol was completely reversed by either propranolol, a nonselective beta-adrenoceptor antagonist, or ICI-118551, a beta2-adrenoceptor-selective antagonist. In contrast, the effect of fenoterol at concentrations exceeding 10(-6) M against superoxide generation with the former stimulus was only partially reversed by antagonists, and the effect of high concentrations of fenoterol against generation with the latter stimulus was not reversed. No drugs scavenged superoxide at the highest concentration used (10(-5) M). Fenoterol at high concentrations has an inhibitory effect on superoxide generation that includes a component not mediated via beta2-adrenoceptors. Direct inhibition at or downstream from protein kinase C may be involved.

  10. Evaluation of the alpha-1 and alpha-2 adrenoceptor-mediated effects of a series of dimethoxy-substituted tolazoline derivatives in the cardiovascular system of the pithed rat.

    PubMed

    Ruffolo, R R; Messick, K

    1985-01-01

    The alpha-1 and alpha-2 adrenoceptor-mediated effects of a series of dimethoxy-substituted tolazoline derivatives were investigated in the cardiovascular system of the pithed rat. The 2,5- and 3,5-dimethoxy-substituted tolazoline derivatives produced vasopressor responses that were inhibited by the alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.), and were not affected by the alpha-2 adrenoceptor antagonist, yohimbine (1 mg/kg i.v.), suggesting that these derivatives selectively activate postsynaptic vascular alpha-1 adrenoceptors. The 2,5- and 3,5-dimethoxy-substituted derivatives of tolazoline did not produce an alpha-2 adrenoceptor-mediated inhibition of neurogenic tachycardia in cord-stimulated pithed rats and were therefore presumed to be devoid of alpha-2 adrenoceptor agonist activity. In contrast, 2,3-dimethoxytolazoline produced a vasopressor effect that was inhibited by yohimbine but not by prazosin, suggesting selective activation of postsynaptic vascular alpha-2 adrenoceptors. Consistent with this observation is the fact that 2,3-dimethoxytolazoline elicited a dose-dependent, alpha-2 adrenoceptor-mediated inhibition of neurogenic tachycardia in cord-stimulated pithed rat. 3,4-Dimethoxytolazoline was a weak alpha-1 adrenoceptor agonist in the vasculature of the pithed rat and was devoid of agonist activity at alpha-2 adrenoceptors. However, 3,4-dimethoxytolazoline was found to be an alpha-2 adrenoceptor antagonist of similar potency as yohimbine. The results of the present study indicate that dimethoxy-substituted derivatives of tolazoline possess different activities and selectivities at alpha-1 and alpha-2 adrenoceptors depending upon the positions of substitution.(ABSTRACT TRUNCATED AT 250 WORDS)

  11. Factors Associated with Tremor Changes during Sedation with Dexmedetomidine in Parkinson's Disease Surgery.

    PubMed

    Honorato-Cia, Cristina; Martínez-Simón, Antonio; Alegre, Manuel; Guridi, Jorge; Cacho-Asenjo, Elena; Panadero, Alfredo; Núñez-Córdoba, Jorge M

    2015-01-01

    Dexmedetomidine is an α2-agonist recently proposed as a potentially ideal drug for sedation during the surgical treatment of Parkinson's disease (PD). This report documents the incidence of changes in motor symptoms (especially tremor) in PD patients sedated with dexmedetomidine for deep brain stimulation or ablation procedures. We reviewed a retrospective cohort of 22 patients who underwent surgery for PD with dexmedetomidine sedation at a single institution from 2010 to 2014. A logistic regression analysis was performed to analyze possible confounding factors. 14 cases of tremor reduction or suppression were recorded (cumulative incidence: 63.6%; 95% CI: 40.7-82.8). No association could be identified between loading dose, β-blocker use and preoperative total Unified Parkinson's Disease Rating Scale III, with tremor changes. The maintenance dose of dexmedetomidine was higher in patients who did not experience changes [median and range for patients with and without tremor alteration 0.75 (0.2-1.0) and 1.0 µg × kg(-1) × h(-1) (0.7-1.4), respectively; p = 0.021]. Dexmedetomidine provides adequate sedation during surgery for PD, but it might affect motor signs making intraoperative testing difficult or even impossible. Dosage appears not to be the determining factor in motor changes, whose cause remains unclear. © 2015 S. Karger AG, Basel.

  12. Modelling the Interaction of Catecholamines with the α1A Adrenoceptor Towards a Ligand-induced Receptor Structure

    NASA Astrophysics Data System (ADS)

    Kinsella, Gemma K.; Rozas, Isabel; Watson, Graeme W.

    2005-06-01

    Adrenoceptors are members of the important G protein coupled receptor family for which the detailed mechanism of activation remains unclear. In this study, we have combined docking and molecular dynamics simulations to model the ligand induced effect on an homology derived human α1A adrenoceptor. Analysis of agonist/α1A adrenoceptor complex interactions focused on the role of the charged amine group, the aromatic ring, the N-methyl group of adrenaline, the beta hydroxyl group and the catechol meta and para hydroxyl groups of the catecholamines. The most critical interactions for the binding of the agonists are consistent with many earlier reports and our study suggests new residues possibly involved in the agonist-binding site, namely Thr-174 and Cys-176. We further observe a number of structural changes that occur upon agonist binding including a movement of TM-V away from TM-III and a change in the interactions of Asp-123 of the conserved DRY motif. This may cause Arg-124 to move out of the TM helical bundle and change the orientation of residues in IC-II and IC-III, allowing for increased affinity of coupling to the G-protein.

  13. Beta-adrenoceptor dysfunction after inhibition of NO synthesis

    NASA Technical Reports Server (NTRS)

    Whalen, E. J.; Johnson, A. K.; Lewis, S. J.

    2000-01-01

    G(s) protein-coupled beta-adrenoceptors rapidly desensitize on exposure to agonists in reconstituted membrane preparations, whereas rapid tachyphylaxis to beta-adrenoceptor-mediated vasodilation does not readily occur in vivo. This study examined the possibility that endothelium-derived nitrosyl factors prevent the rapid desensitization of beta-adrenoceptors in the vascular smooth muscle of resistance arteries in pentobarbital-anesthetized rats. The fall in mean arterial blood pressure and in hindquarter vascular resistance produced by the beta-adrenoceptor agonist isoproterenol (ISO, 0.1 to 10 microg/kg IV) was slightly but significantly smaller in rats treated with the NO synthase inhibitor N:(G)-nitro-L-arginine methyl ester (L-NAME, 100 micromol/kg IV) than in saline-treated rats. The ISO-induced fall in mesenteric resistance was similar in L-NAME-treated and in saline-treated rats. The fall in hindquarter vascular resistance and in mesenteric resistance produced by ISO (8 x 10 microg/kg IV) was subject to tachyphylaxis on repeated injection in rats treated with L-NAME (100 micromol/kg IV) but not in rats treated with saline. Injections of L-S:-nitrosocysteine (1200 nmol/kg IV), a lipophobic S:-nitrosothiol, before each injection of ISO (10 microg/kg IV) prevented tachyphylaxis to ISO in L-NAME-treated rats. The vasodilator effects of ISO (0.1 to 10 microg/kg IV) in L-NAME-treated rats that received 8 injections of ISO (10 microg/kg IV) were markedly smaller than in L-NAME-treated rats that received 8 injections of saline. These results indicate that (1) the vasodilator actions of ISO in pentobarbital-anesthetized rats only minimally involve the release of endothelium-derived nitrosyl factors, (2) the effects of ISO are subject to development of tachyphylaxis in L-NAME-treated rats, and (3) tachyphylaxis to ISO is prevented by L-S:-nitrosocysteine. These findings suggest that endothelium-derived nitrosyl factors may prevent desensitization of beta-adrenoceptors

  14. [Postpartum hemorrhage and pregnancy induced hypertension during emergency lower segment cesarean section: dexmedetomidine to our rescue].

    PubMed

    Hariharan, Uma

    Dexmedetomidine is a highly selective α-2 agonist which has recently revolutionized our anesthesia and intensive care practice. An obstetric patient presented for emergency cesarean delivery under general anesthesia, with pre-eclampsia and postpartum hemorrhage. In carefully selected cases with refractory hypertension and postpartum hemorrhage, dexmedetomidine can be used for improving overall patient outcome. It was beneficial in controlling both the blood pressure and uterine bleeding during cesarean section in our patient. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  15. α2-Adrenoceptor Functionality in Postmortem Frontal Cortex of Depressed Suicide Victims

    PubMed Central

    Valdizán, Elsa M.; Díez-Alarcia, Rebeca; González-Maeso, Javier; Pilar-Cuéllar, Fuencisla; García-Sevilla, Jesús A.; Meana, J. Javier; Pazos, Angel

    2013-01-01

    Background Alterations in brain density and signaling associated with monoamine receptors are believed to play a role in depressive disorders. This study evaluates the functional status of α2A-adrenoceptors in postmortem frontal cortex of depressed subjects. Methods G-protein activation and inhibition of adenylyl cyclase (AC) activity induced by the α2-adrenoceptor agonist UK14304 were measured in triplicate in samples from 15 suicide victims with an antemortem diagnosis of major depression and 15 matched control subjects. Results Basal [35S] guanosine γ thio-phosphate (GTPγS) binding and cyclic adenosine monophosphate accumulation did not differ between groups. In depressed victims, an increase in [35S] GTPγS binding potency (EC50 = .58 μmol/L vs. EC50 = 3.31 μmol/L; p < .01; depressed vs. control) and a significant reduction in the maximal inhibition of AC activity (Imax = 27 ± 4% vs. Imax = 47 ± 5%; p < .01) were observed after incubation with the α2-adrenoceptor agonist UK14304. No differences were found between antidepressant-free and antidepressant-treated subjects. A significant relationship between EC50 values for [35S] GTPγS and Imax values for AC assay was found (n = 30; r = −.43; p < .05). Conclusions The dual regulation of α2A-adrenoceptor signaling pathways raises the possibility that factors affecting the G-protein cycle and/or selective access of Gαi/o–protein to AC might be relevant to receptor abnormalities in depression, providing further support for the involvement of α2A-adrenoceptors in the pathogenesis of depression. PMID:20864091

  16. Proliferation of the human urothelium is induced by atypical β1 -adrenoceptors.

    PubMed

    Winder, M; Wasén, C; Aronsson, P; Giglio, D

    2015-09-01

    We wanted to assess whether β-adrenoceptors mediate proliferation in the normal and malignant urothelial cell lines UROtsa and T24, respectively. Urothelial cells were cultured for 24 h in the presence of the β-adrenoceptor agonists isoprenaline (β1/2/3 ), dobutamine (β1 ), salbutamol (β2 ), BRL 37344 (β3 ), CGP 12177 (a partial β-agonist) or β-adrenoceptor antagonists (metoprolol; β1 , propranolol; β1/2 ). Phosphorylation of kinases was screened with a Human Phospho-Kinase Array Kit (R&D systems). Intracellular pathways activated by proliferation of urothelial cells were characterized by incubating cells with the MEK1/2 inhibitor PD 98,059, the p38 kinase inhibitor losmapimod or with the Akt 1/2 kinase inhibitor. Proliferation was assessed with the MTT proliferation assay (ATCC). Western blot and immunocytochemistry were used for detection of the β1 -adrenoceptor. Isoprenaline and dobutamine induced proliferation, while salbutamol and BRL 37344 did not. Dobutamine-induced proliferation was not affected by metoprolol or propranolol but was instead antagonized by CGP 12177 in T24 but not in UROtsa. In response to stimulation with dobutamine, Akt1/2/3 was phosphorylated in UROtsa, while ERK1/2 and p38 were phosphorylated in T24. MEK1/2 inhibition blocked basal and dobutamine-induced proliferation in T24 but only basal proliferation in UROtsa. Losmapimod slightly inhibited basal proliferation in T24 but not dobutamine-induced proliferation. Akt 1/2 inhibitor blocked basal and dobutamine-induced proliferation in UROtsa. Immunocytochemistry and Western blot revealed expression of β1 -adrenoceptors in both urothelial cell lines. The present data show that the urothelium expresses atypical β1-adrenoceptors that activate intracellular kinases inducing urothelial proliferation. © 2016 John Wiley & Sons Ltd.

  17. Dexmedetomidine attenuates traumatic brain injury: action pathway and mechanisms.

    PubMed

    Wang, Dong; Xu, Xin; Wu, Yin-Gang; Lyu, Li; Zhou, Zi-Wei; Zhang, Jian-Ning

    2018-05-01

    Traumatic brain injury induces potent inflammatory responses that can exacerbate secondary blood-brain barrier (BBB) disruption, neuronal injury, and neurological dysfunction. Dexmedetomidine is a novel α2-adrenergic receptor agonist that exert protective effects in various central nervous system diseases. The present study was designed to investigate the neuroprotective action of dexmedetomidine in a mouse traumatic brain injury model, and to explore the possible mechanisms. Adult male C57BL/6J mice were subjected to controlled cortical impact. After injury, animals received 3 days of consecutive dexmedetomidine therapy (25 µg/kg per day). The modified neurological severity score was used to assess neurological deficits. The rotarod test was used to evaluate accurate motor coordination and balance. Immunofluorescence was used to determine expression of ionized calcium binding adapter molecule-1, myeloperoxidase, and zonula occluden-1 at the injury site. An enzyme linked immunosorbent assay was used to measure the concentration of interleukin-1β (IL-1β), tumor necrosis factor α, and IL-6. The dry-wet weight method was used to measure brain water content. The Evans blue dye extravasation assay was used to measure BBB disruption. Western blot assay was used to measure protein expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1 p20, IL-1β, nuclear factor kappa B (NF-κB) p65, occluding, and zonula occluden-1. Flow cytometry was used to measure cellular apoptosis. Results showed that dexmedetomidine treatment attenuated early neurological dysfunction and brain edema. Further, dexmedetomidine attenuated post-traumatic inflammation, up-regulated tight junction protein expression, and reduced secondary BBB damage and apoptosis. These protective effects were accompanied by down-regulation of the NF-κB and NLRP3 inflammasome pathways. These findings suggest that dexmedetomidine exhibits

  18. The novel β3-adrenoceptor agonist mirabegron reduces carbachol-induced contractile activity in detrusor tissue from patients with bladder outflow obstruction with or without detrusor overactivity.

    PubMed

    Svalø, Julie; Nordling, Jørgen; Bouchelouche, Kirsten; Andersson, Karl-Erik; Korstanje, Cees; Bouchelouche, Pierre

    2013-01-15

    β(3)-Adrenoceptors are major players in detrusor relaxation and have been suggested as a new putative target for the treatment of overactive bladder syndrome. We determined the effects of mirabegron (YM178), a novel β(3)-adrenoceptor agonist, on carbachol-induced tone in isolated human detrusor preparations from patients with bladder outflow obstruction (BOO) with and without detrusor overactivity (DO), and from patients with normal bladder function. We compared the effects to those of isoprenaline, a non-selective β-adrenoceptor agonist. Detrusor specimens were obtained from patients with benign prostatic hyperplasia undergoing cystoscopy and from patients undergoing radical prostatectomy/cystectomy (in total 33 donors). Detrusor contractility was evaluated by organ bath studies and strips were incubated with carbachol (1μM) to induce and enhance tension. Both mirabegron and isoprenaline reduced carbachol-induced tone in tissues from all groups. Isoprenaline decreased tension with higher potency than mirabegron in normal, BOO and BOO+DO detrusor strips with pIC(50) values of 7.49 ± 0.16 vs. 6.23 ± 0.26 (P=0.0002), 6.89 ± 0.34 vs. 6.04 ± 0.31 (P=0.01), and 6.57 ± 0.20 vs. 5.41 ± 0.08 (P<0.0001, n=4), respectively. The maximal relaxant effect of isoprenaline and mirabegron in the normal, BOO and BOO+DO detrusor was 37.7 ± 14.4% and 36.1 ± 23.3%, 14.4 ± 12.2% vs. 33.4 ± 21.0% and 18.3 ± 10.0% vs. 28.3 ± 12.2% (n=4, P>0.05), respectively. Mirabegron and isoprenaline reduced carbachol-induced tone in both normal bladders and obstructed bladder with and without DO. Isoprenaline had higher potency than mirabegron, but the efficacy of mirabegron effect was the same as that of isoprenaline. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Adrenoceptor function and expression in bladder urothelium and lamina propria.

    PubMed

    Moro, Christian; Tajouri, Lotti; Chess-Williams, Russ

    2013-01-01

    To investigate the role of adrenoceptor subtypes in regulating the spontaneous contractile activity of the inner lining of the urinary bladder (urothelium/lamina propria). The responses of isolated strips of porcine urothelium/lamina propria to noradrenaline, phenylephrine, and isoprenaline were obtained in the absence and presence of receptor subtype-selective antagonists. Quantitative reverse-transcriptase polymerase chain reaction was undertaken to assess the expression of adrenoceptor genes. The tissues expressed all α1- and β-adrenoceptor subtypes, with the α1A-, α1B-, and β2-adrenoceptors the predominant receptors at the messenger RNA level. In the functional experiments, the rate of phasic contractions and the basal tension were increased by the α1-adrenoceptor agonists phenylephrine (100 μM) and A61603 (10 μM). The rate and tension responses to phenylephrine were reduced by low concentrations of tamsulosin (3 nM) and RS100329 (10 nM) but were unaffected by BMY7378 (100 nM), prazosin (10 nM), and RS17053 (1 μM). In contrast, isoprenaline and salbutamol (both 1 μM) induced a relaxation of tissues and slowing of phasic contractions. The rate and tension responses to isoprenaline were inhibited by propranolol (100 nM) or a combination of CGP20712A (30 nM) and ICI118551 (70 nM). The rate responses were also significantly inhibited by ICI118551 alone (70 nM). Although all α1- and β-adrenoceptor subtypes were expressed in the pig urothelium/lamina propria, the α1A/L-adrenoceptor appeared to mediate increases in the contractile rate and tension. The β-adrenoceptor induced inhibition of spontaneous contractile activity appears to be predominately mediated by β2-adrenoceptors, with β1- and β2-adrenoceptors possibly involved in the tension responses. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase-Knockout Mice.

    PubMed

    Forkuo, Gloria S; Kim, Hosu; Thanawala, Vaidehi J; Al-Sawalha, Nour; Valdez, Daniel; Joshi, Radhika; Parra, Sergio; Pera, Tonio; Gonnella, Patricia A; Knoll, Brian J; Walker, Julia K L; Penn, Raymond B; Bond, Richard A

    2016-08-01

    Mice lacking the endogenous β2-adrenoceptor (β2AR) agonist epinephrine (phenylethanolamine N-methyltransferase [PNMT]-knockout mice) are resistant to developing an "asthma-like" phenotype in an ovalbumin sensitization and challenge (Ova S/C) model, and chronic administration of β2AR agonists to PNMT-KO mice restores the phenotype. Based on these and other studies showing differential effects of various β2AR ligands on the asthma phenotype, we have speculated that the permissive effect of endogenous epinephrine and exogenous β2AR agonists on allergic lung inflammation can be explained by qualitative β2AR signaling. The β2AR can signal through at least two pathways: the canonical Gαs-cAMP pathway and a β-arrestin-dependent pathway. Previous studies suggest that β-arrestin-2 is required for allergic lung inflammation. On the other hand, cell-based assays suggest antiinflammatory effects of Gαs-cAMP signaling. This study was designed to test whether the in vitro antiinflammatory effects of phosphodiesterase 4 inhibitors, known to increase intracellular cAMP in multiple airway cell types, attenuate the asthma-like phenotype produced by the β2AR agonists formoterol and salmeterol in vivo in PNMT-KO mice, based on the hypothesis that skewing β2AR signaling toward Gαs-cAMP pathway is beneficial. Airway inflammatory cells, epithelial mucus production, and airway hyperresponsiveness were quantified. In Ova S/C PNMT-KO mice, formoterol and salmeterol restored the asthma-like phenotype comparable to Ova S/C wild-type mice. However, coadministration of either roflumilast or rolipram attenuated this formoterol- or salmeterol-driven phenotype in Ova S/C PNMT-KO. These findings suggest that amplification of β2AR-mediated cAMP by phosphodiesterase 4 inhibitors attenuates the asthma-like phenotype promoted by β-agonists.

  1. Alpha-2A Adrenoceptor Agonist Guanfacine Restores Diuretic Efficiency in Experimental Cirrhotic Ascites: Comparison with Clonidine

    PubMed Central

    Sansoè, Giovanni; Aragno, Manuela; Mastrocola, Raffaella; Mengozzi, Giulio; Parola, Maurizio

    2016-01-01

    Background In human cirrhosis, adrenergic hyperfunction causes proximal tubular fluid retention and contributes to diuretic-resistant ascites, and clonidine, a sympatholytic drug, improves natriuresis in difficult-to-treat ascites. Aim To compare clonidine (aspecific α2-adrenoceptor agonist) to SSP-002021R (prodrug of guanfacine, specific α2A-receptor agonist), both associated with diuretics, in experimental cirrhotic ascites. Methods and Results Six groups of 12 rats were studied: controls (G1); controls receiving furosemide and potassium canrenoate (G2); rats with ascitic cirrhosis due to 14-week CCl4 treatment (G3); cirrhotic rats treated (over the 11th-14th CCl4 weeks) with furosemide and canrenoate (G4), furosemide, canrenoate and clonidine (G5), or diuretics and SSP002021R (G6). Three rats of each group had their hormonal status and renal function assessed at the end of 11th, 12th, 13th, and 14th weeks of respective treatments.Cirrhotic rats in G3 and G4 gained weight over the 12th-14th CCl4 weeks. In G4, brief increase in sodium excretion over the 11th-12th weeks preceded worsening of inulin clearance and natriuresis (diuretic resistance). In comparison with G4, the addition of clonidine (G5) or guanfacine (G6) to diuretics improved, respectively, sodium excretion over the 11th-12th CCl4 weeks, or GFR and electrolytes excretion over the 13th-14th CCl4 weeks. Natriuretic responses in G5 and G6 were accompanied by reduced catecholamine serum levels. Conclusions α2A-receptor agonists restore glomerular filtration rate and natriuresis, and delay diuretic-resistant ascites in experimental advanced cirrhosis. Clonidine ameliorates diuretic-dependent natriuresis just for a short time. PMID:27384184

  2. Agonist-induced β2-adrenoceptor desensitization and downregulation enhance pro-inflammatory cytokine release in human bronchial epithelial cells.

    PubMed

    Oehme, Susanne; Mittag, Anja; Schrödl, Wieland; Tarnok, Attila; Nieber, Karen; Abraham, Getu

    2015-02-01

    It is not clear whether increased asthma severity associated with long-term use of β2-adrenoceptor (β2-AR) agonists can be attributed to receptor degradation and increased inflammation. We investigated the cross-talk between β-AR agonist-mediated effects on β2-AR function and expression and cytokine release in human bronchial epithelial cells. In 16HBE14o(-) cells grown in the presence and absence of β-AR agonists and/or antagonists, the β2-AR density was assessed by radioligand binding; the receptor protein and mRNA was determined using laser scanning cytometer and RT-PCR; cAMP generation, the cytokines IL-6 and IL-8 release were determined using AlphaScreen Assay and ELISA, respectively. Isoprenaline (ISO) and salbutamol (Salbu) induced a concentration- and time-dependent significant decrease in β2-AR density. Both Salbu and ISO reduced cAMP generation in a concentration-dependent manner while in same cell culture the IL-6 and IL-8 release was significantly enhanced. These effects were antagonized to a greater extent by ICI 118.551 than by propranolol, but CGP 20712A had no effect. Reduction of the β2-AR protein and mRNA could be seen when cells were treated with ISO for 24 h. Our findings indicate a direct link between cytokine release and altered β2-AR expression and function in airway epithelial cells. β2-AR desensitization and downregulation induced by long-term treatment with β2-AR agonists during asthma may account for adverse reactions also due to enhanced release of pro-inflammatory mediators and should, thus, be considered in asthma therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Blockade of hyperpolarization-activated channels modifies the effect of beta-adrenoceptor stimulation.

    PubMed

    Zefirov, T L; Ziyatdinova, N I; Gainullin, A A; Zefirov, A L

    2002-05-01

    Experiments on rats showed that blockade of hyperpolarization-activated currents moderates tachycardia induced by beta-adrenoceptor agonist isoproterenol and potentiates the increase in stroke volume produced by this agonist. Electrical stimulation of the vagus nerve against the background of isoproterenol treatment augmented bradycardia and increased stroke volume. Blockade of hyperpolarization-activated currents followed by application of isoproterenol moderated vagus-induced bradycardia and had no effect on the dynamics of stroke volume.

  4. Understanding how long‐acting β2‐adrenoceptor agonists enhance the clinical efficacy of inhaled corticosteroids in asthma – an update

    PubMed Central

    Giembycz, Mark A

    2016-01-01

    In moderate‐to‐severe asthma, adding an inhaled long‐acting β2‐adenoceptor agonist (LABA) to an inhaled corticosteroid (ICS) provides better disease control than simply increasing the dose of ICS. Acting on the glucocorticoid receptor (GR, gene NR3C1), ICSs promote anti‐inflammatory/anti‐asthma gene expression. In vitro, LABAs synergistically enhance the maximal expression of many glucocorticoid‐induced genes. Other genes, including dual‐specificity phosphatase 1(DUSP1) in human airways smooth muscle (ASM) and epithelial cells, are up‐regulated additively by both drug classes. Synergy may also occur for LABA‐induced genes, as illustrated by the bronchoprotective gene, regulator of G‐protein signalling 2 (RGS2) in ASM. Such effects cannot be produced by either drug alone and may explain the therapeutic efficacy of ICS/LABA combination therapies. While the molecular basis of synergy remains unclear, mechanistic interpretations must accommodate gene‐specific regulation. We explore the concept that each glucocorticoid‐induced gene is an independent signal transducer optimally activated by a specific, ligand‐directed, GR conformation. In addition to explaining partial agonism, this realization provides opportunities to identify novel GR ligands that exhibit gene expression bias. Translating this into improved therapeutic ratios requires consideration of GR density in target tissues and further understanding of gene function. Similarly, the ability of a LABA to interact with a glucocorticoid may be suboptimal due to low β2‐adrenoceptor density or biased β2‐adrenoceptor signalling. Strategies to overcome these limitations include adding‐on a phosphodiesterase inhibitor and using agonists of other Gs‐coupled receptors. In all cases, the rational design of ICS/LABA, and derivative, combination therapies requires functional knowledge of induced (and repressed) genes for therapeutic benefit to be maximized. PMID:27646470

  5. Incidence of bradycardia in pediatric patients receiving dexmedetomidine anesthesia: a meta-analysis.

    PubMed

    Gong, Maowei; Man, Yuanyuan; Fu, Qiang

    2017-02-01

    Background Dexmedetomidine, an α2-receptor agonist, provides potent sedation, analgesia, and anxiolysis without respiratory depression and is used in a variety of surgical and procedural situations. Aim of the review The aim of this study was to estimate the incidence of bradycardia in pediatric patients who received dexmedetomidine as a sole agent for any procedural, intensive care or surgical sedation. Method Literature was searched in electronic databases and studies were selected by following pre-determined eligibility criteria. Meta-analyses were carried out by pooling the percent incidence of bradycardia to attain a weighted overall effect size. Age-wise subgroup analyses and meta-regression analyses for the identification of factors affecting the incidence were also performed. Results Data of 2835 patients from 21 studies were included. The mean age was 62.21 ± 35.68 months. Initial, maintenance and total doses of dexmedetomidine (mean ± standard deviation) were 1.63 ± 0.33 μg/kg body weight, 0.86 ± 0.68 μg/kg/h, and 26.7 ± 20.8 μg/kg. The overall incidence of bradycardia (95% confidence interval) was 3.067 (2.863, 3.270)%; P < 0.0001. However, range was wider (0-22%) with 9 studies observed 0% incidence. The mean change in the heart rate was -17.26 (-21.60, -12.92); P < 0.00001. In the meta-regression analyses, age, body weight and dexmedetomidine dose were not significantly associated with the incidence of bradycardia. The minimum heart rate observed during the dexmedetomidine treatment period was positively associated with baseline heart rate. Conclusion Incidence of bradycardia in dexmedetomidine treated pediatric patients is 3%.

  6. Serelaxin Elicits Bronchodilation and Enhances β-Adrenoceptor-Mediated Airway Relaxation

    PubMed Central

    Lam, Maggie; Royce, Simon G.; Donovan, Chantal; Jelinic, Maria; Parry, Laura J.; Samuel, Chrishan S.; Bourke, Jane E.

    2016-01-01

    Treatment with β-adrenoceptor agonists does not fully overcome the symptoms associated with severe asthma. Serelaxin elicits potent uterine and vascular relaxation via its cognate receptor, RXFP1, and nitric oxide (NO) signaling, and is being clinically evaluated for the treatment of acute heart failure. However, its direct bronchodilator efficacy has yet to be explored. Tracheal rings were prepared from male Sprague-Dawley rats (250–350 g) and tricolor guinea pigs, and precision cut lung slices (PCLSs) containing intrapulmonary airways were prepared from rats only. Recombinant human serelaxin (rhRLX) alone and in combination with rosiglitazone (PPARγ agonist; recently described as a novel dilator) or β-adrenoceptor agonists (isoprenaline, salbutamol) were added either to pre-contracted airways, or before contraction with methacholine or endothelin-1. Regulation of rhRLX responses by epithelial removal, indomethacin (cyclooxygenase inhibitor), L-NAME (nitric oxide synthase inhibitor), SQ22536 (adenylate cyclase inhibitor) and ODQ (guanylate cyclase inhibitor) were also evaluated. Immunohistochemistry was used to localize RXFP1 to airway epithelium and smooth muscle. rhRLX elicited relaxation in rat trachea and PCLS, more slowly than rosiglitazone or isoprenaline, but potentiated relaxation to both these dilators. It markedly increased β-adrenoceptor agonist potency in guinea pig trachea. rhRLX, rosiglitazone, and isoprenaline pretreatment also inhibited the development of rat tracheal contraction. Bronchoprotection by rhRLX increased with longer pre-incubation time, and was partially reduced by epithelial removal, indomethacin and/or L-NAME. SQ22536 and ODQ also partially inhibited rhRLX-mediated relaxation in both intact and epithelial-denuded trachea. RXFP1 expression in the airways was at higher levels in epithelium than smooth muscle. In summary, rhRLX elicits large and small airway relaxation via epithelial-dependent and -independent mechanisms, likely

  7. Awake craniotomy anesthetic management using dexmedetomidine, propofol, and remifentanil

    PubMed Central

    Prontera, Andrea; Baroni, Stefano; Marudi, Andrea; Valzania, Franco; Feletti, Alberto; Benuzzi, Francesca; Bertellini, Elisabetta; Pavesi, Giacomo

    2017-01-01

    Introduction Awake craniotomy allows continuous monitoring of patients’ neurological functions during open surgery. Anesthesiologists have to sedate patients in a way so that they are compliant throughout the whole surgical procedure, nevertheless maintaining adequate analgesia and anxiolysis. Currently, the use of α2-receptor agonist dexmedetomidine as the primary hypnotic–sedative medication is increasing. Methods Nine patients undergoing awake craniotomy were treated with refined monitored anesthesia care (MAC) protocol consisting of a combination of local anesthesia without scalp block, low-dose infusion of dexmedetomidine, propofol, and remifentanil, without the need of airways management. Results The anesthetic protocol applied in our study has the advantage of decreasing the dose of each drug and thus reducing the occurrence of side effects. All patients had smooth and rapid awakenings. The brain remained relaxed during the entire procedure. Conclusion In our experience, this protocol is safe and effective during awake brain surgery. Nevertheless, prospective randomized trials are necessary to confirm the optimal anesthetic technique to be used. PMID:28424537

  8. Awake craniotomy anesthetic management using dexmedetomidine, propofol, and remifentanil.

    PubMed

    Prontera, Andrea; Baroni, Stefano; Marudi, Andrea; Valzania, Franco; Feletti, Alberto; Benuzzi, Francesca; Bertellini, Elisabetta; Pavesi, Giacomo

    2017-01-01

    Awake craniotomy allows continuous monitoring of patients' neurological functions during open surgery. Anesthesiologists have to sedate patients in a way so that they are compliant throughout the whole surgical procedure, nevertheless maintaining adequate analgesia and anxiolysis. Currently, the use of α2-receptor agonist dexmedetomidine as the primary hypnotic-sedative medication is increasing. Nine patients undergoing awake craniotomy were treated with refined monitored anesthesia care (MAC) protocol consisting of a combination of local anesthesia without scalp block, low-dose infusion of dexmedetomidine, propofol, and remifentanil, without the need of airways management. The anesthetic protocol applied in our study has the advantage of decreasing the dose of each drug and thus reducing the occurrence of side effects. All patients had smooth and rapid awakenings. The brain remained relaxed during the entire procedure. In our experience, this protocol is safe and effective during awake brain surgery. Nevertheless, prospective randomized trials are necessary to confirm the optimal anesthetic technique to be used.

  9. Contribution of α-adrenoceptor stimulation by phenylephrine to basal nitric oxide production in the isolated mouse aorta.

    PubMed

    van Langen, Johanna T H; Van Hove, Cor E; Schrijvers, Dorien M; Martinet, Wim; De Meyer, Guido R Y; Fransen, Paul; Bult, Hidde

    2013-04-01

    In the mouse aorta, contractions evoked by the α(1)-adrenoceptor agonist phenylephrine are strongly suppressed by the continuous production of nitric oxide (NO). We investigated whether phenylephrine itself stimulated NO production by activating endothelial α(2)-adrenoceptors. On a prostaglandin F(2α) contraction, the α(2)-adrenoceptor agonist 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14304) induced 29.3 ± 7.4% relaxation, which was inhibited by 0.1 μM 2-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole (BRL44408) with a pKB' corresponding to α(2)-antagonism. In the presence of NO synthase blockers, UK14304 elicited small contractions above 1 μM that were inhibited by 0.1 μM prazosin, but not influenced by 0.1 μM rauwolscine. At 3 μM or higher concentrations, phenylephrine caused only modest relaxation (up to 7.4 ± 2.3%) of segments constricted with prostaglandin F(2α) in the presence of prazosin, which was abolished with 0.1 μM BRL44408. Furthermore, BRL44408 did not increase contractions induced with 1 μM phenylephrine. These results confirm that α(1)- but not α(2)-adrenoceptors are expressed on aortic smooth muscle cells, whereas endothelial cells only express α(2)-adrenoceptors. Moreover, phenylephrine exerted a very modest relaxing effect through nonspecific stimulation of α(2)-adrenoceptors, but only at concentrations higher than 1 μM. It is concluded that the high basal output of NO in the isolated mouse aorta is not due to stimulation of α-adrenoceptors.

  10. Synthesis and in Vitro and in Vivo Characterization of Highly β1-Selective β-Adrenoceptor Partial Agonists

    PubMed Central

    2013-01-01

    β-Adrenoceptor antagonists boast a 50-year use for symptomatic control in numerous cardiovascular diseases. One might expect highly selective antagonists are available for the human β-adrenoceptor subtype involved in these diseases, yet few truly β1-selective molecules exist. To address this clinical need, we re-evaluated LK 204-545 (1),1 a selective β1-adrenoceptor antagonist, and discovered it possessed significant partial agonism. Removal of 1’s aromatic nitrile afforded 19, a ligand with similar β1-adrenoceptor selectivity and partial agonism (log KD of −7.75 and −5.15 as an antagonist of functional β1- and β2-mediated responses, respectively, and 34% of the maximal response of isoprenaline (β1)). In vitro β-adrenoceptor selectivity and partial agonism of 19 were mirrored in vivo. We designed analogues of 19 to improve affinity, selectivity, and partial agonism. Although partial agonism could not be fully attenuated, SAR suggests that an extended alkoxyalkoxy side chain, alongside substituents at the meta- or para-positions of the phenylurea, increases ligand affinity and β1-selectivity. PMID:23614528

  11. Potentiation of carbachol-induced detrusor smooth muscle contractions by beta-adrenoceptor activation.

    PubMed

    Klausner, Adam P; Rourke, Keith F; Miner, Amy S; Ratz, Paul H

    2009-03-15

    In strips of rabbit bladder free of urothelium, the beta-adrenoceptor agonist, isoproterenol, significantly reduced basal detrusor smooth muscle tone and inhibited contractions produced by low concentrations of the muscarinic receptor agonist, carbachol. During a carbachol concentration-response curve, instead of inhibiting, isoproterenol strengthened contractions produced by high carbachol concentrations. Thus, the carbachol concentration-response curve was shifted by isoproterenol from a shallow, graded relationship, to a steep, switch-like relationship. The tyrosine kinase inhibitor, genistein, inhibited carbachol-induced contractions only in the presence of isoproterenol. Contraction produced by a single high carbachol concentration (1 microM) displayed 1 fast and 1 slow peak. In the presence of isoproterenol, the slow peak was not strengthened, but was delayed, and U-0126 (mitogen-activated protein kinase kinase inhibitor) selectively inhibited this delay concomitantly with inhibition of extracellular signal-regulated kinase (ERK) phosphorylation. Isoproterenol reduced ERK phosphorylation only in the absence of carbachol. These data support the concept that, by inhibiting weak contractions, potentiating strong contractions, and producing a more switch-like concentration-response curve, beta-adrenoceptor stimulation enhanced the effectiveness of muscarinic receptor-induced detrusor smooth muscle contraction. Moreover, beta-adrenoceptor stimulation changed the cellular mechanism by which carbachol produced contraction. The potential significance of multi-receptor and multi-cell crosstalk is discussed.

  12. Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy.

    PubMed

    Bouyssou, Thierry; Hoenke, Christoph; Rudolf, Klaus; Lustenberger, Philipp; Pestel, Sabine; Sieger, Peter; Lotz, Ralf; Heine, Claudia; Büttner, Frank H; Schnapp, Andreas; Konetzki, Ingo

    2010-02-15

    Compound 4p was identified from a series of 6-hydroxy-4H-benzo[1,4]oxazin-3-ones as potent agonist of the human beta2-adrenoceptor with a high beta1/beta2-selectivity. A complete reversal of acetylcholine-induced bronchoconstriction which lasted over the whole study period of 5h was demonstrated for 4p in a guinea pig in vivo model without any signs of cardiovascular effects up to 10-fold above the first dose reaching 100% bronchoprotection. The enantiomerically pure (R)-form of 4p exerted a bronchodilatory efficacy over 24 h in dogs and guinea pigs in the absence of systemic pharmacodynamic effects. Formoterol which was tested as comparator in the same in vivo models of acetylcholine-induced bronchoconstriction did not retain efficacy after 24 h. In summary, the preclinical profile of compound (R)-4p (olodaterol, also known as BI 1744 CL) suggests a potential for once-daily dosing in man accompanied with an improved safety profile. Copyright 2010 Elsevier Ltd. All rights reserved.

  13. Saw palmetto extracts potently and noncompetitively inhibit human alpha1-adrenoceptors in vitro.

    PubMed

    Goepel, M; Hecker, U; Krege, S; Rübben, H; Michel, M C

    1999-02-15

    We wanted to test whether phytotherapeutic agents used in the treatment of lower urinary tract symptoms have alpha1-adrenoceptor antagonistic properties in vitro. Preparations of beta-sitosterol and extracts of stinging nettle, medicinal pumpkin, and saw palmetto were obtained from several pharmaceutical companies. They were tested for their ability to inhibit [3H]tamsulosin binding to human prostatic alpha1-adrenoceptors and [3H]prazosin binding to cloned human alpha1A- and alpha1B-adrenoceptors. Inhibition of phenylephrine-stimulated [3H]inositol phosphate formation by cloned receptors was also investigated. Up to the highest concentration which could be tested, preparations of beta-sitosterol, stinging nettle, and medicinal pumpkin were without consistent inhibitory effect in all assays. In contrast, all tested saw palmetto extracts inhibited radioligand binding to human alpha1-adrenoceptors and agonist-induced [3H]inositol phosphate formation. Saturation binding experiments in the presence of a single saw palmetto extract concentration indicated a noncompetitive antagonism. The relationship between active concentrations in vitro and recommended therapeutic doses for the saw palmetto extracts was slightly lower than that for several chemically defined alpha1-adrenoceptor antagonists. Saw palmetto extracts have alpha1-adrenoceptor-inhibitory properties. If bioavailability and other pharmacokinetic properties of these ingredients are similar to those of the chemically defined alpha1-adrenoceptor antagonists, alpha1-adrenoceptor antagonism might be involved in the therapeutic effects of these extracts in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction.

  14. Possible mechanism of the negative inotropic effect of α1-adrenoceptor agonists in rat isolated left atria after exposure to free radicals

    PubMed Central

    Peters, Stephan L M; Batink, Harry D; Michel, Martin C; Pfaffendorf, Martin; van Zwieten, Pieter A

    1998-01-01

    This study was designed to investigate the mechanism(s) of the negative inotropic effects of α1-adrenoceptor agonists observed in rat isolated left atria after exposure to free radicals.Ouabain and calphostin C were used in contraction experiments to block the sodium pump and protein kinase C. Methoxamine-induced phospholipase C and Na+/K+ ATPase activities were measured.Methoxamine (300 μM) increased contractile force by 1.6±0.2 mN in control atria but decreased contractile force in electrolysis-treated atria by 2.0±0.1 mN (P<0.05), as determined 10 min after methoxamine addition. In contrast, the positive inotropic effects of endothelin-1 (30 nM) and isoprenaline (10 μM) were reduced from 2.6±0.3 to 1.3±0.1 mN and from 2.6±0.3 to 1.7±0.2 mN, respectively, by electrolysis treatment (P<0.05), but not converted into a negative inotropic action.In an inositol phosphate assay we observed that the stimulation of phospholipase C by methoxamine was attenuated by electrolysis when the (electrolyzed) medium from the organ bath was used, but the phospholipase C responses were restored by the use of fresh medium. However, fresh medium did not counteract the negative inotropic effect of methoxamine. Accordingly, the negative inotropic effect of methoxamine is not directly related to the impaired phospholipase C responses seen in atria subjected to electrolysis.Ouabain (10 μM) and the protein kinase C inhibitor calphostin C (50 nM), completely prevented the negative inotropic effect of 300 μM methoxamine in electrolysis-treated atria.Measurement of the Na+/K+ ATPase activity, revealed that in control atria, α1-adrenoceptor stimulation with 300 μM methoxamine, decreased the Na+/K+ ATPase activity by 14.4±7.7%. In contrast, methoxamine increased the Na+/K+ ATPase activity by 48.8±8.9% (P<0.05) in electrolysis-treated atria. Interestingly, this increase in Na+/K+ ATPase activity was completely counteracted by calphostin C (1.4±0.1% over

  15. Immobilization of grizzly bears (Ursus arctos) with dexmedetomidine, tiletamine, and zolazepam.

    PubMed

    Teisberg, Justin E; Farley, Sean D; Nelson, O Lynne; Hilderbrand, Grant V; Madel, Michael J; Owen, Patricia A; Erlenbach, Joy A; Robbins, Charles T

    2014-01-01

    Safe and effective immobilization of grizzly bears (Ursus arctos) is essential for research and management. Fast induction of anesthesia, maintenance of healthy vital rates, and predictable recoveries are priorities. From September 2010 to May 2012, we investigated these attributes in captive and wild grizzly bears anesthetized with a combination of a reversible α2 agonist (dexmedetomidine [dexM], the dextrorotatory enantiomer of medetomidine) and a nonreversible N-methyl-d-aspartate (NMDA) agonist and tranquilizer (tiletamine and zolazepam [TZ], respectively). A smaller-than-expected dose of the combination (1.23 mg tiletamine, 1.23 mg zolazepam, and 6.04 µg dexmedetomidine per kg bear) produced reliable, fast ataxia (3.7 ± 0.5 min, x̄±SE) and workable anesthesia (8.1 ± 0.6 min) in captive adult grizzly bears. For wild bears darted from a helicopter, a dose of 2.06 mg tiletamine, 2.06 mg zolazepam, and 10.1 µg dexmedetomidine/kg produced ataxia in 2.5 ± 0.3 min and anesthesia in 5.5 ± 1.0 min. Contrary to published accounts of bear anesthesia with medetomidine, tiletamine, and zolazepam, this combination did not cause hypoxemia or hypoventilation, although mild bradycardia (<50 beats per min) occurred in most bears during the active season. With captive bears, effective dose rates during hibernation were approximately half those during the active season. The time to first signs of recovery after the initial injection of dexMTZ was influenced by heart rate (P<0.001) and drug dose (P<0.001). Intravenous (IV) injection of the reversal agent, atipamezole, significantly decreased recovery time (i.e., standing on all four feet and reacting to the surrounding environment) relative to intramuscular injection. Recovery times (25 ± 8 min) following IV injections of the recommended dose of atipamezole (10 µg/µg of dexmedetomidine) and half that dose (5 µg/µg) did not differ. However, we recommend use of the full dose based on the appearance of a more complete

  16. Characterization of the hypothermic effects of imidazoline I2 receptor agonists in rats

    PubMed Central

    Thorn, David A; An, Xiao-Fei; Zhang, Yanan; Pigini, Maria; Li, Jun-Xu

    2012-01-01

    BACKGROUND AND PURPOSE Imidazoline I2 receptors have been implicated in several CNS disorders. Although several I2 receptor agonists have been described, no simple and sensitive in vivo bioassay is available for studying I2 receptor ligands. This study examined I2 receptor agonist-induced hypothermia as a functional in vivo assay of I2 receptor agonism. EXPERIMENTAL APPROACH Different groups of rats were used to examine the effects of I2 receptor agonists on the rectal temperature and locomotion. The pharmacological mechanisms were investigated by combining I2 receptor ligands and different antagonists. KEY RESULTS All the selective I2 receptor agonists examined (2-BFI, diphenyzoline, phenyzoline, CR4056, tracizoline, BU224 and S22687, 3.2–56 mg·kg–1, i.p.) dose-dependently and markedly decreased the rectal temperature (hypothermia) in rats, with varied duration of action. Pharmacological mechanism of the observed hypothermia was studied by combining the I2 receptor agonists (2-BFI, BU224, tracizoline and diphenyzoline) with imidazoline I2 receptor/ α2 adrenoceptor antagonist idazoxan, selective I1 receptor antagonist efaroxan, α2 adrenoceptor antagonist/5-HT1A receptor agonist yohimbine. Idazoxan but not yohimbine or efaroxan attenuated the hypothermic effects of 2-BFI, BU224, tracizoline and diphenyzoline, supporting the I2 receptor mechanism. In contrast, both idazoxan and yohimbine attenuated hypothermia induced by the α2 adrenoceptor agonist clonidine. Among all the I2 receptor agonists studied, only S22687 markedly increased the locomotor activity in rats. CONCLUSIONS AND IMPLICATIONS Imidazoline I2 receptor agonists can produce hypothermic effects, which are primarily mediated by I2 receptors. These data suggest that I2 receptor agonist-induced hypothermia is a simple and sensitive in vivo assay for studying I2 receptor ligands. PMID:22324428

  17. Metabolic responses to BRL37344 and clenbuterol in soleus muscle and C2C12 cells via different atypical pharmacologies and β2-adrenoceptor mechanisms

    PubMed Central

    Ngala, R A; O'Dowd, J; Wang, S J; Agarwal, A; Stocker, C; Cawthorne, M A; Arch, J R S

    2008-01-01

    Background and purpose: Picomolar concentrations of the β3-adrenoceptor agonist BRL37344 stimulate 2-deoxyglucose uptake in soleus muscle via undefined receptors. Higher concentrations alter uptake, apparently via β2-adrenoceptors. Effects of BRL37344 and β2-adrenoceptor agonists are compared. Experimental approach: Mouse soleus muscles were incubated with 2-deoxy[1-14C]-glucose, [1-14C]-palmitate or [2-14C]-pyruvate, and BRL37344, β2-adrenoceptor agonists and selective β-adrenoceptor antagonists. Formation of 2-deoxy[1-14C]-glucose-6-phosphate or 14CO2 was measured. 2-Deoxy[1-14C]-glucose uptake and β-adrenoceptor mRNA were measured in C2C12 cells. Key results: 10 pM BRL37344, 10 pM clenbuterol and 100 pM salbutamol stimulated 2-deoxyglucose uptake in soleus muscle by 33–54%. The effect of BRL37344 was prevented by 1 μM atenolol but not by 300 nM CGP20712A or IC3118551, or 1 μM SR59230A; that of clenbuterol was prevented by ICI118551 but not atenolol. 10 nM BRL37344 st4mulated 2-deoxyglucose uptake, whereas 100 nM clenbuterol and salbutamol inhibited uptake. These effects were blocked by ICI118551. Similar results were obtained in C2C12 cells, in which only β2-adrenoceptor mRNA could be detected by RT-PCR. 10 nM BRL37344 and 10 pM clenbuterol stimulated muscle palmitate oxidation. In the presence of palmitate, BRL37344 no longer stimulated 2-deoxyglucose uptake and the effect of clenbuterol was not significant. Conclusions and implications: Stimulation of glucose uptake by 10 pM BRL37344 and clenbuterol involves different atypical pharmacologies. Nanomolar concentrations of BRL37344 and clenbuterol, probably acting via β2-adrenoceptors, have opposite effects on glucose uptake. The agonists preferentially stimulate fat rather than carbohydrate oxidation, but stimulation of endogenous fat oxidation cannot explain why 100 nM clenbuterol inhibited 2-deoxyglucose uptake. PMID:18552870

  18. Rilmenidine produces mydriasis in cats by stimulation of CNS alpha 2-adrenoceptors.

    PubMed

    Koss, M C

    2003-02-01

    1. Experiments were undertaken to determine if the imidazoline/alpha2-adrenoceptor agonist, rilmenidine, would produce mydriasis in cats and, if so, to delineate its site of action and determine if this effect is mediated by imidazoline receptors or alpha2-adrenoceptors. 2. Rilmenidine produced dose-related pupillary dilator responses in pentobarbital anaesthetized cats that were independent of sympathetic innervation to the iris but were dependent upon intact parasympathetic neuronal tone. The ED50 for rilmenidine-induced pupillary dilation was approximately 200 microg kg(-1), i.v., and was sustained for at least 1 h. 3. The highly selective alpha2-adrenoceptor antagonist, RS-79948, administered either before or after rilmenidine, antagonized rilmenidine-induced mydriasis. Neuronally induced reflex inhibition of parasympathetic nerve activity was also inhibited by administration of RS-79948. 4. These results suggest that rilmenidine acts like clonidine to produce pupillary dilation by inhibition of parasympathetic tone to the iris sphincter and that this central nervous system parasympatho-inhibition is mediated by alpha2-adrenoceptors, rather than imidazoline receptors.

  19. Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha 2-adrenergic antagonist atipamezole.

    PubMed

    Hoffman, W E; Kochs, E; Werner, C; Thomas, C; Albrecht, R F

    1991-08-01

    Dexmedetomidine is an alpha 2-adrenergic agonist that decreases central sympathetic activity and reduces the anesthetic requirement for halothane. We evaluated the effect of dexmedetomidine on neurologic and histopathologic outcome from incomplete cerebral ischemia in the rat. Anesthesia was maintained with a 25-micrograms.kg-1.h-1 fentanyl infusion combined with 70% nitrous oxide. Incomplete ischemia was produced by unilateral carotid artery ligation combined with hemorrhagic hypotension to 35 mmHg for 30 min. Arterial blood gas tensions, pH, and head temperature were maintained at normal levels during the experiment. Four ischemic groups were tested: group 1 (n = 15) received an intraperitoneal (ip) saline injection (control); group 2 (n = 10) received an ip injection of 10 micrograms/kg dexmedetomidine 30 min before ischemia; group 3 (n = 10) received 100 micrograms/kg dexmedetomidine; and group 4 (n = 10) received 100 micrograms/kg dexmedetomidine plus 1 mg/kg atipamezole (an alpha 2-adrenergic antagonist). Neurologic outcome was evaluated for 3 days using a graded deficit score. Histopathology was evaluated in coronal section in caudate and hippocampal tissue segments. Dexmedetomidine (10 and 100 micrograms/kg) significantly decreased plasma catecholamines and improved neurologic and histopathologic outcome in a dose-dependent manner compared to control rats (P less than 0.05). Atipamezole abolished the decrease in catecholamines and the improvement in outcome seen with dexmedetomidine, confirming that these effects were mediated by alpha 2-adrenergic receptors. It is concluded that alpha 2-adrenoreceptor stimulation decreases sympathetic activity and decreases ischemic injury in a model of incomplete cerebral ischemia.

  20. Central α- and β-adrenoceptors modifying arterial blood pressure and heart rate in conscious cats

    PubMed Central

    Day, M.D.; Roach, A.G.

    1974-01-01

    1 In conscious unrestrained cats noradrenaline, α-methylnoradrenaline and clonidine, infused into the lateral cerebral ventricles (i.c.v.) caused dose-related falls in blood pressure and heart rate; both effects were abolished after i.c.v. phentolamine. 2 In 12 out of 20 cats, i.c.v. isoprenaline and salbutamol when given caused dose-related pressor responses and tachycardias. These effects were abolished after i.c.v. β-adrenoceptor blocking drugs but were unaffected by α-adrenoceptor blocking agents. 3 In 5 out of 20 cats, i.c.v. isoprenaline regularly produced dose-related falls in blood pressure with associated tachycardias; both effects were abolished after i.c.v. β-adrenoceptor blocking agents. 4 Intracerebroventricular dopamine produced cardiovascular responses which were qualitatively similar to those produced by i.c.v. isoprenaline. 5 Intracerebroventricular adrenaline produced complex responses in untreated animals but typical α-effects were obtained after prior i.c.v. treatment with a β-adrenoceptor blocking agent and typical β-effects after i.c.v. pretreatment with an α-adrenoceptor blocking agent. 6 The cardiovascular changes produced by i.c.v. β-adrenoceptor agonists were abolished after systemic administration of hexamethonium or bethanidine. 7 The results are discussed in the light of the mode of action of β-adrenoceptor stimulants and β-adrenoceptor blocking agents in the treatment of hypertension. PMID:4451747

  1. Modulation of 3H-noradrenaline release by presynaptic opioid, cannabinoid and bradykinin receptors and β-adrenoceptors in mouse tissues

    PubMed Central

    Trendelenburg, A U; Cox, S L; Schelb, V; Klebroff, W; Khairallah, L; Starke, K

    2000-01-01

    Release-modulating opioid and cannabinoid (CB) receptors, β-adrenoceptors and bradykinin receptors at noradrenergic axons were studied in mouse tissues (occipito-parietal cortex, heart atria, vas deferens and spleen) preincubated with 3H-noradrenaline. Experiments using the OP1 receptor-selective agonists DPDPE and DSLET, the OP2-selective agonists U50488H and U69593, the OP3-selective agonist DAMGO, the ORL1 receptor-selective agonist nociceptin, and a number of selective antagonists showed that the noradrenergic axons innervating the occipito-parietal cortex possess release-inhibiting OP3 and ORL1 receptors, those innervating atria OP1, ORL1 and possibly OP3 receptors, and those innervating the vas deferens all four opioid receptor types. Experiments using the non-selective CB agonists WIN 55,212-2 and CP 55,940 and the CB1-selective antagonist SR 141716A indicated that the noradrenergic axons of the vas deferens possess release-inhibiting CB1 receptors. Presynaptic CB receptors were not found in the occipito-parietal cortex, in atria or in the spleen. Experiments using the non-selective β-adrenoceptor agonist isoprenaline and the β2-selective agonist salbutamol, as well as subtype-selective antagonists, demonstrated the occurrence of release-enhancing β2-adrenoceptors at the sympathetic axons of atria and the spleen, but demonstrated their absence in the occipito-parietal cortex and the vas deferens. Experiments with bradykinin and the B2-selective antagonist Hoe 140 showed the operation of release-enhancing B2 receptors at the sympathetic axons of atria, the vas deferens and the spleen, but showed their absence in the occipito-parietal cortex. The experiments document a number of new presynaptic receptor locations. They confirm and extend the existence of marked tissue and species differences in presynaptic receptors at noradrenergic neurons. PMID:10807669

  2. Thiophene/thiazole-benzene replacement on guanidine derivatives targeting α2-Adrenoceptors.

    PubMed

    Flood, Aoife; Trujillo, Cristina; Sanchez-Sanz, Goar; Kelly, Brendan; Muguruza, Carolina; Callado, Luis F; Rozas, Isabel

    2017-09-29

    Searching for improved antagonists of α 2 -adrenoceptors, a thorough theoretical study comparing the aromaticity of phenyl-, pyridinyl-, thiophenyl- and thiazolylguanidinium derivatives has been carried out [at M06-2X/6-311++G(p,d) computational level] confirming that thiophene and thiazole will be good 'ring equivalents' to benzene in these guanidinium systems. Based on these results, a small but chemically diverse library of guanidine derivatives (15 thiophenes and 2 thiazoles) were synthesised to explore the effect that the bioisosteric change has on affinity and activity at α 2 -adrenoceptors in comparison with our previously studied phenyl derivatives. All compounds were tested for their α 2 -adrenoceptor affinity and unsubstituted guanidinothiophenes displayed the strongest affinities in the same range as the phenyl analogues. In the case of cycloakyl systems, thiophenes with 6-membered rings showed the largest affinities, while for the thiazoles the 5-membered analogue presented the strongest affinity. From all the compounds tested for noradrenergic activity, only one compound exhibited agonistic activity, while two compounds showed very promising antagonism of α 2 -adrenoceptors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  3. Effects of dexmedetomidine on microregional O2 balance during reperfusion after focal cerebral ischemia.

    PubMed

    Chi, Oak Z; Grayson, Jeremy; Barsoum, Sylviana; Liu, Xia; Dinani, Aliraza; Weiss, Harvey R

    2015-01-01

    This study was performed to determine whether there is an association between microregional O2 balance and neuronal survival in cerebral ischemia-reperfusion using dexmedetomidine, an α2-adrenoreceptor agonist and a sedative. Rats were subjected to 1 hour middle cerebral artery occlusion and a 2-hour reperfusion. During reperfusion, normal saline (n = 14) or dexmedetomidine 1 μg/kg/minute (n = 14) was infused intravenously. At 2 hours of reperfusion, regional cerebral blood flow using (14)C-iodoantipyrine autoradiography, microregional arterial and venous (20-60 μm in diameter) O2 saturation (SvO2) using cryomicrospectrophotometry, and the size of cortical infarction were determined. Ischemia-reperfusion decreased microregional SvO2 (52.9 ± 3.7% vs. 61.1 ± .6%, P < .005) with increased variation or heterogeneity (P < .0001) with similar regional cerebral blood flow and O2 consumption. Dexmedetomidine during reperfusion decreased the heterogeneity of SvO2 that was analyzed with an analysis of variance (P < .01) and reported as coefficient of variation (100 × standard deviation/Mean) (11.8 vs. 16.4). The number of veins with O2 saturation less than 50% decreased with dexmedetomidine (13/80 vs. 27/81, P < .01). The percentage of cortical infarct in total cortex was smaller with dexmedetomidine (8.3 ± 2.2% vs. 12.6 ± 1.5%, P < .005). In the cerebral ischemic reperfused cortex, dexmedetomidine decreased the heterogeneity of SvO2 and the number of small veins with low O2 saturation suggesting improved microregional O2 supply/consumption balance. The improvement was accompanied by the reduced size of cortical infarction. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  4. Evaluation of adverse events noted in children receiving continuous infusions of dexmedetomidine in the intensive care unit.

    PubMed

    Honey, Brooke L; Harrison, Donald L; Gormley, Andrew K; Johnson, Peter N

    2010-01-01

    Dexmedetomidine is an α(2)-adrenergic receptor agonist with sedative and analgesic effects in mechanically ventilated adults and children. Safety and efficacy data are limited in children. The purpose of this study is to retrospectively identify the incidence and types of adverse events noted in children receiving continuous infusions of dexmedetomidine and evaluate potential risk factors for adverse events. Between July 1, 2006, and July 31, 2007, data were collected on all children (< 18 years) who received continuous infusions of dexmedetomidine. Data collection included demographics, dexmedetomidine regimen, and type/number of adverse events. The primary endpoint was the total number of adverse events noted, including: transient hypertension, hypotension, neurological manifestations, apnea, and bradycardia. Secondary endpoints included categorization of each type of adverse event and an assessment of risk factors. A logistic regression model was used to assess the relationship of adverse events with independent variables including length of ICU stay, cumulative dose, peak infusion rate, duration of therapy, PRISM III score, and bolus dose. Thirty-six patients received dexmedetomidine representing 41 infusions. The median age was 16 months (range, 0.1-204 months) and median PRISM III score was 2 (range, 0-18). Eighteen (43.9%) patients received a bolus dose of dexmedetomidine. The median cumulative dose (mcg/kg) and peak dose (mcg/kg/hr) were 8.5 (range, 2.2-193.7) and 0.5 (range, 0.2-0.7), respectively. Dexmedetomidine was continued for a median of 20 (range, 3-263) hours. Six (14.6%) patients were slowly tapered off the continuous infusions. Twenty-one adverse events were noted in 17 patients, including 4 neurologic manifestations. Fourteen patients required interventions for adverse events. ICU length of stay was the only independent risk factor (p=0.036) for development of adverse events. Several potential adverse events were noted with dexmedetomidine

  5. Effects of fenoterol on beta-adrenoceptor and muscarinic M2 receptor function in bovine tracheal smooth muscle.

    PubMed

    De Vries, B; Roffel, A F; Kooistra, J M; Meurs, H; Zaagsma, J

    2001-05-11

    Prolonged (18 h) incubation of isolated bovine tracheal smooth muscle with the beta2-adrenoceptor agonist fenoterol (10 microM) induced desensitization of isoprenaline-induced adenylyl cyclase activity in bovine tracheal smooth muscle membranes, characterized by a 25% decrease in maximal effect (Emax) (P < 0.05), while the sensitivity to the agonist (pEC50) was unchanged. The Emax value of isoprenaline-induced smooth muscle relaxation of submaximal methacholine-induced contractile tones was similarly reduced by about 25% (P < 0.001), while the pEC50 value was diminished by 1.0 log unit (P < 0.001). As determined by 30 microM gallamine-induced muscarinic M2 receptor antagonism and pertussis toxin-induced inactivation of G(i alpha), muscarinic M2 receptor-mediated functional antagonism did not play a role in isoprenaline-induced relaxation of bovine tracheal smooth muscle contracted by methacholine, both in control and in 18-h fenoterol-treated tissue. In line with these observations, we found no enhanced muscarinic M2 receptor-mediated inhibition of 1 microM forskolin-stimulated adenylyl cyclase activity after 18-h fenoterol treatment. These data indicate that 18-h fenoterol treatment of bovine tracheal smooth muscle induces beta2-adrenoceptor desensitization and reduced functional antagonism of methacholine-induced contraction by beta-adrenoceptor agonists, without a change of muscarinic M2 receptor function.

  6. Homologous regulation of the α2C-adrenoceptor subtype in human hepatocarcinoma, HepG2

    PubMed Central

    Cayla, Cécile; Schaak, Stéphane; Roquelaine, Cyril; Gales, Céline; Quinchon, Françoise; Paris, Hervé

    1999-01-01

    Previous studies of the regulation of the α2C-adrenoceptor in OK and in transfected cells have led to discrepant conclusions. In the present work, we examined the homologous regulation of the human α2C-adrenoceptor in the hepatocarcinoma cell-line, HepG2; a model which expresses this subtype spontaneously.Short-period treatment of the cells with UK14304 provoked neither a diminution of the potency of the α2-agonist to inhibit forskolin-induced cyclic AMP-accumulation nor a change in the degree of receptor coupling to G-proteins.Long-period exposure to UK14304 resulted in a large reduction of [3H]MK912 binding sites (55% decrease). The action of UK14304 was dose-dependent (EC50=190±45 nM), rapid (t1/2 =4.2 h) and reversible. Receptor down-regulation was also observed with clonidine or (−)adrenaline (38 and 36% decrease, respectively) and was blocked by the addition of α2-antagonists.Conversely to that observed with α2-agonists, treatment of the cells with RX821002 or yohimbine alone, but not with phentolamine, promoted a significant increase of the receptor expression.The observed alterations of receptor density are not the reflection of changes at the α2C4 mRNA level. Estimation of the receptor protein turnover and measurement of its half-life demonstrated that down-regulation by α2-agonists and up-regulation by α2-antagonists, with inverse-agonist efficacy, are respectively the consequence of increased and decreased rate of receptor degradation.In conclusion, our data show that α2C-adrenoceptor does not undergo desensitization but is down-regulated in HepG2. The lack of desensitization agrees with previous results obtained in cells transfected with the α2C4 gene, but not with observations made in OK cells. Inversely, down-regulation fits with results obtained in OK but not in transfected cells. The reasons for these discrepancies are discussed. Our results also demonstrated that certain α2-antagonists behave as inverse agonist on the HepG2 model

  7. Dexmedetomidine could enhance surgical satisfaction in Trans-sphenoidal resection of pituitary adenoma.

    PubMed

    Salimi, Alireza; Sharifi, Guive; Bahrani, Houshang; Mohajerani, Seyed A; Jafari, Alireza; Safari, Farhad; Jalessi, Maryam; Mirkheshti, Alireza; Mottaghi, Kamran

    2017-02-01

    Excessive bleeding is an unwanted complication of trans-sphenoidal resection of pituitary adenoma due to increases in intracranial pressure (ICP) and hemodynamic instability. Dexmedetomidine (Dex) anα2-agonists is the drug of choice in intensive care units (ICU) and cardiac surgeries to control abrupt changes in hemodynamic. Severe cardiovascular responses occur during trans-sphenoidal resection (TSR) of the pituitary adenoma despite adequate depth of anesthesia. The aim of this paper was to determine the effect of Dexmedetomidine on bleeding as primary outcome, and surgeon's satisfaction and hemodynamic stability as secondary outcomes in patients undergoing trans-sphenoidal resection of pituitary adenoma. Total numbers of 60 patients between 18-65 years old and candidate for elective trans-sphenoidal resection of pituitary adenoma were randomLy allocated to two groups; Dexmedetomidine infusion (0.6µg/kg/hour) or normal saline infusion. Mean arterial pressure (MAP), heart rate (HR), dose of hypnotics and narcotics during surgery, bleeding, and surgeon's satisfaction were recorded. Propofol maintenance dose (µg/kg/min) and total Fentanyl use (µg) were significantly lower in Dex group compare to control group (P=0.01 and 0.003, respectively). Total bleeding amount during operation in Dex group was significantly lower than control group (P=0.012). Surgeon's satisfaction was significantly higher in Dex group at the end of surgery. MAP and heart rate throughout surgery were significantly lower in Dex group compare to control group (P=0.001). Dexmedetomidine infusion (0.6µg/kg/hour) could reduce bleeding and provide surgeon's satisfaction during trans-sphenoidal resection of pituitary adenoma.

  8. Cholesterol regulates contractility and inotropic response to β2-adrenoceptor agonist in the mouse atria: Involvement of Gi-protein-Akt-NO-pathway.

    PubMed

    Odnoshivkina, Yulia G; Sytchev, Vaycheslav I; Petrov, Alexey M

    2017-06-01

    Majority of cardiac β2-adrenoceptors is located in cholesterol-rich microdomains. Here, we have investigated the underlying mechanisms by which a slight to moderate cholesterol depletion with methyl-β-cyclodextrin (MβCD, 1 and 5mM) interferes with contractility and inotropic effect of β2-adrenergic agonist (fenoterol, 50μM) in the mouse atria. Treatment with MβCD itself increased amplitude of Ca 2+ transient but did not change the contraction amplitude due to a clamping action of elevated NO. Cholesterol depletion significantly attenuated the positive inotropic response to fenoterol which is accompanied by increase in NO generation and decrease in Ca 2+ transient. Influence of 1mM MβCD on the fenoterol-driven changes in both contractility and NO level was strongly attenuated by inhibition of G i -protein (pertussis toxin), Akt (Akt 1/2 kinase inhibitor) or NO-synthase (L-NAME). After exposure to 5mM MβCD, pertussis toxin or Akt inhibitor could recover the β2-agonist effects on contractility, NO production and Ca 2+ transient, while L-NAME only reduced NO level. An adenylyl cyclase activator (forskolin, 50nM) had no influence on the MβCD-induced changes in the β2-agonist effects. Obtained results suggest that slight cholesterol depletion upregulates G i -protein/Akt/NO-synthase signaling that attenuates the positive inotropic response to β2-adrenergic stimulation without altering the Ca 2+ transient. Whilst moderate cholesterol depletion additionally could suppress the enhancement of the Ca 2+ transient amplitude caused by the β2-adrenergic agonist administration in G i -protein/Akt-dependent but NO-independent manner. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Dexmedetomidine: a review of its use for sedation in mechanically ventilated patients in an intensive care setting and for procedural sedation.

    PubMed

    Hoy, Sheridan M; Keating, Gillian M

    2011-07-30

    Dexmedetomidine (Precedex®), a pharmacologically active dextroisomer of medetomidine, is a selective α(2)-adrenergic receptor agonist. It is indicated in the US for the sedation of mechanically ventilated adult patients in an intensive care setting and in non-intubated adult patients prior to and/or during surgical and other procedures. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of dexmedetomidine in randomized, double-blind, placebo-controlled, multicentre studies in these indications. Post-surgical patients in an intensive care setting receiving dexmedetomidine required less rescue sedation with intravenous propofol or intravenous midazolam to achieve and/or maintain optimal sedation during the assisted ventilation period than placebo recipients, according to two randomized, double-blind, multinational studies. Moreover, significantly more dexmedetomidine than placebo recipients acquired and/or maintained optimal sedation without rescue sedation. Sedation with dexmedetomidine was also effective in terms of the total dose of morphine administered, with dexmedetomidine recipients requiring less morphine than placebo recipients; with regard to patient management, dexmedetomidine recipients were calmer and easier to arouse and manage than placebo recipients. Intravenous dexmedetomidine was effective as a primary sedative in two randomized, double-blind, placebo-controlled, multicentre studies in adult patients undergoing awake fibre-optic intubation or a variety of diagnostic or surgical procedures requiring monitored anaesthesia care. In one study, significantly fewer dexmedetomidine than placebo recipients required rescue sedation with intravenous midazolam to achieve and/or maintain optimal sedation; conversely, in another study, rescue sedation with intravenous midazolam was not required by significantly more dexmedetomidine than placebo recipients. Primary sedation with intravenous dexmedetomidine was also

  10. Alpha-adrenoceptor antagonistic and calcium antagonistic effects of nicergoline in the rat isolated aorta.

    PubMed

    Heitz, C; Descombes, J J; Miller, R C; Stoclet, J C

    1986-04-16

    The activity of the alpha-adrenoceptor antagonist nicergoline, a molecule composed of two constituent parts, ergoline and bromonicotinic acid, was investigated in the rat isolated aorta. Nicergoline (10 nM-0.1 microM) displaced concentration-effect curves elicited by noradrenaline and phenylephrine to the right and inhibited maximal responses elicited by both alpha-adrenoceptor agonists without significantly affecting prostaglandin F2 alpha-induced contractions. Higher concentrations of nicergoline (1 microM-50 microM) displaced to the right the concentration-effect curves elicited by calcium in a depolarizing medium. This calcium antagonist activity was not shared by either of the constituent parts. Nicergoline 100 microM abolished the 45Ca influx induced into rat aorta by 100 mM K+-containing physiological solution. The selectivity of nicergoline for alpha 1-adrenoceptors seen in binding experiments also depends on the presence of the bromonicotinic moiety of the molecule. It is concluded that nicergoline, but not its substituent parts, displays both alpha 1-adrenoceptor and calcium antagonism. The latter property may account for some of the observed effects of this compound.

  11. Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review.

    PubMed

    Cruickshank, Moira; Henderson, Lorna; MacLennan, Graeme; Fraser, Cynthia; Campbell, Marion; Blackwood, Bronagh; Gordon, Anthony; Brazzelli, Miriam

    2016-03-01

    Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(®), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(®), Roche) and lorazepam (Ativan(®), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(®), Orion Corporation) and clonidine (Catapres(®), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents. To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs. We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014. Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(®), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta

  12. OPC-28326, a selective femoral vasodilator, is an alpha2C-adrenoceptor-selective antagonist.

    PubMed

    Sun, B; Lockyer, S; Li, J; Chen, R; Yoshitake, M; Kambayashi, J I

    2001-11-01

    OPC-28326 has been reported to selectively increase femoral blood flow in open-chest dogs and autoperfused canine femoral artery preparations. Preliminary data indicated that OPC-28326 has a high affinity at the alpha2-adrenoceptor. In the present study, we tested OPC-28326 in isoflurane anesthetized rats at a dose of 3 mg/kg of body weight, given intraduodenally. OPC-28326 significantly increased femoral blood flow, by 44.7 +/- 13.8%, 45 min after drug administration, whereas carotid blood flow increased by only 3.6 +/- 5.5% (n = 6). Chinese hamster ovary cell lines overexpressing rat alpha2D-, alpha2B-, or alpha2C-adrenoceptor were established. These cells also coexpress luciferase, driven by cAMP elevation. In radioligand binding assays using cell membrane preparations, OPC-28326 dose dependently competed with [3H]RX821002 binding, with calculated K(i) values of 3840 +/- 887, 633 +/- 46, and 13.7 +/- 1.9 nM on alpha2D-, alpha2B-, and alpha2C-adrenoceptor, respectively. A similar affinity and rank order of potency were also found for OPC-28326 on the alpha2-subtypes using epinephrine as agonist in luciferase assays. No agonistic effect of OPC-28326 was detected on any of the alpha2-adrenoceptors. Finally, in situ hybridization performed on skeletal muscle tissue sections collected from rat hind limb (musculus gastrocnemius) demonstrated a high level expression of alpha2C in the vascular tissues. Thus, the abundance of alpha2C in the skeletal muscle may account for the selective effect of OPC-28326 in increasing femoral blood flow.

  13. Effect of intravenous infusion of dexmedetomidine on perioperative haemodynamic changes and postoperative recovery: A study with entropy analysis.

    PubMed

    Patel, Chirag Ramanlal; Engineer, Smita R; Shah, Bharat J; Madhu, S

    2012-11-01

    Dexmedetomidine, an α2 agonist, when used as an adjuvant in general anaesthesia attenuates stress response to various noxious stimuli, maintains perioperative haemodynamic stability and provides sedation without significant respiratory depression postoperatively. Sixty patients were randomly divided into two groups of 30 each. In group A, fentanyl 2 μg/kg and in group B dexmedetomidine were given intravenously as loading dose of 1 μg/kg over 10 min prior to induction. After induction with thiopentone, in group B, dexmedetomidine was given as infusion at a dose of 0.2-0.8 μg/kg. Sevoflurane was used as inhalation agent in both groups. Haemodynamic variables and entropy (response entropy and state entropy) were recorded continuously. Postoperative sedation and recovery were assessed by sedation score and modified Aldrete's score, respectively. Dexmedetomidine significantly attenuates stress response at intubation with lesser increase in heart rate (10% vs. 17%), systolic blood pressure (6% vs. 23%) and diastolic blood pressure (7% vs. 20%) as compared to the control group (P<0.05). Intraoperatively, an average of 8% fall in systolic blood pressure and 8.16% fall in diastolic pressure in the test group as compared to 3.6% rise in systolic and 3.3% in diastolic pressure of the control group was observed. Postoperatively, the test group showed significant sedation at 2 h as compared to the control group (P=0.00) and recovery was better in the control group for the first 2 h post extubation. Dexmedetomidine attenuates various stress responses during surgery and maintains the haemodynamic stability when used as an adjuvant in general anaesthesia. Also, the sedative action of dexmedetomidine delays recovery for the first few hours post extubation.

  14. The beta2- and beta3-adrenoceptor-mediated relaxation induced by fenoterol in guinea pig taenia caecum.

    PubMed

    Akimoto, Yurie; Horinouchi, Takahiro; Tanaka, Yoshio; Koike, Katsuo

    2002-10-01

    Fenoterol, a beta2-adrenoceptor selective agonist, belongs to the arylethanolamine class. To understand the receptor subtypes responsible for beta-adrenoceptor-mediated relaxation of guinea pig taenia caecum, we investigated the effect of fenoterol. Fenoterol caused concentration-dependent relaxation of the guinea pig taenia caecum. Propranolol, bupranolol and butoxamine produced shifts of the concentration-response curve for fenoterol. Schild regression analyses carried out for propranolol, butoxamine and bupranolol against fenoterol gave pA2 values of 8.41, 6.33 and 8.44, respectively. However, in the presence of 3 x 10(-4) M atenolol, 10(-4) M butoxamine and 10(-6) M phentolamine to block the beta1-, beta2- and a-adrenoceptor effects, respectively, Schild regression analysis carried out for bupranolol against fenoterol gave pA2 values of 5.80. These results suggest that the relaxant response to fenoterol in the guinea pig taenia caecum is mediated by both the beta2- and the beta3-adrenoceptors.

  15. Intravenous dexmedetomidine versus clonidine for prolongation of bupivacaine spinal anesthesia and analgesia: A randomized double-blind study

    PubMed Central

    Reddy, Velayudha Sidda; Shaik, Nawaz Ahmed; Donthu, Balaji; Reddy Sannala, Venkata Krishna; Jangam, Venkatsiva

    2013-01-01

    Background: Alpha2-adrenergic agonists have synergistic action with local anesthetics and may prolong the duration of sensory, motor blockade and postoperative analgesia obtained with spinal anesthesia. Aim: The objectives of this study are to compare and evaluate the efficacy of intravenous dexmedetomidine premedication with clonidine and placebo on spinal blockade duration, postoperative analgesia and sedation in patients undergoing surgery under bupivacaine intrathecal block. Materials and Methods: In this prospective, randomized, double-blind placebo-controlled study, 75 patients of the American Society of Anesthesiologists status I or II, scheduled for orthopedic lower limb surgery under spinal anesthesia, were randomly allocated into three groups of 25 each. Group DE received dexmedetomidine 0.5 μgkg−1, group CL received clonidine 1.0 μgkg−1 and placebo group PL received 10 ml of normal saline intravenously before subarachnoid anesthesia with 15 mg of 0.5% hyperbaric bupivacaine. Onset time and regression times of sensory and motor blockade, the maximum upper level of sensory blockade were recorded. Duration of postoperative analgesia and sedation scores along with side effects were also recorded. Data was analyzed using analysis of variance or Chi-square test, and the value of P < 0.05 was considered statistically significant. Results: The sensory block level was higher with dexmedetomidine (T4 ± 1) than clonidine (T6 ± 1) or placebo (T6 ± 2). Dexmedetomidine also increased the time (243.35 ± 56.82 min) to first postoperative analgesic request compared with clonidine (190.93 ± 42.38 min, P < 0.0001) and placebo (140.75 ± 28.52 min, P < 0.0001). The maximum Ramsay sedation score was greater in the dexmedetomidine group than other two groups (P < 0.0001). Conclusion: Premedication with intravenous dexmedetomidine is better than intravenous clonidine to provide intraoperative sedation and postoperative analgesia during bupivacaine spinal anesthesia

  16. Intravenous Dexmedetomidine Provides Superior Patient Comfort and Tolerance Compared to Intravenous Midazolam in Patients Undergoing Flexible Bronchoscopy

    PubMed Central

    Goneppanavar, Umesh; Periyadka Janardhana, Bhavya; Krishna Achar, Shreepathi

    2015-01-01

    Dexmedetomidine, an α 2 agonist, has demonstrated its effectiveness as a sedative during awake intubation, but its utility in fiberoptic bronchoscopy (FOB) is not clear. We evaluated the effects of midazolam and dexmedetomidine on patient's response to FOB. The patients received either midazolam, 0.02 mg/kg (group M, n = 27), or dexmedetomidine, 1 µg/kg (group D, n = 27). A composite score of five different parameters and a numerical rating scale (NRS) for pain intensity and distress were used to assess patient response during FOB. Patients rated the quality of sedation and level of discomfort 24 h after the procedure. Ease of bronchoscopy, rescue medication requirement, and haemodynamic variables were noted. Ideal or acceptable composite score was observed in 15 and 26 patients, respectively, in group M (14.48 ± 3.65) and group D (9.41 ± 3.13), p < 0.001. NRS showed that 11 patients in group M had severe pain and discomfort as compared to one patient with severe pain and two with severe discomfort in group D during the procedure, p < 0.001. Rescue midazolam requirement was significantly higher in group M (p = 0.023). We conclude that during FOB, under topical airway anaesthesia, IV dexmedetomidine (1 µg/kg) provides superior patient comfort and tolerance as compared to IV midazolam (0.02 mg/kg). PMID:26543645

  17. The effect of dexmedetomidine continuous infusion as an adjuvant to general anesthesia on sevoflurane requirements: A study based on entropy analysis.

    PubMed

    Patel, Chirag Ramanlal; Engineer, Smita R; Shah, Bharat J; Madhu, S

    2013-07-01

    Dexmedetomidine, a α2 agonist as an adjuvant in general anesthesia, has anesthetic and analgesic-sparing property. To evaluate the effect of continuous infusion of dexmedetomidine alone, without use of opioids, on requirement of sevoflurane during general anesthesia with continuous monitoring of depth of anesthesia by entropy analysis. Sixty patients were randomly divided into 2 groups of 30 each. In group A, fentanyl 2 mcg/kg was given while in group B, dexmedetomidine was given intravenously as loading dose of 1 mcg/kg over 10 min prior to induction. After induction with thiopentone in group B, dexmedetomidine was given as infusion at a dose of 0.2-0.8 mcg/kg. Sevoflurane was used as inhalation agent in both groups. Hemodynamic variables, sevoflurane inspired fraction (FIsevo), sevoflurane expired fraction (ETsevo), and entropy (Response entropy and state entropy) were continuously recorded. Statistical analysis was done by unpaired student's t-test and Chi-square test for continuous and categorical variables, respectively. A P-value < 0.05 was considered significant. The use of dexmedetomidine with sevoflurane was associated with a statistical significant decrease in ETsevo at 5 minutes post-intubation (1.49 ± 0.11) and 60 minutes post-intubation (1.11 ±0.28) as compared to the group A [1.73 ±0.30 (5 minutes); 1.68 ±0.50 (60 minutes)]. There was an average 21.5% decrease in ETsevo in group B as compared to group A. Dexmedetomidine, as an adjuvant in general anesthesia, decreases requirement of sevoflurane for maintaining adequate depth of anesthesia.

  18. Effect of intravenous infusion of dexmedetomidine on perioperative haemodynamic changes and postoperative recovery: A study with entropy analysis

    PubMed Central

    Patel, Chirag Ramanlal; Engineer, Smita R; Shah, Bharat J; Madhu, S

    2012-01-01

    Background: Dexmedetomidine, an α2 agonist, when used as an adjuvant in general anaesthesia attenuates stress response to various noxious stimuli, maintains perioperative haemodynamic stability and provides sedation without significant respiratory depression postoperatively. Methods: Sixty patients were randomly divided into two groups of 30 each. In group A, fentanyl 2 μg/kg and in group B dexmedetomidine were given intravenously as loading dose of 1 μg/kg over 10 min prior to induction. After induction with thiopentone, in group B, dexmedetomidine was given as infusion at a dose of 0.2–0.8 μg/kg. Sevoflurane was used as inhalation agent in both groups. Haemodynamic variables and entropy (response entropy and state entropy) were recorded continuously. Postoperative sedation and recovery were assessed by sedation score and modified Aldrete's score, respectively. Results: Dexmedetomidine significantly attenuates stress response at intubation with lesser increase in heart rate (10% vs. 17%), systolic blood pressure (6% vs. 23%) and diastolic blood pressure (7% vs. 20%) as compared to the control group (P<0.05). Intraoperatively, an average of 8% fall in systolic blood pressure and 8.16% fall in diastolic pressure in the test group as compared to 3.6% rise in systolic and 3.3% in diastolic pressure of the control group was observed. Postoperatively, the test group showed significant sedation at 2 h as compared to the control group (P=0.00) and recovery was better in the control group for the first 2 h post extubation. Conclusion: Dexmedetomidine attenuates various stress responses during surgery and maintains the haemodynamic stability when used as an adjuvant in general anaesthesia. Also, the sedative action of dexmedetomidine delays recovery for the first few hours post extubation. PMID:23325938

  19. The influence of hormonal and neuronal factors on rat heart adrenoceptors

    PubMed Central

    Kunos, George; Mucci, Lucia; O'Regan, Seana

    1980-01-01

    1 The influence of hormonal and neuronal factors on adrenoceptors mediating increased cardiac force and rate of contraction were studied in rat isolated atria. The pharmacological properties of these receptors were deduced from the relative potencies of agonists and from the effects of selective α- and β-adrenoceptor antagonists. The numbers and affinities of α- and β-adrenoceptors were also determined by radioligand binding to ventricular membrane fragments. 2 Hypophysectomy reduced the inotropic potency of isoprenaline and increased the potency of phenylephrine and methoxamine in left atria. The effect of phenylephrine was inhibited by propranolol less effectively and by phentolamine or phenoxybenzamine more effectively in hypophysectomized than in control rats. The difference in block was smaller at low than at high antagonist concentrations. Similar but smaller changes were observed for chronotropic responses of right atria. 3 The decreased β- and increased α-receptor response after hypophysectomy was similar to that observed earlier in thyroidectomized rats (Kunos, 1977). These changes developed slowly after hypophysectomy (>2 weeks), they were both reversed within 2 days of thyroxine treatment (0.2 mg/kg daily), but were not affected by cortisone treatment (50 mg/kg every 12 h for 4 days). 4 Treatment of hypophysectomized rats for 2 days with thyroxine increased the density of [3H]-dihydroalprenolol ([3H]-DHA) binding sites from 27.5 ± 2.7 to 45.5 ± 5.7 fmol/mg protein and decreased the density of [3H]-WB-4101 binding sites from 38.7 ± 3.1 to 18.7 ± 2.5 fmol/mg protein. The affinity of either type of binding site for agonists or antagonist was not significantly altered by thyroxine treatment and the sum total of α1- and β-receptors remained the same. 5 Sympathetic denervation of thyroidectomized rats by 6-hydroxydopamine increased the inotropic potency of isoprenaline and noradrenaline and the blocking effect of propranolol, and decreased the

  20. Cardiovascular effects of constant rate infusions of lidocaine, lidocaine and dexmedetomidine, and dexmedetomidine in dogs anesthetized at equipotent doses of sevoflurane.

    PubMed

    Moran-Muñoz, Rafael; Valverde, Alexander; Ibancovichi, J A; Acevedo-Arcique, Carlos M; Recillas-Morales, Sergio; Sanchez-Aparicio, Pedro; Osorio-Avalos, Jorge; Chavez-Monteagudo, Julio Raul

    2017-07-01

    This study evaluated the cardiovascular effects of a constant rate infusion (CRI) of lidocaine, lidocaine and dexmedetomidine, and dexmedetomidine in dogs anesthetized with sevoflurane at equipotent doses. Treatments consisted of T1-Lidocaine [loading dose 2 mg/kg body weight (BW), IV, and CRI of 100 μg/kg BW per min] at 1.4% end-tidal of sevoflurane (FE SEV ); T2-Dexmedetomidine (loading dose 2 μg/kg BW, IV, and CRI of 2 μg/kg BW per hour) and FE SEV 1.1%; and T3-Lidocaine-Dexmedetomidine using the same doses of T1 and T2 and FE SEV 0.8%. Constant rate infusion of lidocaine did not induce any cardiovascular changes; lidocaine and dexmedetomidine resulted in cardiovascular effects similar to dexmedetomidine alone. These effects were characterized by a significant ( P < 0.001) decrease in heart rate, cardiac output, cardiac index, oxygen delivery, and pulmonary vascular resistance index, and a significant ( P < 0.001) increase in mean and diastolic arterial pressure, systemic vascular resistance index, pulmonary arterial occlusion pressure and oxygen extraction ratio, compared with baseline values. In conclusion, a CRI of lidocaine combined with dexmedetomidine produces significant cardiovascular changes similar to those observed with dexmedetomidine alone.

  1. [Beta-1 adrenoceptor blockade decreases the firing rate to painful stimuli in spinal wide-dynamic range neurons in rats].

    PubMed

    Lamothe-Molina, Paul J; Lamothe-Molina, Pedro A; López-Ávila, Alberto

    2014-01-01

    It is known that epinephrine/norepinephrine inhibit acute pain transmission. However, the role of ß-adrenoceptors is not clear. Thus, we analyzed if beta-1 and/or beta-2 adrenoceptors can modulate acute pain transmission by performing in vivo single unit recordings during painful and non-painful peripheral stimulation in rats. Longitudinal study in which we analyzed seven groups of male rats Wistar: control group (n = 11): saline (0.9 %); EPI group (n = 8): epinephrine 100 mcg; beta-1 agonist group (n = 8): dobutamine 125 mcg; beta-1-antagonist group (n = 9): metoprolol 100 mcg; beta-2-agonist group (n = 7): clenbuterol 100 mcg; beta-2-antagonist group (n = 8): butoxamine 100 mcg; beta-1-antagonist + EPI group (n = 10): metoprolol 100 mcg + epinephrine 100 mcg. For the statistical analysis we used ANOVA. Epinephrine significantly reduced the basal firing rate (BFR) in 34.1 % (p < 0.05) and also the evoked response by painful stimulation in 56 % (p < 0.05). No change was observed in the evoked response by non-painful stimulation. ANTß1 was the only beta-adrenoceptor acting drug that significantly reduced the evoked response by painful stimulation in 41 % (p < 0.05). None of the other drugs alone affected either the BFR or the evoked response to non-painful or painful stimulation. It is the first time that a beta-1-adrenoceptor antagonist (metoprolol) probes to be effective in reducing the response to painful stimulation in WDR neurons.

  2. The newer aspect of dexmedetomidine use in dentistry: As an additive to local anesthesia, initial experience, and review of literature.

    PubMed

    Kumar, Prashant; Thepra, Manju; Bhagol, Amrish; Priya, Kannu; Singh, Virendra

    2016-01-01

    Despite the availability of a wide variety of pharmacological agents in the field of anesthesia, there has always been a continuous search for newer local anesthetic agents with improved efficacy, potency, and better handling properties. Dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, is an emerging agent for provision of additive local anesthetic effect if used with conventional local anesthetics, which can be implicated in dentistry for performing many minor oral surgical procedures. The present paper reports a pilot study comparing clinical efficacy and potency of this newer emerging drug in combination with lignocaine. Ten patients undergoing orthodontic extraction for correction of malocclusion and other dentofacial deformities requiring orthodontic treatment were locally infiltrated with 2% lignocaine plus dexmedetomidine 1μ/ml and 2% lignocaine plus adrenaline in 1:200,000 dilution at two different appointments. The onset of action, duration of action, and pain threshold were assessed. Onset of action was found to be faster with longer duration of action with the newer drug dexmedetomidine and lignocaine combination when compared with combination of lignocaine and adrenaline. The study demonstrated that the combination of dexmedetomidine with lignocaine enhances the local anesthetic potency of lignocaine without significant systemic effects when locally injected into oral mucosa.

  3. Alpha2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment.

    PubMed

    Yanpallewar, Sudhirkumar U; Fernandes, Kimberly; Marathe, Swananda V; Vadodaria, Krishna C; Jhaveri, Dhanisha; Rommelfanger, Karen; Ladiwala, Uma; Jha, Shanker; Muthig, Verena; Hein, Lutz; Bartlett, Perry; Weinshenker, David; Vaidya, Vidita A

    2010-01-20

    Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. alpha(2)-Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of alpha(2)-adrenoceptors on adult hippocampal neurogenesis. Our results indicate that alpha(2)-adrenoceptor agonists, clonidine and guanabenz, decrease adult hippocampal neurogenesis through a selective effect on the proliferation, but not the survival or differentiation, of progenitors. These effects persist in dopamine beta-hydroxylase knock-out (Dbh(-/-)) mice lacking norepinephrine, supporting a role for alpha(2)-heteroceptors on progenitor cells, rather than alpha(2)-autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippocampal progenitors in vitro express all the alpha(2)-adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of alpha(2)-adrenoceptor stimulation on progenitors. Furthermore, coadministration of the alpha(2)-adrenoceptor antagonist yohimbine with the antidepressant imipramine significantly accelerates effects on hippocampal progenitor proliferation, the morphological maturation of newborn neurons, and the increase in expression of brain derived neurotrophic factor and vascular endothelial growth factor implicated in the neurogenic and behavioral effects of antidepressants. Finally, short-duration (7 d) yohimbine and imipramine treatment results in robust behavioral responses in the novelty suppressed feeding test, which normally requires 3 weeks of treatment with classical antidepressants. Our results demonstrate that alpha(2)-adrenoceptors, expressed by progenitor cells, decrease adult hippocampal neurogenesis, while their blockade speeds up antidepressant action

  4. α2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment

    PubMed Central

    Yanpallewar, Sudhirkumar U.; Fernandes, Kimberly; Marathe, Swananda V.; Vadodaria, Krishna C.; Jhaveri, Dhanisha; Rommelfanger, Karen; Ladiwala, Uma; Jha, Shanker; Muthig, Verena; Hein, Lutz; Bartlett, Perry; Weinshenker, David; Vaidya, Vidita A.

    2010-01-01

    Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. α2-adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of α2-adrenoceptors on adult hippocampal neurogenesis. Our results indicate that α2-adrenoceptor agonists, clonidine and guanabenz, decrease adult hippocampal neurogenesis through a selective effect on the proliferation, but not the survival or differentiation, of progenitors. These effects persist in dopamine β-hydroxylase knockout (Dbh −/−) mice lacking norepinephrine, supporting a role for α2-heteroceptors on progenitor cells, rather than α2-autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippocampal progenitors in vitro express all the α2-adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of α2-adrenoceptor stimulation on progenitors. Further, co-administration of the α2-adrenoceptor antagonist yohimbine with the antidepressant imipramine significantly accelerates effects on hippocampal progenitor proliferation, the morphological maturation of newborn neurons, and the increase in expression of brain derived neurotrophic factor and vascular endothelial growth factor implicated in the neurogenic and behavioral effects of antidepressants. Finally, short duration (7 day) yohimbine and imipramine treatment results in robust behavioral responses in the novelty suppressed feeding test, which normally requires 3 weeks of treatment with classical antidepressants. Our results demonstrate that α2-adrenoceptors, expressed by progenitor cells, decrease adult hippocampal neurogenesis, while their blockade speeds up antidepressant action, highlighting their importance as targets for

  5. Novelty response of rats determines the effect of prefrontal alpha-2 adrenoceptor modulation on anxiety.

    PubMed

    Uzsoki, B; Tóth, M; Hernádi, I

    2011-07-25

    In this study we provide evidence that animals of the same population, although identical in age and sex, have individual reactions to the prefrontal modulation of adrenoceptors. We have examined the dose-dependent action of α(2)-adrenoceptor agents on the anxiety of rats with different response to novelty in the elevated plus maze (EPM) apparatus. Rats were divided into high (HR) and low responder (LR) groups based on their locomotor activity in a novel open field environment. HR rats also showed increased locomotion and low anxiety in the EPM. Prefrontal injection of α(2)-receptor antagonist yohimbine, BRL44408 or imiloxan caused anxiety only in HR rats. The α(2A/D)-receptor agonist guanfacine increased anxiety levels of both groups. However, the effective dose was lower in HR rats. The present results propose different prefrontal adrenoceptor sensitivity of rats showing distinct baseline activity levels. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  6. Interaction of berberine with human platelet. alpha. sub 2 adrenoceptors

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hui, Ka Kit; Yu, Jun Liang; Chan, Wai Fong A.

    1991-01-01

    Berberine was found to inhibit competitively the specific binding of ({sup 3}H)-yohimbine. The displacement curve was parallel to those of clonidine, epinephrine, norepinephrine, with the rank order of potency (IC{sub 50}) being clonidine {gt} epinephrine {gt} norepinephrine (14.5 {mu}M) = berberine. Increasing concentrations of berberine from 0.1 {mu}M to 10 {mu}M inhibited ({sup 3}H)-yohimbine binding, shifting the saturation binding curve to the right without decreasing the maximum binding capacity. In platelet cyclic AMP accumulation experiments, berberine at concentrations of 0.1 {mu}M to 0.1 mM inhibited the cAMP accumulation induced by 10 {mu}M prostaglandin E{sub 1} in a dose dependent manner,more » acting as an {alpha}{sub 2} adrenoceptor agonist. In the presence of L-epinephrine, berberine blocked the inhibitory effect of L-epinephrine behaving as an {alpha}{sub 2} adrenoceptor antagonist.« less

  7. Activation of β-adrenoceptors in the bed nucleus of the stria terminalis induces food intake reduction and anxiety-like behaviors.

    PubMed

    Naka, Tomonori; Ide, Soichiro; Nakako, Tomokazu; Hirata, Mikie; Majima, Yuki; Deyama, Satoshi; Takeda, Hiroshi; Yoshioka, Mitsuhiro; Minami, Masabumi

    2013-04-01

    We previously demonstrated the critical role of noradrenergic transmission within the ventral part of the bed nucleus of the stria terminalis (vBNST) in pain-induced aversion. We showed that activation of β-adrenoceptors in this brain region by intra-vBNST injection of isoproterenol, a β-adrenoceptor agonist, produced aversive responses. In the present study, we examined the effects of a β-adrenoceptor agonist injected into the vBNST on food intake and anxiety-like behaviors in male Sprague-Dawley rats. Bilateral intra-vBNST injection of isoproterenol (3 and 10 nmol/side) caused a dose-dependent decrease in food intake; this suppressive effect was reversed by co-administration of timolol, a β-adrenoceptor antagonist. Dose-dependent (10 and 30 nmol/side) induction of anxiety-like behaviors by isoproterenol was observed in the elevated plus maze (EPM) test, which was also reversed by co-administration of timolol. Off-site control injections of isoproterenol into the lateral ventricle did not show any significant effect in the food consumption and EPM tests. These results suggest that the vBNST is one of the neuroanatomical substrates which may be involved in the close relationship between negative affective states and reduction of food intake, and that noradrenergic transmission within this brain region plays a critical role in inducing anxiety-like behaviors and reduced food intake. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. alpha2-Adrenergic agonists antagonise the anxiolytic-like effect of antidepressants in the four-plate test in mice.

    PubMed

    Massé, Fabienne; Hascoët, Martine; Bourin, Michel

    2005-10-14

    Selective serotonin reuptake inhibitors (SSRIs) and serotonin/noradrenaline reuptake inhibitors (SNRIs) has been reported to be efficient in anxiety disorders. Some animal models have demonstrated an anxiolytic-like effect following acute administration, however, it is not yet known how noradrenergic receptors are implicated in the therapeutic effects of antidepressants (ADs) in anxiety. The effects of two alpha(2)-adrenoceptor agonists (clonidine, guanabenz) on anxiolytic-like effect of two SSRIs (paroxetine and citalopram) and two SNRIs (venlafaxine and milnacipran) were evaluated in the four-plate test (FPT) in mice. Paroxetine (4 mg/kg), citalopram (8 mg/kg), venlafaxine (8 mg/kg), and milnacipran (8 mg/kg) administered intraperitoneally (i.p.) increased the number of punishments accepted by mice in the FPT. Clonidine (0.0039-0.5 mg/kg) and guanabenz (0.03-0.5mg/kg) had no effect on the number of punishments accepted by mice. Clonidine (0.03 and 0.06 mg/kg) and guanabenz (0.125 and 0.5 mg/kg) (i.p. -45 min) reversed the anti-punishment effect of paroxetine, citalopram, venlafaxine and milnacipran (i.p. -30 min). But if the antidepressants are administered 45 min before the test and alpha(2)-adrenoceptor agonists 30 min before the test, alpha(2)-adrenoceptor agonists failed to alter the anti-punishment effect of antidepressants. The results of this present study indicate that alpha(2)-adrenoceptor agonists antagonise the anxiolytic-like effect of antidepressants in mice when they are administered 15 min before the administration of antidepressant suggesting a close inter-regulation between noradrenergic and serotoninergic system in the mechanism of SSRIs and SNRIs in anxiety-like behaviour.

  9. The effect of dexmedetomidine continuous infusion as an adjuvant to general anesthesia on sevoflurane requirements: A study based on entropy analysis

    PubMed Central

    Patel, Chirag Ramanlal; Engineer, Smita R; Shah, Bharat J; Madhu, S

    2013-01-01

    Background: Dexmedetomidine, a α2 agonist as an adjuvant in general anesthesia, has anesthetic and analgesic-sparing property. Aims: To evaluate the effect of continuous infusion of dexmedetomidine alone, without use of opioids, on requirement of sevoflurane during general anesthesia with continuous monitoring of depth of anesthesia by entropy analysis. Materials and Methods: Sixty patients were randomly divided into 2 groups of 30 each. In group A, fentanyl 2 mcg/kg was given while in group B, dexmedetomidine was given intravenously as loading dose of 1 mcg/kg over 10 min prior to induction. After induction with thiopentone in group B, dexmedetomidine was given as infusion at a dose of 0.2-0.8 mcg/kg. Sevoflurane was used as inhalation agent in both groups. Hemodynamic variables, sevoflurane inspired fraction (FIsevo), sevoflurane expired fraction (ETsevo), and entropy (Response entropy and state entropy) were continuously recorded. Statistical analysis was done by unpaired student's t-test and Chi-square test for continuous and categorical variables, respectively. A P-value < 0.05 was considered significant. Results: The use of dexmedetomidine with sevoflurane was associated with a statistical significant decrease in ETsevo at 5 minutes post-intubation (1.49 ± 0.11) and 60 minutes post-intubation (1.11 ±0.28) as compared to the group A [1.73 ±0.30 (5 minutes); 1.68 ±0.50 (60 minutes)]. There was an average 21.5% decrease in ETsevo in group B as compared to group A. Conclusions: Dexmedetomidine, as an adjuvant in general anesthesia, decreases requirement of sevoflurane for maintaining adequate depth of anesthesia. PMID:24106354

  10. Selective regulation of beta 1- and beta 2-adrenoceptors in the human heart by chronic beta-adrenoceptor antagonist treatment.

    PubMed Central

    Michel, M. C.; Pingsmann, A.; Beckeringh, J. J.; Zerkowski, H. R.; Doetsch, N.; Brodde, O. E.

    1988-01-01

    1. In 44 patients undergoing coronary artery bypass grafting, the effect of chronic administration of the beta-adrenoceptor antagonists sotalol, propranolol, pindolol, metoprolol and atenolol on beta-adrenoceptor density in right atria (containing 70% beta 1- and 30% beta 2-adrenoceptors) and in lymphocytes (having only beta 2-adrenoceptors) was studied. 2. beta-Adrenoceptor density in right atrial membranes and in intact lymphocytes was assessed by (-)-[125I]-iodocyanopindolol (ICYP) binding; the relative amount of right atrial beta 1- and beta 2-adrenoceptors was determined by inhibition of ICYP binding by the selective beta 2-adrenoceptor antagonist ICI 118,551 and analysis of the resulting competition curves by the iterative curve fitting programme LIGAND. 3. With the exception of pindolol, all beta-adrenoceptor antagonists increased right atrial beta-adrenoceptor density compared to that observed in atria from patients not treated with beta-adrenoceptor antagonists. 4. All beta-adrenoceptor antagonists increased right atrial beta 1-adrenoceptor density; on the other hand, only sotalol and propranolol also increased right atrial beta 2-adrenoceptor density, whereas metoprolol and atenolol did not affect it and pindolol decreased it. 5. Similarly, in corresponding lymphocytes, only sotalol or propranolol increased beta 2-adrenoceptor density, while metoprolol and atenolol did not affect it and pindolol decreased it. 6. It is concluded that beta-adrenoceptor antagonists subtype-selectively regulate cardiac and lymphocyte beta-adrenoceptor subtypes. The selective increase in cardiac beta 1-adrenoceptor density evoked by metoprolol and atenolol may be one of the reasons for the beneficial effects observed in patients with end-stage congestive cardiomyopathy following intermittent treatment with low doses of selective beta 1-adrenoceptor antagonists. PMID:2902891

  11. Investigation of the prejunctional α2-adrenoceptor mediated actions of MDMA in rat atrium and vas deferens

    PubMed Central

    Lavelle, Aisling; Honner, Valerie; Docherty, J R

    1999-01-01

    We have investigated the effects of methylenedioxymethamphetamine (MDMA, ‘ecstasy') on peripheral noradrenergic neurotransmission in the rat.In rat atrial slices pre-incubated with [3H]-noradrenaline and in the presence of desipramine (1 μM) to prevent effects of MDMA on basal outflow of tritium, MDMA (10 μM) significantly inhibited the release of tritium evoked by short trains of six pulses at 100 Hz every 10 s for 3 min. This effect did not occur in the presence of the α2-adrenoceptor antagonist yohimbine (1 μM).In epididymal portions of rat vas deferens in the presence of nifedipine (10 μM), MDMA produced a concentration-dependent inhibition of single pulse nerve stimulation-evoked contractions with a pD2 of 5.88±0.16 (n=4). Inhibitory effects of MDMA were antagonized by the α2-adrenoceptor antagonist yohimbine (0.3 μM), but not by the 5-hydroxytryptamine receptor antagonist cyanopindolol in a concentration (1 μM) which markedly antagonized the inhibitory actions of the 5-HT-1 receptor agonist 5-carboxamidotryptamine.In prostatic portions of rat vas deferens in the presence of cocaine (3 μM), MDMA produced a concentration-dependent inhibition of single pulse nerve stimulation-evoked contractions with a pD2 of 5.12±0.21 (n=4). In the absence of cocaine, only the highest concentration of MDMA (30 μM) produced an inhibition, but the α2-adrenoceptor antagonist yohimbine (0.3 μM) converted the response to MDMA from inhibition to potentiation of the stimulation-evoked contraction.In radioligand binding studies, MDMA showed similar affinities for α2B, α2C and α2D-adrenoceptor sites, with pKi values of 5.14±0.16, 5.11±0.05 and 5.31±0.14, respectively.It is concluded that MDMA has significant α2-adrenoceptor agonist actions. PMID:10556934

  12. The Perioperative Use of Dexmedetomidine in Pediatric Patients with Congenital Heart Disease: An Analysis from the Congenital Cardiac Anesthesia Society-Society of Thoracic Surgeons Congenital Heart Disease Database.

    PubMed

    Schwartz, Lawrence I; Twite, Mark; Gulack, Brian; Hill, Kevin; Kim, Sunghee; Vener, David F

    2016-09-01

    Dexmedetomidine is a selective α-2 receptor agonist with a sedative and cardiopulmonary profile that makes it an attractive anesthetic for pediatric patients with congenital heart disease (CHD). Although several smaller, single-center studies suggest that dexmedetomidine use is gaining traction in the perioperative setting in children with CHD, there are limited multicenter data, with little understanding of the variation in use across age ranges, procedural complexity, and centers. The aim of this study was to use the Congenital Cardiac Anesthesia Society-Society of Thoracic Surgeons (CCAS-STS) registry to describe patient- and center-level variability in the use of dexmedetomidine in the perioperative setting in children with heart disease. To describe the use of dexmedetomidine in patients for CHD surgery, we analyzed all index cardiopulmonary bypass operations entered in the CCAS-STS database from 2010 to 2013. Patient and operative characteristics were compared between those who received intraoperative dexmedetomidine and those who did not. Selective outcomes associated with dexmedetomidine use were also described. Of the 12,142 operations studied, 3600 (29.6%) received perioperative dexmedetomidine (DEX) and 8542 did not receive the drug (NoDEX). Patient characteristics were different between the 2 groups with the DEX group generally exhibiting both lower patient and procedural risk factors. Patients who received dexmedetomidine were more likely to have a lower level of Society of Thoracic Surgeons mortality complexity than patient who did not receive it. Consistent with their overall lower risk profile, children in the DEX group also demonstrated improved outcomes compared with patients who did not receive dexmedetomidine. We described the growing use of dexmedetomidine in children anesthetized for surgical repair of CHD. Dexmedetomidine appears to be preferentially given to older and larger children who are undergoing less complex CHD surgery. We believe

  13. Effects of preanesthetic administration of midazolam, clonidine, or dexmedetomidine on postoperative pain and anxiety in children.

    PubMed

    Schmidt, André P; Valinetti, Emilia A; Bandeira, Denise; Bertacchi, Maria F; Simões, Cláudia M; Auler, José Otávio C

    2007-07-01

    A growing interest in the possible influences of pre- and postoperative anxiety and pain scores as outcomes of surgical treatment and benefits of anxiety or pain-reducing interventions has emerged. The aim of this study was to evaluate the influence of three different premedication regimens on postoperative pain and anxiety in children. A prospective, randomized, open-label clinical trial enrolled 60 schoolchildren. They were randomized for premedication with oral midazolam 0.5 mgxkg(-1), oral clonidine 4 microgxkg(-1), or transmucosal dexmedetomidine (DEX) 1 mug.kg(-1), submitted to a pre- and postoperative evaluation of anxiety with the State-Trait Anxiety Inventory for Children and asked to report any pain in verbal and visual analog scales. We also evaluated secondary outcomes such as parents' anxiety, sedation, separation from parents, adverse effects and hemodynamic status. Dexmedetomidine and clonidine were related to lower scores of pain than midazolam. alpha(2)-agonists produced lower scores of peroperative mean arterial pressure and heart rate than midazolam. Both groups had similar levels of postoperative state-anxiety in children. There was no difference in preanesthesia levels of sedation and response to separation from parents between groups. These findings indicate that children receiving clonidine or DEX preoperatively have similar levels of anxiety and sedation postoperatively as those receiving midazolam. However, children given alpha(2)-agonists had less perioperative sympathetic stimulation and less postoperative pain than those given midazolam.

  14. Characterizations of the α1-adrenoceptor subtypes mediating contractions of the human internal anal sphincter.

    PubMed

    Owaki, Hiroyuki; Sadahiro, Sotaro; Takaki, Miyako

    2015-04-01

    Human internal anal sphincter (IAS) is contracted by α1-adrenoceptor stimulation and thus α1-adrenoceptor agonists may be useful in treating fecal incontinence. This study characterizes the contribution of α1-adrenoceptor subtypes in contraction of human IAS and to investigate the age-related risk of patients with fecal incontinence. IAS and inferior mesenteric artery (IMA), as a predictor of systemic arterial pressure, were obtained from 11 patients. Both muscle strips were assessed by isometric-contraction experiments using phenylephrine, further in IAS, in the presence of various subtype selective α1-adrenoceptor antagonists. Immunohistochemistry and gene expression studies were performed in the same samples. The mean pEC50 values with SEM of phenylephrine in IAS (6.30 ± 0.13) were higher than those of IMA (5.60 ± 0.10). Furthermore, the age-related pEC50 change of IAS was observed between age <70 and ≥70 (6.58 ± 0.13 and 6.07 ± 0.16, respectively (P < 0.05)). In IAS, rightward shift of the concentration-response curves of phenylephrine was observed with three α1-adrenoceptor antagonists. Each pKB value of silodosin, BMY-7378 and prazosin was 9.36 ± 0.53, 7.28 ± 0.20 and 8.89 ± 0.12, respectively. These pKB values and gene expression studies indicated that α1A-adrenoceptor subtypes predominantly contributed to human IAS contraction. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  15. Case report: polyuria related to dexmedetomidine.

    PubMed

    Pratt, Alexandra; Aboudara, Matthew; Lung, Linn

    2013-07-01

    Dexmedetomidine has become a popular sedative in the intensive care unit for patients undergoing mechanical ventilation because of its highly selective α-2 agonism, which exerts a combination of anesthetic, analgesic, and anxiolytic effects. Bradycardia and hypotension have been reported as the most common side effects of its use in large studies. Dexmedetomidine has been reported to induce polyuria by suppressing vasopressin secretion and increasing permeability of the collecting ducts in a dose-dependent fashion. We report a case of dexmedetomidine-related polyuria that occurred with a high-dose continuous infusion and subsequently resolved with discontinuation of the drug. (Anesth Analg 2013;117:150-2).

  16. The use of sub-anesthetic intravenous ketamine and adjuvant dexmedetomidine when treating acute pain from CRPS.

    PubMed

    Nama, Sharanya; Meenan, Daniel R; Fritz, William T

    2010-01-01

    Complex regional pain syndrome (CRPS) is a pain condition of the extremities that presents with pain and allodynia, decreased range of motion, swelling and skin changes. There are 2 forms of CRPS - Type I which does not have demonstrable nerve lesions and Type 2, which has evidence of obvious nerve damage. Management of refractory CRPS has been challenging. Some studies have revealed that the N-methyl-D-aspartic acid receptor (NMDAR) may be involved in the etiology of the pain in CRPS and perhaps that a NMDA receptor antagonist like ketamine is a potential treatment for CRPS. However, the side effect profile of ketamine is concerning, and limiting the adverse effects of the drug is beneficial. Dexmedetomidine is an alpha 2 agonist similar to clonidine with analgesic properties that can be used in combination with ketamine to provide additional analgesia in CRPS. This case describes the treatment of acute pain symptoms from Chronic Regional Pain Syndrome-Type 1 (CRPS-1) with sub-anesthetic intravenous infusion of ketamine with adjunct dexmedetomidine. A 47-year-old female patient presented with severe pain, burning and allodynia from CRPS-1 refractory to conventional therapy. She was then admitted to a monitored bed, received a sub-anesthetic intravenous infusion of ketamine with adjunct dexmedetomidine for 19 hours and subsequently discharged with complete resolution of her pain and associated symptoms. Here, the synergistic effect of the ketamine and dexmedetomidine together is shown to provide excellent symptom relief while decreasing the total ketamine administered. The combination minimized unwanted side effects and eliminated the need for intensive care unit admission secondary to anesthetic doses of ketamine.

  17. Computer-assisted determination of minimum energy conformations. 7: A pharmacophore model of the active region of the alpha2-adrenoceptor

    NASA Astrophysics Data System (ADS)

    Ashman, William P.; Mickiewicz, A. P.; Nelson, Todd M.

    1992-09-01

    Molecular modeling and computational chemistry techniques are used to analyze compounds in developing pharmacophores of biological receptors to use as templates in structure activity relationship studies and to design new chemicals having physiological activity of interest. In this study, the results of x-ray crystal analyses and PM3 semi-empirical molecular orbital conformational analyses are used to determine the three-dimensional representations of selected adrenergic compounds known to be agonists with the alpha2-adrenoceptor in achieving optimized geometries and electrostatic parameters. The alpha2-adrenergic agonists interact with the adrenergic system receptors to produce various increases or decreases in hemodynamic responses (i.e., hypertension, hypotension, and bradycardia) and sedation. A pharmacophore model of the active region of the alpha2-adrenoceptor is described based on the superimposition of common structural, electrostatic, and physicochemical features of the compounds. Using the model to predict compound adrenergic activity and to design alpha2-adrenergic compounds is discussed.

  18. Behaviour of beta 2-adrenoceptors on lymphocytes under continuous and pulsatile tocolysis with Fenoterol.

    PubMed

    Schmidt-Rhode, Peter; Brunke, Björn; Schröer, Heinrich; Obert, Kirstin; Schlegel, Kerstin; Sturm, Gerhard; Schulz, Klaus-Dieter; von Wichert, Peter

    2003-01-01

    The present study investigates the population of beta 2-receptors on lymphocytes in pregnant women with premature labor between the 29th and 34th week of pregnancy. The population of receptors on lymphocytes correlates with that on the myometrium, which is not accessible for study during pregnancy. Fourteen patients received a pulsatile tocolysis, while ten women received a continuous tocolysis with Fenoterol. Assuming an equal population of receptors in both groups before commencement of therapy, the numbers of receptors in the patients with continuous tocolysis fell to about 35% of the initial value after 72 hours. Under pulsatile tocolysis, the numbers of receptors remained unchanged for a period of three days and was still only just below 70% of the initial value by the seventh day. Our data demonstrate that continuous administration of the short-acting beta 2-agonist Fenoterol resulted in a substantial loss of beta 2-adrenoceptors on lymphocytes. In contrast, intermittent administration of the same beta 2-adrenergic agonist prevented the onset of receptor down-regulation in pregnant women with preterm labor. Further studies are required to investigate the impact of the decreased loss of beta 2-adrenoceptor density on the good clinical experience with intermittent tocolysis.

  19. Role of transglutaminase 2 in A1 adenosine receptor- and β2-adrenoceptor-mediated pharmacological pre- and post-conditioning against hypoxia-reoxygenation-induced cell death in H9c2 cells.

    PubMed

    Vyas, Falguni S; Nelson, Carl P; Dickenson, John M

    2018-01-15

    Pharmacologically-induced pre- and post-conditioning represent attractive therapeutic strategies to reduce ischaemia/reperfusion injury during cardiac surgery and following myocardial infarction. We have previously reported that transglutaminase 2 (TG2) activity is modulated by the A 1 adenosine receptor and β 2 -adrenoceptor in H9c2 cardiomyoblasts. The primary aim of this study was to determine the role of TG2 in A 1 adenosine receptor and β 2 -adrenoceptor-induced pharmacological pre- and post-conditioning in the H9c2 cells. H9c2 cells were exposed to 8h hypoxia (1% O 2 ) followed by 18h reoxygenation, after which cell viability was assessed by monitoring mitochondrial reduction of MTT, lactate dehydrogenase release and caspase-3 activation. N 6 -cyclopentyladenosine (CPA; A 1 adenosine receptor agonist), formoterol (β 2 -adrenoceptor agonist) or isoprenaline (non-selective β-adrenoceptor agonist) were added before hypoxia/reoxygenation (pre-conditioning) or at the start of reoxygenation following hypoxia (post-conditioning). Pharmacological pre- and post-conditioning with CPA and isoprenaline significantly reduced hypoxia/reoxygenation-induced cell death. In contrast, formoterol did not elicit protection. Pre-treatment with pertussis toxin (G i/o -protein inhibitor), DPCPX (A 1 adenosine receptor antagonist) or TG2 inhibitors (Z-DON and R283) attenuated the A 1 adenosine receptor-induced pharmacological pre- and post-conditioning. Similarly, pertussis toxin, ICI 118,551 (β 2 -adrenoceptor antagonist) or TG2 inhibition attenuated the isoprenaline-induced cell survival. Knockdown of TG2 using small interfering RNA (siRNA) attenuated CPA and isoprenaline-induced pharmacological pre- and post-conditioning. Finally, proteomic analysis following isoprenaline treatment identified known (e.g. protein S100-A6) and novel (e.g. adenine phosphoribosyltransferase) protein substrates for TG2. These results have shown that A 1 adenosine receptor and β 2 -adrenoceptor

  20. Divergent agonist selectivity in activating β1- and β2-adrenoceptors for G-protein and arrestin coupling.

    PubMed

    Casella, Ida; Ambrosio, Caterina; Grò, Maria Cristina; Molinari, Paola; Costa, Tommaso

    2011-08-15

    The functional selectivity of adrenergic ligands for activation of β1- and β2-AR (adrenoceptor) subtypes has been extensively studied in cAMP signalling. Much less is known about ligand selectivity for arrestin-mediated signalling pathways. In the present study we used resonance energy transfer methods to compare the ability of β1- and β2-ARs to form a complex with the G-protein β-subunit or β-arrestin-2 in response to a variety of agonists with various degrees of efficacy. The profiles of β1-/β2-AR selectivity of the ligands for the two receptor-transducer interactions were sharply different. For G-protein coupling, the majority of ligands were more effective in activating the β2-AR, whereas for arrestin coupling the relationship was reversed. These data indicate that the β1-AR interacts more efficiently than β2-AR with arrestin, but less efficiently than β2-AR with G-protein. A group of ligands exhibited β1-AR-selective efficacy in driving the coupling to arrestin. Dobutamine, a member of this group, had 70% of the adrenaline (epinephrine) effect on arrestin via β1-AR, but acted as a competitive antagonist of adrenaline via β2-AR. Thus the structure of such ligands appears to induce an arrestin-interacting form of the receptor only when bound to the β1-AR subtype. © The Authors Journal compilation © 2011 Biochemical Society

  1. Influence of dexmedetomidine on cognitive function in volunteers.

    PubMed

    Yatabe, Tomoaki; Tamura, Takahiko; Yamashita, Koichi; Yokoyama, Masataka

    2016-09-01

    Some outpatient procedures are performed under sedation with dexmedetomidine, although the effect of dexmedetomidine on cognitive function remains unclear. This study investigated the effect of dexmedetomidine on cognitive function in healthy volunteers. Observation study in volunteers. University-affiliated teaching hospital. Six healthy volunteers. After infusion of a 6-μg/kg per hour loading dose of dexmedetomidine for 10 minutes, a maintenance infusion of 0.4 μg/kg per hour was administered for 4 hours. Cognitive function was evaluated before infusion (baseline) and at 2, 4, 6, and 8 hours after infusion. Cognitive function, response speed, accuracy, and consistency were measured by CogHealth. Depth of sedation was evaluated at 1-hour intervals by evaluating the Bispectral Index. Data are presented as the change from baseline. The Bispectral Index value was significantly lower from 10 minutes to 6 hours after infusion versus the pre-infusion value. Response speed was also significantly lower at 2 hours and 4 hours after infusion (92 ± 8%, P< .0001; 93 ± 6%, P< .0001), as was consistency (96 ± 7%, P= .0009; 96 ± 5%, P= .0003). Response accuracy was unaltered by the infusion. Dexmedetomidine slightly reduced response speed and consistency, but did not affect response accuracy. Cognitive function was restored to pre-administration values 2 hours after the infusion of dexmedetomidine was discontinued. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Effects of ovarian steroids upon responses mediated by adrenoceptors in separated layers of the myometrium and in the costo-uterine muscle of the guinea-pig

    PubMed Central

    Hartley, Margaret L.; Pennefather, Jocelyn N.; Story, Margot E.

    1983-01-01

    1 This study describes the effects of ovarian steroid hormones upon the responses to adrenoceptor agonists of isolated myometrium, separated into its longitudinal and circular layers, and of costo-uterine muscle from guinea-pigs. The preparations were field-stimulated at 100 s intervals, and the adrenoceptor agonists phenylephrine and isoprenaline produced enhancement or inhibition of the evoked contractions. 2 Isoprenaline produced propranolol-sensitive inhibitory effects in longitudinal and circular myometrium and costo-uterine muscle preparations from animals from all experimental groups: i.e. from nonsteroid-treated animals (ovariectomized and intact); intact animals treated with either oestrogen or progesterone alone; ovariectomized animals treated with oestrogen; ovariectomized and intact animals treated with progesterone following oestrogen priming; and from animals 1-4 days post-partum. Longitudinal myometrial preparations from progesterone-treated oestrogen-primed and from post-partum animals were most sensitive to this agonist. 3 Phenylephrine produced phentolamine-sensitive excitatory effects in circular myometrial and costo-uterine muscle preparations from animals from all the experimental groups. In contrast, propranolol-sensitive inhibitory responses to phenylephrine occurred in longitudinal myometrial preparations taken from animals treated with progesterone following oestrogen priming, and from post-partum animals. Longitudinal myometrium from animals from the remaining experimental groups exhibited phentolamine-sensitive excitatory responses to phenylephrine. 4 The basis for the selective effect upon the longitudinal myometrium of exposure to progesterone following a period of oestrogen priming, is discussed. The results described are consistent with the possibility that in the longitudinal layer of guinea-pig uterus exposed to progesterone following oestrogen priming there is an increase in the proportion of β-adrenoceptors in this layer. This

  3. Activation of β-adrenoceptor facilitates active avoidance learning through enhancement of glutamate levels in the hippocampal dentate gyrus.

    PubMed

    Lv, Jing; Feng, Hao; Chen, Ling; Wang, Wei-Yao; Yue, Xue-Ling; Jin, Qing-Hua

    2017-10-18

    Long-term potentiation (LTP) is widely accepted as the best studied model for neurophysiological mechanisms that could underlie learning and memory formation. Despite a number of studies indicating that β-adrenoceptors in the hippocampal dentate gyrus (DG) is involved in the modulation of learning and memory as well as LTP, few studies have used glutamate release as a visual indicator in awake animals to explore the role of β-adrenoceptors in learning-dependent LTP. Therefore, in the present study, the effects of propranolol (an antagonist of β-adrenoceptor) and isoproterenol (an agonist of β-adrenoceptor) on extracellular concentrations of glutamate and amplitudes of field excitatory postsynaptic potential were measured in the DG region during active avoidance learning in freely moving conscious rats. In the control group, the glutamate level in the DG was significantly increased during the acquisition of active avoidance behavior and returned to basal level following extinction training. In propranolol group, antagonism of β-adrenoceptors in the DG significantly reduced the change in glutamate level, and the acquisition of the active avoidance behavior was significantly inhibited. In contrast, the change in glutamate level was significantly enhanced by isoproterenol, and the acquisition of the active avoidance behavior was significantly accelerated. Furthermore, in all groups, the changes in glutamate level were accompanied by corresponding changes in field excitatory postsynaptic potential amplitude and active avoidance behavior. Our results suggest that activation of β-adrenoceptors in the hippocampal DG facilitates active avoidance learning by modulations of glutamate level and synaptic efficiency in rats.

  4. Initial Assessment of β3-Adrenoceptor-Activated Brown Adipose Tissue in Streptozotocin-Induced Type 1 Diabetes Rodent Model Using [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

    PubMed

    Baranwal, Aparna; Mirbolooki, M Reza; Mukherjee, Jogeshwar

    2015-01-01

    Metabolic activity of brown adipose tissue (BAT) is activated by β3-adrenoceptor agonists and norepinephrine transporter (NET) blockers and is measurable using [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography/computed tomography (PET/CT) in rats. Using the streptozotocin (STZ)-treated rat model of type 1 diabetes mellitus (T1DM), we investigated BAT activity in this rat model under fasting and nonfasting conditions using [(18)F]FDG PET/CT. Drugs that enhance BAT activity may have a potential for therapeutic development in lowering blood sugar in insulin-resistant diabetes. Rats were rendered diabetic by administration of STZ and confirmed by glucose measures. [(18)F]FDG was injected in the rats (fasted or nonfasted) pretreated with either saline or β3-adrenoceptor agonist CL316,243 or the NET blocker atomoxetine for PET/CT scans. [(18)F]FDG metabolic activity was computed as standard uptake values (SUVs) in interscapular brown adipose tissue (IBAT) and compared across the different drug treatment conditions. Blood glucose levels > 500 mg/dL were established for the STZ-treated diabetic rats. Under fasting conditions, average uptake of [(18)F]FDG in the IBAT of STZ-treated diabetic rats was approximately 70% lower compared to that of normal rats. Both CL316,243 and atomoxetine activated IBAT in normal rats had an SUV > 5, whereas activation in STZ-treated rats was significantly lower. The agonist CL316,243 activated IBAT up to threefold compared to saline in the fasted STZ-treated rat. In the nonfasted rat, the IBAT activation was up by twofold by CL316243. Atomoxetine had a greater effect on lowering blood sugar levels compared to CL316,243 in the nonfasted rats. A significant reduction in metabolic activity was observed in the STZ-treated diabetic rodent model. Increased IBAT activity in the STZ-treated diabetic rat under nonfasted conditions using the β3-adrenoceptor agonist CL316,243 suggests a potential role of BAT in modulating blood

  5. The effects of SB 216469, an antagonist which discriminates between the alpha 1A-adrenoceptor and the human prostatic alpha 1-adrenoceptor.

    PubMed Central

    Chess-Williams, R.; Chapple, C. R.; Verfurth, F.; Noble, A. J.; Couldwell, C. J.; Michel, M. C.

    1996-01-01

    1. The affinity of the alpha 1-adrenoceptor antagonist SB 216469 (also known as REC 15/2739) has been determined at native and cloned alpha 1-adrenoceptor subtypes by radioligand binding and at functional alpha 1-adrenoceptor subtypes in isolated tissues. 2. In radioligand binding studies with [3H]-prazosin, SB 216469 had a high affinity at the alpha 1A-adrenoceptors of the rat cerebral cortex and kidney (9.5-9.8) but a lower affinity at the alpha 1B-adrenoceptors of the rat spleen and liver (7.7-8.2). 3. At cloned rat alpha 1-adrenoceptor subtypes transiently expressed in COS-1 cells and also at cloned human alpha 1-adrenoceptor subtypes stably transfected in Rat-1 cells, SB 216469 exhibited a high affinity at the alpha 1a-adrenoceptors (9.6-10.4) with a significantly lower affinity at the alpha 1b-adrenoceptor (8.0-8.4) and an intermediate affinity at the alpha 1d-adrenoceptor (8.7-9.2). 4. At functional alpha 1-adrenoceptors, SB 216469 had a similar pharmacological profile, with a high affinity at the alpha 1A-adrenoceptors of the rat vas deferens and anococcygeus muscle (pA2 = 9.5-10.0), a low affinity at the alpha 1B-adrenoceptors of the rat spleen (6.7) and guinea-pig aorta (8.0), and an intermediate affinity at the alpha 1D-adrenoceptors of the rat aorta (8.8). 5. Several recent studies have concluded that the alpha 1-adrenoceptor present in the human prostate has the pharmacological characteristics of the alpha 1A-adrenoceptor subtype. However, the affinity of SB 216469 at human prostatic alpha 1-adrenoceptors (pA2 = 8.1) determined in isolated tissue strips, was significantly lower than the values obtained at either the cloned alpha 1a-adrenoceptors (human, rat, bovine) or the native alpha 1A-adrenoceptors in radioligand binding and functional studies in the rat. 6. Our results with SB 216469, therefore, suggest that the alpha 1-adrenoceptor mediating contractile responses of the human prostate has properties which distinguish it from the cloned alpha 1a-adrenoceptor

  6. Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury.

    PubMed

    Lu, Pan; Lei, Shan; Li, Weisong; Lu, Yang; Zheng, Juan; Wang, Ning; Xia, Yongjun; Lu, Haixia; Chen, Xinlin; Liu, Yong; Zhang, Peng-Bo

    2018-06-19

    Ketamine inhibits the proliferation of neural stem cells (NSCs) and disturbs normal neurogenesis. Dexmedetomidine provides neuroprotection against volatile anesthetic-induced neuroapoptosis and cognitive impairment in the developing brain. Whether it may protect NSCs from ketamine-induced injury remains unknown. In this study, we investigated the protective effects of dexmedetomidine on ketamine-exposed NSCs and explored the mechanisms potentially involved. Primary NSC cultures were characterized using immunofluorescence. Cell viability was determined using a Cell Counting Kit 8 assay. Proliferation and apoptosis were assessed with BrdU incorporation and TUNEL assays, respectively. Protein levels of cleaved caspase-3, phosphorylated protein kinase B (p-Akt), and glycogen synthase kinase-3β (p-GSK-3β) were quantified using western blotting. Ket-amine significantly decreased NSC viability and proliferation and increased their apoptosis. Dexmedetomidine increased NSC proliferation and decreased their apoptosis in a dose-dependent manner. Furthermore, dexmedetomidine pretreatment notably augmented the viability and proliferation of ketamine-exposed NSCs and reduced their apoptosis. Moreover, dexmedetomidine lessened caspase-3 activation and increased p-Akt and p-GSK-3β levels in NSCs exposed to ketamine. The protective effects of dexmedetomidine on ketamine-exposed NSCs could be partly reversed by the PI3K inhibitor LY294002. Collectively, these findings indicate that dexmedetomidine may protect NSCs from ketamine-induced injury via the PI3K/Akt/GSK-3β signaling pathway. © 2018 The Author(s). Published by S. Karger AG, Basel.

  7. Effects of dexmedetomidine on heart arrhythmia prevention in off-pump coronary artery bypass surgery: A randomized clinical trial.

    PubMed

    Soltani, Ghasem; Jahanbakhsh, Saeed; Tashnizi, Mohammad Abbasi; Fathi, Mehdi; Amini, Shahram; Zirak, Nahid; Sheybani, Shima

    2017-10-01

    Arrhythmia occurring during and after surgery is one of the major complications in open-heart surgery. Dexmedetomidine is an intravenous alpha-2 agonist and very specific short-acting drug to protect the various organs against ischemic injuries and blood reflow. However, the effect of dexmedetomidine for preventing intraoperative heart arrhythmias has not been recognized. This study aimed to determine the effect of dexmedetomidine on the incidence rate of heart arrhythmias and anesthetic required in off-pump coronary artery bypass surgery. This randomized clinical trial was conducted on patients who were candidates for off-pump coronary artery bypass referring to Imam Reza Hospital of Mashhad, Iran, from July 2016 through January 2017. The patients were randomly assigned to two groups of intervention (infusion of 0.5 mcg/kg/h dexmedetomidine together with induction followed by infusion of 0.5 mcg/kg/h by the end of the surgery) or control (saline infusion). Mean arterial pressure (MAP) and heart rate (HR) were measured before induction, during surgery operation and ICU admission. Data were analyzed by SPSS version 18 using Chi Square and independent-samples t-test. A total of 76 patients with a mean age of 59.8 ± 8.2 years (in two groups of 38) were studied. The two groups had no statistically significant difference in terms of background variables. The MAP and HR values before induction, during surgery and ICU admission were significantly higher in the control group than in the intervention group (p=0.001). Out of the studied arrhythmias, the values of PAC (55.2% vs. 15.7%), PVC (81.5% vs. 21.0%), AF (26.3% vs. 7.8%), VTAC (21.0% vs. 2.6%) were significantly lower in dexmedetomidine group (p=0.001). It seems that dexmedetomidine administration during induction and surgery can cause significant reduction in most of the common arrhythmias in off-pump coronary bypass surgery. The use of dexmedetomidine maintains MAP and HR at significantly lower values, and changes

  8. Effects of dexmedetomidine on heart arrhythmia prevention in off-pump coronary artery bypass surgery: A randomized clinical trial

    PubMed Central

    Soltani, Ghasem; Jahanbakhsh, Saeed; Tashnizi, Mohammad Abbasi; Fathi, Mehdi; Amini, Shahram; Zirak, Nahid; Sheybani, Shima

    2017-01-01

    Background Arrhythmia occurring during and after surgery is one of the major complications in open-heart surgery. Dexmedetomidine is an intravenous alpha-2 agonist and very specific short-acting drug to protect the various organs against ischemic injuries and blood reflow. However, the effect of dexmedetomidine for preventing intraoperative heart arrhythmias has not been recognized. Objective This study aimed to determine the effect of dexmedetomidine on the incidence rate of heart arrhythmias and anesthetic required in off-pump coronary artery bypass surgery. Methods This randomized clinical trial was conducted on patients who were candidates for off-pump coronary artery bypass referring to Imam Reza Hospital of Mashhad, Iran, from July 2016 through January 2017. The patients were randomly assigned to two groups of intervention (infusion of 0.5 mcg/kg/h dexmedetomidine together with induction followed by infusion of 0.5 mcg/kg/h by the end of the surgery) or control (saline infusion). Mean arterial pressure (MAP) and heart rate (HR) were measured before induction, during surgery operation and ICU admission. Data were analyzed by SPSS version 18 using Chi Square and independent-samples t-test. Results A total of 76 patients with a mean age of 59.8 ± 8.2 years (in two groups of 38) were studied. The two groups had no statistically significant difference in terms of background variables. The MAP and HR values before induction, during surgery and ICU admission were significantly higher in the control group than in the intervention group (p=0.001). Out of the studied arrhythmias, the values of PAC (55.2% vs. 15.7%), PVC (81.5% vs. 21.0%), AF (26.3% vs. 7.8%), VTAC (21.0% vs. 2.6%) were significantly lower in dexmedetomidine group (p=0.001). Conclusion It seems that dexmedetomidine administration during induction and surgery can cause significant reduction in most of the common arrhythmias in off-pump coronary bypass surgery. The use of dexmedetomidine maintains MAP

  9. Alpha-1 adrenoceptor hyperresponsiveness in three neuropathic pain states: complex regional pain syndrome 1, diabetic peripheral neuropathic pain and central pain states following spinal cord injury.

    PubMed

    Teasell, Robert W; Arnold, J Malcolm O

    2004-01-01

    The pathophysiology of the pain associated with complex regional pain syndrome, spinal cord injury and diabetic peripheral neuropathy is not known. The pain of complex regional pain syndrome has often been attributed to abnormal sympathetic nervous system activity based on the presence of vasomotor instability and a frequently reported positive response, albeit a temporary response, to sympathetic blockade. In contrast, the pain below the level of spinal cord injury and diabetic peripheral neuropathy are generally seen as deafferentation phenomena. Each of these pain states has been associated with abnormal sympathetic nervous system function and increased peripheral alpha-1 adrenoceptor activity. This increased responsiveness may be a consequence of alpha-1 adrenoceptor postsynaptic hypersensitivity, or alpha-2 adrenoceptor presynaptic dysfunction with diminished noradrenaline reuptake, increased concentrations of noradrenaline in the synaptic cleft and increased stimulation of otherwise normal alpha-1 adrenoceptors. Plausible mechanisms based on animal research by which alpha-1 adrenoceptor hyperresponsiveness can lead to chronic neuropathic-like pain have been reported. This raises the intriguing possibility that sympathetic nervous system dysfunction may be an important factor in the generation of pain in many neuropathic pain states. Although results to date have been mixed, there may be a greater role for new drugs which target peripheral alpha-2 adrenoceptors (agonists) or alpha-1 adrenoceptors (antagonists).

  10. Dual interaction of agmatine with the rat α2D-adrenoceptor: competitive antagonism and allosteric activation

    PubMed Central

    Molderings, G J; Menzel, S; Kathmann, M; Schlicker, E; Göthert, M

    2000-01-01

    In segments of rat vena cava preincubated with [3H]-noradrenaline and superfused with physiological salt solution, the influence of agmatine on the electrically evoked [3H]-noradrenaline release, the EP3 prostaglandin receptor-mediated and the α2D-adrenoceptor-mediated inhibition of evoked [3H]-noradrenaline release was investigated. Agmatine (0.1–10 μM) by itself was without effect on evoked [3H]-noradrenaline release. In the presence of 10 μM agmatine, the prostaglandin E2(PGE2)-induced EP3-receptor-mediated inhibition of [3H]-noradrenaline release was not modified, whereas the α2D-adrenoceptor-mediated inhibition of [3H]-noradrenaline release induced by noradrenaline, moxonidine or clonidine was more pronounced than in the absence of agmatine. However, 1 mM agmatine antagonized the moxonidine-induced inhibition of [3H]-noradrenaline release. Agmatine concentration-dependently inhibited the binding of [3H]-clonidine and [3H]-rauwolscine to rat brain cortex membranes (Ki values 6 μM and 12 μM, respectively). In addition, 30 and 100 μM agmatine increased the rate of association and decreased the rate of dissociation of [3H]-clonidine resulting in an increased affinity of the radioligand for the α2D-adrenoceptors. [14C]-agmatine labelled specific binding sites on rat brain cortex membranes. In competition experiments. [14C]-agmatine was inhibited from binding to its specific recognition sites by unlabelled agmatine, but not by rauwolscine and moxonidine. In conclusion, the present data indicate that agmatine both acts as an antagonist at the ligand recognition site of the α2D-adrenoceptor and enhances the effects of α2-adrenoceptor agonists probably by binding to an allosteric binding site of the α2D-adrenoceptor which seems to be labelled by [14C]-agmatine. PMID:10928978

  11. Dexmedetomidine metabolic clearance is not affected by fat mass in obese patients.

    PubMed

    Rolle, A; Paredes, S; Cortínez, L I; Anderson, B J; Quezada, N; Solari, S; Allende, F; Torres, J; Cabrera, D; Contreras, V; Carmona, J; Ramírez, C; Oliveros, A M; Ibacache, M

    2018-05-01

    Obesity has been associated with reduced dexmedetomidine clearance, suggesting impaired hepatic function or reduced hepatic blood flow. The aim of this study was to clarify the effect of obesity in dexmedetomidine metabolic clearance. Forty patients, ASA I-III, 18-60 yr old, weighing 47-126 kg, scheduled for abdominal laparoscopic surgery, were enrolled. Anaesthetic agents (propofol, remifentanil, and dexmedetomidine) were dosed based on lean body weight measured by dual X-ray absorptiometry. Serial venous samples were drawn during and after dexmedetomidine infusion. A pharmacokinetic analysis was undertaken using non-linear mixed-effect models. In the modelling approach, the total body weight, lean body weight, and adjusted body weight were first tested as size descriptors for volumes and clearances. Hepatic blood flow, liver histopathology, liver enzymes, and gene expression of metabolic enzymes (UGT2B10 and UGT1A4) were tested as covariates of dexmedetomidine metabolic clearance. A decrease in NONMEM objective function value (ΔOFV) of 3.84 points, for an added parameter, was considered significant at the 0.05 level. A total of 637 dexmedetomidine serum samples were obtained. A two-compartmental model scaled to measured lean weight adequately described the dexmedetomidine pharmacokinetics. Liver blood flow was a covariate for dexmedetomidine clearance (ΔOFV=-5.878). Other factors, including fat mass, histopathological damage, and differential expression of enzymes, did not affect the dexmedetomidine clearance in the population studied (ΔOFV<3.84). We did not find a negative influence of obesity in dexmedetomidine clearance when doses were adjusted to lean body weight. Liver blood flow showed a significant effect on dexmedetomidine clearance. NCT02557867. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

  12. Anti-nociceptive effect of dexmedetomidine in a rat model of monoarthritis via suppression of the TLR4/NF-κB p65 pathway

    PubMed Central

    Ji, Dong; Zhou, Yalan; Li, Shuangshuang; Li, Dai; Chen, Hui; Xiong, Yuanchang; Zhang, Yuqiu; Xu, Hua

    2017-01-01

    As a therapeutic target for neuropathic pain, the anti-nociceptive effects of α 2-adrenoceptors (α2AR) have attracted attention. Dexmedetomidine (DEX), a potent and highly selective α2AR agonist, has exhibited significant analgesic effects in neuropathic pain, but the underlying mechanism has remained elusive. The present study investigated the effect of DEX on Toll-like receptor (TLR)4 and nuclear factor (NF)-κB p65 expression, as well as the production of pro-inflammatory cytokines. The rat monoarthritis (MA) model was induced by intra-articular injection of complete Freund's adjuvant (CFA) at the ankle joint. After induction of MA, the rats were intrathecally treated with normal saline or DEX (2.5 µg) for 3 consecutive days. The concentration of interleukin-1β and −6 as well as tumor necrosis factor-α was examined by ELISA. The expression levels of TLR4 and NF-κB p65 were determined by western blot analysis and immunohistochemistry. The results indicated that the pro-inflammatory cytokines TLR4 and NF-κB p65 were significantly upregulated in MA rats. DEX treatment markedly reduced mechanical and thermal hyperalgesia, suppressed MA-induced elevation of the pro-inflammatory cytokines and inhibited the TLR4/NF-κB p65 pathway, while these effects were blocked by pre-treatment with the selective α2AR antagonist BRL44408 (15 µg) at 30 min prior to CFA injection. These results suggested that DEX has an anti-nociceptive effect via suppressing the TLR4/NF-κB p65 pathway. PMID:29201195

  13. alpha(2)-adrenoceptor antagonist properties of OPC-28326, a novel selective peripheral vasodilator.

    PubMed

    Orito, K; Kishi, M; Imaizumi, T; Nakazawa, T; Hashimoto, A; Mori, T; Kambe, T

    2001-10-01

    1. Antagonistic properties of OPC-28326 ([4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl)] piperidine hydrochloride monohydrate), a selective peripheral vasodilator, were investigated by analysing the data from functional studies in various tissues from the rat and binding studies of the drug to alpha(2)-adrenoceptor subtypes. 2. Using a human recombinant receptor and rat kidney cortex, we found that OPC-28326 displays affinities to alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors with K(i) values of 2040, 285, and 55 nM, respectively. The K(i) values of yohimbine for alpha(2A)-, alpha(2B)-, and alpha(2C)-adrenoceptors were 3.0, 2.0 and 11.0 nM, respectively. 3. B-HT 920, an alpha(2)-adrenoceptor agonist, produced a pressor response via peripheral postsynaptic alpha(2)-adrenoceptor stimulation (thought to be an alpha(2B)-subtype) in a reserpine-pretreated pithed rat preparation. OPC-28326 (3 - 30 mg kg(-1), i.v.) and yohimbine (0.3 - 3 mg kg(-1), i.v.) caused dose-dependent rightward shift in the pressor dose-response curve induced by B-HT 920. The apparent pA(2) values were 1.55 (0.87 - 2.75, 95% confidence interval) and 0.11 (0.06 - 0.21) mg kg(-1), respectively. The potency of OPC-28326 was about 14 times less than that of yohimbine. 4. Clonidine inhibited the tension developed by electrical stimulation, of the rat vas deferens, by its peripheral presynaptic alpha(2A/D)-adrenoceptor action. OPC-28326 (1 - 100 microM) and yohimbine (10 - 1000 nM) caused a rightward shift in the concentration-response curve of clonidine. The pA(2) values were 5.73 (5.54 - 5.91) and 7.92 (7.84 - 8.01), respectively, providing evidence for a potency of OPC-28326 of about 155 times less than that of yohimbine. 5. Mydriasis was induced by brimonidine via stimulation of central alpha(2A/D)-adrenoceptors in anaesthetized rats. Intravenous OPC-28326 had no effect on this action, even at a very high dose of 10 mg kg(-1) i.v., while yohimbine (0.1 - 0.3 mg kg(-1

  14. beta. -Adrenoceptors in human tracheal smooth muscle: characteristics of binding and relaxation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    van Koppen, C.J.; Hermanussen, M.W.; Verrijp, K.N.

    1987-06-29

    Specific binding of (/sup 125/I)-(-)-cyanopindolol to human tracheal smooth muscle membranes was saturable, stereo-selective and of high affinity (K/sub d/ = 5.3 +/- 0.9 pmol/l and R/sub T/ = 78 +/- 7 fmol/g tissue). The ..beta../sub 1/-selective antagonists atenolol and LK 203-030 inhibited specific (/sup 125/I)-(-)-cyanopindolol binding according to a one binding site model with low affinity in nearly all subjects, pointing to a homogeneous BETA/sub 2/-adrenoceptor population. In one subject using LK 203-030 a small ..beta../sub 1/-adrenoceptor subpopulation could be demonstrated. The beta-mimetics isoprenaline, fenoterol, salbutamol and terbutaline recognized high and low affinity agonist binding sites. Isoprenaline's pK/sub H/-more » and pK/sub L/-values for the high and low affinity sites were 8.0 +/- 0.2 and 5.9 +/- 0.3 respectively. In functional experiments isoprenaline relaxed tracheal smooth muscle strips having intrinsic tone with a pD/sub 2/-value of 6.63 +/- 0.19. 32 references, 4 figures, 2 tables.« less

  15. β2-adrenoceptor-induced modulation of transglutaminase 2 transamidase activity in cardiomyoblasts.

    PubMed

    Vyas, Falguni S; Nelson, Carl P; Freeman, Fiona; Boocock, David J; Hargreaves, Alan J; Dickenson, John M

    2017-10-15

    Tissue transglutaminase 2 (TG2) is modulated by protein kinase A (PKA) mediated phosphorylation: however, the precise mechanism(s) of its modulation by G-protein coupled receptors coupled to PKA activation are not fully understood. In the current study we investigated the potential regulation of TG2 activity by the β 2 -adrenoceptor in rat H9c2 cardiomyoblasts. Transglutaminase transamidation activity was assessed using amine-incorporating and protein cross-linking assays. TG2 phosphorylation was determined via immunoprecipitation and Western blotting. The long acting β 2 -adrenoceptor agonist formoterol induced time- and concentration-dependent increases in TG2 transamidation. Increases in TG2 activity were reduced by the TG2 inhibitors Z-DON (Benzyloxycarbonyl-(6-Diazo-5-oxonorleucinyl)-L-valinyl-L-prolinyl-L-leucinmethylester) and R283 ((1,3,dimethyl-2[2-oxo-propyl]thio)imidazole chloride). Responses to formoterol were blocked by pharmacological inhibition of PKA, extracellular signal-regulated kinase 1 and 2 (ERK1/2), or phosphatidylinositol 3-kinase (PI-3K) signalling. Furthermore, the removal of extracellular Ca 2+ also attenuated formoterol-induced TG2 activation. Fluorescence microscopy demonstrated TG2-induced biotin-X-cadaverine incorporation into proteins. Formoterol increased the levels of TG2-associated phosphoserine and phosphothreonine, which were blocked by inhibition of PKA, ERK1/2 or PI-3K signalling. Subsequent proteomic analysis identified known (e.g. lactate dehydrogenase A chain) and novel (e.g. Protein S100-A6) protein substrates for TG2. Taken together, the data obtained suggest that β 2 -adrenoceptor-induced modulation of TG2 represents a novel paradigm in β 2 -adrenoceptor cell signalling, expanding the repertoire of cellular functions responsive to catecholamine stimulation. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Fenoterol functionally activates the β₃-adrenoceptor in human urinary bladder, comparison with rat and mouse: implications for drug discovery.

    PubMed

    Palea, Stefano; Rekik, Moèz; Rouget, Céline; Camparo, Philippe; Botto, Henri; Rischmann, Pascal; Lluel, Philippe; Westfall, Timothy D

    2012-09-05

    Fenoterol has been reported to be a potent and selective β(2)-adrenoceptor agonist and is currently used clinically to treat asthma. Electrical field stimulation (EFS) of isolated urinary bladder mimics the voiding contraction by stimulating parasympathetic nerves, resulting in neurogenic contractions. To determine if stimulation of β(2)-adrenoceptors can inhibit this response, fenoterol was tested against EFS-induced contractions in human isolated urinary bladder and compared with mouse and rat. Bladder strips were mounted in organ baths and reproducible contractions induced by EFS. Fenoterol was added cumulatively in the presence of the β(2)-adrenoceptor antagonist ICI118551 or the β(3)-adrenoceptor antagonist L-748337. Fenoterol inhibited neurogenic contractions in all three species in a concentration-dependent manner with pEC(50) values of 6.66 ± 0.11, 6.86 ± 0.06 and 5.71 ± 0.1 in human, mouse and rat respectively. In human bladder strips ICI118551 (100 nM) did not affect responses to fenoterol, while L-748337 (0.3-3 μM) produced rightward shifts of the concentration-response curves with a pA(2) value of 8.10. In mouse bladder strips ICI118551 (30 nM) blocked the inhibitory effect of fenoterol (pA(2)=8.80), while L-748337 (10 μM) inhibited the response with a pA(2) of 5.79. In rat bladder ICI118551 (30 nM) was without effect, while L-748,337 (10 μM) inhibited the response to fenoterol with a pA(2) of 5.40. From these results it is clear that fenoterol potently activates β(3)-adrenoceptors in human isolated urinary bladder to inhibit EFS-induced contractions. Fenoterol also activates β(3)-adrenoceptors in rat, but β(2)-adrenoceptors in mouse bladder to inhibit EFS-induced contractions. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. Effect of partial agonist activity in beta blockers in severe angina pectoris: a double blind comparison of pindolol and atenolol.

    PubMed Central

    Quyyumi, A A; Wright, C; Mockus, L; Fox, K M

    1984-01-01

    The use of beta adrenoceptor blockade in the treatment of rest angina is controversial, and the effects on severe angina of partial agonist activity in beta blockers are unknown. Eight patients with effort angina and seven with effort and nocturnal angina and severe coronary artery disease were studied initially when they were not taking any antianginal drugs. Pindolol 5 mg thrice daily (with partial agonist activity) and atenolol 100 mg daily (without partial agonist activity) were given for five days each in a double blind randomised manner. Diaries of angina were kept and treadmill exercise testing and ambulatory ST monitoring performed during the last 48 hours of each period of treatment. Daytime and nocturnal resting heart rates and the frequency of angina were significantly reduced by atenolol compared with pindolol (p less than 0.01). The duration of exercise was significantly increased and the frequency, duration, and magnitude of daytime and nocturnal episodes of ST segment depression on ambulatory monitoring were reduced by atenolol. Reduction in resting heart rate is important in the treatment of both effort and nocturnal angina. Partial agonist activity in beta adrenoceptor antagonists may be deleterious in patients with severe angina pectoris. PMID:6148991

  18. The beta-3 adrenoceptor agonist, mirabegron relaxes isolated prostate from human and rabbit: new therapeutic indication?

    PubMed

    Calmasini, Fabiano B; Candido, Tuany Z; Alexandre, Eduardo C; D'Ancona, Carlos A; Silva, Daniel; de Oliveira, Marco Antonio; De Nucci, Gilberto; Antunes, Edson; Mónica, Fabíola Z

    2015-03-01

    Alpha1 (α1)-blockers, 5-alpha reductase and phosphodiesterase type-5 inhibitors are pharmacological classes currently available for benign prostatic hyperplasia (BPH) treatment. Mirabegron, a beta-3 adrenoceptor (β3-AR) agonist has been approved for the therapy of overactive bladder and may constitute a new therapeutic option for BPH treatment. This study is aimed to evaluate the in vitro effects of mirabegron in human and rabbit prostatic smooth muscle. In rabbit prostate, electrical field stimulation (EFS)-induced contraction and concentration-response curve (CRC) to mirabegron in phenylephrine pre-contracted tissues were carried out. The potency (pEC50 ) and maximal response (Emax ) values were determined. In human prostate, CRC to phenylephrine was carried out in the absence and presence of mirabegron. Immunohistochemistry analysis for β3-AR was also carried out. In human prostate, immunohistochemistry analysis revealed the presence of β3-AR on the transition zone and mirabegron reduced by 42% the phenylephrine-induced contractions. In rabbit prostate, mirabegron produced concentration-dependent relaxations (pEC50 : 6.01 ± 0.12; Emax : 106 ± 3%), which were fully resistant to the blockade of β1-AR and β2-AR. The β3-AR blocker L748,337 caused a six-fold rightward shift in mirabegron-induced relaxations. Mirabegron (10 μM) reduced by 63% the EFS-induced contractions. Inhibitors of nitric oxide (L-NAME) and of soluble guanylate cyclase (ODQ) along with a cocktail of K+ channel blockers (apamin, charybdotoxin, glibenclamide, tetraethylammonium) all failed to significantly affect the mirabegron-induced rabbit relaxations. Mirabegron relaxes prostatic smooth muscle, providing an experimental support for the clinical investigation of its combination with an α1-blockers or PDE5 inhibitors in the treatment of BPH. Prostate 75:440-447, 2015. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.

  19. Modulatory effects of the basolateral amygdala α2-adrenoceptors on nicotine-induced anxiogenic-like behaviours of rats in the elevated plus maze.

    PubMed

    Bashiri, Hamideh; Rezayof, Ameneh; Sahebgharani, Mousa; Tavangar, Seyed Mohammad; Zarrindast, Mohammad-Reza

    2016-06-01

    The present study was designed to clarify whether α2-adrenoceptors of the basolateral amygdala (BLA) are involved in nicotine-induced anxiogenic-like behaviours. Adult male Wistar rats were bilaterally cannulated in the BLA and anxiety-like behaviours were assessed in an elevated plus maze (EPM) task. Systemic intraperitoneal (i.p.) administration of nicotine (0.3, 0.5 and 0.7 mg/kg) dose-dependently decreased open arm time (%OAT) and open arm entry (%OAE), indicating the anxiogenic-like effect of nicotine. The activation of the BLA α2-adrenoceptors by the injection of α2-receptor agonist, clonidine (0.1, 0.3 and 0.5 μg/rat) into the BLA (intra-BLA) reversed nicotine-induced anxiogenic-like behaviours. It is important to note that intra-BLA injection of a higher dose of clonidine (0.5 μg/rat) by itself increased %OAT, but not %OAE which showed an anxiolytic effect of the agonist. On the other hand, intra-BLA injection of different doses of α2-adrenoceptor antagonist, yohimbine (1, 3 and 5 μg/rat) in combination with an ineffective dose of nicotine (0.3 mg/kg) decreased %OAT and %OAE, suggesting a potentiative effect of the antagonist on nicotine response. In addition, intra-BLA injection of the same doses of yohimbine did not alter %OAT and %OAE. Interestingly, intra-BLA injection of yohimbine (0.5 and 1 μg/rat) significantly reversed the inhibitory effect of clonidine on nicotine-induced anxiogenic-like behaviours. It should be considered that the drug treatments had no effect on locomotor activity in all experiments. Taken together, it can be concluded that nicotine produces anxiogenic-like behaviours which may be mediated through the BLA α2-adrenoceptor mechanism. Copyright © 2016. Published by Elsevier Ltd.

  20. Intravenous labetolol in treating hypertensive crisis following dexmedetomidine infusion for procedural sedation.

    PubMed

    Muthiah, Thilaka; Moni, Amarnath; Mathews, Lailu; Balaji, Sudarshan

    2016-03-01

    Dexmedetomidine is widely used for procedural sedation because of its unique combination of sedation, analgesia, and anxiolysis with minimal respiratory depression. Transient hypertension has been reported during the use of dexmedetomidine which is usually benign and is taken over by the hypotensive response on continuing the infusion. We report a case of hypertensive crisis following dexmedetomidine infusion used for procedural sedation, necessitating discontinuation of the infusion and treatment of hypertension. The dilemmas involved in treating hypertension caused by dexmedetomidine are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. 5-Methoxy-N,N-dimethyltryptamine-induced analgesia is blocked by alpha-adrenoceptor antagonists in rats.

    PubMed Central

    Archer, T.; Danysz, W.; Jonsson, G.; Minor, B. G.; Post, C.

    1986-01-01

    The effects of the alpha-adrenoceptor antagonists prazosin, phentolamine and yohimbine upon 5-methoxy-N,N-dimethyltryptamine (5-MeODMT)-induced analgesia were tested in the hot-plate, tail-flick and shock-titration tests of nociception with rats. Intrathecally injected yohimbine and phentolamine blocked or attenuated the analgesia produced by systemic administration of 5-MeODMT in all three nociceptive tests. Intrathecally administered prazosin attenuated the analgesic effects of 5-MeODMT in the hot-plate and tail-flick tests, but not in the shock titration test. Intrathecal yohimbine showed a dose-related lowering of pain thresholds in saline and 5-MeODMT-treated animals. Phentolamine and prazosin produced normal dose-related curves in the hot-plate test and biphasic effects in the shock titration and tail-flick tests. These results demonstrate a functional interaction between alpha 2-adrenoceptors and 5-HT agonist-induced analgesia at a spinal level in rats. PMID:2877697

  2. Membrane Potential Controls the Efficacy of Catecholamine-induced β1-Adrenoceptor Activity*

    PubMed Central

    Birk, Alexandra; Rinne, Andreas; Bünemann, Moritz

    2015-01-01

    G protein-coupled receptors (GPCRs) are membrane-located proteins and, therefore, are exposed to changes in membrane potential (VM) in excitable tissues. These changes have been shown to alter receptor activation of certain Gi-and Gq-coupled GPCRs. By means of a combination of whole-cell patch-clamp and Förster resonance energy transfer (FRET) in single cells, we demonstrate that the activation of the Gs-coupled β1-adrenoreceptor (β1-AR) by the catecholamines isoprenaline (Iso) and adrenaline (Adr) is regulated by VM. This voltage-dependence is also transmitted to G protein and arrestin 3 signaling. Voltage-dependence of β2-AR activation, however, was weak compared with β1-AR voltage-dependence. Drug efficacy is a major target of β1-AR voltage-dependence as depolarization attenuated receptor activation, even under saturating concentrations of agonists, with significantly faster kinetics than the deactivation upon agonist withdrawal. Also the efficacy of the endogenous full agonist adrenaline was reduced by depolarization. This is a unique finding since reports of natural full agonists at other voltage-dependent GPCRs only show alterations in affinity during depolarization. Based on a Boltzmann function fit to the relationship of VM and receptor-arrestin 3 interaction we determined the voltage-dependence with highest sensitivity in the physiological range of membrane potential. Our data suggest that under physiological conditions voltage regulates the activity of agonist-occupied β1-adrenoceptors on a very fast time scale. PMID:26408198

  3. Brain α2-adrenoceptors in monoamine-depleted rats: increased receptor density, G coupling proteins, receptor turnover and receptor mRNA

    PubMed Central

    Ribas, Catalina; Miralles, Antonio; Busquets, Xavier; García-Sevilla, Jesús A

    2001-01-01

    This study was designed to assess the molecular and cellular events involved in the up-regulation (and receptor supersensitivity) of brain α2-adrenoceptors as a result of chronic depletion of noradrenaline (and other monoamines) by reserpine. Chronic reserpine (0.25 mg kg−1 s.c., every 48 h for 6 – 14 days) increased significantly the density (Bmax values) of cortical α2-adrenoceptor agonist sites (34 – 48% for [3H]-UK14304, 22 – 32% for [3H]-clonidine) but not that of antagonist sites (11 – 18% for [3H]-RX821002). Competition of [3H]-RX821002 binding by (−)-adrenaline further indicated that chronic reserpine was associated with up-regulation of the high-affinity state of α2-adrenoceptors. In cortical membranes of reserpine-treated rats (0.25 mg kg−1 s.c., every 48 h for 20 days), the immunoreactivities of various G proteins (Gαi1/2, Gαi3, Gαo and Gαs) were increased (25 – 34%). Because the high-affinity conformation of the α2-adrenoceptor is most probably related to the complex with Gαi2 proteins, these results suggested an increase in signal transduction through α2-adrenoceptors (and other monoamine receptors) induced by chronic reserpine. After α2-adrenoceptor alkylation, the analysis of receptor recovery (Bmax for [3H]-UK14304) indicated that the increased density of cortical α2-adrenoceptors in reserpine-treated rats was probably due to a higher appearance rate constant of the receptor (Δr=57%) and not to a decreased disappearance rate constant (Δk=7%). Northern- and dot-blot analyses of RNA extracted from the cerebral cortex of saline- and reserpine-treated rats (0.25 mg kg−1, s.c., every 48 h for 20 days) revealed that reserpine markedly increased the expression of α2a-adrenoceptor mRNA in the brain (125%). This transcriptional activation of the receptor gene expression appears to be the cellular mechanism by which reserpine induces up-regulation in the density of brain α2-adrenoceptors

  4. Pharmacy-Driven Dexmedetomidine Stewardship and Appropriate Use Guidelines in a Community Hospital Setting.

    PubMed

    Schickli, M Alexandra; Eberwein, Kip A; Short, Marintha R; Ratliff, Patrick D

    2017-01-01

    Dexmedetomidine is a widely utilized agent in the intensive care unit (ICU) because it does not suppress respiratory drive and may be associated with less delirium than midazolam or propofol. Cost of dexmedetomidine therapy and debate as to the proper duration of use has brought its use to the forefront of discussion. To validate the efficacy and cost savings associated with pharmacy-driven dexmedetomidine appropriate use guidelines and stewardship in mechanically ventilated patients. This was a retrospective cohort study of adult patients who received dexmedetomidine for ICU sedation while on mechanical ventilation at a 433-bed not-for-profit community hospital. Included patients were divided into pre-enactment (PRE) and postenactment (POST) of dexmedetomidine guideline groups. A total of 100 patients (50 PRE and 50 POST) were included in the analysis. A significant difference in duration of mechanical ventilation (11.1 vs 6.2 days, P = 0.006) and incidence of reintubation (36% vs 18% of patients, P = 0.043) was seen in the POST group. Aggregate use of dexmedetomidine 200-µg vials (37.1 vs 18.4 vials, P = 0.010) and infusion days (5.4 vs 2.5 days, P = 0.006) were significantly lower in the POST group. Dexmedetomidine acquisition cost savings were calculated at $374 456.15 in the POST group. There was no difference between the PRE and POST groups with regard to ICU length of stay, expected mortality, and observed mortality. Pharmacy-driven dexmedetomidine appropriate use guidelines decreased the use of dexmedetomidine and increased cost savings at a community hospital without adversely affecting clinical outcomes.

  5. Dexmedetomidine-related polyuria in a pediatric patient.

    PubMed

    Adams, Phillip S; Cassara, Antonio

    2016-04-01

    Polyuria related to pharmacologic α2-adrenoreceptor agonism has been well described in vitro and in animal models and is thought to be the result of functional antagonism of arginine vasopressin. Despite its widespread use as a sedative and anesthetic adjunct, very few reports of dexmedetomidine-related polyuria in humans exist in the literature. We present the first description of a pediatric patient manifesting polyuria and hypernatremia in association with dexmedetomidine infusion for posterior spinal fusion.

  6. Physiologic and biochemical effects of electroacupuncture combined with intramuscular administration of dexmedetomidine to provide analgesia in goats.

    PubMed

    Shah, Zahir; Hu, Man L; Qiu, Zheng Y; Zhou, Fei Y; Zeng, Jie; Wan, Juan; Wang, Shao W; Zhang, Wei; Ding, Ming X

    2016-03-01

    To investigate physiologic and biochemical effects of electroacupuncture and dexmedetomidine administration to goats. 30 healthy adult goats. Goats were allotted to 5 groups (6 goats/group) and received electroacupuncture, dexmedetomidine (5 or 20 μg/kg, IM), electroacupuncture plus dexmedetomidine (5 μg/kg, IM), or saline (0.9% NaCl) solution (IM [control treatment]). Pain threshold, cardiorespiratory effects, rectal temperature, and hematologic and biochemical variables were assessed. Dexmedetomidine (20 μg/kg) increased pain threshold and decreased heart rate, respiratory rate, and rectal temperature. Pain threshold of goats receiving electroacupuncture plus dexmedetomidine (5 μg/kg) was higher than that of goats receiving electroacupuncture or of goats receiving dexmedetomidine at 5 μg/kg at 30 minutes, but did not differ from that of goats receiving dexmedetomidine at 20 μg/kg. Compared with goats administered dexmedetomidine at 20 μg/kg, goats receiving electroacupuncture plus dexmedetomidine at 5 μg/kg had a higher heart rate from 30 to 60 minutes and a higher respiratory rate from 5 to 60 minutes. Electroacupuncture plus dexmedetomidine (5 μg/kg) did not affect rectal temperature. Serum glucose concentrations of goats receiving electroacupuncture plus dexmedetomidine (5 μg/kg) were higher than for goats receiving dexmedetomidine at 5 μg/kg at 30 minutes but not for goats receiving dexmedetomidine at 20 μg/kg. Creatinine and BUN concentrations, alanine or aspartate aminotransferase activities, and hematologic variables of treated goats did not change. Electroacupuncture in combination with a low dose of dexmedetomidine (5 μg/kg, IM) administered to goats provided antinociception.

  7. Management of exaggerated gag reflex in dental patients using intravenous sedation with dexmedetomidine.

    PubMed

    Reshetnikov, Aleksei P; Kasatkin, Anton A; Urakov, Aleksandr L; Baimurzin, Dmitrii Y

    2017-01-01

    Pharmacological sedation is one of the effective ways of prevention of gag reflex development in patients experiencing anxiety and fright before dental treatment. We are reporting a case where we could successfully eliminate exaggerated gag reflex (intravenous [IV] Gagging Severity Index) in a dental patient using IV sedation with dexmedetomidine. IV administration of dexmedetomidine provided elimination of gag reflex at a depth of sedation for the patient with the Richmond Agitation-Sedation Scale score of -2 and -1. The patient received dexmedetomidine 1.0 μg/kg for 10 min and then a continuous infusion of dexmedetomidine 0.4 μg/kg/h. The use of dexmedetomidine for sedation may be an alternative to other pharmacological agents in patients with dental anxiety accompanied by exaggerated gag reflex.

  8. Comparison of rescue techniques for failed chloral hydrate sedation for magnetic resonance imaging scans--additional chloral hydrate vs intranasal dexmedetomidine.

    PubMed

    Zhang, Wenhua; Wang, Zixin; Song, Xingrong; Fan, Yanting; Tian, Hang; Li, Bilian

    2016-03-01

    Chloral hydrate, a commonly used sedative in children during noninvasive diagnostic procedures, is associated with side effects like prolonged sedation, paradoxical excitement, delirium, and unpleasant taste. Dexmedetomidine, a highly selective α-2 agonist, has better pharmacokinetic properties than chloral hydrate. We conducted this prospective, double-blind, randomized controlled trial to evaluate efficacy of intranasal dexmedetomidine with that of a second oral dose of chloral hydrate for rescue sedation during magnetic resonance imaging (MRI) studies in infants. One hundred and fifty infants (age group: 1-6 months), who were not adequately sedated after initial oral dose of 50 mg · kg(-1) chloral hydrate, were randomly divided into three groups with the following protocol for each group. Group C: second oral dose chloral hydrate 25 mg · kg(-1); Group L and Group H: intranasal dexmedetomidine in a dosage of 1 and 2 mcg · kg(-1), respectively. Status of sedation, induction time, time to wake up, vital signs, oxygen saturation, and recovery characteristics were recorded. Successful rescue sedation in Groups C, L, and H were achieved in 40 (80%), 47 (94%), and 49 (98%) of infants, respectively, on an intention to treat analysis, and the proportion of infants successfully sedated in Group H was more than that of Group L (P ˂ 0.01). There were no significant differences in sedation induction time; however, the time to wake up was significantly shorter in Group L as compared to that in Group C or H (P < 0.01). No significant adverse hemodynamic or hypoxemic effects were observed in the study. Intranasal dexmedetomidine induced satisfactory rescue sedation in 1- to 6-month-old infants during MRI study, and appears to cause sedation in a dose-dependent manner. © 2015 John Wiley & Sons Ltd.

  9. β-Adrenoceptor-Mediated Relaxation of Carbachol-Pre-Contracted Mouse Detrusor.

    PubMed

    Propping, Stefan; Newe, Manja; Lorenz, Kristina; Wirth, Manfred P; Ravens, Ursula

    2015-01-01

    To study the β-adrenoceptor subtypes involved in the relaxation responses to (-)-isoprenaline in carbachol-pre-contracted (CCh) mouse detrusor muscle with intact and denuded mucosa. Isolated muscle strips from the urinary bladder of male C57BL6 mice or β2-adrenoceptor knockout mice were pre-contracted with CCh, 1 µM and relaxed with increasing concentrations of the β-adrenoceptor (β-AR) agonist (-)-isoprenaline and forskolin. For estimating the β-AR subtypes involved, subtype-selective receptor blockers were used, that is, CGP 20712A (β1-ARs), ICI 118,551 (β2-ARs), and L748,337 (β3-ARs). Unlike in KCl-pre-contracted muscle, the mucosa did not affect the sensitivity of the relaxation response to (-)-isoprenaline in CCh-pre-contracted murine detrusor strips. Increasing concentrations of (-)-isoprenaline produced a biphasic concentration-relaxation response without any difference both during the presence and absence of mucosa. The relaxation fraction produced by low (-)-isoprenaline concentrations was mediated by β2-AR as evidenced by a shift of the concentration-response curve to higher concentrations with ICI 118,551, but not with CGP 20712A and L748,337, and by the absence of this fraction in β2-AR-KO mice. The relaxation response with low sensitivity to (-)-isoprenaline was not affected by any of the β-AR subtype-selective blockers and was the only response detected in detrusor strips from β2-AR-KO mice. In CCh-pre-contracted mouse detrusor, β2-ARs are responsible for the relaxation component with high sensitivity to (-)-isoprenaline as indicated by the conversion of a biphasic into a monophasic CRC with ICI 118,551 or by its absence in β2-AR KO mice. The mucosa does not impair relaxation under these conditions. © 2015 S. Karger AG, Basel.

  10. Mathematical modeling physiological effects of the overexpression of β2-adrenoceptors in mouse ventricular myocytes.

    PubMed

    Rozier, Kelvin; Bondarenko, Vladimir E

    2018-03-01

    Transgenic (TG) mice overexpressing β 2 -adrenergic receptors (β 2 -ARs) demonstrate enhanced myocardial function, which manifests in increased basal adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo. To gain insights into the mechanisms of these effects, we developed a comprehensive mathematical model of the mouse ventricular myocyte overexpressing β 2 -ARs. We found that most of the β 2 -ARs are active in control conditions in TG mice. The simulations describe the dynamics of major signaling molecules in different subcellular compartments, increased basal adenylyl cyclase activity, modifications of action potential shape and duration, and the effects on L-type Ca 2+ current and intracellular Ca 2+ concentration ([Ca 2+ ] i ) transients upon stimulation of β 2 -ARs in control, after the application of pertussis toxin, upon stimulation with a specific β 2 -AR agonist zinterol, and upon stimulation with zinterol in the presence of pertussis toxin. The model also describes the effects of the β 2 -AR inverse agonist ICI-118,551 on adenylyl cyclase activity, action potential, and [Ca 2+ ] i transients. The simulation results were compared with experimental data obtained in ventricular myocytes from TG mice overexpressing β 2 -ARs and with simulation data on wild-type mice. In conclusion, a new comprehensive mathematical model was developed that describes multiple experimental data on TG mice overexpressing β 2 -ARs and can be used to test numerous hypotheses. As an example, using the developed model, we proved the hypothesis of the major contribution of L-type Ca 2+ current to the changes in the action potential and [Ca 2+ ] i transient upon stimulation of β 2 -ARs with zinterol. NEW & NOTEWORTHY We developed a new mathematical model for transgenic mouse ventricular myocytes overexpressing β 2 -adrenoceptors that describes the experimental findings in transgenic mice. The model reveals mechanisms of the

  11. Dexmedetomidine-induced sedation does not mimic the neurobehavioral phenotypes of sleep in Sprague Dawley rat.

    PubMed

    Garrity, Abigail G; Botta, Simhadri; Lazar, Stephanie B; Swor, Erin; Vanini, Giancarlo; Baghdoyan, Helen A; Lydic, Ralph

    2015-01-01

    Dexmedetomidine is used clinically to induce states of sedation that have been described as homologous to nonrapid eye movement (NREM) sleep. A better understanding of the similarities and differences between NREM sleep and dexmedetomidine-induced sedation is essential for efforts to clarify the relationship between these two states. This study tested the hypothesis that dexmedetomidine-induced sedation is homologous to sleep. This study used between-groups and within-groups designs. University of Michigan. Adult male Sprague Dawley rats (n = 40). Independent variables were administration of dexmedetomidine and saline or Ringer's solution (control). Dependent variables included time spent in states of wakefulness, sleep, and sedation, electroencephalographic (EEG) power, adenosine levels in the substantia innominata (SI), and activation of pCREB and c-Fos in sleep related forebrain regions. Dexmedetomidine significantly decreased time spent in wakefulness (-49%), increased duration of sedation (1995%), increased EEG delta power (546%), and eliminated the rapid eye movement (REM) phase of sleep for 16 h. Sedation was followed by a rebound increase in NREM and REM sleep. Systemically administered dexmedetomidine significantly decreased (-39%) SI adenosine levels. Dialysis delivery of dexmedetomidine into SI did not decrease adenosine level. Systemic delivery of dexmedetomidine did not alter c-Fos or pCREB expression in the horizontal diagonal band, or ventrolateral, median, and medial preoptic areas of the hypothalamus. Dexmedetomidine significantly altered normal sleep phenotypes, and the dexmedetomidine-induced state did not compensate for sleep need. Thus, in the Sprague Dawley rat, dexmedetomidine-induced sedation is characterized by behavioral, electrographic, and immunohistochemical phenotypes that are distinctly different from similar measures obtained during sleep. © 2014 Associated Professional Sleep Societies, LLC.

  12. Effect of Locally Administered Dexmedetomidine as Adjuvant to Levobupivacaine in Supraclavicular Brachial Plexus Block: Double-blind Controlled Study.

    PubMed

    Bisui, Bikash; Samanta, Swastika; Ghoshmaulik, Sumanta; Banerjee, Amit; Ghosh, Tirtha R; Sarkar, Suman

    2017-01-01

    Brachial plexus block is effective with good postoperative analgesia in upper limb surgery has gained importance as it safe, low cost, and maintains stable hemodynamics intraoperatively. To decrease the onset time and prolong the duration of nerve block bicarbonate, opioids (morphine, fentanyl, etc.), sympathomimetic agents (epinephrine, phenylephrine, etc.), α-2 agonists (clonidine and dexmedetomidine), calcium channel blocker (verapamil), magnesium sulfate, etc., were studied with local anesthetics and their isomers. For their sedative, analgesic, perioperative sympatholytic, and cardiovascular stabilizing effects with reduced anesthetic requirements, α-2 adrenergic receptor agonists, such as more potent and highly selective dexmedetomidine, have been the focus of interest for regional anesthesia. Intravenous dexmedetomidine infusion resulted in significant opioid-sparing effects as well as a decrease in inhalational anesthetic requirements. Animal studies proved that dexmedetomidine enhances sensory and motor blockade along with increased duration of analgesia. In humans, dexmedetomidine has also shown to prolong the duration of block and postoperative analgesia when added to local anesthetic in various regional blocks. Bupivacaine, the widely used local anesthetic in regional anesthesia, is available in a commercial preparation as a racemic mixture (50:50) of its two enantiomers: levobupivacaine, S (-) isomer and dextrobupivacaine, R (+) isomer. Severe central nervous system and cardiovascular adverse reactions reported in the literature after inadvertent intravascular injection or intravenous regional anesthesia have been linked to the R (+) isomer of bupivacaine. The levorotatory isomers were shown to have a safer pharmacological profile with less cardiac and neurotoxic adverse effects. The decreased toxicity of levobupivacaine is attributed to its faster protein binding rate. The pure S (-) enantiomers of bupivacaine, i.e., ropivacaine and levobupivacaine

  13. Thermal antinociception after dexmedetomidine administration in cats: a dose-finding study.

    PubMed

    Slingsby, L S; Taylor, P M

    2008-04-01

    The optimum dose of dexmedetomidine for antinociception to a thermal stimulus was determined in a crossover study of 12 cats. In five treatment groups (n = 10 per group), dexmedetomidine was administered intramuscularly (i.m.) at 2, 5, 10, 20 and 40 microg/kg; positive and negative controls were administered buprenorphine (20 microg/kg, i.m.) and 0.9% saline (0.006 mL/kg, i.m.) respectively. Baseline thermal thresholds and visual analogue scale (VAS) sedation scores were obtained prior to drug treatment and then at regular intervals until 24 h after administration. The summary measures of overall mean thresholds and overall mean VAS scores were investigated using a univariate general linear model for multiple factors with post hoc Tukey's tests (P < 0.05). Only dexmedetomidine at 40 microg/kg displayed an analgesic effect (less than that of buprenorphine). The VAS for sedation did not significantly affect the thresholds obtained and treatment was the only significant factor to influence VAS. Dexmedetomidine resulted in higher VAS for sedation than saline and buprenorphine. Dexmedetomidine at 40 microg/kg significantly increased nociceptive thresholds compared with saline control, but less than buprenorphine. Dexmedetomidine produced dose-dependent sedation, but only the highest dose produced analgesia, suggesting that induction of analgesia requires the highest dose (or an additional analgesic) in the clinical setting.

  14. Nitric oxide donor beta2-agonists: furoxan derivatives containing the fenoterol moiety and related furazans.

    PubMed

    Buonsanti, M Federica; Bertinaria, Massimo; Stilo, Antonella Di; Cena, Clara; Fruttero, Roberta; Gasco, Alberto

    2007-10-04

    The structure of fenoterol, a beta2-adrenoceptor agonist used in therapy, has been joined with furoxan NO-donor moieties to give new NO-donor beta2-agonists. The furazan analogues, devoid of the property to release NO, were also synthesized for comparison. All the compounds retained beta2-agonistic activity at micromolar or submicromolar concentration when tested on guinea pig tracheal rings precontracted with carbachol. Among the furoxan derivatives, the NO contribution to trachea relaxation was evident with product 15b at micromolar concentrations. All the new NO-donor hybrids were able to dilate rat aortic strips precontracted with phenylephrine. Both furoxan and furazan derivatives displayed antioxidant activity greater than that of fenoterol.

  15. Effect of Two Different Doses of Dexmedetomidine as Adjuvant in Bupivacaine Induced Subarachnoid Block for Elective Abdominal Hysterectomy Operations: A Prospective, Double-blind, Randomized Controlled Study

    PubMed Central

    Das, Anjan; Halder, Susanta; Chattopadhyay, Surajit; Mandal, Parthajit; Chhaule, Subinay; Banu, Rezina

    2015-01-01

    Objectives Improvements in perioperative pain management for lower abdominal operations has been shown to reduce morbidity, induce early ambulation, and improve patients’ long-term outcomes. Dexmedetomidine, a selective alpha-2 agonist, has recently been used intrathecally as adjuvant to spinal anesthesia to prolong its efficacy. We compared two different doses of dexmedetomidine added to hyperbaric bupivacaine for spinal anesthesia. The primary endpoints were the onset and duration of sensory and motor block, and duration of analgesia.   Methods A total of 100 patients, aged 35–60 years old, assigned to have elective abdominal hysterectomy under spinal anesthesia were divided into two equally sized groups (D5 and D10) in a randomized, double-blind fashion. The D5 group was intrathecally administered 3ml 0.5% hyperbaric bupivacaine with 5µg dexmedetomidine in 0.5ml of normal saline and the D10 group 3ml 0.5% bupivacaine with 10µg dexmedetomidine in 0.5ml of normal saline. For each patient, sensory and motor block onset times, block durations, time to first analgesic use, total analgesic need, postoperative visual analogue scale (VAS) scores, hemodynamics, and side effects were recorded.   Results Although both groups had a similar demographic profile, sensory and motor block in the D10 group (p<0.050) was earlier than the D5 group. Sensory and motor block duration and time to first analgesic use were significantly longer and the need for rescue analgesics was lower in the D10 group than the D5 group. The 24-hour VAS score was significantly lower in the D10 group (p<0.050). Intergroup hemodynamics were comparable (p>0.050) without any appreciable side effects.   Conclusion Spinal dexmedetomidine increases the sensory and motor block duration and time to first analgesic use, and decreases analgesic consumption in a dose-dependent manner. PMID:26366259

  16. Evaluation of the effects of intra-arterial sugammadex and dexmedetomidine: an experimental study.

    PubMed

    Hancı, Volkan; Özbilgin, Şule; Özbal, Seda; Kamacı, Gonca; Ateş, Hasan; Boztaş, Nilay; Ergür, Bekir Uğur; Arıkanoğlu, Ahmet; Yılmaz, Osman; Yurtlu, Bülent Serhan

    2016-01-01

    Intra-arterial injection of medications may cause acute and severe ischemia and result in morbidity and mortality. There is no information in the literature evaluating the arterial endothelial effects of sugammadex and dexmedetomidine. The hypothesis of our study is that sugammadex and dexmedetomidine will cause histological changes in arterial endothelial structure when administered intra-arterially. Rabbits were randomly divided into 4 groups. Group Control (n=7); no intervention performed. Group Catheter (n=7); a cannula inserted in the central artery of the ear, no medication was administered. Group Sugammadex (n=7); rabbits were given 4mg/kg sugammadex into the central artery of the ear, and Group Dexmedetomidine (n=7); rabbits were given 1μg/kg dexmedetomidine into the central artery of the ear. After 72h, the ears were amputated and histologically investigated. There was no significant difference found between the control and catheter groups in histological scores. The endothelial damage, elastic membrane and elastic fiber damage, smooth muscle hypertrophy and connective tissue increase scores in the dexmedetomidine and sugammadex groups were significantly higher than both the control and the catheter groups (p<0.05). There was no significant difference found between the dexmedetomidine and sugammadex groups in histological scores. Administration of sugammadex and dexmedetomidine to rabbits by intra-arterial routes caused histological arterial damage. To understand the histological changes caused by sugammadex and dexmedetomidine more clearly, more experimental research is needed. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

  17. [Evaluation of the effects of intra-arterial sugammadex and dexmedetomidine: an experimental study].

    PubMed

    Hancı, Volkan; Özbilgin, Şule; Özbal, Seda; Kamacı, Gonca; Ateş, Hasan; Boztaş, Nilay; Ergür, Bekir Uğur; Arıkanoğlu, Ahmet; Yılmaz, Osman; Yurtlu, Bülent Serhan

    2016-01-01

    Intra-arterial injection of medications may cause acute and severe ischemia and result in morbidity and mortality. There is no information in the literature evaluating the arterial endothelial effects of sugammadex and dexmedetomidine. The hypothesis of our study is that sugammadex and dexmedetomidine will cause histological changes in arterial endothelial structure when administered intra-arterially. Rabbits were randomly divided into 4 groups. Group Control (n=7); no intervention performed. Group Catheter (n=7); a cannula inserted in the central artery of the ear, no medication was administered. Group Sugammadex (n=7); rabbits were given 4mg/kg sugammadex into the central artery of the ear, and Group Dexmedetomidine (n=7); rabbits were given 1μg/kg dexmedetomidine into the central artery of the ear. After 72h, the ears were amputated and histologically investigated. There was no significant difference found between the control and catheter groups in histological scores. The endothelial damage, elastic membrane and elastic fiber damage, smooth muscle hypertrophy and connective tissue increase scores in the dexmedetomidine and sugammadex groups were significantly higher than both the control and the catheter groups (p<0.05). There was no significant difference found between the dexmedetomidine and sugammadex groups in histological scores. Administration of sugammadex and dexmedetomidine to rabbits by intra-arterial routes caused histological arterial damage. To understand the histological changes caused by sugammadex and dexmedetomidine more clearly, more experimental research is needed. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  18. Blunted beta-adrenoceptor-mediated fat oxidation in overweight subjects: a role for the hormone-sensitive lipase gene.

    PubMed

    Jocken, Johan W E; Blaak, Ellen E; van der Kallen, Carla J H; van Baak, Marleen A; Saris, Wim H M

    2008-03-01

    Obesity is associated with blunted beta-adrenoceptor-mediated lipolysis and fat oxidation, which persist after weight reduction. We investigated whether dinucleotide (CA)(n) repeat polymorphisms in intron 6 (i6) or 7 (i7) and a C-60G promoter substitution of the hormone-sensitive lipase (HSL) gene are associated with a blunted in vivo beta-adrenoceptor-mediated increase in circulating fatty acids and glycerol (estimation of lipolytic response) and fat oxidation in overweight-obese subjects. A total of 103 overweight (25 kg/m(2) < or = body mass index < 30 kg/m(2)) and obese (body mass index > or =30 kg/m(2)) subjects (62 men, 41 women) were included. Energy expenditure, respiratory quotient (RQ), and circulating fatty acid and glycerol were determined after stepwise infusion of increasing doses of the nonselective beta-agonist isoprenaline. The i6, i7 (CA)(n) repeat polymorphisms were determined by size-resolved capillary electrophoresis; and a C-60G promoter substitution was determined by restriction enzyme digestion assay. Female noncarriers of allele 184 i7 (n = 18) and female carriers of allele 240 i6 (n = 12) showed an overall reduced fat oxidation (as indicated by changes in RQ) after beta-adrenoceptor-mediated stimulation, explaining, respectively, 6.9% and 20.8% of the variance in RQ. These effects were not seen in male subjects. In conclusion, our results suggest that variation in i7 and i6 of the HSL gene might be associated with a physiological effect on in vivo beta-adrenoceptor-mediated fat oxidation, at least in overweight-obese female subjects.

  19. Prevention of neutrophil extravasation by α2-adrenoceptor-mediated endothelial stabilization.

    PubMed

    Herrera-García, Ada María; Domínguez-Luis, María Jesús; Arce-Franco, María; Armas-González, Estefanía; Álvarez de La Rosa, Diego; Machado, José David; Pec, Martina K; Feria, Manuel; Barreiro, Olga; Sánchez-Madrid, Francisco; Díaz-González, Federico

    2014-09-15

    Adrenergic receptors are expressed on the surface of inflammation-mediating cells, but their potential role in the regulation of the inflammatory response is still poorly understood. The objectives of this work were to study the effects of α2-adrenergic agonists on the inflammatory response in vivo and to determine their mechanism of action. In two mouse models of inflammation, zymosan air pouch and thioglycolate-induced peritonitis models, the i.m. treatment with xylazine or UK14304, two α2-adrenergic agonists, reduced neutrophil migration by 60%. The α2-adrenergic antagonist RX821002 abrogated this effect. In flow cytometry experiments, the basal surface expression of L-selectin and CD11b was modified neither in murine nor in human neutrophils upon α2-agonist treatment. Similar experiments in HUVEC showed that UK14304 prevented the activation-dependent upregulation of ICAM-1. In contrast, UK14304 augmented electrical resistance and reduced macromolecular transport through a confluent HUVEC monolayer. In flow chamber experiments, under postcapillary venule-like flow conditions, the pretreatment of HUVECs, but not neutrophils, with α2-agonists decreased transendothelial migration, without affecting neutrophil rolling. Interestingly, α2-agonists prevented the TNF-α-mediated decrease in expression of the adherens junctional molecules, VE-cadherin, β-catenin, and plakoglobin, and reduced the ICAM-1-mediated phosphorylation of VE-cadherin by immunofluorescence and confocal analysis and Western blot analysis, respectively. These findings indicate that α2-adrenoceptors trigger signals that protect the integrity of endothelial adherens junctions during the inflammatory response, thus pointing at the vascular endothelium as a therapeutic target for the management of inflammatory processes in humans. Copyright © 2014 by The American Association of Immunologists, Inc.

  20. α1-Adrenoceptors in the hippocampal dentate gyrus involved in learning-dependent long-term potentiation during active-avoidance learning in rats.

    PubMed

    Lv, Jing; Zhan, Su-Yang; Li, Guang-Xie; Wang, Dan; Li, Ying-Shun; Jin, Qing-Hua

    2016-11-09

    The hippocampus is the key structure for learning and memory in mammals and long-term potentiation (LTP) is an important cellular mechanism responsible for learning and memory. The influences of norepinephrine (NE) on the modulation of learning and memory, as well as LTP, through β-adrenoceptors are well documented, whereas the role of α1-adrenoceptors in learning-dependent LTP is not yet clear. In the present study, we measured extracellular concentrations of NE in the hippocampal dentate gyrus (DG) region using an in-vivo brain microdialysis and high-performance liquid chromatography techniques during the acquisition and extinction of active-avoidance behavior in freely moving conscious rats. Next, the effects of prazosin (an antagonist of α1-adrenoceptor) and phenylephrine (an agonist of the α1-adrenoceptor) on amplitudes of field excitatory postsynaptic potential were measured in the DG region during the active-avoidance behavior. Our results showed that the extracellular concentration of NE in the DG was significantly increased during the acquisition of active-avoidance behavior and gradually returned to the baseline level following extinction training. A local microinjection of prazosin into the DG significantly accelerated the acquisition of the active-avoidance behavior, whereas a local microinjection of phenylephrine retarded the acquisition of the active-avoidance behavior. Furthermore, in all groups, the changes in field excitatory postsynaptic potential amplitude were accompanied by corresponding changes in active-avoidance behavior. Our results suggest that NE activation of α1-adrenoceptors in the hippocampal DG inhibits active-avoidance learning by modulation of synaptic efficiency in rats.

  1. Comparison of Local Wound Infiltration with Ropivacaine Alone or Ropivacaine Plus Dexmedetomidine for Postoperative Pain Relief after Lower Segment Cesarean Section.

    PubMed

    Bhardwaj, Shaman; Devgan, Sumeet; Sood, Dinesh; Katyal, Sunil

    2017-01-01

    Dexmedetomidine, α 2 -adrenergic agonist, when coadministered with local anesthetics, improves the speed of onset, duration of analgesia and decreases the dose of local anesthetic used. The aim of this study was to compare the efficacy of local subcutaneous wound infiltration of ropivacaine alone with ropivacaine plus dexmedetomidine for postoperative pain relief following lower segment cesarean section (LSCS). The study was a prospective, randomized control, double-blind study. Sixty female patients belonging to physical status American Society of Anesthesiologists Grade I or II scheduled for LSCS under spinal anesthesia were randomly allocated into two groups of thirty patients each. Group A: local subcutaneous wound infiltration of 0.75% ropivacaine (3 mg/kg) diluted with normal saline to 40 ml. Group B: local subcutaneous wound infiltration of 0.75% ropivacaine (3 mg/kg) plus dexmedetomidine (1.5 μg/kg) of the body weight diluted with normal saline to 40 ml. Standard spinal anesthesia technique was used and LSCS was conducted. The allocated drug was administered by local subcutaneous wound infiltration before closure of the skin. In postoperative period, pain was assessed using visual analog scale (VAS) over a period of 24 h, time of giving first rescue analgesic consumption, mean analgesic consumption, patient satisfaction, and incidence of side effects in 24 h postoperative period was noted. All observations were tabulated and statistically analyzed using Chi-square test and unpaired t -test. A total number of patients requiring rescue analgesic, mean VAS each time rescue analgesic was given, and the mean analgesic required in 24 h postoperative period was lesser in Group B than in Group A. Dexmedetomidine added to ropivacaine for the surgical wound infiltration significantly reduces postoperative pain and rescue analgesic consumption in patients undergoing LSCS. No serious adverse effects were noted.

  2. Physiological and biochemical variables in captive tigers (Panthera tigris) immobilised with dexmedetomidine and ketamine or dexmedetomidine, midazolam and ketamine.

    PubMed

    Clark-Price, S C; Lascola, K M; Schaeffer, D J

    2015-12-05

    Physiological and biochemical variables in captive tigers (Panthera tigris) immobilised with dexmedetomidine and ketamine or dexmedetomidine, midazolam and ketamine were evaluated. Thirty tigers received either dexmedetomidine (0.025 mg/kg) and ketamine (3 mg/kg) (group DK) or dexmedetomidine (0.0125 mg/kg), midazolam (0.1 mg/kg) and ketamine (3 mg/kg) (group DMK). Heart rate, SPO2 and blood pressure were measured at five-minute intervals. Arterial pH, PO2, PCO2, glucose, K+ and arterial and venous lactate were measured at 15 and 45 minutes after immobilisation. A generalised linear mixed model was used for statistical comparison. There was no difference within or between groups at any time point for any measured variable. Measured PO2 was 73.2±17.5 mm Hg and SPO2 was 88.9±10.8 per cent. Systolic, mean and diastolic blood pressures were 170.5±48.4, 138.9±41.8 and 121.8±37.2 mm Hg, respectively. Venous lactate was higher than arterial lactate within groups at each time point. Seizure-like behaviour was observed in 25 per cent of tigers in group DK but not in group DMK. The addition of midazolam into a protocol for immobilisation of tigers did not result in a difference in any of the measured variables but may have prevented the development of seizure-like behaviour. British Veterinary Association.

  3. Inhibition of agonist-induced smooth muscle contraction by picotamide in the male human lower urinary tract outflow region.

    PubMed

    Hennenberg, Martin; Tamalunas, Alexander; Wang, Yiming; Keller, Patrick; Schott, Melanie; Strittmatter, Frank; Herlemann, Annika; Yu, Qingfeng; Rutz, Beata; Ciotkowska, Anna; Stief, Christian G; Gratzke, Christian

    2017-05-15

    Male lower urinary tract symptoms (LUTS) due to bladder outlet obstruction are characterized by abnormal smooth muscle contractions in the lower urinary tract. Alpha 1 -adrenoceptor antagonists may induce smooth muscle relaxation in the outflow region and represent the current gold standard of medical treatment. However, results may be unsatisfactory or inadequate. Apart from α 1 -adrenoceptor agonists, smooth muscle contraction in the outflow region may be induced by thromboxane A 2 (TXA 2 ), endothelins, or muscarinic receptor agonists. Here, we studied effects of the thromboxane A 2 receptor (TP receptor) antagonist picotamide on contraction in the human male bladder trigone and prostate. Carbachol, the α 1 -adrenoceptor agonist phenylephrine, the thromboxane A 2 analog U46619, and electric field stimulation (EFS) induced concentration- or frequency-dependent contractions of trigone tissues in an organ bath. Picotamide (300µM) inhibited carbachol-, phenylephrine-, U46619-, and EFS-induced contractions. Endothelins 1-3 induced concentration-dependent contractions of prostate tissues, which were inhibited by picotamide. Analyses using real time polymerase chain reaction and antibodies suggested expression of thromboxane A 2 receptors and synthase in trigone smooth muscle cells. Thromboxane B 2 (the stable metabolite of thromboxane A 2 ) was detectable by enzyme immune assay in trigone samples, with most values ranging between 50 and 150pg/mg trigone protein. Picotamide inhibits contractions induced by different stimuli in the human lower urinary tract, including cholinergic, adrenergic, thromboxane A 2 - and endothelin-induced, and neurogenic contractions in different locations of the outflow region. This distinguishes picotamide from current medical treatments for LUTS, and suggests that picotamide may induce urodynamic effects in vivo. Copyright © 2017. Published by Elsevier B.V.

  4. Dexmedetomidine in the Supratentorial Craniotomy

    PubMed Central

    Ilhan, Osman; Koruk, Senem; Serin, Gokcen; Erkutlu, Ibrahim; Oner, Unsal

    2010-01-01

    Objective: In this double-blind prospective clinical study, we investigated the effects of fentanyl and dexmedetomidine as adjuvant agents in supratentorial craniotomies on the following: hemodynamic changes during perioperative and recovery periods, brain edema perioperatively, recovery times and side effects, such as hypertension, shivering, nausea and vomiting. Materials and Methods: Thirty consenting ASA physical status I–II patients undergoing intracranial tumor surgery were randomly divided in two groups. In group D (n=15), dexmedetomidine was infused as a 1 μg/kg bolus dose 10 minutes before induction of anesthesia and maintained with 0.4–0.5 μg/kg/min during the operation. In group F (n=15), animals were given fentanyl 0.02 μg/kg/min as an infusion for anesthesia maintenance. At induction, fentanyl was given as a 2 μg/kg dose in group D and as a 4 μg/kg dose in group F. Hemodynamic changes, recovery times and postoperative side effects were recorded before induction, during the perioperative period and 24 hours postoperatively. Results: In group D; MAP and HR values after intubation, after skull clamp insertion and after extubation were lower than in group F (p<0.05). In group D, cerebral relaxation scores were also significantly lower. Recovery times were found to be shorter in group D as compared to group F; the same trend was observed for the supplemental opioid requirement. During the postoperative period, there was no shivering, nausea or vomiting in group D, but in group F, 3 patients complained of shivering, and 2 patients experienced nausea and vomiting. Conclusion: In our study, we found that dexmedetomidine controlled the hemodynamic changes better than fentanyl perioperatively, after extubation and during the early postoperative period. Our results suggest that that dexmedetomidine is safer and more effective in controlling hemodynamic changes during surgical stimulation than the standard agents used in neuroanesthesia. PMID:25610125

  5. Comparative Evaluation of Partial α2 -Adrenoceptor Agonist and Pure α2 -Adrenoceptor Antagonist on the Behavioural Symptoms of Withdrawal after Chronic Alcohol Administration in Mice.

    PubMed

    Arora, Shivani; Vohora, Divya

    2016-08-01

    As an addictive drug, alcohol produces withdrawal symptoms if discontinued abruptly after chronic use. Clonidine (CLN), a partial α2 -adrenergic agonist, and mirtazapine (MRT), an antagonist of α2 -adrenoceptor, both clinically aid alcohol withdrawal. Considering different mechanisms of action of the two drugs, this study was designed to see how far these two mechanistically different drugs differ in their ability to decrease the severity of ethanol withdrawal syndrome. The effect of CLN and MRT on ethanol withdrawal-induced anxiety, depression and memory impairment was analysed using EPM, FST and PAR tests, respectively. Animals received distilled water, ethanol and/or either of the drugs (CLN and MRT) in different doses. Relapse to alcohol use was analysed by CPP test. Animals received ethanol as a conditioning drug and distilled water, CLN or MRT as test drug. CLN and MRT both alleviated anxiety in a dose-dependent manner. MRT (4 mg/kg) was more effective than CLN (0.1 mg/kg) in ameliorating the anxiogenic effect of alcohol withdrawal. However, CLN treatment increased depression. It significantly decreased swimming time and increased immobility time, whereas MRT treatment decreased immobility time and increased climbing and swimming time during abstinence. The effect was dose dependent for both drugs. The results of PAR test show that CLN treatment worsens working memory. Significant increase in SDE and TSZ and decrease in SDL were observed in CLN-treated animals. MRT treatment, on the other hand, improved working memory at both doses. Further, both CLN and MRT alleviated craving. A significant decrease in time spent in the ethanol-paired chamber was seen. MRT treatment at both doses showed better effect than CLN in preventing the development of preference in CPP test. These findings indicate a potential therapeutic use and better profile of mirtazapine over clonidine in improving memory, as well as in alleviating depression, anxiety and craving associated

  6. [Upper airway morphology in Down Syndrome patients under dexmedetomidine sedation].

    PubMed

    Subramanyam, Rajeev; Fleck, Robert; McAuliffe, John; Radhakrishnan, Rupa; Jung, Dorothy; Patino, Mario; Mahmoud, Mohamed

    2016-01-01

    Children with Down Syndrome are vulnerable to significant upper airway obstruction due to relative macroglossia and dynamic airway collapse. The objective of this study was to compare the upper airway dimensions of children with Down Syndrome and obstructive sleep apnea with normal airway under dexmedetomidine sedation. IRB approval was obtained. In this retrospective study, clinically indicated dynamic sagittal midline magnetic resonance images of the upper airway were obtained under low (1mcg/kg/h) and high (3mcg/kg/h) dose dexmedetomidine. Airway anteroposterior diameters and sectional areas were measured as minimum and maximum dimensions by two independent observers at soft palate (nasopharyngeal airway) and at base of the tongue (retroglossal airway). Minimum anteroposterior diameter and minimum sectional area at nasopharynx and retroglossal airway were significantly reduced in Down Syndrome compared to normal airway at both low and high dose dexmedetomidine. However, there were no significant differences between low and high dose dexmedetomidine in both Down Syndrome and normal airway. The mean apnea hypopnea index in Down Syndrome was 16±11. Under dexmedetomidine sedation, children with Down Syndrome and obstructive sleep apnea when compared to normal airway children show significant reductions in airway dimensions most pronounced at the narrowest points in the nasopharyngeal and retroglossal airways. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  7. Upper airway morphology in Down Syndrome patients under dexmedetomidine sedation.

    PubMed

    Subramanyam, Rajeev; Fleck, Robert; McAuliffe, John; Radhakrishnan, Rupa; Jung, Dorothy; Patino, Mario; Mahmoud, Mohamed

    2016-01-01

    Children with Down Syndrome are vulnerable to significant upper airway obstruction due to relative macroglossia and dynamic airway collapse. The objective of this study was to compare the upper airway dimensions of children with Down Syndrome and obstructive sleep apnea with normal airway under dexmedetomidine sedation. IRB approval was obtained. In this retrospective study, clinically indicated dynamic sagittal midline magnetic resonance images of the upper airway were obtained under low (1mcg/kg/h) and high (3mcg/kg/h) dose dexmedetomidine. Airway anteroposterior diameters and sectional areas were measured as minimum and maximum dimensions by two independent observers at soft palate (nasopharyngeal airway) and at base of the tongue (retroglossal airway). Minimum anteroposterior diameter and minimum sectional area at nasopharynx and retroglossal airway were significantly reduced in Down Syndrome compared to normal airway at both low and high dose dexmedetomidine. However, there were no significant differences between low and high dose dexmedetomidine in both Down Syndrome and normal airway. The mean apnea hypopnea index in Down Syndrome was 16±11. Under dexmedetomidine sedation, children with Down Syndrome and obstructive sleep apnea when compared to normal airway children show significant reductions in airway dimensions most pronounced at the narrowest points in the nasopharyngeal and retroglossal airways. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.

  8. COMPARISON OF TWO α2-ADRENERGIC AGONISTS ON URINE CONTAMINATION OF SEMEN COLLECTED BY ELECTROEJACULATION IN CAPTIVE AND SEMI-FREE-RANGING CHEETAH (ACINONYX JUBATUS).

    PubMed

    Marrow, Judilee C; Woc-Colburn, Margarita; Hayek, Lee-Ann C; Marker, Laurie; Murray, Suzan

    2015-06-01

    Alpha2-adrenergic agonists are used to immobilize many veterinary species, but use has been infrequently linked to urine contamination of semen collected via electroejaculation. The objective of the study was to compare the α2-agonists medetomidine and dexmedetomidine on urine contamination of semen in anesthetized cheetahs (Acinonyx jubatus) during electroejaculation procedures. From 2009-2012, a retrospective medical record review revealed 21 anesthesia events in 12 adult male cheetahs. Animals were immobilized with combinations of Telazol® (2.33±0.43 mg/kg) and ketamine (2.38±1 mg/kg); Telazol (1.17±0.14 mg/kg), ketamine (1.17±0.14 mg/kg), and medetomidine (0.012±0.0017 mg/kg); or Telazol (1.59±0.1 mg/kg), ketamine (1.59±0.1 mg/kg) and dexmedetomidine (0.01±0.001 mg/kg). Semen was successfully collected in all animals; four animals anesthetized with medetomidine had urine contamination (P=0.037). Medetomidine may contribute to urine contamination; however, further investigation is needed to determine significance in cheetahs.

  9. Additive anticonvulsant effects of agmatine and lithium chloride on pentylenetetrazole-induced clonic seizure in mice: involvement of α₂-adrenoceptor.

    PubMed

    Bahremand, Arash; Ziai, Pouya; Payandemehr, Borna; Rahimian, Reza; Amouzegar, Afsaneh; Khezrian, Mina; Montaser-Kouhsari, Laleh; Meibodi, Maryam Aghaei; Ebrahimi, Ali; Ghasemi, Abbas; Ghasemi, Mehdi; Dehpour, Ahmad Reza

    2011-09-01

    After 60 years, lithium is still the mainstay in the treatment of mood disorders and widely used in clinic. In addition to its mood stabilizer effects, lithium also shows some anticonvulsant properties. Similar to lithium, agmatine also plays a protective role in the CNS against seizures and has been reported to enhance the effect of different antiepileptic agents. Moreover, both agmatine and lithium have modulatory effects on α(2)-adrenoceptors. So, we designed this study: 1) to investigate whether agmatine and lithium show an additive effect against clonic seizures induced by pentylenetetrazole; 2) to assess whether this additive effect is mediated through the α(2)-adrenoceptor or not. In our study, acute administration of a single effective dose of lithium chloride (30 mg/kg, i.p.) increased the seizure threshold. Pre-treatment with low and, per se, non-effective doses of agmatine (1 and 3mg/kg) potentiated a sub-effective dose of lithium (10mg/kg). Interestingly, the anticonvulsant effects of these effective combinations of lithium and agmatine were prevented by pre-treatment with low and non-effective doses of yohimbine [α(2)-adrenoceptor antagonist] (0.1 and 0.5mg/kg). On the other hand, clonidine [α(2)-adrenoceptor agonist] augmented the anticonvulsant effect of a sub-effective combination of lithium (5mg/kg i.p.) and agmatine (1mg/kg) at relatively low doses (0.1 and 0.25mg/kg). In summary, our findings demonstrate that agmatine and lithium chloride exhibit additive anticonvulsant properties which seem to be mediated through α(2)-adrenoceptor. Copyright © 2011. Published by Elsevier B.V.

  10. Wnt/β-catenin signaling modulates human airway sensitization induced by β2-adrenoceptor stimulation.

    PubMed

    Faisy, Christophe; Grassin-Delyle, Stanislas; Blouquit-Laye, Sabine; Brollo, Marion; Naline, Emmanuel; Chapelier, Alain; Devillier, Philippe

    2014-01-01

    Regular use of β2-agonists may enhance non-specific airway responsiveness. The wingless/integrated (Wnt) signaling pathways are responsible for several cellular processes, including airway inflammation and remodeling while cAMP-PKA cascade can activate the Wnt signaling. We aimed to investigate whether the Wnt signaling pathways are involved in the bronchial hyperresponsiveness induced by prolonged exposure to β2-adrenoceptor agonists in human isolated airways. Bronchi were surgically removed from 44 thoracic surgery patients. After preparation, bronchial rings and primary cultures of bronchial epithelial cells were incubated with fenoterol (0.1 µM, 15 hours, 37 °C), a β2-agonist with high intrinsic efficacy. The effects of inhibitors/blockers of Wnt signaling on the fenoterol-induced airway sensitization were examined and the impact of fenoterol exposure on the mRNA expression of genes interacting with Wnt signaling or cAMP-PKA cascade was assessed in complete bronchi and in cultured epithelial cells. Compared to paired controls, fenoterol-sensitization was abolished by inhibition/blockage of the Wnt/β-catenin signaling, especially the cell-surface LRP5/6 co-receptors or Fzd receptors (1 µM SFRP1 or 1 µM DKK1) and the nuclear recruitment of TCF/LEF transcriptions factors (0.3 µM FH535). Wnt proteins secretion did not seem to be involved in the fenoterol-induced sensitization since the mRNA expression of Wnt remained low after fenoterol exposure and the inactivator of Wnt secretion (1 µM IWP2) had no effect on the fenoterol-sensitization. Fenoterol exposure did not change the mRNA expression of genes regulating Wnt signaling or cAMP-PKA cascade. Collectively, our pharmacological investigations indicate that fenoterol-sensitization is modulated by the inhibition/blockage of canonical Wnt/β-catenin pathway, suggesting a phenomenon of biased agonism in connection with the β2-adrenoceptor stimulation. Future experiments based on the results of the present

  11. Comparison of dexmedetomidine versus propofol on hemodynamics in surgical critically ill patients.

    PubMed

    Chang, Ya-Fei; Chao, Anne; Shih, Po-Yuan; Hsu, Yen-Chun; Lee, Chen-Tse; Tien, Yu-Wen; Yeh, Yu-Chang; Chen, Lee-Wei

    2018-08-01

    Sedation with dexmedetomidine and propofol may cause hypotension or bradycardia. This study aimed to compare the effects of dexmedetomidine and propofol on hemodynamics and clinical outcomes in surgical intensive care unit (ICU) patients after major abdominal surgery. Enrolled patients were randomly allocated to the dexmedetomidine or propofol group. Cardiac index was measured using a continuous noninvasive cardiac output monitor on the basis of chest bioreactance. Heart rate, blood pressure, opioid requirement, urine output, delirium incidence, ICU length of stay, and total hospital length of stay were compared between the two groups. The incidences of bradycardia, hypotension, and severe low cardiac index were compared. We enrolled 60 patients. Heart rate and mean arterial pressure were significantly lower in the dexmedetomidine group than in the propofol group. Cardiac index did not differ significantly between the two groups (dexmedetomidine group 3.1 L/min/m 2 , [95% confidence interval {95% CI} 2.8-3.3] versus propofol group 3.2 L/min/m 2 [95% CI 2.9-3.5], P = 0.578). The incidences of bradycardia, hypotension, and severe low cardiac index did not differ significantly between the two groups. Cardiac index did not differ significantly between the dexmedetomidine and propofol groups in surgical ICU patients after major abdominal surgery. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Dexmedetomidine Disrupts the Local and Global Efficiencies of Large-scale Brain Networks.

    PubMed

    Hashmi, Javeria A; Loggia, Marco L; Khan, Sheraz; Gao, Lei; Kim, Jieun; Napadow, Vitaly; Brown, Emery N; Akeju, Oluwaseun

    2017-03-01

    A clear understanding of the neural basis of consciousness is fundamental to research in clinical and basic neuroscience disciplines and anesthesia. Recently, decreased efficiency of information integration was suggested as a core network feature of propofol-induced unconsciousness. However, it is unclear whether this finding can be generalized to dexmedetomidine, which has a different molecular target. Dexmedetomidine was administered as a 1-μg/kg bolus over 10 min, followed by a 0.7-μg · kg · h infusion to healthy human volunteers (age range, 18 to 36 yr; n = 15). Resting-state functional magnetic resonance imaging data were acquired during baseline, dexmedetomidine-induced altered arousal, and recovery states. Zero-lag correlations between resting-state functional magnetic resonance imaging signals extracted from 131 brain parcellations were used to construct weighted brain networks. Network efficiency, degree distribution, and node strength were computed using graph analysis. Parcellated brain regions were also mapped to known resting-state networks to study functional connectivity changes. Dexmedetomidine significantly reduced the local and global efficiencies of graph theory-derived networks. Dexmedetomidine also reduced the average brain connectivity strength without impairing the degree distribution. Functional connectivity within and between all resting-state networks was modulated by dexmedetomidine. Dexmedetomidine is associated with a significant drop in the capacity for efficient information transmission at both the local and global levels. These changes result from reductions in the strength of connectivity and also manifest as reduced within and between resting-state network connectivity. These findings strengthen the hypothesis that conscious processing relies on an efficient system of information transfer in the brain.

  13. Intranasal Dexmedetomidine for Procedural Sedation in Children, a Suitable Alternative to Chloral Hydrate.

    PubMed

    Cozzi, Giorgio; Norbedo, Stefania; Barbi, Egidio

    2017-04-01

    Sedation is often required for children undergoing diagnostic procedures. Chloral hydrate has been one of the sedative drugs most used in children over the last 3 decades, with supporting evidence for its efficacy and safety. Recently, chloral hydrate was banned in Italy and France, in consideration of evidence of its carcinogenicity and genotoxicity. Dexmedetomidine is a sedative with unique properties that has been increasingly used for procedural sedation in children. Several studies demonstrated its efficacy and safety for sedation in non-painful diagnostic procedures. Dexmedetomidine's impact on respiratory drive and airway patency and tone is much less when compared to the majority of other sedative agents. Administration via the intranasal route allows satisfactory procedural success rates. Studies that specifically compared intranasal dexmedetomidine and chloral hydrate for children undergoing non-painful procedures showed that dexmedetomidine was as effective as and safer than chloral hydrate. For these reasons, we suggest that intranasal dexmedetomidine could be a suitable alternative to chloral hydrate.

  14. Renal denervation improves cardiac function in rats with chronic heart failure: Effects on expression of β-adrenoceptors

    PubMed Central

    Zheng, Hong; Liu, Xuefei; Sharma, Neeru M.

    2016-01-01

    Chronic activation of the sympathetic drive contributes to cardiac remodeling and dysfunction during chronic heart failure (HF). The present study was undertaken to assess whether renal denervation (RDN) would abrogate the sympathoexcitation in HF and ameliorate the adrenergic dysfunction and cardiac damage. Ligation of the left coronary artery was used to induce HF in Sprague-Dawley rats. Four weeks after surgery, RDN was performed, 1 wk before the final measurements. At the end of the protocol, cardiac function was assessed by measuring ventricular hemodynamics. Rats with HF had an average infarct area >30% of the left ventricle and left ventricular end-diastolic pressure (LVEDP) >20 mmHg. β1- and β2-adrenoceptor proteins in the left ventricle were reduced by 37 and 49%, respectively, in the rats with HF. RDN lowered elevated levels of urinary excretion of norepinephrine and brain natriuretic peptide levels in the hearts of rats with HF. RDN also decreased LVEDP to 10 mmHg and improved basal dP/dt to within the normal range in rats with HF. RDN blunted loss of β1-adrenoceptor (by 47%) and β2-adrenoceptor (by 100%) protein expression and improved isoproterenol (0.5 μg/kg)-induced increase in +dP/dt (by 71%) and −dP/dt (by 62%) in rats with HF. RDN also attenuated the increase in collagen 1 expression in the left ventricles of rats with HF. These findings demonstrate that RDN initiated in chronic HF condition improves cardiac function mediated by adrenergic agonist and blunts β-adrenoceptor expression loss, providing mechanistic insights for RDN-induced improvements in cardiac function in the HF condition. PMID:27288440

  15. Association of a beta-2 adrenoceptor (ADRB2) gene variant with a blunted in vivo lipolysis and fat oxidation.

    PubMed

    Jocken, J W E; Blaak, E E; Schiffelers, S; Arner, P; van Baak, M A; Saris, W H M

    2007-05-01

    Obesity is associated with a blunted beta-adrenoceptor-mediated lipolysis and fat oxidation. We investigated whether polymorphisms in codon 16, 27 and 164 of the beta (2)-adrenoceptor gene (ADRB2) and exon 10 of the G protein beta (3)-subunit gene (GNB3) are associated with alterations in in vivo lipolysis and fat oxidation. Sixty-five male and 43 female overweight and obese subjects (body mass index (BMI) range: 26.1-48.4 kg/m(2)) were included. Energy expenditure (EE), respiratory quotient (RQ), circulating free fatty acid (FFA) and glycerol levels were determined after stepwise infusion of increasing doses of the non-selective beta-agonist isoprenaline (ISO). In women, the Arg16 allele of the ADRB2 gene was associated with a blunted increase in circulating FFA, glycerol and a decreased fat oxidation during ISO stimulation. In men, the Arg16 allele was significantly associated with a blunted increase in FFA but not in glycerol or fat oxidation. These results suggest that genetic variation in the ADRB2 gene is associated with disturbances in in vivo beta-adrenoceptor-mediated lipolysis and fat oxidation during beta-adrenergic stimulation in overweight and obese subjects; these effects are influenced by gene-gender interactions.

  16. Enzyme-inducing anticonvulsants increase plasma clearance of dexmedetomidine: a pharmacokinetic and pharmacodynamic study.

    PubMed

    Flexman, Alana M; Wong, Harvey; Riggs, K Wayne; Shih, Tina; Garcia, Paul A; Vacas, Susana; Talke, Pekka O

    2014-05-01

    Dexmedetomidine is useful during mapping of epileptic foci as it facilitates electrocorticography unlike most other anesthetic agents. Patients with seizure disorders taking enzyme-inducing anticonvulsants appear to be resistant to its sedative effects. The objective of the study was to compare the pharmacokinetic and pharmacodynamic profile of dexmedetomidine in healthy volunteers with volunteers with seizure disorders receiving enzyme-inducing anticonvulsant medications. Dexmedetomidine was administered using a step-wise, computer-controlled infusion to healthy volunteers (n = 8) and volunteers with seizure disorders (n = 8) taking phenytoin or carbamazapine. Sedation and dexmedetomidine plasma levels were assessed at baseline, during the infusion steps, and after discontinuation of the infusion. Sedation was assessed by using the Observer's Assessment of Alertness/Sedation Scale, Ramsay Sedation Scale, and Visual Analog Scale and processed electroencephalography (entropy) monitoring. Pharmacokinetic analysis was performed on both groups, and differences between groups were determined using the standard two-stage approach. A two-compartment model was fit to dexmedetomidine concentration-time data. Dexmedetomidine plasma clearance was 43% higher in the seizure group compared with the control group (42.7 vs. 29.9 l/h; P = 0.007). In contrast, distributional clearance and the volume of distribution of the central and peripheral compartments were similar between the groups. No difference in sedation was detected between the two groups during a controlled range of target plasma concentrations. This study demonstrates that subjects with seizure disorders taking enzyme-inducing anticonvulsant medications have an increased plasma clearance of dexmedetomidine as compared with healthy control subjects.

  17. Dexmedetomidine Increases Tau Phosphorylation Under Normothermic Conditions In Vivo and In Vitro

    PubMed Central

    Whittington, Robert A.; Virág, László; Gratuze, Maud; Petry, Franck R.; Noël, Anastasia; Poitras, Isabelle; Truchetti, Geoffrey; Marcouiller, François; Papon, Marie-Amélie; Khoury, Noura El; Wong, Kevin; Bretteville, Alexis; Morin, Françoise; Planel, Emmanuel

    2015-01-01

    There is developing interest in the potential association between anesthesia and the onset and progression of Alzheimer's disease. Several anesthetics have thus been demonstrated to induce tau hyperphosphorylation, an effect mostly mediated by anesthesia-induced hypothermia. Here, we tested the hypothesis that acute normothermic administration of dexmedetomidine, an intravenous sedative used in intensive care units, would result in tau hyperphosphorylation in vivo and in vitro. When administered to non-transgenic mice, dexmedetomidine induced tau hyperphosphorylation persisting up to 6h in the hippocampus for the AT8 epitope. Pretreatment with atipamezole, a highly specific α2-adrenergic receptor (α2-AR) antagonist, blocked dexmedetomidine-induced tau hyperphosphorylation. Furthermore, dexmedetomidine dose-dependently increased tau phosphorylation at AT8 in SH-SY5Y cells, impaired mice spatial memory in the Barnes maze, and promoted tau hyperphosphorylation and aggregation in transgenic hTau mice. These findings suggest that dexmedetomidine: i) increases tau phosphorylation, in vivo and in vitro, in the absence of anesthetic-induced hypothermia and through α2-AR activation, ii) promotes tau aggregation in a mouse model of tauopathy, and iii) impacts spatial reference memory. PMID:26058840

  18. Involvement of α₂-adrenoceptors, imidazoline, and endothelin-A receptors in the effect of agmatine on morphine and oxycodone-induced hypothermia in mice.

    PubMed

    Bhalla, Shaifali; Andurkar, Shridhar V; Gulati, Anil

    2013-10-01

    Potentiation of opioid analgesia by endothelin-A (ET(A)) receptor antagonist, BMS182874, and imidazoline receptor/α₂-adrenoceptor agonists such as clonidine and agmatine are well known. It is also known that agmatine blocks morphine hyperthermia in rats. However, the effect of agmatine on morphine or oxycodone hypothermia in mice is unknown. The present study was carried out to study the role of α₂-adrenoceptors, imidazoline, and ET(A) receptors in morphine and oxycodone hypothermia in mice. Body temperature was determined over 6 h in male Swiss Webster mice treated with morphine, oxycodone, agmatine, and combination of agmatine with morphine or oxycodone. Yohimbine, idazoxan, and BMS182874 were used to determine involvement of α₂-adrenoceptors, imidazoline, and ET(A) receptors, respectively. Morphine and oxycodone produced significant hypothermia that was not affected by α₂-adrenoceptor antagonist yohimbine, imidazoline receptor/α₂ adrenoceptor antagonist idazoxan, or ET(A) receptor antagonist, BMS182874. Agmatine did not produce hypothermia; however, it blocked oxycodone but not morphine-induced hypothermia. Agmatine-induced blockade of oxycodone hypothermia was inhibited by idazoxan and yohimbine. The blockade by idazoxan was more pronounced compared with yohimbine. Combined administration of BMS182874 and agmatine did not produce changes in body temperature in mice. However, when BMS182874 was administered along with agmatine and oxycodone, it blocked agmatine-induced reversal of oxycodone hypothermia. This is the first report demonstrating that agmatine does not affect morphine hypothermia in mice, but reverses oxycodone hypothermia. Imidazoline receptors and α₂-adrenoceptors are involved in agmatine-induced reversal of oxycodone hypothermia. Our findings also suggest that ET(A) receptors may be involved in blockade of oxycodone hypothermia by agmatine. © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de

  19. The involvement of peripheral alpha 2-adrenoceptors in the antihyperalgesic effect of oxcarbazepine in a rat model of inflammatory pain.

    PubMed

    Tomić, Maja A; Vucković, Sonja M; Stepanović-Petrović, Radica M; Ugresić, Nenad D; Paranos, Sonja Lj; Prostran, Milica S; Bosković, Bogdan

    2007-11-01

    We studied whether peripheral alpha2-adrenergic receptors are involved in the antihyperalgesic effects of oxcarbazepine by examining the effects of yohimbine (selective alpha2-adrenoceptor antagonist), BRL 44408 (selective alpha(2A)-adrenoceptor antagonist), MK-912 (selective alpha2C-adrenoceptor antagonist), and clonidine (alpha2-adrenoceptor agonist) on the antihyperalgesic effect of oxcarbazepine in the rat model of inflammatory pain. Rats were intraplantarly (i.pl.) injected with the proinflammatory compound concanavalin A (Con A). A paw-pressure test was used to determine: 1) the development of hyperalgesia induced by Con A; 2) the effects of oxcarbazepine (i.pl.) on Con A-induced hyperalgesia; and 3) the effects of i.pl. yohimbine, BRL 44408, MK-912 and clonidine on the oxcarbazepine antihyperalgesia. Both oxcarbazepine (1000-3000 nmol/paw; i.pl.) and clonidine (1.9-7.5 nmol/paw; i.pl.) produced a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by Con A. Yohimbine (260 and 520 nmol/paw; i.pl.), BRL 44408 (100 and 200 nmol/paw; i.pl.) and MK-912 (10 and 20 nmol/paw; i.pl.) significantly depressed the antihyperalgesic effects of oxcarbazepine (2000 nmol/paw; i.pl.) in a dose-dependent manner. The effects of antagonists were due to local effects since they were not observed after administration into the contralateral hindpaw. Oxcarbazepine and clonidine administered jointly in fixed-dose fractions of the ED(50) (1/4, 1/2, and 3/4) caused significant and dose-dependent reduction of hyperalgesia induced by Con A. Isobolographic analysis revealed an additive antihyperalgesic effect. Our results indicate that the peripheral alpha2A and alpha2C adrenoceptors could be involved in the antihyperalgesic effects of oxcarbazepine in a rat model of inflammatory hyperalgesia.

  20. Intrathecal dexmedetomidine as adjuvant for spinal anaesthesia for perianal ambulatory surgeries: A randomised double-blind controlled study.

    PubMed

    Nethra, S S; Sathesha, M; Dixit, Aanchal; Dongare, Pradeep A; Harsoor, S S; Devikarani, D

    2015-03-01

    The newer trend in regional anaesthesia for ambulatory anorectal surgeries advocate use of lower dose of local anaesthetic, providing segmental block with adjuvants such as opioids and α2 agonists to prolong analgesia. The current study investigated effects of addition of 5 μg of dexmedetomidine to 6 mg of hyperbaric bupivacaine on duration of analgesia, sensory and motor block characteristics for perianal ambulatory surgeries. This study is a prospective randomised controlled double blind study. Forty adult patients between 18 and 55 years of age were divided into 2 groups. Group D received intrathecal 0.5% hyperbaric bupivacaine 6 mg (1.2 ml) with injection dexmedetomidine 5 μg in 0.5 ml of normal saline and Group N received intrathecal 0.5% hyperbaric bupivacaine 6 mg (1.2 ml) with 0.5 ml of normal saline. The parameters assessed were time to regression of sensory blockade, motor blockade, ambulation, time to void, first administration of analgesic. Statistical analysis was done using appropriate tests. Time for regression of sensory level and time for first administration of analgesic were prolonged in Group D (430.05 ± 89.13 min, 459.8 ± 100.9 min, respectively) in comparison to Group N (301.10 ± 94.86 min, 321.85 ± 95.08 min, respectively). However, the duration of motor blockade, time to ambulation, and time to void were also significantly prolonged in Group D (323.05 ± 54.58 min, 329.55 ± 54.06 min, 422.30 ± 87.59 min) than in Group N (220.10 ± 63.61 min, 221.60 ± 63.84 min, 328.45 ± 113.38 min). Intrathecal dexmedetomidine 5 μg added to intrathecal bupivacaine 6 mg as adjuvant may not be suitable for ambulatory perianal surgeries due to prolongation of motor blockade.

  1. Comparison of sedation by intranasal dexmedetomidine and oral chloral hydrate for pediatric ophthalmic examination.

    PubMed

    Cao, Qianzhong; Lin, Yiquan; Xie, Zhubin; Shen, Weihua; Chen, Ying; Gan, Xiaoliang; Liu, Yizhi

    2017-06-01

    Pediatric ophthalmic examinations can be conducted under sedation either by chloral hydrate or by dexmedetomidine. The objective was to compare the success rates and quality of ophthalmic examination of children sedated by intranasal dexmedetomidine vs oral chloral hydrate. One hundred and forty-one children aged from 3 to 36 months (5-15 kg) scheduled to ophthalmic examinations were randomly sedated by either intranasal dexmedetomidine (2 μg·kg -1 , n = 71) or oral chloral hydrate (80 mg·kg -1 , n = 70). The primary endpoint was successful sedation to complete the examinations including slit-lamp photography, tonometry, anterior segment analysis, and refractive error inspection. The secondary endpoints included quality of eye position, intraocular pressure, onset time, duration of examination, recovery time, discharge time, any side effects during examination, and within 48 h after discharge. Sixty-one children were sedated by dexmedetomidine with a success rate of 85.9%, which is significantly higher than that by chloral hydrate (64.3%) [OR 3.39, 95% CI: 1.48-7.76, P = 0.003]. Furthermore, children in the dexmedetomidine group displayed better eye position in anterior segment analysis than in chloral hydrate group median difference. All children displayed stable hemodynamics and none suffered hypoxemia in both groups. Oral chloral hydrate induced higher percentages of vomiting and altered bowel habit after discharge than dexmedetomidine. Intranasal dexmedetomidine provides more successful sedation and better quality of ophthalmic examinations than oral chloral hydrate for small children. © 2017 John Wiley & Sons Ltd.

  2. Effects of dexmedetomidine infusion during spinal anesthesia on hemodynamics and sedation

    PubMed Central

    Tarıkçı Kılıç, Ebru; Aydın, Gaye

    2018-01-01

    ABSTRACT Background: We evaluated the effects of intravenous dexmedetomidine during spinal anesthesia on hemodynamics, respiratory rate, oxygen saturation, sedpain, and compared them with those of saline infusion. Sixty American Society of Anesthesiologists physical status I and II cases were randomly divided into two groups. Patients were connected to the monitor after premedication, and spinal anesthesia was administered. Sensory and motor blockades were assessed using pinprick test and Bromage scale, respectively. Group I received dexmedetomidine infusion and Group II received saline infusion. Throughout the infusion process, hemodynamic data, respiratory rate, oxygen saturation, sedation, pain, Bromage score, amnesia, bispectral index, and side effects were recorded. Postoperative hemodynamic measurements, oxygen saturation, sedation, pain scores were obtained. Sedation and pain were evaluated using the Ramsay and visual analog scales, respectively. Analgesics were administered in cases with high scores on the visual analog scale. Postoperative analgesic consumption, side effects, treatments were recorded. No significant differences were found between the groups with respect to oxygen saturation, respiratory rate, pain, and side effects in the intraoperative period. Time to onset of sensorial block, maximum sensorial block, onset of motor block, and maximum motor block; bispectral index values; and apex heartbeat until 80 min of infusion, systolic arterial blood pressure until 90 min, and diastolic arterial blood pressure until 50 min were lower, whereas amnesia and sedation levels were higher in dexmedetomidine group. Postoperative pain and analgesic requirement were not different. Apex heartbeat at 15 min and systolic arterial blood pressure at 30 min were lower and sedation scores were higher in the dexmedetomidine infusion group. We demonstrated dexmedetomidine infusion had a hemodynamic depressant effect intraoperatively whereas it had no significant

  3. Beta 2-agonist fenoterol has greater effects on contractile function of rat skeletal muscles than clenbuterol.

    PubMed

    Ryall, James G; Gregorevic, Paul; Plant, David R; Sillence, Martin N; Lynch, Gordon S

    2002-12-01

    Potential treatments for skeletal muscle wasting and weakness ideally possess both anabolic and ergogenic properties. Although the beta(2)-adrenoceptor agonist clenbuterol has well-characterized effects on skeletal muscle, less is known about the therapeutic potential of the related beta(2)-adrenoceptor agonist fenoterol. We administered an equimolar dose of either clenbuterol or fenoterol to rats for 4 wk to compare their effects on skeletal muscle and tested the hypothesis that fenoterol would produce more powerful anabolic and ergogenic effects. Clenbuterol treatment increased fiber cross-sectional area (CSA) by 6% and maximal isometric force (P(o)) by 20% in extensor digitorum longus (EDL) muscles, whereas fiber CSA in soleus muscles decreased by 3% and P(o) was unchanged, compared with untreated controls. In the EDL muscles, fenoterol treatment increased fiber CSA by 20% and increased P(o) by 12% above values achieved after clenbuterol treatment. Soleus muscles of fenoterol-treated rats exhibited a 13% increase in fiber CSA and a 17% increase in P(o) above that of clenbuterol-treated rats. These data indicate that fenoterol has greater effects on the functional properties of rat skeletal muscles than clenbuterol.

  4. Oral dexmedetomidine for preoperative sedation in an adult uncooperative autistic patient.

    PubMed

    Konia, Mojca Remskar

    2016-11-01

    We describe preoperative sedation with oral dexmedetomidine 5 mcg/kg in an uncooperative adult with autism and developmental delay. The sedation with oral dexmedetomidine achieved good sedation level (Ramsey 4-5), allowing for calm transfer of the patient to the operating room and uneventful induction of anesthesia. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. [Indications of dexmedetomidine in the current sedoanalgesia tendencies in critical patients].

    PubMed

    Romera Ortega, M A; Chamorro Jambrina, C; Lipperheide Vallhonrat, I; Fernández Simón, I

    2014-01-01

    Recently, dexmedetomidine has been marketed in Spain and other European countries. The published experience regarding its use has placed dexmedetomidine on current trends in sedo-analgesic strategies in the adult critically ill patient. Dexmedetomidine has sedative and analgesic properties, without respiratory depressant effects, inducing a degree of depth of sedation in which the patient can open its eyes to verbal stimulation, obey simple commands and cooperate in nursing care. It is therefore a very useful drug in patients who can be maintained on mechanical ventilation with these levels of sedation avoiding the deleterious effects of over or infrasedation. Because of its effects on α2-receptors, it's very useful for the control and prevention of tolerance and withdrawal to other sedatives and psychotropic drugs. The use of dexmedetomidine has been associated with lower incidence of delirium when compared with other sedatives. Moreover, it's a potentially useful drug for sedation of patients in non-invasive ventilation. Copyright © 2013 Elsevier España, S.L. y SEMICYUC. All rights reserved.

  6. Reactive oxygen species are involved in regulating alpha1-adrenoceptor-activated vascular smooth muscle contraction.

    PubMed

    Tsai, Ming-Ho; Jiang, Meei Jyh

    2010-08-23

    Reactive oxygen species (ROS) were shown to mediate aberrant contractility in hypertension, yet the physiological roles of ROS in vascular smooth muscle contraction have remained elusive. This study aimed to examine whether ROS regulate alpha1-adrenoceptor-activated contraction by altering myosin phosphatase activities. Using endothelium-denuded rat tail artery (RTA) strips, effects of anti-oxidants on isometric force, ROS production, phosphorylation of the 20-kDa myosin light chain (MLC20), and myosin phosphatase stimulated by alpha1-adrenoceptor agonist phenylephrine were examined. An antioxidant, N-acetyl-L-cysteine (NAC), and two NADPH oxidase inhibitors, apocynin and VAS2870, dose-dependently inhibited contraction activated by phenylephrine. Phenylephrine stimulated superoxide anion production that was diminished by the pretreatment of apocynin, VAS2870, superoxide scavenger tiron or mitochondria inhibitor rotenone, but not by xanthine oxidase inhibitor allopurinol or cyclooxygenase inhibitor indomethacin. Concurrently, NADPH oxidase activity in RTA homogenates increased within 1 min upon phenylephrine stimulation, sustained for 10 min, and was abolished by the co-treatment with apocynin, but not allopurinol or rotenone. Phenylephrine-induced MLC20 phosphorylation was dose-dependently decreased by apocynin. Furthermore, apocynin inhibited phenylephrine-stimulated RhoA translocation to plasma membrane and phosphorylation of both myosin phosphatase regulatory subunit MYPT1Thr855 and myosin phosphatase inhibitor CPI-17Thr38. ROS, probably derived from NADPH oxidase and mitochondria, partially regulate alpha1-adrenoceptor-activated smooth muscle contraction by altering myosin phosphatase-mediated MLC20 phosphorylation through both RhoA/Rho kinase- and CPI-17-dependent pathways.

  7. Postoperative bradycardia following adenotonsillectomy in children: Does intraoperative administration of dexmedetomidine play a role?

    PubMed

    Bush, Benjamin; Tobias, Joseph D; Lin, Chen; Ruda, James; Jatana, Kris R; Essig, Garth; Cooper, Jennifer; Tumin, Dmitry; Elmaraghy, Charles A

    2018-01-01

    Dexmedetomidine is a novel pharmacologic agent that has become a frequently used adjunct during care of pediatric patients with obstructive sleep apnea (OSA) undergoing tonsillectomy. While generally safe and effective, dexmedetomidine is associated with adverse effects of hypotension and bradycardia from its central sympatholytic effects. Due to safety concerns, our institution routinely admits patients with OSA for overnight cardiorespiratory monitoring following tonsillectomy. With such monitoring, we have anecdotally noted bradycardia in our patients and sought to investigate whether this was related to the increased use of intra-operative dexmedetomidine. We retrospectively reviewed records over an 11-month period to compare the incidence of postoperative bradycardia following hospital admission for tonsillectomy in patients who received dexmedetomidine versus those who did not. The study cohort included 921 patients (371 received dexmedetomidine and 550 did not). Bradycardia was asymptomatically noted in 66 patients (7.2%). No patient required medical intervention for the bradycardia or developed clinical symptoms. There was no association of bradycardia with the intra-operative administration of dexmedetomidine (8.9% of patients who received dexmetomidine vs. 9.4% who did not). In multivariable analysis, bradycardia was more common among older patients, with the administration of topical or injected lidocaine, and with specific associated procedures (inferior turbinate coblation with out-fracture or direct laryngoscopy and bronchoscopy). The increased incidence of asymptomatic bradycardia in our post-adenotonsillectomy patients seemed to relate more to increased utilization of postoperative cardiac telemetry, and did not appear associated with the use of dexmedetomidine use intra-operatively. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Neural control of renal function: role of renal alpha adrenoceptors.

    PubMed

    DiBona, G F

    1985-01-01

    Adrenoceptors of various subtypes mediate the renal functional responses to alterations in efferent renal sympathetic nerve activity, the neural component, and renal arterial plasma catecholamine concentrations, the humoral component, of the sympathoadrenergic nervous system. Under normal physiologic as well as hypertensive conditions, the influence of the renal sympathetic nerves predominates over that of circulating plasma catecholamines. In most mammalian species, increases in efferent renal sympathetic nerve activity elicit renal vasoconstrictor responses mediated predominantly by renal vascular alpha-1 adrenoceptors, increases in renin release mediated largely by renal juxtaglomerular granular cell beta-1 adrenoceptors with involvement of renal vascular alpha-1 adrenoceptors only when renal vasoconstriction occurs, and direct increases in renal tubular sodium and water reabsorption mediated predominantly by renal tubular alpha-1 adrenoceptors. In most mammalian species, alpha-2 adrenoceptors do not play a significant role in the renal vascular or renin release responses to renal sympathoadrenergic stimulation. Although renal tubular alpha-2 adrenoceptors do not mediate the increases in renal tubular sodium and water reabsorption produced by increases in efferent renal sympathetic nerve activity, they may be involved through their inhibitory effect on adenylate cyclase in modulating the response to other hormonal agents that influence renal tubular sodium and water reabsorption via stimulation of adenylate cyclase.

  9. Utility and Clinical Profile of Dexmedetomidine in Pediatric Cardiac Catheterization Procedures: A Matched Controlled Analysis.

    PubMed

    Riveros, Ricardo; Makarova, Natalya; Riveros-Perez, Efrain; Chodavarapu, Praneeta; Saasouh, Wael; Yılmaz, Hüseyin Oğuz; Cuko, Evis; Babazade, Rovnat; Kimatian, Stephen; Turan, Alparslan

    2017-12-01

    Dexmedetomidine is increasingly used in children undergoing cardiac catheterization procedures. We compared the percentage of surgical time with hemodynamic instability and the incidence of postoperative agitation between pediatric cardiac catheterization patients who received dexmedetomidine infusion and those who did not and the incidence of postoperative agitation. We matched 653 pediatric patients scheduled for cardiac catheterization. Two separate multivariable linear mixed models were used to assess the association between dexmedetomidine use and intraoperative blood pressure and heart rate instability. A multivariate logistic regression was used for relationship between dexmedetomidine and postoperative agitation. No difference between the study groups was found in the duration of MAP ( P = .867) or heart rate (HR) instabilities ( P = .224). The relationship between dexmedetomidine use and the duration of negative hemodynamic effects does not depend on any of the considered CHD types (all P > .001) or intervention ( P = .453 for MAP and P = .023 for HR). No difference in postoperative agitation was found between the study groups ( P = .590). Our study demonstrated no benefit in using dexmedetomidine infusion compared with other general anesthesia techniques to maintain hemodynamic stability or decrease agitation in pediatric patients undergoing cardiac catheterization procedures.

  10. Interactions of xylazine and detomidine with alpha2-adrenoceptors in brain tissue from cattle, swine and rats.

    PubMed

    Törneke, K; Bergström, U; Neil, A

    2003-06-01

    Xylazine is an alpha2-adrenoceptor agonist sedative with a much higher interspecies variability in effect than detomidine, another alpha2-agonist used in veterinary practice. In the present study, we have used radioligand binding in brain tissue to investigate if the high species variation in sensitivity to xylazine could be explained in terms of receptor interactions. Species known to be more (cattle) or less (swine and rats) sensitive to xylazine were used. There was no variation in the density or the subtype pattern of the alpha2-adrenoceptors that could explain the species variation recorded in vivo, as a homogenous population of the alpha2A/D-subtype (200-300 fmol/mg protein) was found in all species. The species differences in the affinities of xylazine and detomidine were minor and similar for the two drugs. The only parameter investigated where a significant species difference was found for xylazine but not for detomidine was the slope of the inhibition binding curve when the G-protein coupling was diminished. For xylazine this slope was considerably lower than unity (i.e. 0.77 +/- 0.075) using cattle preparations compared with 0.92 +/- 0.037 (mean +/- SE) and 0.90 +/- 0.028, respectively for swine and rats, while for detomidine this parameter was close to unity in all species (cattle, swine, rat). This finding indicates that the species variation in effect for xylazine could be due to differences at the G-protein level or further down-stream in the effect cascade.

  11. Dexmedetomidine Does Not Affect Evoked Potentials During Spine Surgery.

    PubMed

    Rozet, Irene; Metzner, Julia; Brown, Marcia; Treggiari, Miriam M; Slimp, Jefferson C; Kinney, Greg; Sharma, Deepak; Lee, Lorri A; Vavilala, Monica S

    2015-08-01

    The effect of dexmedetomidine on evoked potentials (EPs) has not been elucidated. We aimed to investigate the effect of dexmedetomidine on somatosensory, motor, and visual EPs. After IRB approval, 40 adult patients scheduled for elective spine surgery using total IV anesthesia with propofol and remifentanil were randomly assigned to receive either dexmedetomidine (n = 20) or placebo (n = 20) in a double-blind, placebo-controlled trial. After obtaining informed consent, positioning, and baseline EPs recording, patients were randomly assigned to either IV dexmedetomidine 0.6 μg/kg infused over 10 minutes, followed by 0.6 μg/kg/h, or a corresponding volume of IV normal saline (placebo). EP measures at 60 ± 30 minutes after initiation of study drug were defined as T1 and at 150 ± 30 minutes were defined as T2. Changes from baseline to T1 (primary end point) and from baseline to T2 (secondary end point) in EP latencies (milliseconds) and amplitudes (microvolts) were compared between groups. Data presented as mean ± SD (95% confidence interval). Data from 40 patients (dexmedetomidine: n = 20; age, 54 ± 3 years; 10 males; placebo: n = 20; age, 52 ± 2 years; 5 males) were analyzed. There was no difference between dexmedetomidine versus placebo groups in primary end points: change of somatosensory EPs at T1, latency: 0.01 ± 1.3 (-0.64, 0.65) vs 0.01 ± 1.3 (-0.64, 0.65), P = 0.43 (-1.24, 0.45); amplitude: 0.03 ± 0.14 (-0.06, 0.02) vs -0.01 ± 0.13 (-0.07, 0.05), P = 0.76 (-0.074, 0.1); motor EPs amplitude at T1: 65.1 ± 194.8 (-35, 165; n = 18) vs 109.2 ± 241.4 (-24, 243; n = 16), P = 0.57 (-113.5, 241.57); visual EPs at T1 (right eye), amplitude: 2.3 ± 3.6 (-0.4, 5.1; n = 11) vs 0.3 ± 6.0 (-3.3, 3.9; n = 16), P = 0.38 (-6.7, 2.6); latency N1: 2.3 ± 3.6 (-0.4, 5.1) vs 0.3 ± 6.0 (-3.3, 3.9), P = 0.38 (-6.7, 2.6); latency P1: -1.6 ± 13.4 (-11.9, 8.7) vs -1.4 ± 8.1 (-6.3, 3.5), P = 0.97 (-9.3, 9.7) or secondary end points. There were no differences between

  12. Disruption of thalamic functional connectivity is a neural correlate of dexmedetomidine-induced unconsciousness

    PubMed Central

    Akeju, Oluwaseun; Loggia, Marco L; Catana, Ciprian; Pavone, Kara J; Vazquez, Rafael; Rhee, James; Contreras Ramirez, Violeta; Chonde, Daniel B; Izquierdo-Garcia, David; Arabasz, Grae; Hsu, Shirley; Habeeb, Kathleen; Hooker, Jacob M; Napadow, Vitaly; Brown, Emery N; Purdon, Patrick L

    2014-01-01

    Understanding the neural basis of consciousness is fundamental to neuroscience research. Disruptions in cortico-cortical connectivity have been suggested as a primary mechanism of unconsciousness. By using a novel combination of positron emission tomography and functional magnetic resonance imaging, we studied anesthesia-induced unconsciousness and recovery using the α2-agonist dexmedetomidine. During unconsciousness, cerebral metabolic rate of glucose and cerebral blood flow were preferentially decreased in the thalamus, the Default Mode Network (DMN), and the bilateral Frontoparietal Networks (FPNs). Cortico-cortical functional connectivity within the DMN and FPNs was preserved. However, DMN thalamo-cortical functional connectivity was disrupted. Recovery from this state was associated with sustained reduction in cerebral blood flow and restored DMN thalamo-cortical functional connectivity. We report that loss of thalamo-cortical functional connectivity is sufficient to produce unconsciousness. DOI: http://dx.doi.org/10.7554/eLife.04499.001 PMID:25432022

  13. Perineural Dexmedetomidine Attenuates Inflammation in Rat Sciatic Nerve via the NF-κB Pathway

    PubMed Central

    Huang, Yan; Lu, Yi; Zhang, Lei; Yan, Jia; Jiang, Jue; Jiang, Hong

    2014-01-01

    Recent studies have shown that dexmedetomidine exerts an anti-inflammatory effect by reducing serum levels of inflammatory factors, however, the up-stream mechanism is still unknown. The transcription factor NF-κB enters the nucleus and promotes the transcription of its target genes, including those encoding the pro-inflammatory cytokines IL-6 and TNF-α. In this study, we established a rat model that simulates a clinical surgical procedure to investigate the anti-inflammatory effect of perineural administration of dexmedetomidine and the underlying mechanism. Dexmedetomidine reduced the sciatic nerve levels of IL-6 and TNF-α at both the mRNA and protein level. Dexmedetomidine also inhibited the translocation of activated NF-κB to the nucleus and the binding activity of NF-κB. The anti-inflammatory effect is confirmed to be dose-dependent. Finally, pyrrolidine dithiocarbamate also reduced the levels of IL-6 and TNF-α and the activation of NF-κB. In conclusion, dexmedetomidine inhibited the nuclear translocation and binding activity of activated NF-κB, thus reducing inflammatory cytokines. PMID:24663080

  14. Wnt/β-Catenin Signaling Modulates Human Airway Sensitization Induced by β2-Adrenoceptor Stimulation

    PubMed Central

    Faisy, Christophe; Grassin-Delyle, Stanislas; Blouquit-Laye, Sabine; Brollo, Marion; Naline, Emmanuel; Chapelier, Alain; Devillier, Philippe

    2014-01-01

    Background Regular use of β2-agonists may enhance non-specific airway responsiveness. The wingless/integrated (Wnt) signaling pathways are responsible for several cellular processes, including airway inflammation and remodeling while cAMP–PKA cascade can activate the Wnt signaling. We aimed to investigate whether the Wnt signaling pathways are involved in the bronchial hyperresponsiveness induced by prolonged exposure to β2-adrenoceptor agonists in human isolated airways. Methods Bronchi were surgically removed from 44 thoracic surgery patients. After preparation, bronchial rings and primary cultures of bronchial epithelial cells were incubated with fenoterol (0.1 µM, 15 hours, 37°C), a β2-agonist with high intrinsic efficacy. The effects of inhibitors/blockers of Wnt signaling on the fenoterol-induced airway sensitization were examined and the impact of fenoterol exposure on the mRNA expression of genes interacting with Wnt signaling or cAMP–PKA cascade was assessed in complete bronchi and in cultured epithelial cells. Results Compared to paired controls, fenoterol-sensitization was abolished by inhibition/blockage of the Wnt/β-catenin signaling, especially the cell-surface LRP5/6 co-receptors or Fzd receptors (1 µM SFRP1 or 1 µM DKK1) and the nuclear recruitment of TCF/LEF transcriptions factors (0.3 µM FH535). Wnt proteins secretion did not seem to be involved in the fenoterol-induced sensitization since the mRNA expression of Wnt remained low after fenoterol exposure and the inactivator of Wnt secretion (1 µM IWP2) had no effect on the fenoterol-sensitization. Fenoterol exposure did not change the mRNA expression of genes regulating Wnt signaling or cAMP–PKA cascade. Conclusions Collectively, our pharmacological investigations indicate that fenoterol-sensitization is modulated by the inhibition/blockage of canonical Wnt/β-catenin pathway, suggesting a phenomenon of biased agonism in connection with the β2-adrenoceptor stimulation. Future

  15. Cardiovascular, respiratory and sedative effects of intramuscular alfaxalone, butorphanol and dexmedetomidine compared with ketamine, butorphanol and dexmedetomidine in healthy cats.

    PubMed

    Cremer, Jeannette; Riccó, Carolina H

    2017-11-01

    Objectives The aim of the study was to evaluate the cardiorespiratory effects, quality of sedation and recovery of intramuscular alfaxalone-dexmedetomidine-butorphanol (ADB) and ketamine-dexmedetomidine-butorphanol (KDB), in cats. Methods Nine adult, healthy cats (6.63 ± 1.42 kg) were enrolled in a blinded, randomized, crossover experimental design. Cats were sedated twice intramuscularly, once with ADB (alfaxalone 1 mg/kg, dexmedetomidine 0.005 mg/kg, butorphanol 0.2 mg/kg), and once with KDB (ketamine 5 mg/kg, dexmedetomidine 0.005 mg/kg, butorphanol 0.2 mg/kg), in random order. Data collected included heart rate (HR), arterial blood pressure and blood gas analysis, respiratory rate, and sedation score. Analysis of variance with Bonferroni post-hoc correction was used for parametric data, and a Wilcoxon signed rank test was used for non-parametric data. Significance was set at P <0.05. Results Total sedation time was shorter for ADB (90.71 ± 15.12 mins vs 147.00 ± 47.75 mins). Peak sedation was observed within 15 mins in both groups. Quality of recovery was excellent in both groups. HR decreased over time in both groups. Diastolic and mean arterial pressure decreased over time for ADB, becoming significant after 30 mins. All cardiovascular variables were within the clinically acceptable range in both groups. Arterial partial pressure of oxygen was significantly decreased from baseline for KDB at all time points (73 ± 2.5 mmHg [9.7 ± 0.3 kPa] vs ADB 83 ± 2.6 mmHg [11 ± 0.3 kPa]). Hypoventilation was not observed. Conclusions and relevance Both protocols produced acceptable cardiovascular stability. Sedation and recovery quality were good, albeit sedation was shorter with ADB. Although oxygenation was better maintained in the ADB group, all sedated cats should receive oxygen supplementation.

  16. Choline+ is a low-affinity ligand for alpha 1-adrenoceptors.

    PubMed

    Unelius, L; Cannon, B; Nedergaard, J

    1994-10-07

    The effect of choline+, a commonly used Na+ substitute, on ligand binding to alpha 1-adrenoceptors was investigated. It was found that replacement of 25% of the Na+ in a Krebs-Ringer bicarbonate buffer with choline+ led to a 3-fold decrease in the apparent affinity of [3H]prazosin for its binding site (i.e. the alpha 1-receptor) in a membrane preparation from brown adipose tissue, while no decrease in the total number of binding sites was observed. Similar effects were seen in membrane preparations from liver and brain. In competition experiments, it was found that choline+ could inhibit [3H]prazosin binding; from the inhibition curve, an affinity (Ki) of 31 mM choline+ for the [3H]prazosin-binding site could be calculated. In fully choline(+)-substituted buffers, where the level of [3H]prazosin binding was substantially reduced, both phentolamine and norepinephrine could still compete with [3H]prazosin for its binding site, with virtually unaltered affinity; thus choline+ did not substantially affect the characteristics of those receptors to which it did not bind. Choline+ did not affect the binding characteristics of the beta 1/beta 2 radioligand [3H]CGP-12177; thus, the effect on alpha 1-receptors was not due to general, unspecific effects on the membrane preparations. It is concluded that choline+ possesses characteristics similar to those of a competitive ligand for the alpha 1-adrenoceptor; it has a low affinity but the competitive type of interaction of choline may nonetheless under experimental conditions interfere with agonist interaction with the alpha 1-receptor.

  17. Dexmedetomidine Use in Critically-Ill Children with Acute Respiratory Failure

    PubMed Central

    Grant, Mary Jo C.; Schneider, James B.; Asaro, Lisa A.; Dodson, Brenda L.; Hall, Brent A.; Simone, Shari L.; Cowl, Allison S.; Munkwitz, Michele M.; Wypij, David; Curley, Martha A.Q.

    2016-01-01

    Objective Care of critically-ill children includes sedation but current therapies are suboptimal. To describe dexmedetomidine (DEX) use in children supported on mechanical ventilation for acute respiratory failure. Design Secondary analysis of data from the RESTORE clinical trial. Setting Thirty-one pediatric ICUs. Patients Data from 2449 children; 2 weeks to 17 years old. Interventions Sedation practices were unrestrained in the usual care arm. Patients were categorized as receiving dexmedetomidine as a primary sedative (DEXp), secondary sedative (DEXs), periextubation agent (DEXe), or never prescribed. DEX exposure and sedation and clinical profiles are described. Measurements and Main Results Of 1224 usual care patients, 596 (49%) received DEX. DEXp patients (N=138; 11%) were less critically ill (PRISM III-12 score median 6 [IQR 3–11]) and when compared to all other cohorts, experienced more episodic agitation. In the intervention group, time in sedation target improved from 28% to 50% within one day of initiating DEXp. DEXs usual care patients (N=280; 23%) included more children with severe PARDS or organ failure. DEXs patients experienced more inadequate pain (22% vs 11%) and sedation (31% vs 16%) events. DEXe patients (N=178; 15%) were those known to not tolerate an awake, intubated state and experienced a shorter ventilator weaning process (2.1 vs 2.3 days). Conclusions Our data support the use of dexmedetomidine as a primary agent in low criticality patients offering the benefit of rapid achievement of targeted sedation levels. Dexmedetomidine as a secondary agent does not appear to add benefit. The use of dexmedetomidine to facilitate extubation in children intolerant of an awake, intubated state may abbreviate ventilator weaning. These data support a broader armamentarium of pediatric critical care sedation. PMID:27654816

  18. The effect of intraoperative dexmedetomidine on postoperative analgesia and sedation in pediatric patients undergoing tonsillectomy and adenoidectomy.

    PubMed

    Olutoye, Olutoyin A; Glover, Chris D; Diefenderfer, John W; McGilberry, Michael; Wyatt, Matthew M; Larrier, Deidre R; Friedman, Ellen M; Watcha, Mehernoor F

    2010-08-01

    The immediate postoperative period after tonsillectomy and adenoidectomy, one of the most common pediatric surgical procedures, is often difficult. These children frequently have severe pain but postoperative airway edema along with increased sensitivity to the respiratory-depressant effects of opioids may result in obstructive symptoms and hypoxemia. Opioid consumption may be reduced by nonsteroidal antiinflammatory drugs, but these drugs may be associated with increased bleeding after this operation. Dexmedetomidine has mild analgesic properties, causes sedation without respiratory depression, and does not have an effect on coagulation. We designed a prospective, double-blind, randomized controlled study to determine the effects of intraoperative dexmedetomidine on postoperative recovery including pain, sedation, and hemodynamics in pediatric patients undergoing tonsillectomy and adenoidectomy. One hundred nine patients were randomized to receive a single intraoperative dose of dexmedetomidine 0.75 microg/kg, dexmedetomidine 1 microg/kg, morphine 50 microg/kg, or morphine 100 microg/kg over 10 minutes after endotracheal intubation. There were no significant differences among the 4 groups in patient demographics, ASA physical status, postoperative opioid requirements, sedation scores, duration of oxygen supplementation in the postanesthetic care unit, and time to discharge readiness. The median time to first postoperative rescue analgesic was similar in patients receiving dexmedetomidine 1 microg/kg and morphine 100 microg/kg, but significantly longer compared with patients receiving dexmedetomidine 0.75 microg/kg or morphine 50 microg/kg (P < 0.01). In addition, the number of patients requiring >1 rescue analgesic dose was significantly higher in the dexmedetomidine 0.75 microg/kg group compared with the dexmedetomidine 1 microg/kg and morphine 100 microg/kg groups, but not the morphine 50 microg/kg group. Patients receiving dexmedetomidine had significantly

  19. Effect of Dexmedetomidine on Mortality and Ventilator-Free Days in Patients Requiring Mechanical Ventilation With Sepsis

    PubMed Central

    Kawazoe, Yu; Miyamoto, Kyohei; Morimoto, Takeshi; Yamamoto, Tomonori; Fuke, Akihiro; Hashimoto, Atsunori; Koami, Hiroyuki; Beppu, Satoru; Katayama, Yoichi; Itoh, Makoto; Ohta, Yoshinori

    2017-01-01

    Importance Dexmedetomidine provides sedation for patients undergoing ventilation; however, its effects on mortality and ventilator-free days have not been well studied among patients with sepsis. Objectives To examine whether a sedation strategy with dexmedetomidine can improve clinical outcomes in patients with sepsis undergoing ventilation. Design, Setting, and Participants Open-label, multicenter randomized clinical trial conducted at 8 intensive care units in Japan from February 2013 until January 2016 among 201 consecutive adult patients with sepsis requiring mechanical ventilation for at least 24 hours. Interventions Patients were randomized to receive either sedation with dexmedetomidine (n = 100) or sedation without dexmedetomidine (control group; n = 101). Other agents used in both groups were fentanyl, propofol, and midazolam. Main Outcomes and Measures The co–primary outcomes were mortality and ventilator-free days (over a 28-day duration). Sequential Organ Failure Assessment score (days 1, 2, 4, 6, 8), sedation control, occurrence of delirium and coma, intensive care unit stay duration, renal function, inflammation, and nutrition state were assessed as secondary outcomes. Results Of the 203 screened patients, 201 were randomized. The mean age was 69 years (SD, 14 years); 63% were male. Mortality at 28 days was not significantly different in the dexmedetomidine group vs the control group (19 patients [22.8%] vs 28 patients [30.8%]; hazard ratio, 0.69; 95% CI, 0.38-1.22; P = .20). Ventilator-free days over 28 days were not significantly different between groups (dexmedetomidine group: median, 20 [interquartile range, 5-24] days; control group: median, 18 [interquartile range, 0.5-23] days; P = .20). The dexmedetomidine group had a significantly higher rate of well-controlled sedation during mechanical ventilation (range, 17%-58% vs 20%-39%; P = .01); other outcomes were not significantly different between groups. Adverse events

  20. Improvement of postoperative cognitive dysfunction and attention network function of patients with ischemic cerebrovascular disease via dexmedetomidine.

    PubMed

    Zhang, Jingchao; Wang, Guoliang; Zhang, Fangxiang; Zhao, Qian

    2018-03-01

    The protective effect of dexmedetomidine on cognitive dysfunction and decreased attention network function of patients with ischemic cerebrovascular disease after stenting was investigated. Fifty-eight patients with ischemic cerebrovascular disease undergoing stenting in Guizhou Provincial People's Hospital were selected and randomly divided into control group (n=29) and dexmedetomidine group (n=29). The dexmedetomidine group was treated with dexmedetomidine before induced anesthesia, while the control group was given the same dose of normal saline; and the normal volunteers of the same age were selected as the normal group (n=29). At 3 days after operation, the levels of serum S100B and nerve growth factor (NGF) in each group were detected using the enzyme-linked immunosorbent assay, and the level of brain-derived neurotrophic factor (BDNF) was detected via western blotting. Montreal cognitive assessment (MoCA) and attention network test (ANT) were performed. Moreover, the cognitive function and attention network function, and the effects of dexmedetomidine on cognitive function and attention network function were evaluated. The concentrations of serum S100B and NGF in dexmedetomidine group was lower than those in control group (P<0.01). The results of western blotting showed that the levels of serum BDNF in control group and dexmedetomidine group were significantly lower than that in normal group (P<0.01), and it was higher in dexmedetomidine group than that in control group (P<0.01). Besides, both MoCA and ANT results revealed that the visual space and executive function scores, attention scores, delayed memory scores, targeted network efficiency and executive control network efficiency in dexmedetomidine group were obviously higher than those in control group (P<0.01). The cognitive function and attention network function of patients with ischemic cerebrovascular disease have a certain degree of damage, and the preoperative administration of dexmedetomidine can

  1. A randomised controlled trial of oral chloral hydrate vs. intranasal dexmedetomidine before computerised tomography in children.

    PubMed

    Yuen, V M; Li, B L; Cheuk, D K; Leung, M K M; Hui, T W C; Wong, I C; Lam, W W; Choi, S W; Irwin, M G

    2017-10-01

    Chloral hydrate is commonly used to sedate children for painless procedures. Children may recover more quickly after sedation with dexmedetomidine, which has a shorter half-life. We randomly allocated 196 children to chloral hydrate syrup 50 mg.kg -1 and intranasal saline spray, or placebo syrup and intranasal dexmedetomidine spray 3 μg.kg -1 , 30 min before computerised tomography studies. More children resisted or cried after drinking chloral hydrate syrup than placebo syrup, 72 of 107 (67%) vs. 42 of 87 (48%), p = 0.009, but there was no difference after intranasal saline vs. dexmedetomidine, 49 of 107 (46%) vs. 40 of 87 (46%), p = 0.98. Sedation was satisfactory in 81 of 107 (76%) children after chloral hydrate and 64 of 87 (74%) children after dexmedetomidine, p = 0.74. Of the 173 children followed up for at least 4 h after discharge, 38 of 97 (39%) had recovered normal function after chloral hydrate and 32 of 76 (42%) after dexmedetomidine, p = 0.76. Six children vomited after chloral hydrate syrup and placebo spray vs. none after placebo syrup and dexmedetomidine spray, p = 0.03. © 2017 The Association of Anaesthetists of Great Britain and Ireland.

  2. Stability of Dexmedetomidine in 0.9% Sodium Chloride in Two Types of Intravenous Infusion Bags.

    PubMed

    Marquis, Kathleen; Hohlfelder, Benjamin; Szumita, Paul M

    2017-01-01

    Dexmedetomidine is a frequently used sedative in the critical care setting. It is commercially available as a 4-mg/mL premixed compound or as 200-mcg/2-mL vials that must be further diluted prior to administration. However, limited data exist regarding the stability of dexmedetomidine admixtures compounded from the 200-mcg/2-mL vials, particularly for durations greater than 48 hours. Therefore, we performed stability testing on compounded dexmedetomidine prepared in two types of intravenous infusion bags for 14 days. Dexmedetomidine is available as 200-mcg/2-mL vials for dilution, 80-mcg/20-mL single-dose vials, and as 200-mcg/50-mL and 400-mcg/100-mL glass bottles. The stability of dexmedetomidine admixtures has previously been tested for 48 hours. The purpose of this analysis was to test the stability of dexmedetomidine admixtures for 14 days. Six dexmedetomidine admixtures of 200 mcg/50 mL were compounded in polyvinyl chloride and non-polyvinyl chloride bags, three of which were stored under refrigeration and three of which were kept at room temperature. High-performance liquid chromatography testing was performed to determine the concentration at Days 1 through 14. Stability was determined by taking the mean concentration of samples taken from each bag. All samples were tested in duplicate. A sample was considered stable if the concentration was greater than 90% of the original concentration. All samples retained over 90% of the drug under their respective storage conditions for the duration of the study. At time 0, the concentration of dexmedetomidine was between 3.99 mcg/mL and 4.01 mcg/mL. On Day 14, the mean concentration was between 95.8% and 98.9%, depending on the bag type and storage condition. The pH remained between 4.7 and 5.8 during the study period as has previously been reported in the literature. Dexmedetomidine admixtures of 200 mcg/50 mL were stable in both polyvinyl chloride bags and non-polyvinyl chloride bags for 14 days under refrigeration

  3. Different mechanisms of action of beta2-adrenergic receptor agonists: a comparison of reproterol, fenoterol and salbutamol on monocyte cyclic-AMP and leukotriene B4 production in vitro.

    PubMed

    Juergens, Uwe R; Stöber, M; Libertus, H; Darlath, W; Gillissen, A; Vetter, H

    2004-07-30

    Beta2-adrenergic receptor agonists have several effects on airway function, most of which are mediated in a variety of cell types resulting in increased c-AMP-production and inhibition of inflammatory mediator production. However, their stimulating effects on cAMP-production became known to be inversed by increasing phosphodiesterase (PDE) activity and degradation of cAMP. Therefore, in this study we have evaluated the efficacy of reproterol, a dual acting beta2-adrenoceptor agonist and PDE-inhibitor, as compared to salbutamol and fenoterol with respect to production of cAMP and LTB4 in cultured monocytes. Isolated human monocytes (10(5)/ml) were incubated (n = 9) in suspension with beta2-adrenoceptor agonists (10(-10) -10(-4) M) for 30 minutes with and without IBMX. Then, cAMP production was determined following treatment with Triton-X100. Production of LTB4 was measured following incubation of beta2-adrenoceptor agonists for 4 hrs in the presence of LPS (10 mg/ml). cAMP and LTB subset 4 were measured in culture supernatants by enzyme immunoassay. At 10(-5) M, production of cAMP was significantly stimulated by reproterol > fenoterol > salbutamol in a dose-dependent manner to an extent of *128%, *65%, 13% (*p<0.04) respectively. In contrast, LTB4-production was inhibited significantly to a similar degree by salbutamol and reproterol in a dose-dependent manner by 59% and 49% (10(-5) M, p<0.03), respectively, with decreasing inhibition (15%) after fenoterol. Following co-incubation with IBMX, cAMP production only increased significantly (p<0.002) after fenoterol (+110%) compared to salbutamol (+29%) and reproterol (+50%) (ANOVA, p<0.001). These data suggest effects of the theophylline constituent of reproterol to inhibit adenylyl cyclase induced phosphodiesterase activity. The advantageous synergistic effects of reproterol on cAMP-production need to be further explored in trials.

  4. Hypnotic hypersensitivity to volatile anesthetics and dexmedetomidine in dopamine β-hydroxylase knockout mice.

    PubMed

    Hu, Frances Y; Hanna, George M; Han, Wei; Mardini, Feras; Thomas, Steven A; Wyner, Abraham J; Kelz, Max B

    2012-11-01

    Multiple lines of evidence suggest that the adrenergic system can modulate sensitivity to anesthetic-induced immobility and anesthetic-induced hypnosis as well. However, several considerations prevent the conclusion that the endogenous adrenergic ligands norepinephrine and epinephrine alter anesthetic sensitivity. Using dopamine β-hydroxylase knockout (Dbh) mice genetically engineered to lack the adrenergic ligands and their siblings with normal adrenergic levels, we test the contribution of the adrenergic ligands upon volatile anesthetic induction and emergence. Moreover, we investigate the effects of intravenous dexmedetomidine in adrenergic-deficient mice and their siblings using both righting reflex and processed electroencephalographic measures of anesthetic hypnosis. We demonstrate that the loss of norepinephrine and epinephrine and not other neuromodulators co-packaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia. However, the most profound effect of adrenergic deficiency is retarding emergence from anesthesia, which takes two to three times as long in Dbh mice for sevoflurane, isoflurane, and halothane. Having shown that Dbh mice are hypersensitive to volatile anesthetics, we further demonstrate that their hypnotic hypersensitivity persists at multiple doses of dexmedetomidine. Dbh mice exhibit up to 67% shorter latencies to loss of righting reflex and up to 545% longer durations of dexmedetomidine-induced general anesthesia. Central rescue of adrenergic signaling restores control-like dexmedetomidine sensitivity. A novel continuous electroencephalographic analysis illustrates that the longer duration of dexmedetomidine-induced hypnosis is not due to a motor confound, but occurs because of impaired anesthetic emergence. Adrenergic signaling is essential for normal emergence from general anesthesia. Dexmedetomidine-induced general anesthesia does not depend on inhibition of adrenergic neurotransmission.

  5. Hypnotic Hypersensitivity to Volatile Anesthetics and Dexmedetomidine in Dopamine β-Hydroxylase Knockout Mice

    PubMed Central

    Hu, Frances Y.; Hanna, George M.; Han, Wei; Mardini, Feras; Thomas, Steven A.; Wyner, Abraham J.; Kelz, Max B.

    2012-01-01

    BACKGROUND Multiple lines of evidence suggest that the adrenergic system can modulate sensitivity to anesthetic-induced immobility and anesthetic-induced hypnosis as well. However, several considerations prevent the conclusion that the endogenous adrenergic ligands norepinephrine and epinephrine alter anesthetic sensitivity. METHODS Using dopamine β-hydroxylase (Dbh−/−) mice genetically engineered to lack the adrenergic ligands and their siblings with normal adrenergic levels, we test the contribution of the adrenergic ligands upon volatile anesthetic induction and emergence. Moreover, we investigate the effects of intravenous dexmedetomidine in adrenergic-deficient mice and their siblings using both righting reflex and processed electroencephalographic measures of anesthetic hypnosis. RESULTS We demonstrate that the loss of norepinephrine and epinephrine and not other neuromodulators copackaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia. However, the most profound effect of adrenergic deficiency is retarding emergence from anesthesia, which takes two to three times as long in Dbh−/− mice for sevoflurane, isoflurane, and halothane. Having shown that Dbh−/− mice are hypersensitive to volatile anesthetics, we further demonstrate that their hypnotic hypersensitivity persists at multiple doses of dexmedetomidine. Dbh−/− mice exhibit up to 67% shorter latencies to loss of righting reflex and up to 545% longer durations of dexmedetomidine-induced general anesthesia. Central rescue of adrenergic signaling restores control-like dexmedetomidine sensitivity. A novel continuous electroencephalographic analysis illustrates that the longer duration of dexmedetomidine-induced hypnosis is not due to a motor confound, but occurs because of impaired anesthetic emergence. CONCLUSIONS Adrenergic signaling is essential for normal emergence from general anesthesia. Dexmedetomidine-induced general anesthesia does

  6. Comparison of Dexmedetomidine and Remifentanil on Airway Reflex and Hemodynamic Changes during Recovery after Craniotomy

    PubMed Central

    Kim, Hyunzu; Min, Kyeong Tae; Lee, Jeong Rim; Ha, Sang Hee; Lee, Woo Kyung; Seo, Jae Hee

    2016-01-01

    Purpose During emergence from anesthesia for a craniotomy, maintenance of hemodynamic stability and prompt evaluation of neurological status is mandatory. The aim of this prospective, randomized, double-blind study was to compare the effects of dexmedetomidine and remifentanil on airway reflex and hemodynamic change in patients undergoing craniotomy. Materials and Methods Seventy-four patients undergoing clipping of unruptured cerebral aneurysm were recruited. In the dexmedetomidine group, patients were administered dexmedetomidine (0.5 µg/kg) for 5 minutes, while the patients of the remifentanil group were administered remifentanil with an effect site concentration of 1.5 ng/mL until endotracheal extubation. The incidence and severity of cough and hemodynamic variables were measured during the recovery period. Hemodynamic variables, respiration rate, and sedation scale were measured after extubation and in the post-anesthetic care unit (PACU). Results The incidence of grade 2 and 3 cough at the point of extubation was 62.5% in the dexmedetomidine group and 53.1% in the remifentanil group (p=0.39). Mean arterial pressure (p=0.01) at admission to the PACU and heart rate (p=0.04 and 0.01, respectively) at admission and at 10 minutes in the PACU were significantly lower in the dexmedetomidine group. Respiration rate was significantly lower in the remifentanil group at 2 minutes (p<0.01) and 5 minutes (p<0.01) after extubation. Conclusion We concluded that a single bolus of dexmedetomidine (0.5 µg/kg) and remifentanil infusion have equal effectiveness in attenuating coughing and hemodynamic changes in patients undergoing cerebral aneurysm clipping; however, dexmedetomidine leads to better preservation of respiration. PMID:27189295

  7. Oral transmucosal administration of dexmedetomidine for sedation in 4 dogs.

    PubMed

    Cohen, Anne E; Bennett, Sara L

    2015-11-01

    Injectable dexmedetomidine (DM) is widely used for sedation, restraint, anxiolysis, and analgesia in veterinary medicine. Oral transmucosal dexmedetomidine (OTM DM) has been evaluated in horses, cats, and humans, but not in dogs. In this case series, OTM DM (mean dose of 32.6 μg/kg body weight) was given in the buccal pouch to 4 aggressive dogs in a hospital setting. Two of the dogs were subsequently euthanized, and in the other 2, sedation was reversed with atipamezole. Satisfactory sedation was achieved in all cases.

  8. Acute systemic effects of inhaled salbutamol in asthmatic subjects expressing common homozygous beta2-adrenoceptor haplotypes at positions 16 and 27.

    PubMed

    Lee, Daniel K C; Bates, Caroline E; Lipworth, Brian J

    2004-01-01

    The relationship between beta2-adrenoceptor polymorphisms at positions 16 and 27, and the acute systemic beta2-adrenoceptor effects of inhaled salbutamol is unclear. We therefore elected to evaluate the influence of common homozygous beta2-adrenoceptor haplotypes on the acute systemic beta2-adrenoceptor effects following inhaled salbutamol in asthmatic subjects. An initial database search of 531 asthmatic subjects identified the two commonest homozygous haplotypes at positions 16 and 27 to be Arg16-Gln27 (12%) and Gly16-Glu27 (19%). After a 1-week washout period where all beta2-adrenoceptor agonists were withdrawn, 16 Caucasian subjects (Arg16-Gln27: n = 8 and Gly16-Glu27: n = 8) were given a single dose of inhaled salbutamol (1200 microg), followed by serial blood sampling for serum potassium, along with measurements of diastolic blood pressure and heart rate, at 5-min intervals for 20 min. The two groups were well matched for age, sex, FEV1, and inhaled corticosteroid dose. Baseline values for serum potassium, diastolic blood pressure and heart rate were not significantly different comparing Arg16-Gln27 vs Gly16-Glu27. The mean +/- SEM maximum serum potassium change from baseline over 20 min was significantly greater (P = 0.04) for Arg16-Gln27: -0.37 +/- 0.05 mmol l(-1) vs Gly16-Glu27: -0.23 +/- 0.04 mmol l(-1); 95% CI for difference: -0.01 to -0.28 mmol l(-1). The maximum diastolic blood pressure change from baseline over 20 min was significantly greater (P = 0.0008) for Arg16-Gln27: -13 +/- 1 mmHg vs Gly16-Glu27: -4 +/- 2 mmHg; 95% CI for difference: -5, 14 mmHg. There was no significant difference comparing the maximum heart rate change from baseline for Arg16-Gln27: 10 +/- 3 beats min(-1) vs Gly16-Glu27: 10 +/- 3 beats min(-1). Caucasian asthmatic subjects with the Arg16-Gln27 haplotype exhibited a greater systemic response to inhaled salbutamol, compared with those with the Gly16-Glu27 haplotype. The attenuated beta2-adrenoceptor response in the Gly16-Glu27

  9. Effect of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]ethyl} acetanilide (YM178), a novel selective beta3-adrenoceptor agonist, on bladder function.

    PubMed

    Takasu, Toshiyuki; Ukai, Masashi; Sato, Shuichi; Matsui, Tetsuo; Nagase, Itsuro; Maruyama, Tatsuya; Sasamata, Masao; Miyata, Keiji; Uchida, Hisashi; Yamaguchi, Osamu

    2007-05-01

    We evaluated the pharmacological characteristics of (R)-2-(2-aminothiazol-4-yl)-4'-{2-[(2-hydroxy-2-phenylethyl)amino]-ethyl} acetanilide (YM178). YM178 increased cyclic AMP accumulation in Chinese hamster ovary (CHO) cells expressing human beta3-adrenoceptor (AR). The half-maximal effective concentration (EC50) value was 22.4 nM. EC50 values of YM178 for human beta1- and beta2-ARs were 10,000 nM or more, respectively. The ratio of intrinsic activities of YM178 versus maximal response induced by isoproterenol (nonselective beta-AR agonist) was 0.8 for human beta3-ARs, 0.1 for human beta1-ARs, and 0.1 for human beta2-ARs. The relaxant effects of YM178 were evaluated in rats and humans bladder strips precontracted with carbachol (CCh) and compared with those of isoproterenol and 4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (CGP-12177A) (beta3-AR agonist). EC50 values of YM178 and isoproterenol in rat bladder strips precontracted with 10(-6) M CCh were 5.1 and 1.4 microM, respectively, whereas those in human bladder strips precontracted with 10(-7) M CCh were 0.78 and 0.28 microM, respectively. In in vivo study, YM178 at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. These findings suggest the suitability of YM178 as a therapeutic drug for the treatment of symptoms of overactive bladder such as urinary frequency, urgency, and urge incontinence.

  10. Use of Optical Mapping to Evaluate Mechanisms and New Therapies for Bladder Dysfunction Due to Spinal Cord Injury

    DTIC Science & Technology

    2013-10-01

    TERMS Lower urinary tract symptoms (LUTS), spinal cord injury (SCI), Botulinum Toxin Type A and β3 adrenoceptor agonists 16. SECURITY...focused on the therapeutic benefits of β3 adrenoceptor agonists, botulinum neurotoxin type A (BTX-A) intradetrusor injections and their combination...compromised by the toxin . Thus, β3 adrenoceptor agonists in combination with BTX-A are beneficial in improving bladder function in SCI patients. 15. SUBJECT

  11. Dexmedetomidine as an adjuvant to bupivacaine in caudal analgesia in children

    PubMed Central

    Goyal, Vigya; Kubre, Jyotsna; Radhakrishnan, Krishnaprabha

    2016-01-01

    Context: Postoperative pain management is becoming an integral part of anesthesia care. Various techniques of pediatric pain relief have been designed among which the most commonly practiced is caudal epidural block. Several adjuvants have been used to prolong the duration of caudal analgesia such as clonidine, neostigmine, ketamine, opioids, and ephedrine. We have designed the study using dexmedetomidine as an adjuvant to assess analgesic efficacy, duration of postoperative analgesia, hemodynamic stability, postoperative sedation, and any adverse effects in children. Aims: The aim is to study the effects of dexmedetomidine as an adjuvant to bupivacaine in caudal analgesia in pediatric patients posted for infraumbilical surgeries. Settings and Design: This is a randomized, double-blind study in which effect of dexmedetomidine is studied when added to bupivacaine in the caudal epidural block. The observations are made intraoperatively for hemodynamic stability and postoperatively for the duration of analgesia. Subjects and Methods: This study was conducted in 100 children of American Society of Anesthesiologists physical status I and II, aged 2–10 years, undergoing elective infraumbilical surgeries. They were divided into two groups as follows: Group A: (0.25%) bupivacaine 1 ml/kg + normal saline (NS) 1 ml. Group B: (0.25%) bupivacaine 1 ml/kg + 1 μg/kg dexmedetomidine in 1 ml NS. As this study was double-blind, patients were randomly assigned to receive either (bupivacaine + saline) or (bupivacaine + dexmedetomidine) in each group. The patients were observed for hemodynamic stability, respiratory depression, and postoperative pain using face, legs, activity, cry, consolability (FLACC) pain scale for 24 h postoperatively. Statistical Analysis Used: Unpaired Student's t-test. Results: The mean duration of effective analgesia in Group A patients was 4.33 ± 0.98 h versus 9.88 ± 0.90 h in Group B patients. Likewise, the difference in mean FLACC score of both the

  12. Oral transmucosal administration of dexmedetomidine for sedation in 4 dogs

    PubMed Central

    Cohen, Anne E.; Bennett, Sara L.

    2015-01-01

    Injectable dexmedetomidine (DM) is widely used for sedation, restraint, anxiolysis, and analgesia in veterinary medicine. Oral transmucosal dexmedetomidine (OTM DM) has been evaluated in horses, cats, and humans, but not in dogs. In this case series, OTM DM (mean dose of 32.6 μg/kg body weight) was given in the buccal pouch to 4 aggressive dogs in a hospital setting. Two of the dogs were subsequently euthanized, and in the other 2, sedation was reversed with atipamezole. Satisfactory sedation was achieved in all cases. PMID:26538668

  13. Relative myotoxic and haemodynamic effects of the beta-agonists fenoterol and clenbuterol measured in conscious unrestrained rats.

    PubMed

    Burniston, Jatin G; Tan, Lip-Bun; Goldspink, David F

    2006-11-01

    The beta(2)-adrenoceptor (beta(2)-AR) agonists clenbuterol and fenoterol have similar beneficial effects in animal models of heart failure. However, large doses of clenbuterol can induce cardiomyocyte death, and it is not known which of these agents has the most favourable therapeutic profile. We have investigated the cardiotoxicity of clenbuterol and fenoterol alongside that of isoprenaline, and compared their haemodynamic effects. Wistar rats (n = 6 per group) were subcutaneously injected with each beta-agonist (0.003-3 mmol kg(-1)) or saline, and cardiomyocyte apoptosis was detected by caspase 3 immunohistochemistry. In a separate experiment, rats (n = 4) were given equivalent doses to those used in the myotoxicity studies, in a randomized cross-over design, and their blood pressure recorded via radiotelemetry. Injection of 0.3 mmol kg(-1) fenoterol or isoprenaline, but not clenbuterol, induced significant cardiomyocyte apoptosis (0.4 +/- 0.05%; P < 0.05). At 3 mmol kg(-1), all agonists induced apoptosis (fenoterol, 1.1 +/- 0.1%; isoprenaline, 0.9 +/- 0.8%; and clenbuterol, 0.4 +/- 0.07%; P < 0.05). beta(1)-Adrenoceptor antagonism (10 mg kg(-1) bisoprolol) prevented 92% (P < 0.05) of apoptosis induced by all three agonists, but clenbuterol-induced apoptosis could also be prevented by 96% (P < 0.05) by beta(2)-AR antagonism (10 mg kg(-1) ICI 118 551). Clenbuterol decreased diastolic (1.3- to 1.6-fold; P < 0.05) and systolic blood pressure (1.3-fold; P < 0.05), and doses > 0.3 mmol kg(-1) increased heart rate (1.4-fold; P < 0.05). Fenoterol increased heart rate (1.2- to 1.4-fold; P < 0.05), and doses > 0.3 mmol kg(-1) decreased diastolic blood pressure (1.3-fold; P < 0.05). In conclusion, the cardiotoxicity of fenoterol was similar to isoprenaline and greater than clenbuterol, and fenoterol had less desirable haemodynamic effects.

  14. Dexmedetomidine protects from post-myocardial ischaemia reperfusion lung damage in diabetic rats

    PubMed Central

    Kip, Gülay; Çelik, Ali; Bilge, Mustafa; Alkan, Metin; Kiraz, Hasan Ali; Özer, Abdullah; Şıvgın, Volkan; Erdem, Özlem; Arslan, Mustafa; Kavutçu, Mustafa

    2015-01-01

    Objective Diabetic complications and lipid peroxidation are known to have a close association. Lipid peroxidation commonly occurs at sites exposed to ischaemia, but distant organs and tissues also get damaged during ischaemia/reperfusion (I/R). Some of these targets are vital organs, such as the lung, liver, and kidney; the lung is the most frequently affected. The aim of our study was to investigate the effects of dexmedetomidine on I/R damage in lung tissue and on the oxidant/anti-oxidant system in diabetic rats. Material and methods Diabetes was induced with streptozotocin (55 mg/kg) in 18 Wistar Albino rats, which were then randomly divided into three groups (diabetes control (DC), diabetes plus ischaemia-reperfusion (DIR), and diabetes plus dexmedetomidine-ischaemia/reperfusion (DIRD)) after the effects of diabetes were clearly evident. The rats underwent a left thoracotomy and then ischaemia was produced in the myocardium muscle by a left anterior descending artery ligation for 30 min in the DIR and DIRD groups. I/R was performed for 120 min. The DIRD group received a single intraperitoneal dose of dexmedetomidine (100 µg/kg); the DIR group received no dexmedetomidine. Group DC was evaluated as the diabetic control group and also included six rats (C group) in which diabetes was not induced. These mice underwent only left thoracotomy and were closed without undergoing myocardial ischaemia. Histopathological changes, activities of catalase (CAT) and glutathione-S-transferase anti-oxidant enzymes, and malondialdehyde (MDA) levels were evaluated in the lung tissues of all rats. Results Neutrophil infiltration/aggregation was higher in the DIR group than in the C, DC, and DIRD groups (p=0.001, p=0.013, and p=0.042, respectively). The lung injury score was significantly higher in the DIR group than in the C and DC groups (p<0.0001 and p=0.024, respectively). The levels of MDA were significantly higher in the DIR group than in the C and DIRD groups. CAT activity

  15. Adrenoceptor Polymorphisms in Hypertension and Diabetes with obesity-update in 2014.

    PubMed

    Masuo, K

    2014-08-12

    Hypertension, diabetes mellitus (especially type 2 diabetes mellitus) and metabolic syndrome associated with obesity are rapidly growing public health problems. Sympathetic nerve activation is well documented in hypertension, diabetes mellitus, and obesity, hypertension and diabetes are determined by genetic background and environmental factors. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of sympathetic nervous system in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphisms of the -adrenoceptor gene have been shown to alter the function of several adrenoceptor subtype and thus to modify the response to catecholamine. Among β2-adrenoceptor polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile are considered the most functionally important. β2-adrenoceptor genes have been studied in relation to hypertension. Genetic variations in the β3-adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. This review is an update of several versions published of the relationships between adrenoceptor polymorphisms and hypertension, diabetes and obesiy based on the my own review on the relationship with obesity in 2011 in "Journal of Obesity" [1], and another of my own reviews on the relationships with hypertension in 2010 in "International journal of Hypertension" [2], with 37 articles provided by the "PubMed" with the keywords of "adrenoceptor polymorphisms, obesity, hypertension and diabetes" searched on December 2013. However, the relationships of the polymorphisms of β2- and β3-adrenoceptor genes with sympathetic nervous system activity, hypertension and metabolic syndrome have been still discordant, it might be

  16. Aucubin protects against pressure overload-induced cardiac remodelling via the β3 -adrenoceptor-neuronal NOS cascades.

    PubMed

    Wu, Qing-Qing; Xiao, Yang; Duan, Ming-Xia; Yuan, Yuan; Jiang, Xiao-Han; Yang, Zheng; Liao, Hai-Han; Deng, Wei; Tang, Qi-Zhu

    2018-05-01

    Aucubin, the predominant component of Eucommia ulmoides Oliv., has been shown to have profound effects on oxidative stress. As oxidative stress has previously been demonstrated to contribute to acute and chronic myocardial injury, we tested the effects of aucubin on cardiac remodelling and heart failure. Initially, H9c2 cardiomyocytes and neonatal rat cardiomyocytes pretreated with aucubin (1, 3, 10, 25 and 50 μM) were challenged with phenylephrine. Secondly, the transverse aorta was constricted in C57/B6 and neuronal NOS (nNOS)-knockout mice, then aucubin (1 or 5 mg·kg -1 body weight day -1 ) was injected i.p. for 25 days. Hypertrophy was evaluated by assessing morphological changes, echocardiographic parameters, histological analyses and hypertrophic markers. Oxidative stress was evaluated by examining ROS generation, oxidase activity and NO generation. NOS expression was determined by Western blotting. Aucubin effectively suppressed cardiac remodelling; in mice, aucubin substantially inhibited pressure overload-induced cardiac hypertrophy, fibrosis and inflammation, whereas knocking out nNOS abolished these cardioprotective effects of aucubin. Blocking or knocking down the β 3 -adrenoceptor abolished the protective effects of aucubin in vitro. Furthermore, aucubin enhanced the protective effects of a β 3 -adrenoceptor agonist in vitro by increasing cellular cAMP levels, whereas treatment with an adenylate cyclase (AC) inhibitor abolished the cardioprotective effects of aucubin. Aucubin suppresses oxidative stress during cardiac remodelling by increasing the expression of nNOS in a process that requires activation of the β 3 -adrenoceptor/AC/cAMP pathway. These findings suggest that aucubin could have potential as a treatment for cardiac remodelling and heart failure. © 2018 The British Pharmacological Society.

  17. Effects of small-dose dexmedetomidine on hyperdynamic responses to electroconvulsive therapy.

    PubMed

    Li, Xiang; Tan, Fang; Jian, Chao-Jun; Guo, Na; Zhong, Zhi-Yong; Hei, Zi-Qing; Zhou, Shao-Li

    2017-08-01

    Acute hemodynamic responses to electroconvulsive therapy (ECT) may increase the risk of cardiovascular complications in vulnerable patients. The aim of the current study was to assess the effect of small-dose dexmedetomidine on hyperdynamic responses to ECT. Seventy-eight patients were enrolled and randomly allocated to receive either 0.2 μg/kg dexmedetomidine (Dex group, n = 39) or saline (Control group, n = 39) prior to ECT. Heart rate (HR) and mean arterial pressure (MAP) were recorded immediately after the administration of dexmedetomidine (T1), and 0, 1, 3, 5 and 10 min after the electrical stimuli ended (T2, T3, T4, T5 and T6). In addition, the peak HR after ECT, seizure duration, recovery time, and incidence rates of post-ECT adverse effects (agitation, headache and nausea) were also recorded. HR and MAP in the Dex group were significantly lower than those in the Control group from T2 to T5. In addition, peak HR was significantly lower in the Dex group compared with that in the Control group. Seizure length and time to spontaneous breathing, eye opening, and obeying commands in the Dex group were similar to those in the Control group. The incidence rates of post-ECT agitation and headache in the Dex group were significantly lower than that in the Control group. The administration of 0.2 μg/kg dexmedetomidine to patients receiving ECT leads to a significant reduction in HR, MAP, and peak HR responses to ECT without altering seizure duration or delaying recovery. Furthermore, dexmedetomidine effectively reduced the incidence rates of post-ECT adverse effects such as agitation and headache. Copyright © 2017. Published by Elsevier Taiwan LLC.

  18. Effect of dexmedetomidine on the QT interval in pediatric patients undergoing general anesthesia.

    PubMed

    Kako, Hiromi; Krishna, Senthil G; Sebastian, Roby; Smith, Kyle; Tobias, Joseph D

    2015-12-01

    Recent years have seen an increase in the use of dexmedetomidine in pediatric patients presenting for surgical procedures. However, only a limited number of studies have evaluated its effects on the QT interval in this patient group. To address this lack of knowledge, we have evaluated the effects of dexmedetomidine on the QT interval in children receiving sevoflurane anesthesia. This study was a prospective case-control study in which pediatric patients presenting for anesthetic care were divided into two groups--the dexmedetomidine (D) and control (C) groups. Three electrocardiograms (ECGs) were obtained on each patient, including a baseline ECG (T1) prior to anesthetic induction and an ECG after the induction of anesthesia with sevoflurane (T2). In group D, the third ECG was obtained 2 min after the administration of dexmedetomidine, which in turn was started immediately after the T2 ECG reading (T3D); in group C, it was obtained 2 min after the T2 reading (T3C). Statistical analysis was performed using analysis of variance to compare the QT intervals at the three time points outlined above. A total of 50 patients were recruited to the study, ranging in age from 1 to 16 [mean 7.9 ± 4.1 (SD) years]. There were 25 patients in group C and 25 in group D. There were no statistical differences in the demographics between the 2 groups. In group C, the QTc was noted to increase progressively with the administration of sevoflurane (T3C vs. T1; P = 0.006). In group D, following the administration of dexmedetomidine, there was a significant decrease in the QTc relative to the post-induction value [436 ± 25 (T2) vs. 418 ± 17 ms (T3D); P < 0.01]. A progressive lengthening of the QTc interval following the administration of sevoflurane was observed in the control group. In the dexmedetomidine group, there was a significant shortening of the QTc interval following the administration of dexmedetomidine compared to the length of the post-induction QTc interval and when

  19. Activation of beta- and alpha-2-adrenoceptors in the basolateral amygdala has opposing effects on hippocampal-prefrontal long-term potentiation.

    PubMed

    Lim, Ee Peng; Dawe, Gavin S; Jay, Thérèse M

    2017-01-01

    Noradrenaline (NA), released by the locus coeruleus (LC), plays a key role in mediating the effects of stress on memory functions. The LC provides diffuse projections to many forebrain nuclei including the hippocampus, the prefrontal cortex (PFC), and the basolateral amygdala (BLA). These three structures are intricately interlinked. The hippocampal-prefrontal (H-PFC) pathway is involved in various cognitive functions. The first aim of this study was to examine the role of BLA in H-PFC plasticity by infusion of drugs to activate and inactivate the BLA and studying the effects on H-PFC long-term potentiation (LTP) in the rat in vivo. Activation of the BLA with glutamate impaired, while inactivation with muscimol augmented, H-PFC LTP. This study also aimed to demonstrate how directly applying noradrenaline and other noradrenergic agents in the BLA can affect H-PFC LTP. Noradrenaline at 1μg/0.2μl enhanced H-PFC LTP. Stimulating alpha-2-adrenoceptors in the BLA with clonidine enhanced LTP while blocking alpha-2 adrenoceptors with idazoxan impaired it. Propranolol, a non-selective beta antagonist, enhanced H-PFC LTP while isoprenaline, a non-selective beta agonist, decreased H-PFC LTP. These results suggest that the BLA regulates H-PFC plasticity negatively and also provide a mechanism by which noradrenaline in the BLA can affect H-PFC plasticity via alpha-2 and beta adrenoceptors. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Effects of short-term propofol and dexmedetomidine on pulmonary morphofunction and biological markers in experimental mild acute lung injury.

    PubMed

    Cavalcanti, Vinícius; Santos, Cintia Lourenço; Samary, Cynthia Santos; Araújo, Mariana Neves; Heil, Luciana Boavista Barros; Morales, Marcelo Marcos; Silva, Pedro Leme; Pelosi, Paolo; Fernandes, Fatima Carneiro; Villela, Nivaldo; Rocco, Patricia Rieken Macedo

    2014-11-01

    We evaluated whether the short-term use of dexmedetomidine and propofol may attenuate inflammatory response and improve lung morphofunction in experimental acute lung injury (ALI). Thirty-six Wistar rats were randomly divided into five groups. Control (C) and ALI animals received sterile saline solution and Escherichia coli lipopolysaccharide by intraperitoneal injection respectively. After 24h, ALI animals were randomly treated with dexmedetomidine, propofol, or thiopental sodium for 1h. Propofol reduced static lung elastance and resistive pressure and was associated with less alveolar collapse compared to thiopental sodium and dexmedetomidine. Dexmedetomidine improved oxygenation, but did not modify lung mechanics or histology. Propofol was associated with lower IL (interleukin)-6 and IL-1β expression, whereas dexmedetomidine led to reduced inducible nitric oxide (iNOS) and increased nuclear factor erythroid 2-related factor 2 (Nrf2) expression in lung tissue compared to thiopental sodium. In conclusion, in this model of mild ALI, short-term use of dexmedetomidine and propofol led to different functional effects and activation of biological markers associated with pulmonary inflammation. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Effect of adrenaline and alpha-agonists on net rate of liquid absorption from the pleural space of rabbits.

    PubMed

    Zocchi, L; Raffaini, A; Agostoni, E

    1997-05-01

    Indirect evidence supporting a solute-coupled liquid absorption from the pleural space of rabbits has recently been provided; moreover, the beta 2-adrenoceptor agonist terbutaline has been found to increase this absorption. In this study the effect of adrenaline and alpha-adrenoceptor agonists on net rate of liquid absorption (Jnet) from albumin Ringer hydrothoraces of various sizes has been determined in anaesthetized rabbits. In hydrothoraces with adrenaline (5 x 10(-6) M) the relationship between Jnet and volume of liquid injected was displaced upwards by 0.09 ml h-1 relative to that in control hydrothoraces (P < 0.01). This displacement did not occur with lower adrenaline concentrations or after pretreatment with the beta-blocker propranolol. Hence, this increase in Jnet is mediated by stimulation of beta-receptors. It seems to be caused by an increase in solute-coupled liquid absorption, since beta-agonists inhibit lymphatic activity while, at relatively high concentrations, they may increase active transport. Conversely, the strong stimulation of lymphatic alpha-receptors that should occur with adrenaline after beta-blockade may fail to increase lymphatic drainage, because it has been shown that the increase in contraction frequency of lymphatics may be balanced by the decrease in their stroke volume. Arterial blood pressure during the hydrothoraces with adrenaline was unchanged. In hydrothoraces with the alpha 2-agonist clonidine (5 x 10(-6) M; a less potent agent than adrenaline) the slope of the relationship between Jnet and volume injected increased by 26% (P < 0.01), while its origin did not change. This increase in slope did not occur with a lower clonidine concentration or after pretreatment with the alpha-blocker phentolamine. Hence, it is caused by stimulation of alpha 2-receptors, which probably lead to an increase in lymphatic drainage related to liquid load. In hydrothoraces with the alpha 1-agonist phenylephrine (5 x 10(-6) or 10(-7) M) Jnet was

  2. Dexmedetomidine reduces pain associated with rocuronium injection without causing a decrease in BIS values: a dose-response study.

    PubMed

    Joo, Jin; Baek, Jungwon; Lee, Jaemin

    2014-09-01

    To examine whether dexmedetomidine reduces the injection pain of propofol and rocuronium and to investigate whether the decrease in injection pain is associated with the known sedative action of dexmedetomidine. Randomized, double-blind, placebo-controlled clinical comparison study. Patients undergoing general anesthesia with intubation received 40 mg of 1% lidocaine (lidocaine group; n = 28), 0.25 μg/kg of dexmedetomidine (low-dose group; n = 27), 0.5 μg/kg of dexmedetomidine (subclinical dose group; n = 28), 1.0 μg/kg of dexmedetomidine (clinical dose group, n = 27), or normal saline (saline group; n = 28) before anesthetic induction. Pain associated with propofol and rocuronium injection was assessed using a 10-point verbal analog scale (VAS) and a 4-point withdrawal movement scale, respectively. The BIS value was measured 60 seconds after administration of the study drug, and at the time of rocuronium injection and intubation. The overall incidence of withdrawal movements due to rocuronium decreased significantly as the dose of dexmedetomidine increased (92.8%, 85.2%, 78.6%, and 51.9% in the saline, low-dose, subclinical dose, and clinical dose groups, respectively; P = 0.001). There was no significant difference in BIS values among the groups 60 seconds after study drug administration or at the time of rocuronium injection. Dexmedetomidine reduced pain associated with rocuronium injection in a dose-dependent manner. This effect was not associated with the decrease in BIS value. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Pharmacokinetics of Mirabegron, a β3-Adrenoceptor Agonist for Treatment of Overactive Bladder, in Healthy East Asian Subjects.

    PubMed

    Iitsuka, Hiromi; van Gelderen, Marcel; Katashima, Masataka; Takusagawa, Shin; Sawamoto, Taiji

    2015-05-01

    The objective of these studies was to evaluate the pharmacokinetic profile, safety, and tolerability of mirabegron, a β3-adrenoceptor agonist for the treatment of overactive bladder, including food effects (low- or high-fat meals) and sex, in healthy East Asian subjects. In total, 5 pharmacokinetic studies of mirabegron were conducted in healthy East Asian subjects. Food effects were assessed in 3 randomized, single-dose studies in young Japanese male subjects (study 1), male and female subjects (study 2), and young Taiwanese male and female subjects (study 3). In the other 2 single- and multiple-dose studies in young Chinese male and female subjects (study 4 and study 5), mirabegron was administered as a single dose under fasted conditions. After the washout period, mirabegron was administered once daily under fed conditions for 8 days. Pharmacokinetic parameters were determined using noncompartmental methods. Safety and tolerability assessments included physical examinations, vital signs, 12-lead ECG, clinical laboratory tests (biochemistry, hematology, and urinalysis), and adverse event monitoring. After administration of single oral doses of mirabegron, exposure under fed conditions was lower than under fasted conditions in Japanese and Taiwanese subjects. In Japanese subjects, a greater reduction in mirabegron Cmax and AUC0-∞ was observed after a low-fat meal compared with a high-fat meal. In Chinese subjects, Cmax was reached at approximately 4.0 hours after single oral doses. Mirabegron accumulated 2- to 3-fold on once-daily dosing of multiple-dose relative to single-dose data. Steady state was reached within 7 days. After administration of mirabegron, mean values for Cmax and AUC in female subjects were higher than those in male subjects. Mirabegron was well tolerated in Japanese, Taiwanese, and Chinese subjects. Our studies confirm the higher exposure levels of mirabegron in female compared with male East Asian subjects as found earlier in Western

  4. L-arginine and Arginase Products Potentiate Dexmedetomidine-induced Contractions in the Rat Aorta.

    PubMed

    Wong, Emily S W; Man, Ricky Y K; Ng, Kwok F J; Leung, Susan W S; Vanhoutte, Paul M

    2018-03-01

    The α2-adrenergic sedative/anesthetic agent dexmedetomidine exerts biphasic effects on isolated arteries, causing endothelium-dependent relaxations at concentrations at or below 30 nM, followed by contractions at higher concentrations. L-arginine is a common substrate of endothelial nitric oxide synthase and arginases. This study was designed to investigate the role of L-arginine in modulating the overall vascular response to dexmedetomidine. Isometric tension was measured in isolated aortic rings of Sprague Dawley rats. Cumulative concentrations of dexmedetomidine (10 nM to 10 μM) were added to quiescent rings (with and without endothelium) after previous incubation with vehicle, N-nitro-L-arginine methyl ester hydrochloride (L-NAME; nitric oxide synthase inhibitor), prazosin (α1-adrenergic antagonist), rauwolscine (α2-adrenergic antagonist), L-arginine, (S)-(2-boronethyl)-L-cysteine hydrochloride (arginase inhibitor), N-hydroxy-L-arginine (arginase inhibitor), urea and/or ornithine. In some preparations, immunofluorescent staining, immunoblotting, or measurement of urea content were performed. Dexmedetomidine did not contract control rings with endothelium but evoked concentration-dependent increases in tension in such rings treated with L-NAME (Emax 50 ± 4%) or after endothelium-removal (Emax 74 ± 5%; N = 7 to 12). Exogenous L-arginine augmented the dexmedetomidine-induced contractions in the presence of L-NAME (Emax 75 ± 3%). This potentiation was abolished by (S)-(2-boronethyl)-L-cysteine hydrochloride (Emax 16 ± 4%) and N-hydroxy-L-arginine (Emax 18 ± 4%). Either urea or ornithine, the downstream arginase products, had a similar potentiating effect as L-arginine. Immunoassay measurements demonstrated an upregulation of arginase I by L-arginine treatment in the presence of L-NAME (N = 4). These results suggest that when vascular nitric oxide homeostasis is impaired, the potentiation of the vasoconstrictor effect of

  5. Dexmedetomidine and general anesthesia: a narrative literature review of its major indications for use in adults undergoing non-cardiac surgery.

    PubMed

    Davy, Arthur; Fessler, Julien; Fischler, Marc; LE Guen, Morgan

    2017-12-01

    In Europe, dexmedetomidine has marketing approval only for sedation in intensive care units. However, its use during general anesthesia has been widely reported. The aim of this narrative review is to draw a picture of potential indications in anesthesia. We searched in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials using the keywords "Dexmedetomidine, Dexdor, Precedex and Dexdomitor." The research ended in December 2016. Studies were eligible for inclusion if they reported the use of dexmedetomidine in adults receiving general anesthesia. We excluded studies related to cardiac surgery and studies reporting the use of dexmedetomidine as an adjuvant of locoregional anesthesia. Several potential uses for dexmedetomidine during general anesthesia are described, especially: awake fiber optic intubation, the sparing effect of dexmedetomidine on hypnotic and opioid drugs, prevention of postoperative pain, nausea and vomiting and shivering, improvement of postoperative sleep and postoperative recovery, opioid-free anesthesia, use in craniotomy, endovascular stroke treatment and drug-induced sleep endoscopy. A protective effect against cardiac complications, an anti-inflammatory effect, and side effects, particularly bradycardia, are also described. The properties of dexmedetomidine lead to its use for elective indications such as awake fiberoptic intubation and neurosurgical anesthesia. New topics are under debate. These subjects must be studied thoroughly because of their implication in the patients' surgical course. These advantages must be weighed against the major drawback of dexmedetomidine administration which is the potential for hemodynamic abnormalities.

  6. Dexmedetomidine Inhibits Maturation and Function of Human Cord Blood-Derived Dendritic Cells by Interfering with Synthesis and Secretion of IL-12 and IL-23

    PubMed Central

    Chen, Gong; Le, Yuan; Zhou, Lei; Gong, Li; Li, Xiaoxiao; Li, Yunli; Liao, Qin; Duan, Kaiming; Tong, Jianbin; Ouyang, Wen

    2016-01-01

    Aims To investigate the effects and underlying mechanism of dexmedetomidine on the cultured human dendritic cells (DCs). Methods Human DCs and cytotoxic T lymphocytes (CTLs) were obtained from human cord blood mononuclear cells by density gradient centrifugation. Cultured DCs were divided into three groups: dexmedetomidine group, dexmedetomidine plus yohimbine (dexmedetomidine inhibitor) group and control group. DCs in the three groups were treated with dexmedetomidine, dexmedetomidine plus yohimbine and culture medium, respectively. After washing, the DCs were co-incubated with cultured CTLs. The maturation degree of DCs was evaluated by detecting (1) the ratios of HLA-DR-, CD86-, and CD80-positive cells (flow cytometry), and (2) expression of IL-12 and IL-23 (PCR and Elisa). The function of DCs was evaluated by detecting the proliferation (MTS assay) and cytotoxicity activity (the Elisa of IFN-γ) of CTLs. In addition, in order to explore the mechanisms of dexmedetomidine modulating DCs, α2-adrenergic receptor and its downstream signals in DCs were also detected. Results The ratios of HLA-DR-, CD86-, and CD80-positive cells to total cells were similar among the three groups (P>0.05). Compared to the control group, the protein levels of IL-12 and IL-23 in the culture medium and the mRNA levels of IL-12 p35, IL-12 p40 and IL-23 p19 in the DCs all decreased in dexmedetomidine group (P<0.05). In addition, the proliferation of CTLs and the secretion of IFN-γ also decreased in the dexmedetomidine group, compared with the control group (P<0.05). Moreover, these changes induced by dexmedetomidine in the dexmedetomidine group were reversed by α2-adrenergic receptor inhibitor yohimbine in the dexmedetomidine plus yohimbine group. It was also found the decrease of mRNA levels of IL-12 p35, IL-12 p40 and IL-23 p19 in the dexmedetomidine group could be reversed by ERK1/2 or AKT inhibitors. Conclusion Dexmedetomidine could negatively modulate human immunity by inhibiting

  7. Sedative and echocardiographic effects of dexmedetomidine combined with butorphanol in healthy dogs.

    PubMed

    Kellihan, H B; Stepien, R L; Hassen, K M; Smith, L J

    2015-12-01

    To evaluate the echocardiographic variables and sedation after two dosages of dexmedetomidine combined with butorphanol in healthy dogs. Fourteen healthy dogs. The dogs received dexmedetomidine 5 mcg/kg IM and butorphanol 0.4 mg/kg (low dose (LD), n = 6) or dexmedetomidine 10 mcg/kg IM and butorphanol 0.4 mg/kg (recommended dose (RD), n = 8). Sedation scoring, noninvasive blood pressure measurement, and echocardiography were performed before sedation at baseline, at 20 minutes (T20), and 60 minutes (T60) after drug administration. The median sedation scores were increased at both T20 and T60 in the RD group, and at T60 in the LD group, compared with baseline (p < 0.0001, p = 0.012). At T60, the RD dogs were more sedated than the LD dogs (p = 0.0093). The median cardiac output (CO) decreased at both T20 (63%) and T60 (65%) in the RD group and at T60 (42%) in the LD group, compared with baseline (p = 0.0011, p = 0.0055). The median heart rate (HR) was decreased at both T20 and T60 in the RD group and at T60 in the LD group, compared with baseline (p = 0.0009, p = 0.0001). In both RD and LD dogs, valvular regurgitation developed and was identified by color Doppler imaging. There were significant hemodynamic changes, mainly related to HR and indices of systolic function, following administration of dexmedetomidine in these healthy dogs. The changes also included decreases in systolic function and CO, as well as appearance of 'new' valvular regurgitation. Caution should be used when considering dexmedetomidine for sedation in dogs with, or being screened for, cardiovascular disease. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. The effect of dexmedetomidine sedation on patient and surgeon satisfaction during retinal surgery under sub-tenon's anesthesia: a randomized controlled trial.

    PubMed

    Yoo, Jae-Hwa; Kim, Soon Im; Cho, Ana; Lee, Sung Jin; Sun, Hae Jung; Cho, Ho Bum; Lee, Dong Ryun

    2015-10-01

    The purpose of this study was to evaluate the effect of intraoperative dexmedetomidine sedation on patient's and surgeon's satisfaction during retinal surgery under sub-tenon's anesthesia. Forty-four patients scheduled for elective retinal surgery under sub-tenon's anesthesia were enrolled in this randomized controlled trial. The patients were divided into Dexmedetomidine (n = 22) and Control (n = 22) groups. Intravenous dexmedetomidine or 0.9% saline via infusion pump were administered continuously to the dexmedetomidine or control group, respectively. Ramsay sedation scale with a target level of 3-4 was used to assess adequacy of sedation. Perioperative pain, hemodynamic and respiratory data were collected, while satisfaction from patients and surgeon were assessed post-surgery using a 5-point satisfaction scale. Patient and surgeon satisfaction was higher in the dexmedetomidine group (P < 0.001, P = 0.002, respectively). The pain associated with sub-tenon's anesthesia and peripheral vitrectomy was lesser in the dexmedetomidine group than in the control group (P = 0.020). There was significant reduction of heart rate in the dexmedetomidine group (P = 0.001), but only one patient needed treatment with atropine. There was no respiratory effect on both groups. Dexmedetomidine sedation during retinal surgery improved satisfaction from both patient and surgeon without respiratory complication. It is a safe and preferable choice of sedation for retinal surgery.

  9. A dose-response study of dexmedetomidine administered as the primary sedative in infants following open heart surgery.

    PubMed

    Su, Felice; Nicolson, Susan C; Zuppa, Athena F

    2013-06-01

    To evaluate the dose-response relationship of dexmedetomidine in infants with congenital heart disease postoperative from open heart surgery. Prospective open-label dose-escalation pharmacokinetic-pharmacodynamic study. Tertiary pediatric cardiac ICU. Thirty-six evaluable infants, 1-24 months old, postoperative from open heart surgery requiring mechanical ventilation. Cohorts of 12 infants were enrolled sequentially to one of the three IV loading doses of dexmedetomidine (0.35, 0.7, and 1 mcg/kg) over 10 minutes followed by respective continuous infusions (0.25, 0.5, and 0.75 mcg/kg/hr) for up to 24 hours. Dexmedetomidine plasma concentrations were obtained at timed intervals during and following discontinuation of infusion. Pharmacodynamic variables evaluated included sedation scores, supplemental sedation and analgesia medication administration, time to tracheal extubation, respiratory function, and hemodynamic parameters. Infants achieved a deeper sedation measured by the University of Michigan Sedation Scale score (2.6 vs 1) despite requiring minimal supplemental sedation (0 unit doses/hr) and fewer analgesic medications (0.07 vs 0.15 unit doses/hr) while receiving dexmedetomidine compared with the 12-hour follow-up period. Thirty-one patients were successfully extubated while receiving the dexmedetomidine infusion. Only one patient remained intubated due to oversedation during the infusion. While receiving dexmedetomidine, there was a decrease in heart rate compared with baseline, 132 versus 161 bpm, but there was an increase in heart rate compared with postinfusion values, 132 versus 128 bpm. There was no statistically or clinically significant change in mean arterial blood pressure. Dexmedetomidine administration in infants following open heart surgery can provide improved sedation with reduction in supplemental medication requirements, leading to successful extubation while receiving a continuous infusion. The postoperative hemodynamic changes that occur in

  10. [A prospective, randomized, double-blinded control study on comparison of tramadol, clonidine and dexmedetomidine for post spinal anesthesia shivering].

    PubMed

    Venkatraman, Rajagopalan; Karthik, Krishnamoorthy; Pushparani, Anand; Mahalakshmi, Annadurai

    Shivering, a common intraoperative problem under spinal anesthesia increases the oxygen consumption considerably and is uncomfortable and distressing to the patient, anesthesiologist as well as surgeon. The present study was designed to explore the effectiveness of tramadol, clonidine and dexmedetomidine in the treatment of post spinal anesthesia shivering and to look for their adverse effects. This prospective, randomized, double blinded control study was done on 90 patients who developed shivering under spinal anesthesia. They were randomly allocated into three groups with Group T receiving tramadol 1mg.kg -1 , Group C getting clonidine 1mcg.kg -1 and Group D patients receiving dexmedetomidine 0.5mcg.kg -1 . The time taken to control shivering, recurrence rate, hemodynamic variables, sedation score and adverse effects were observed. Dexmedetomidine was faster in the control of shivering in 5.7±0.79minutes (min) whereas tramadol took 6.76±0.93min and clonidine was slower with 9.43±0.93min. The recurrence rate was much lower in the dexmedetomidine group with 3.3% than for clonidine (10%) and tramadol (23.3%) group. The sedation achieved with dexmedetomidine was better than clonidine and tramadol. The tramadol group had more cases of vomiting (four) and dexmedetomidine group had six cases of hypotension and two cases of bradycardia. Two of the clonidine patients encountered bradycardia and hypotension. Dexmedetomidine is better than tramadol and clonidine in the control of shivering because of its faster onset and less recurrence rate. Though complications are encountered in the dexmedetomidine group, they are treatable. Copyright © 2016 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  11. Dexmedetomidine and Mannitol for Awake Craniotomy in a Pregnant Patient.

    PubMed

    Handlogten, Kathryn S; Sharpe, Emily E; Brost, Brian C; Parney, Ian F; Pasternak, Jeffrey J

    2015-05-01

    We describe the use of dexmedetomidine for an awake neurosurgical procedure in a pregnant patient and quantify the effect of mannitol on intrauterine volume. A 27-year-old woman underwent a craniotomy, with intraprocedural motor and speech mapping, at 20 weeks of gestation. Sedation was maintained with dexmedetomidine. Mannitol at 0.25 g/kg IV was administered to control brain volume during surgery. Internal uterine volume was estimated at 1092 cm before surgery and decreased to 770 and 953 cm at 9 and 48 hours, respectively, after baseline assessment. No adverse maternal or fetal effects were noted during the intraoperative period or up to 48 hours postoperatively.

  12. Comparing the efficacy and safety between propofol and dexmedetomidine for sedation in claustrophobic adults undergoing magnetic resonance imaging (PADAM trial).

    PubMed

    Loh, Pui-San; Ariffin, Mohd Azlan; Rai, Vineya; Lai, Lee-Lee; Chan, Lucy; Ramli, Norlisah

    2016-11-01

    To determine the efficacy of sedation with dexmedetomidine compared to propofol for claustrophobic adults undergoing magnetic resonance imaging (MRI) in our institution. Randomized, prospective, double-blinded study. University-based tertiary referral center. Thirty claustrophobic adults with American Society of Anesthesiologists physical status I and II who were planned for MRI. Patients were randomly assigned to target-controlled infusion propofol or dexmedetomidine loading followed by maintenance dose for procedural sedation. The primary end point was adequate reduction in patient anxiety levels to allow successful completion of the MRI sequence. Both methods of sedation adequately reduced anxiety levels in visual analog scale scores and Spielberger Strait Test Anxiety Inventory (P<.001). Dexmedetomidine required a longer time to achieve anxiolysis, 7.36minutes (SD, 2.59), and required increasing maintenance dose to induce sleep compared to 10.71minutes (SD, 4.63) for propofol. In terms of image quality, 2 patients (16.67%) in the dexmedetomidine group were satisfactory, whereas all with propofol were graded as good to excellent. Adverse effects were seen in patients sedated with dexmedetomidine with number needed to harm 8 for hypotension and 15 for bradycardia compared to none recorded in the propofol arm. There was no significant difference in patient satisfaction scores or home readiness after the MRI. Both dexmedetomidine and propofol can effectively reduce anxiety levels of claustrophobic adults undergoing MRI, but dexmedetomidine takes longer to achieve adequate anxiolysis and sleep and may have an effect on image quality. Hypotension and bradycardia are common adverse effects observed with dexmedetomidine. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Conopeptide ρ-TIA defines a new allosteric site on the extracellular surface of the α1B-adrenoceptor.

    PubMed

    Ragnarsson, Lotten; Wang, Ching-I Anderson; Andersson, Åsa; Fajarningsih, Dewi; Monks, Thea; Brust, Andreas; Rosengren, K Johan; Lewis, Richard J

    2013-01-18

    The G protein-coupled receptor (GPCR) superfamily is an important drug target that includes over 1000 membrane receptors that functionally couple extracellular stimuli to intracellular effectors. Despite the potential of extracellular surface (ECS) residues in GPCRs to interact with subtype-specific allosteric modulators, few ECS pharmacophores for class A receptors have been identified. Using the turkey β(1)-adrenergic receptor crystal structure, we modeled the α(1B)-adrenoceptor (α(1B)-AR) to help identify the allosteric site for ρ-conopeptide TIA, an inverse agonist at this receptor. Combining mutational radioligand binding and inositol 1-phosphate signaling studies, together with molecular docking simulations using a refined NMR structure of ρ-TIA, we identified 14 residues on the ECS of the α(1B)-AR that influenced ρ-TIA binding. Double mutant cycle analysis and docking confirmed that ρ-TIA binding was dominated by a salt bridge and cation-π between Arg-4-ρ-TIA and Asp-327 and Phe-330, respectively, and a T-stacking-π interaction between Trp-3-ρ-TIA and Phe-330. Water-bridging hydrogen bonds between Asn-2-ρ-TIA and Val-197, Trp-3-ρ-TIA and Ser-318, and the positively charged N terminus and Glu-186, were also identified. These interactions reveal that peptide binding to the ECS on transmembrane helix 6 (TMH6) and TMH7 at the base of extracellular loop 3 (ECL3) is sufficient to allosterically inhibit agonist signaling at a GPCR. The ligand-accessible ECS residues identified provide the first view of an allosteric inhibitor pharmacophore for α(1)-adrenoceptors and mechanistic insight and a new set of structural constraints for the design of allosteric antagonists at related GPCRs.

  14. Long-Acting Beta Agonists Enhance Allergic Airway Disease.

    PubMed

    Knight, John M; Mak, Garbo; Shaw, Joanne; Porter, Paul; McDermott, Catherine; Roberts, Luz; You, Ran; Yuan, Xiaoyi; Millien, Valentine O; Qian, Yuping; Song, Li-Zhen; Frazier, Vincent; Kim, Choel; Kim, Jeong Joo; Bond, Richard A; Milner, Joshua D; Zhang, Yuan; Mandal, Pijus K; Luong, Amber; Kheradmand, Farrah; McMurray, John S; Corry, David B

    2015-01-01

    Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6.

  15. Curcumin and dexmedetomidine prevents oxidative stress and renal injury in hind limb ischemia/reperfusion injury in a rat model.

    PubMed

    Karahan, M A; Yalcin, S; Aydogan, H; Büyükfirat, E; Kücük, A; Kocarslan, S; Yüce, H H; Taskın, A; Aksoy, N

    2016-06-01

    Curcumin and dexmedetomidine have been shown to have protective effects in ischemia-reperfusion injury on various organs. However, their protective effects on kidney tissue against ischemia-reperfusion injury remain unclear. We aimed to determine whether curcumin or dexmedetomidine prevents renal tissue from injury that was induced by hind limb ischemia-reperfusion in rats. Fifty rats were divided into five groups: sham, control, curcumin (CUR) group (200 mg/kg curcumin, n = 10), dexmedetomidine (DEX) group (25 μg/kg dexmedetomidine, n = 10), and curcumin-dexmedetomidine (CUR-DEX) group (200 mg/kg curcumin and 25 μg/kg dexmedetomidine). Curcumin and dexmedetomidine were administered intraperitoneally immediately after the end of 4 h ischemia, just 5 min before reperfusion. The extremity re-perfused for 2 h and then blood samples were taken and total antioxidant capacity (TAC), total oxidative status (TOS) levels, and oxidative stress index (OSI) were measured, and renal tissue samples were histopathologically examined. The TAC activity levels in blood samples were significantly lower in the control than the other groups (p < 0.01 for all comparisons). The TOS activity levels in blood samples were significantly higher in Control group and than the other groups (p <  0.01 for all comparison). The OSI were found to be significantly increased in the control group compared to others groups (p < 0.001 for all comparisons). Histopathological examination revealed less severe lesions in the sham, CUR, DEX, and CUR-DEX groups, compared with the control group (p < 0.01). Rat hind limb ischemia-reperfusion causes histopathological changes in the kidneys. Curcumin and dexmedetomidine administered intraperitoneally was effective in reducing oxidative stress and renal histopathologic injury in an acute hind limb I/R rat model.

  16. Effect of Two Different Doses of Dexmedetomidine on Stress Response in Laparoscopic Pyeloplasty: A Randomized Prospective Controlled Study.

    PubMed

    Shamim, Rafat; Srivastava, Shashi; Rastogi, Amit; Kishore, Kamal; Srivastava, Aneesh

    2017-01-01

    Clonidine, opioids, β-blockers, and dexmedetomidine have been tried to attenuate stress responses during laparoscopic surgery. We evaluated the efficacy of dexmedetomidine in two different doses in attenuating stress responses on patients undergoing laparoscopic pyeloplasty. Ninety patients were assigned to one of the three groups: Group A, Group B, and Group C. Group B received dexmedetomidine 1 mcg/kg as loading dose, followed by 0.7 mcg/kg/h for maintenance; Group C received dexmedetomidine 0.7 mcg/kg as a loading dose, followed by 0.5 mcg/kg/h for maintenance. Group A received normal saline. Stress responses were assessed by the variations in heart rate (HR), mean arterial pressure (MAP), blood glucose levels, and serum cortisol levels. One-way analysis of variance test was applied. Multiple comparisons between groups were done with post hoc Bonferroni test. The HR and MAP were found to be higher in Group A. The difference was statistically significant ( P < 0.05) during intubation, carbon dioxide insufflation, and extubation when compared with Groups B and C. Blood glucose levels at postintubation and at extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. Serum cortisol levels at postintubation, during midsurgery, and 2 h after extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. However, HR, MAP, blood glucose levels, and serum cortisol levels were similar in dexmedetomidine groups. Dexmedetomidine decreases stress response and provides good condition for maintenance of anesthesia. Dexmedetomidine when used in lower dose in Group C decreases stress response comparable to higher dose in Group B.

  17. Alfaxalone versus alfaxalone-dexmedetomidine anaesthesia by immersion in oriental fire-bellied toads (Bombina orientalis).

    PubMed

    Adami, Chiara; d'Ovidio, Dario; Casoni, Daniela

    2016-05-01

    To determine a dexmedetomidine concentration, to be added to an alfaxalone-based bath solution, that will enhance the anaesthetic and analgesic effects of alfaxalone; and to compare the quality of anaesthesia and analgesia provided by immersion with either alfaxalone alone or alfaxalone with dexmedetomidine in oriental fire-bellied toads (Bombina orientalis). Pilot study followed by a prospective, randomized, experimental trial. Fourteen oriental fire-bellied toads. The pilot study aimed to identify a useful dexmedetomidine concentration to be added to an anaesthetic bath containing 20 mg 100 mL(-1) alfaxalone. Thereafter, the toads were assigned to one of two groups, each comprising eight animals, to be administered either alfaxalone (group A) or alfaxalone-dexmedetomidine (group AD). After immersion for 20 minutes, the toads were removed from the anaesthetic bath and the righting, myotactic and nociceptive reflexes, cardiopulmonary variables and von Frey filaments threshold were measured at 5 minute intervals and compared statistically between groups. Side effects and complications were noted and recorded. In the pilot study, a dexmedetomidine concentration of 0.3 mg 100 mL(-1) added to the alfaxalone-based solution resulted in surgical anaesthesia. The toads in group AD showed higher von Frey thresholds and lower nociceptive withdrawal reflex scores than those in group A. However, in group AD, surgical anaesthesia was observed in two out of eight toads only, and induction of anaesthesia was achieved in only 50% of the animals, as compared with 100% of the toads in group A. The addition of dexmedetomidine to an alfaxalone-based solution for immersion anaesthesia provided some analgesia in oriental fire-bellied toads, but failed to potentiate the level of unconsciousness and appeared to lighten the depth of anaesthesia. This limitation renders the combination unsuitable for anaesthetizing oriental fire-bellied toads for invasive procedures. © 2015

  18. Dexmedetomidine-related atrial standstill and loss of capture in a pediatric patient after congenital heart surgery.

    PubMed

    Shepard, Suzanne M; Tejman-Yarden, Shai; Khanna, Sandeep; Davis, Christopher K; Batra, Anjan S

    2011-01-01

    Dexmedetomidine (DEX; Precedex) is an alpha-2 adrenergic receptor agonist that produces anxiolysis and sleep-like sedation without narcosis or respiratory depression and has relatively few cardiovascular side effects. Given its favorable sedative properties combined with its limited effects on hemodynamic and respiratory function, it is widely used in pediatric intensive care and anesthesia settings. Case report. Pediatric intensive care unit. A three-yr-old girl was admitted after mitral valve replacement for persistent severe mitral insufficiency. Her prior history was significant for tetralogy of Fallot which was repaired at nine months of age. A year later the patient developed mitral and tricuspid valve insufficiency and subsequently underwent mitral and tricuspid valve repair, pulmonary valve replacement, and a maze procedure (the latter was performed for persistent atrial flutter). Following that operation she developed sinus node dysfunction and had a permanent epicardial dual-chamber pacemaker implanted. Due to remaining severe mitral insufficiency the patient had increasing pulmonary symptoms, necessitating the most recent surgery to replace her mitral valve. On postoperative day two the patient was hemodynamically stable and weaning off mechanical ventilation. Tracheal extubation was anticipated to occur within the next 24 hrs. A DEX infusion of 0.6 mcg/kg/hr was initiated. A pacemaker interrogation performed on postoperative day three, 21 hrs after the initiation of DEX, revealed unsuccessful atrial capture. Dexmedetomidine was subsequently discontinued and the patient's pacemaker was reinterrogated. The interrogation findings were similar to those seen prior to the initiation of DEX. As a result of these findings, caution is warranted in the administration of DEX to patients with predisposing conduction abnormalities and patients who are pacemaker-dependent.

  19. Oxysterol, 5α-cholestan-3-one, modulates a contractile response to β2-adrenoceptor stimulation in the mouse atria: Involvement of NO signaling.

    PubMed

    Sytchev, Vaycheslav I; Odnoshivkina, Yulia G; Ursan, Roman V; Petrov, Alexey M

    2017-11-01

    Atrial β2-adrenoceptors provide an important mechanism for regulation of cardiac function and changes in their downstream signaling are involved in processes underlying heart disorders. We have investigated the mechanism by which the cholesterol metabolite 5α-cholestan-3-one (5ɑCh3) modulates inotropic effect of β2-adrenoceptor agonist fenoterol. Atria from mice were electrically stimulated and changes in contraction amplitude in response to fenoterol were studied in 5ɑCh3-pretreated samples. Intracellular Ca 2+ and NO levels were estimated using fluorescent dyes Fluo-4 and DAF-FM, respectively. By itself 5αCh3 that appears in the circulation under some pathological conditions had a negligible influence on contraction, Ca 2+ -transient and NO production. However, pretreatment with 5αCh3 markedly attenuated the positive inotropic effect of fenoterol which was accompanied by an increase in the NO synthesis. Unexpectedly, the oxysterol also augmented an enhancement of Ca 2+ -transient amplitude in response to fenoterol. Under conditions of a pharmacological inhibition of G i -protein/Akt/NO synthase/protein kinase G signaling, 5αCh3 augmented the inotropic effect of fenoterol. Herein, Akt antagonist suppressed the increase in NO production, while inhibition of NO synthesis did not modify the increased amplitude of the Ca 2+ -transient. Along similar lines, enrichment of plasma membranes with cholesterol reduced the stimulatory effect of 5αCh3 on β2-adrenoceptor-evoked NO production, but not on the Ca2+-transient amplitude, leading to an elevation of the positive inotropic response to fenoterol. These data suggest that 5ɑCh3 potentiates the effect of pharmacological β2-adrenoceptor activation on both NO production and Ca 2+ transient via independent mechanisms, thereby affecting the positive inotropy. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Do saw palmetto extracts block human alpha1-adrenoceptor subtypes in vivo?

    PubMed

    Goepel, M; Dinh, L; Mitchell, A; Schäfers, R F; Rübben, H; Michel, M C

    2001-02-15

    To test whether saw palmetto extracts, which act as alpha1-adrenoceptor antagonists in vitro, also do so in vivo in man. In a placebo-controlled, double-blind, four-way cross-over study 12 healthy young men were treated with three different saw palmetto extract preparations (320 mg o.d.) for 8 days each. On the last day, before and 2, 4 and 6 hr after drug intake blood pressure and heart rate were determined and blood samples obtained, which were used in an ex vivo radioreceptor assay with cloned human alpha1-adrenoceptor subtypes. Saw palmetto extract treatment did not result in alpha1-adrenoceptor subtype occupancy in the radioreceptor assay. Although the saw palmetto extracts caused minor reductions of supine blood pressure, they did not affect blood pressure during orthostatic stress testing and did not alter heart rate under either condition. Moreover, plasma catecholamines remained largely unaltered. Despite their alpha1-adrenoceptor antagonist effects in vitro, therapeutically used doses of saw palmetto extracts do not cause alpha1-adrenoceptor antagonism in man in vivo. Copyright 2001 Wiley-Liss, Inc.

  1. The effect of prolonged ethanol administration on central alpha 2-adrenoceptors sensitivity.

    PubMed

    Szmigielski, A; Szmigielska, H; Wejman, I

    1989-01-01

    The response of an endogenous inhibitor of protein kinases (type II inhibitor) to clonidine was used as an index of sensitivity of central alpha 2-adrenoceptors. Low doses of clonidine (20-50 micrograms/kg) induced an increase in type II inhibitor activity in the nucleus accumbens, hippocampus and in the anterior and posterior hypothalamus by stimulating presynaptic alpha 2-adrenoceptors. Stimulation of postsynaptic alpha 2-adrenoceptors by high doses of clonidine 0.5-1.0 mg/kg resulted in a dose-dependent decrease in type II inhibitor activity. Prolonged treatment with ethanol (5 g/kg/day po for 21 days) greatly reduced the action of high doses of clonidine in all the examined brain areas, suggesting subsensitivity of postsynaptic alpha 2-adrenoceptors lasting for at least 48 h after the last ethanol administration. A single dose of ethanol induced a short lasting subsensitivity of postsynaptic alpha 2-adrenoceptors in the anterior hypothalamus. 12 h after administration of alcohol the response of type II inhibitor to high doses of clonidine in this brain area was the same as in untreated rats.

  2. Modulation of resistance artery tone by the trace amine β-phenylethylamine: dual indirect sympathomimetic and α1-adrenoceptor blocking actions.

    PubMed

    Narang, Deepak; Kerr, Paul M; Lunn, Stephanie E; Beaudry, Rhys; Sigurdson, Julie; Lalies, Margaret D; Hudson, Alan L; Light, Peter E; Holt, Andrew; Plane, Frances

    2014-10-01

    The trace amine β-phenylethylamine (PEA) is normally present in the body at low nanomolar concentrations but can reach micromolar levels after ingestion of drugs that inhibit monoamine oxidase and primary amine oxidase. In vivo, PEA elicits a robust pressor response, but there is no consensus regarding the underlying mechanism, with both vasodilation and constriction reported in isolated blood vessels. Using functional and biochemical approaches, we found that at low micromolar concentrations PEA (1-30 μM) enhanced nerve-evoked vasoconstriction in the perfused rat mesenteric bed but at a higher concentration (100 μM) significantly inhibited these responses. The α2-adrenoceptor antagonist rauwolscine (1 µM) also enhanced nerve-mediated vasoconstriction, but in the presence of both rauwolscine (1 µM) and PEA (30 µM) together, nerve-evoked responses were initially potentiated and then showed time-dependent rundown. PEA (10 and 100 μM) significantly increased noradrenaline outflow from the mesenteric bed as determined by high-pressure liquid chromatography coupled with electrochemical detection. In isolated endothelium-denuded arterial segments, PEA (1 µM to 1 mM) caused concentration-dependent reversal of tone elicited by the α1-adrenoceptor agonists noradrenaline (EC50 51.69 ± 10.8 μM; n = 5), methoxamine (EC50 68.21 ± 1.70 μM; n = 5), and phenylephrine (EC50 67.74 ± 16.72 μM; n = 5) but was ineffective against tone induced by prostaglandin F2 α or U46619 (9,11-dideoxy-9α,11α-methanoepoxyprostaglandin F2 α). In rat brain homogenates, PEA displaced binding of both [(3)H]prazosin (Ki ≈ 25 μM) and [(3)H]rauwolscine (Ki ≈ 1.2 μM), ligands for α1- and α2-adrenoceptors, respectively. These data provide the first demonstration that dual indirect sympathomimetic and α1-adrenoceptor blocking actions underlie the vascular effects of PEA in resistance arteries. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

  3. Selective blockade by nicergoline of vascular responses elicited by stimulation of alpha 1A-adrenoceptor subtype in the rat.

    PubMed

    Alvarez-Guerra, M; Bertholom, N; Garay, R P

    1999-01-01

    The alpha 1-adrenergic blocking activity of nicergoline was re-examined in rats, with a particular emphasis on alpha 1-adrenoceptor subtypes. In pithed rats, nicergoline and prazosin infused at a single small dose (0.5 microgram/kg/min i.v.) produced a substantial and identical shift to the right of the control dose pressor response curve to the specific alpha 1-agonist cirazoline (ED50 = 4.0 +/- 0.1, 4.0 +/- 0.1 and 0.9 +/- 0.01 microgram/kg i.v. for nicergoline, prazosin and vehicle respectively). In the isolated perfused mesenteric vascular bed, nicergoline strongly inhibited the pressor responses elicited by cirazoline, with approximately 40-fold higher potency (pA2 = 11.1 +/- 0.3) than prazosin (pA2 = 9.5 +/- 0.3). Conversely, nicergoline was 20-fold less potent than prazosin to antagonize the contractile effects of cirazoline in isolated endothelium-denuded aorta (pA2 = 8.6 +/- 0.2 and 9.9 +/- 0.2 for nicergoline and prazosin respectively). Pretreatment of mesenteric vascular beds with chloroethylclonidine did not significantly modify nicergoline antagonistic potency (pA2 = 10.6 +/- 0.2). Nicergoline displaced [3H]-prazosin bound to rat forebrain membranes pretreated with chloroethylclonidine (pKi = 9.9 +/- 0.2) at concentrations 60-fold lower than in rat liver membranes (pKi = 8.1 +/- 0.2). Finally, of the nicergoline metabolites studied, lumilysergol acted as a modest alpha 1 antagonist (bromonicotinic acid was devoid of alpha 1 antagonist activity). In conclusion, nicergoline is a potent and selective alpha 1A-adrenoceptor subtype antagonist, an alpha 1-adrenoceptor subtype which is mainly represented in resistance arteries.

  4. Conopeptide ρ-TIA Defines a New Allosteric Site on the Extracellular Surface of the α1B-Adrenoceptor*♦

    PubMed Central

    Ragnarsson, Lotten; Wang, Ching-I Anderson; Andersson, Åsa; Fajarningsih, Dewi; Monks, Thea; Brust, Andreas; Rosengren, K. Johan; Lewis, Richard J.

    2013-01-01

    The G protein-coupled receptor (GPCR) superfamily is an important drug target that includes over 1000 membrane receptors that functionally couple extracellular stimuli to intracellular effectors. Despite the potential of extracellular surface (ECS) residues in GPCRs to interact with subtype-specific allosteric modulators, few ECS pharmacophores for class A receptors have been identified. Using the turkey β1-adrenergic receptor crystal structure, we modeled the α1B-adrenoceptor (α1B-AR) to help identify the allosteric site for ρ-conopeptide TIA, an inverse agonist at this receptor. Combining mutational radioligand binding and inositol 1-phosphate signaling studies, together with molecular docking simulations using a refined NMR structure of ρ-TIA, we identified 14 residues on the ECS of the α1B-AR that influenced ρ-TIA binding. Double mutant cycle analysis and docking confirmed that ρ-TIA binding was dominated by a salt bridge and cation-π between Arg-4-ρ-TIA and Asp-327 and Phe-330, respectively, and a T-stacking-π interaction between Trp-3-ρ-TIA and Phe-330. Water-bridging hydrogen bonds between Asn-2-ρ-TIA and Val-197, Trp-3-ρ-TIA and Ser-318, and the positively charged N terminus and Glu-186, were also identified. These interactions reveal that peptide binding to the ECS on transmembrane helix 6 (TMH6) and TMH7 at the base of extracellular loop 3 (ECL3) is sufficient to allosterically inhibit agonist signaling at a GPCR. The ligand-accessible ECS residues identified provide the first view of an allosteric inhibitor pharmacophore for α1-adrenoceptors and mechanistic insight and a new set of structural constraints for the design of allosteric antagonists at related GPCRs. PMID:23184947

  5. The tremorolytic action of beta-adrenoceptor blockers in essential, physiological and isoprenaline-induced tremor is mediated by beta-adrenoceptors located in a deep peripheral compartment.

    PubMed

    Abila, B; Wilson, J F; Marshall, R W; Richens, A

    1985-10-01

    The effects of intravenous propranolol 100 micrograms kg-1, sotalol 500 micrograms kg-1, timolol 7.8 micrograms kg-1, atenolol 125 micrograms kg-1 and placebo on essential, physiological and isoprenaline-induced tremor were studied. These beta-adrenoceptor blocker doses produced equal reduction of standing-induced tachycardia in essential tremor patients. Atenolol produced significantly less reduction of essential and isoprenaline-induced tremor than the non-selective drugs, confirming the importance of beta 2-adrenoceptor blockade in these effects. Propranolol and sotalol produced equal maximal inhibition of isoprenaline-induced tremor but propranolol was significantly more effective in reducing essential tremor. The rate of development of the tremorolytic effect was similar in essential, physiological and isoprenaline-induced tremors but all tremor responses developed significantly more slowly than the heart rate responses. It is proposed that these results indicate that the tremorolytic activity of beta-adrenoceptor blockers in essential, physiological and isoprenaline-induced tremor is exerted via the same beta 2-adrenoceptors located in a deep peripheral compartment which is thought to be in the muscle spindles.

  6. The tremorolytic action of beta-adrenoceptor blockers in essential, physiological and isoprenaline-induced tremor is mediated by beta-adrenoceptors located in a deep peripheral compartment.

    PubMed Central

    Abila, B; Wilson, J F; Marshall, R W; Richens, A

    1985-01-01

    The effects of intravenous propranolol 100 micrograms kg-1, sotalol 500 micrograms kg-1, timolol 7.8 micrograms kg-1, atenolol 125 micrograms kg-1 and placebo on essential, physiological and isoprenaline-induced tremor were studied. These beta-adrenoceptor blocker doses produced equal reduction of standing-induced tachycardia in essential tremor patients. Atenolol produced significantly less reduction of essential and isoprenaline-induced tremor than the non-selective drugs, confirming the importance of beta 2-adrenoceptor blockade in these effects. Propranolol and sotalol produced equal maximal inhibition of isoprenaline-induced tremor but propranolol was significantly more effective in reducing essential tremor. The rate of development of the tremorolytic effect was similar in essential, physiological and isoprenaline-induced tremors but all tremor responses developed significantly more slowly than the heart rate responses. It is proposed that these results indicate that the tremorolytic activity of beta-adrenoceptor blockers in essential, physiological and isoprenaline-induced tremor is exerted via the same beta 2-adrenoceptors located in a deep peripheral compartment which is thought to be in the muscle spindles. PMID:2866785

  7. Preventive effects of dexmedetomidine on the liver in a rat model of acid-induced acute lung injury.

    PubMed

    Sen, Velat; Güzel, Abdulmenap; Şen, Hadice Selimoğlu; Ece, Aydın; Uluca, Unal; Söker, Sevda; Doğan, Erdal; Kaplan, İbrahim; Deveci, Engin

    2014-01-01

    The aim of this study was to examine whether dexmedetomidine improves acute liver injury in a rat model. Twenty-eight male Wistar albino rats weighing 300-350 g were allocated randomly to four groups. In group 1, normal saline (NS) was injected into the lungs and rats were allowed to breathe spontaneously. In group 2, rats received standard ventilation (SV) in addition to NS. In group 3, hydrochloric acid was injected into the lungs and rats received SV. In group 4, rats received SV and 100 µg/kg intraperitoneal dexmedetomidine before intratracheal HCl instillation. Blood samples and liver tissue specimens were examined by biochemical, histopathological, and immunohistochemical methods. Acute lung injury (ALI) was found to be associated with increased malondialdehyde (MDA), total oxidant activity (TOA), oxidative stress index (OSI), and decreased total antioxidant capacity (TAC). Significantly decreased MDA, TOA, and OSI levels and significantly increased TAC levels were found with dexmedetomidine injection in group 4 (P < 0.05). The highest histologic injury scores were detected in group 3. Enhanced hepatic vascular endothelial growth factor (VEGF) expression and reduced CD68 expression were found in dexmedetomidine group compared with the group 3. In conclusion, the presented data provide the first evidence that dexmedetomidine has a protective effect on experimental liver injury induced by ALI.

  8. Chronic β2 -adrenoceptor agonist treatment alters muscle proteome and functional adaptations induced by high intensity training in young men.

    PubMed

    Hostrup, Morten; Onslev, Johan; Jacobson, Glenn A; Wilson, Richard; Bangsbo, Jens

    2018-01-15

    While several studies have investigated the effects of exercise training in human skeletal muscle and the chronic effect of β 2 -agonist treatment in rodent muscle, their effects on muscle proteome signature with related functional measures in humans are still incompletely understood. Herein we show that daily β 2 -agonist treatment attenuates training-induced enhancements in exercise performance and maximal oxygen consumption, and alters muscle proteome signature and phenotype in trained young men. Daily β 2 -agonist treatment abolished several of the training-induced enhancements in muscle oxidative capacity and caused a repression of muscle metabolic pathways; furthermore, β 2 -agonist treatment induced a slow-to-fast twitch muscle phenotype transition. The present study indicates that chronic β 2 -agonist treatment confounds the positive effect of high intensity training on exercise performance and oxidative capacity, which is of interest for the large proportion of persons using inhaled β 2 -agonists on a daily basis, including athletes. Although the effects of training have been studied for decades, data on muscle proteome signature remodelling induced by high intensity training in relation to functional changes in humans remains incomplete. Likewise, β 2 -agonists are frequently used to counteract exercise-induced bronchoconstriction, but the effects β 2 -agonist treatment on muscle remodelling and adaptations to training are unknown. In a placebo-controlled parallel study, we randomly assigned 21 trained men to 4 weeks of high intensity training with (HIT+β 2 A) or without (HIT) daily inhalation of β 2 -agonist (terbutaline, 4 mg dose -1 ). Of 486 proteins identified by mass-spectrometry proteomics of muscle biopsies sampled before and after the intervention, 32 and 85 were changing (false discovery rate (FDR) ≤5%) with the intervention in HIT and HIT+β 2 A, respectively. Proteome signature changes were different in HIT and HIT+β 2 A (P

  9. [Ocular hypotensive effect of alpha-adrenoceptor agonist and antagonist in the conscious pigmented rabbit].

    PubMed

    Moriwaki, Y; Iizuka, T; Nakamura, A; Nakata, K; Masaoka, Y; Ueda, T; Koide, R; Inatomi, M; Fukado, Y; Uchida, E

    1992-02-01

    It has been reported that some of the topically-used antiglaucomatics have a central ocular hypotensive effect. In this study, the influence of topical and intracerebroventricular (i.c.v.) administration of phenylephrine, clonidine, guanfacine, prazosin, yohimbine on the intraocular pressure (IOP) was investigated in the rabbit. Male pigmented rabbits were used throughout the experiments. For measurement of IOP, an applanation pneumatonograph was used. By unilateral topical administration of phenylephrine, an increase in IOP in the eye in which instillation was performed was observed. On the other hand, a slight decrease in IOP was observed by similar treatment of prazosin and yohimbine. No significant change of IOP in the contralateral eye was observed with these drugs. On the contrary, unilateral topical administration of clonidine or guanfacine decreased the IOP of both eyes. Furthermore, the decrease of IOP was more remarkable in the contralateral eye compared to the eye which received instillation. The IOP of both eyes was decreased in a dose-related fashion by i.c.v. administration of clonidine or guanfacine. The ocular hypotensive effects of clonidine were diminished by the pretreatment by i.c.v. administration with yohimbine. These results suggest that the ocular hypotensive effect of clonidine and guanfacine is due to their alpha 2-adrenoceptor stimulation in the central nervous system.

  10. A randomized, double-blind pilot study of dexmedetomidine versus midazolam for intensive care unit sedation: patient recall of their experiences and short-term psychological outcomes.

    PubMed

    MacLaren, Robert; Preslaski, Candice R; Mueller, Scott W; Kiser, Tyree H; Fish, Douglas N; Lavelle, James C; Malkoski, Stephen P

    2015-03-01

    Sedation with dexmedetomidine may facilitate ventilator liberation and limit the occurrence of delirium. No trial has assessed patient recall or the development of psychological outcomes after dexmedetomidine sedation. This pilot study evaluated whether transitioning benzodiazepine sedation to dexmedetomidine alters patient recall and the incidence of anxiety, depression, or acute stress disorder (ASD). This investigation was a randomized, double-blind, single-center study. Existing continuous benzodiazepine sedation was converted to dexmedetomidine or midazolam when patients qualified for daily awakenings. Sedation was titrated to achieve Riker sedation agitation scores of 3 to 4. The intensive care unit (ICU) Stressful Experiences Questionnaire, hospital anxiety and depression scale, and the impact of event scale-revised were administered before hospital discharge to assess recall, anxiety, depression, and manifestations of ASD. A total of 11 patients received dexmedetomidine, and 12 patients received midazolam. Median dosing was 0.61 µg/kg/h for 3.5 days for dexmedetomidine and 3.7 mg/h for 3 days for midazolam. Attainment of goal sedation and analgesia was similar; however, more dexmedetomidine patients experienced agitation and pain. The median duration of mechanical ventilation from study drug initiation to extubation was 3.4 days in dexmedetomidine patients and 2.9 days in midazolam patients. Dexmedetomidine patients remembered 18.5 experiences compared with 8.5 in midazolam patients (P = .015). Rates of anxiety and depression were similar. In all, 5 (62.5%) dexmedetomidine patients and 1 (12.5%) midazolam patient manifested ASD (P = .063), and 1 dexmedetomidine patient and 5 midazolam patients developed new-onset delirium (P = .07). Hypotension occurred in 10 (90.9%) dexmedotomidine patients and 6 (50%) midazolam patients (P = .069). Transitioning benzodiazepine sedation to dexmedetomidine when patients qualify for daily awakenings may reduce the

  11. The effect of low-dose dexmedetomidine on hemodynamics and anesthetic requirement during bis-spectral index-guided total intravenous anesthesia.

    PubMed

    Park, Hee Yeon; Kim, Jong Yeop; Cho, Sang Hyun; Lee, Dongchul; Kwak, Hyun Jeong

    2016-08-01

    The purpose of this study was to evaluate the effects of low-dose dexmedetomidine on hemodynamics and anesthetic requirements during propofol and remifentanil anesthesia for laparoscopic cholecystectomy. Thirty adult patients were randomly allocated to receive dexmedetomidine infusion of 0.3 μg/kg/h (dexmedetomidine group, n = 15) or comparable volumes of saline infusion (control group, n = 15). Target controlled infusion of propofol and remifentanil was used for anesthetic induction and maintenance, and adjusted in order to maintain a bispectral index of 40-55 and hemodynamic stability. We measured hemodynamics and recorded total and mean infused dosages of propofol and remifentanil. For anesthesia induction and maintenance, mean infused doses of propofol (121 ± 27 vs. 144 ± 29 μg/kg/min, P = 0.04) and remifentanil (118 ± 27 vs. 150 ± 36 ng/kg/min, P = 0.01) were lower in the dexmedetomidine group than in the control group, respectively. The dexmedetomidine group required 16 % less propofol and 23 % less remifentanil. During anesthetic induction and maintenance, the dexmedetomidine group required fewer total doses of propofol (9.6 ± 2.3 vs. 12.4 ± 3.3 mg/kg, P = 0.01) and remifentanil (9.6 ± 3.4 vs. 12.7 ± 2.6 μg/kg, P = 0.01). The change in mean arterial pressure over time differed between the groups (P < 0.05). Significantly lower mean arterial pressure was observed in the dexmedetomidine group than in the control group at immediately and 5 min after pneumoperitoneum. The time to extubation after completion of drug administration did not differ between the groups (P = 0.25). This study demonstrated that a low-dose dexmedetomidine infusion of 0.3 μg/kg/h reduced propofol and remifentanil requirements as well as hemodynamic change by pneumoperitoneum without delayed recovery during propofol-remifentanil anesthesia for laparoscopic cholecystectomy.

  12. The effects of alpha2-adrenoceptor agents on anti-hyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory pain.

    PubMed

    Vucković, Sonja M; Tomić, Maja A; Stepanović-Petrović, Radica M; Ugresić, Nenad; Prostran, Milica S; Bosković, Bogdan

    2006-11-01

    In this study, the effects of yohimbine (alpha2-adrenoceptor antagonist) and clonidine (alpha2-adrenoceptor agonist) on anti-hyperalgesia induced by carbamazepine and oxcarbazepine in a rat model of inflammatory pain were investigated. Carbamazepine (10-40 mg/kg; i.p.) and oxcarbazepine (40-160 mg/kg; i.p.) caused a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A, intraplantarly) in a paw pressure test in rats. Yohimbine (1-3 mg/kg; i.p.) significantly depressed the anti-hyperalgesic effects of carbamazepine and oxcarbazepine, in a dose- and time-dependent manner. Both drug mixtures (carbamazepine-clonidine and oxcarbazepine-clonidine) administered in fixed-dose fractions of the ED50 (1/2, 1/4 and 1/8) caused significant and dose-dependent reduction of the hyperalgesia induced by Con A. Isobolographic analysis revealed a significant synergistic (supra-additive) anti-hyperalgesic effect of both combinations tested. These results indicate that anti-hyperalgesic effects of carbamazepine and oxcarbazepine are, at least partially, mediated by activation of adrenergic alpha2-receptors. In addition, synergistic interaction for anti-hyperalgesia between carbamazepine and clonidine, as well as oxcarbazepine and clonidine in a model of inflammatory hyperalgesia, was demonstrated.

  13. Evaluation of oral maropitant as an antiemetic in cats receiving morphine and dexmedetomidine.

    PubMed

    Martin-Flores, Manuel; Sakai, Daniel M; Mastrocco, Alicia; Learn, McKenzie M; Campoy, Luis; Kirch, Pati J; Boesch, Jordyn M; Gleed, Robin D

    2016-11-01

    Objectives The aim of the study was to evaluate the antiemetic effects of maropitant, after oral administration, in cats receiving morphine and dexmedetomidine. Methods This prospective, blinded, randomized controlled trial involved 98 healthy female domestic shorthair cats. Cats were randomly assigned to receive maropitant PO 8 mg total (group M) administered 18 h prior to sedation with intramuscular dexmedetomidine 20 µg/kg and morphine 0.1 mg/kg, or no antiemetic treatment (group C). The occurrence of signs of nausea (sialorrhea and lip-licking), retching and emesis during the 30 mins following administration of dexmedetomidine and morphine was measured for each group. Results Two cats were excluded from the investigation. Cats in group M (n = 46) received an average of 2.5 mg/kg of maropitant PO. Compared with group C (n = 50), cats in group M had lower incidences of emesis (M: 4% vs C: 40%), retching (M: 8% vs C: 40%) and lip-licking (M: 30% vs C: 52%) (all P <0.05). The incidence of sialorrhea was not different between groups (M: 21% vs C: 22%). Conclusions and relevance Maropitant 8 mg total PO was effective in reducing morphine and dexmedetomidine-induced emesis by 10-fold, when administered as early as 18 h in advance to healthy cats. Maropitant PO could be useful for administration the evening prior to a scheduled procedure requiring sedation/anesthesia to decrease the incidence of emesis.

  14. Optimal effect-site concentration of remifentanil when combined with dexmedetomidine in patients undergoing cystoscopy

    PubMed Central

    Heo, Bongha; Kim, Minsun; Lee, Hyunjung; Park, Sanghee

    2014-01-01

    Background Cystoscopic procedure is a very common practice in the field of urology due to its ability to survey the bladder for a variety of indications. However, patients who undergo cystoscopy feel intense pain and discomfort. This study investigated the half maximal effective concentration (EC50) of remifentanil in preventing cystoscope insertion pain under sedation using dexmedetomidine. Methods The study was prospectively conducted on 18 male patients, aged 18 to 65. Remifentail infusion was initiated together with dexmedetomidine, and started at a dose of 2.4 ng/ml on the first patient. The effect-site concentration (Ce) of remifentanil for each subsequent patient was determined by the previous patient's response using Dixon's up-and-down method with an interval of 0.3 ng/ml. Patients received a loading dose of 1.0 µg/kg dexmedetomidine over 10 minutes, followed by a maintenance dose of 0.6 µg/kg/hr. After the patient's OAA/S score (Observer's Assessment of Alertness/Sedation scale) reached 3-4, and the Ce of remifentanil reached target concentration, the urologist was allowed to insert the cystoscope and the pain responses were observed. Results The effect-site concentration of remifentanil required to prevent cystoscope insertion pain in 50% of patients under sedation using dexmedetomidine was 1.30 ± 0.12 ng/ml by Dixon's up-and-down method. The logistic regression curve of the probability of response showed that the EC50 and EC95 values (95% confidence limits) of remifentanil were 1.33 ng/ml (1.12-1.52 ng/ml) and 1.58 ng/ml (1.44-2.48 ng/ml), respectively. Conclusions Cystoscopic procedure can be carried out successfully without any pain or adverse effects by optimal remifentanil effect-site concentration (EC50, 1.33 ng/ml; EC95, 1.58 ng/ ml) combined with sedation using dexmedetomidine. PMID:24567812

  15. Effect of pioglitazone on vasopressor responses to adrenergic agonists and angiotensin II in diabetic and non-diabetic spontaneously hypertensive rats.

    PubMed

    Afzal, Sheryar; Sattar, Munavvar Abdul; Akhtar, Safia; Binti Abdullah, Nor Azizan; Eseyin, Olorunfemi A; Abdulla, Mohammed H; Johns, Edward James

    2018-05-01

    Pioglitazone, peroxisome proliferator-activated receptor (PPAR-γ) agonist, is a therapeutic drug for diabetes. Present study investigated the interaction between PPAR-γ and alpha adrenoceptors in modulating vasopressor responses to Angiotensin II (Ang II) and adrenergic agonists, in diabetic & non-diabetic Spontaneously Hypertensive Rats (SHRs). Diabetes was induced with an i.p injection of streptozotocin (40 mg/kg) in two groups (STZ-CON, STZ-PIO), whereas two groups remained non diabetic (ND-CO, ND-PIO). One diabetic and non-diabetic group received Pioglitazone (10mg/kg) orally for 21 days. On day 28, the animals were anaesthetized with sodium pentobarbitone (60mg/kg) and prepared for measurement of systemic haemodynamics. Basal mean arterial pressure of STZ-CON was higher than ND-CON, whereas following pioglitazone treatment, MAP was lower compared to respective controls. MAP responses to i.v administration of NA, PE, ME and ANG II were significantly lower in diabetic SHRs: STZ-CON vs ND-CON (35%). Pioglitazone significantly decreased responses to NA, PE, ME and ANG II in ND-PIO versus ND-CON by 63%. Responses to NA and ANG II were significantly attenuated in STZ-PIO vs. ND-PIO (40%). PPAR-γ regulates systemic hemodynamic in diabetic model and cross-talk relationship exists between PPAR-γ and α1-adrenoceptors, ANG II in systemic vasculature of SHRs.

  16. Pharmacokinetic and pharmacodynamic study of dexmedetomidine in elderly patients during spinal anesthesia.

    PubMed

    Kuang, Yun; Zhang, Ran-Ran; Pei, Qi; Tan, Hong-Yi; Guo, Cheng-Xian; Huang, Jie; Xiang, Yu-Xia; Ouyang, Wen; Duan, Kai-Ming; Wang, Sai-Ying; Yang, Guo-Ping

    2015-12-01

    The application of dexmedetomidine in patient sedation is generally accepted, though its clinical application is limited because of the lack of information detailing the specific properties among diverse populations of patients. The aim of this study was to compare the pharmacokinetic and pharmacodynamic characteristics of dexmedetomidine between elderly and young patients during spinal anesthesia. 34 subjects (elderly group: n = 15; young group: n = 19) with spinal anesthesia were enrolled in the present study following the inclusion/exclusion criteria detailed below. All subjects received intravenous infusion of dexmedetomidine with a loading dose of 0.5 µg x kg⁻¹ for 10 minutes and a maintenance dose of 0.5 µg x kg⁻¹ x h⁻¹ for 50 minutes. Plasma concentrations of dexmedetomidine were detected by the HPLC-MS/MS method and pharmacokinetic parameters were calculated using WinNolin software. There was no significant difference between the elderly and young subjects in major pharmacokinetic parameters. There was a marked gender difference in the Cmax (peak plasma concentration) and tmax (time to reach Cmax) between genders in elderly subjects, though in this cohort the other pharmacokinetic parameters were not significantly different. In the young subjects there were no noteworthy variations between genders in pharmacokinetic parameters. There was no significant difference between the two groups in BISAUC(0-t) (the area under the bispectral index-time curve from time 0 to t hours), BISmin (the minimum value of the bispectral index after drug delivery), and or tmin-BIS (bispectral index for the minimum value of time). SBP (systolic blood pressure), DBP (diastolic blood pressure), HR (heart rate), and SpO₂(pulse oxygen saturation) developed substantive differences in a time-dependent manner, but there were no statistically significant differences in these four indicators in the time*group at three time points (1 hour, 2 hours, and 3 hours after drug

  17. Clinical efficacy and cardiorespiratory effects of intramuscular administration of alfaxalone alone or in combination with dexmedetomidine in cats.

    PubMed

    Rodrigo-Mocholí, Diego; Belda, Eliseo; Bosmans, Tim; Laredo, Francisco G

    2016-05-01

    To investigate the sedative, anaesthetic and cardiorespiratory effects of intramuscular (IM) administration of alfaxalone alone or in combination with dexmedetomidine in cats. Blinded, randomized crossover study with a washout period of 15 days. Seven adult cats, weighing 3.5 ± 0.7 kg. Cats were assigned randomly to each of three treatments: A5 (alfaxalone 5 mg kg(-1) ), D20 A5 (dexmedetomidine 20 μg kg(-1) and alfaxalone 5 mg kg(-1) ) and D40 A5 (dexmedetomidine 40 μg kg(-1) and alfaxalone 5 mg kg(-1) ). Drugs were administered IM into the epaxial muscles. Sedation or anaesthesia scores were evaluated by a modified numerical rating scale. Times to extubation, head-lift, sternal recumbency and standing were recorded. Heart and respiratory rates, systolic arterial pressure, arterial oxygen saturation of haemoglobin, end-tidal carbon dioxide tension and rectal temperature were measured at 5, 10, 15, 20, 30, 45, 60, 90, 120 and 150 minutes after drug administration. Adverse events were recorded. Data were analysed by one-way anova with Tukey's post-hoc test for parametric values and, for non-normally distributed parameters, a Kruskal-Wallis test and Mann-Whitney U-test for two independent samples (p < 0.05). Sedation scores were significantly different among the treatments. Cats in A5 were deeply sedated, whereas cats administered dexmedetomidine were anaesthetized. The onset of action and the duration of anaesthesia were related to the dose of dexmedetomidine. Cardiorespiratory parameters remained stable in the A5 group. Lower heart rates, higher systolic blood pressures and occasional low pulse oximetry readings were observed in the dexmedetomidine groups. A limited number of adverse events (hyperkinesia, emesis) occurred during recovery. Alfaxalone administered IM induced sedation in cats. The addition of dexmedetomidine to alfaxalone induced general anaesthesia with a mild decrease in the heart rate and arterial oxygen saturation of haemoglobin

  18. Lidocaine, Dexmedetomidine and Their Combination Reduce Isoflurane Minimum Alveolar Concentration in Dogs

    PubMed Central

    Acevedo-Arcique, Carlos M.; Ibancovichi, José A.; Chavez, Julio R.; Gutierrez-Blanco, Eduardo; Moran-Muñoz, Rafael; Victoria-Mora, José M.; Tendillo-Cortijo, Francisco; Santos-González, Martín; Sanchez-Aparicio, Pedro

    2014-01-01

    The effects of intravenous (IV) lidocaine, dexmedetomidine and their combination delivered as a bolus followed by a constant rate infusion (CRI) on the minimum alveolar concentration of isoflurane (MACISO) in dogs were evaluated. Seven healthy adult dogs were included. Anaesthesia was induced with propofol and maintained with isoflurane. For each dog, baseline MAC (MACISO/BASAL) was determined after a 90-minute equilibration period. Thereafter, each dog received one of the following treatments (loading dose, CRI): lidocaine 2 mg kg−1, 100 µg kg−1 minute−1; dexmedetomidine 2 µg kg−1, 2 µg kg−1 hour−1; or their combination. MAC was then determined again after 45- minutes of treatment by CRI. At the doses administered, lidocaine, dexmedetomidine and their combination significantly reduced MACISO by 27.3% (range: 12.5–39.2%), 43.4% (33.3–53.3%) and 60.9% (46.1–78.1%), respectively, when compared to MACISO/BASAL. The combination resulted in a greater MACISO reduction than the two drugs alone. Their use, at the doses studied, provides a clinically important reduction in the concentration of ISO during anaesthesia in dogs. PMID:25232737

  19. Lack of effect of the alpha2C-adrenoceptor Del322-325 polymorphism on inhibition of cyclic AMP production in HEK293 cells.

    PubMed

    Montgomery, M D; Bylund, D B

    2010-02-01

    The alpha(2C)-adrenoceptor has multiple functions, including inhibiting release of noradrenaline from presynaptic nerve terminals. A human alpha(2C) polymorphism, Del322-325, a potential risk factor for heart failure, has been reported to exhibit reduced signalling in CHO cells. To further understand the role of the Del322-325 polymorphism on receptor signalling, we attempted to replicate and further study the reduced signalling in HEK293 cells. Human alpha(2C) wild-type (WT) and Del322-325 adrenoceptors were stably transfected into HEK293 cells. Radioligand binding was performed to determine affinities for both receptors. In intact cells, inhibition of forskolin-stimulated cyclic AMP production by WT and Del322-325 clones with a range of receptor densities (200-2320 fmol.mg(-1) protein) was measured following agonist treatment. Noradrenaline, brimonidine and clonidine exhibited similar binding affinities for WT and Del322-325. Brimonidine and clonidine also had similar efficacies and potencies for both receptors for the inhibition of cyclic AMP production at all receptor densities tested. A linear regression analysis comparing efficacy and potency with receptor expression levels showed no differences in slopes between WT and Del322-325. The alpha(2C) WT and Del322-325 adrenoceptors exhibited similar binding properties. Additionally, inhibition of cyclic AMP production by Del322-325 was similar to that of WT over a range of receptor densities. Therefore, in intact HEK293 cells, the alpha(2C)-Del322-325 polymorphism does not exhibit reduced signalling to adenylyl cyclase and may not represent a clinically important phenotype.

  20. Intraoperative Infusion of Dexmedetomidine for Prevention of Postoperative Delirium and Cognitive Dysfunction in Elderly Patients Undergoing Major Elective Noncardiac Surgery: A Randomized Clinical Trial.

    PubMed

    Deiner, Stacie; Luo, Xiaodong; Lin, Hung-Mo; Sessler, Daniel I; Saager, Leif; Sieber, Frederick E; Lee, Hochang B; Sano, Mary; Jankowski, Christopher; Bergese, Sergio D; Candiotti, Keith; Flaherty, Joseph H; Arora, Harendra; Shander, Aryeh; Rock, Peter

    2017-08-16

    Postoperative delirium occurs in 10% to 60% of elderly patients having major surgery and is associated with longer hospital stays, increased hospital costs, and 1-year mortality. Emerging literature suggests that dexmedetomidine sedation in critical care units is associated with reduced incidence of delirium. However, intraoperative use of dexmedetomidine for prevention of delirium has not been well studied. To evaluate whether an intraoperative infusion of dexmedetomidine reduces postoperative delirium. This study was a multicenter, double-blind, randomized, placebo-controlled trial that randomly assigned patients to dexmedetomidine or saline placebo infused during surgery and for 2 hours in the recovery room. Patients were assessed daily for postoperative delirium (primary outcome) and secondarily for postoperative cognitive decline. Participants were elderly (>68 years) patients undergoing major elective noncardiac surgery. The study dates were February 2008 to May 2014. Dexmedetomidine infusion (0.5 µg/kg/h) during surgery and up to 2 hours in the recovery room. The primary hypothesis tested was that intraoperative dexmedetomidine administration would reduce postoperative delirium. Secondarily, the study examined the correlation between dexmedetomidine use and postoperative cognitive change. In total, 404 patients were randomized; 390 completed in-hospital delirium assessments (median [interquartile range] age, 74.0 [71.0-78.0] years; 51.3% [200 of 390] female). There was no difference in postoperative delirium between the dexmedetomidine and placebo groups (12.2% [23 of 189] vs 11.4% [23 of 201], P = .94). After adjustment for age and educational level, there was no difference in the postoperative cognitive performance between treatment groups at 3 months and 6 months. Adverse events were comparably distributed in the treatment groups. Intraoperative dexmedetomidine does not prevent postoperative delirium. The reduction in delirium previously demonstrated

  1. Effect of Selective Prostaglandin E2 EP2 Receptor Agonist CP-533,536 on Voiding Efficiency in Rats with Midodrine-Induced Functional Urethral Obstruction.

    PubMed

    Kurihara, Ryoko; Imazumi, Katsunori; Takamatsu, Hajime; Ishizu, Kenichiro; Yoshino, Taiji; Masuda, Noriyuki

    2016-05-01

    We investigated the effect of the selective prostaglandin E2 EP2 receptor agonist CP-533,536 on voiding efficiency in rats with midodrine-induced functional urethral obstruction. The effect of CP-533,536 (0.03-0.3 mg/kg, intravenous [i.v.]) on urethral perfusion pressure (UPP) was investigated in anesthetized rats pre-treated with midodrine (1 mg/kg, i.v.), which forms an active metabolite that acts as an α1 -adrenoceptor agonist. The effect of CP-533,536 (0.03-0.3 mg/kg, i.v.) on cystometric parameters was also investigated in anesthetized rats. In addition, the effect of CP-533,536 (0.03-0.3 mg/kg, i.v.) on residual urine volume (RV) and voiding efficiency (VE) was investigated in conscious rats treated with midodrine (1 mg/kg, i.v.). CP-533,536 dose-dependently decreased UPP elevated by midodrine in anesthetized rats. In contrast, CP-533,536 did not affect maximum voiding pressure, intercontraction interval, or intravesical threshold pressure. In conscious rats, midodrine (1 mg/kg, i.v.) markedly increased RV and reduced VE. CP-533,536 dose-dependently ameliorated increases in RV and decreases in VE induced by midodrine. These results suggest that a selective EP2 receptor agonist could ameliorate the elevation of RV and improve the reduction of VE in rats with functional urethral obstruction caused by stimulation of α1 -adrenoceptors. The mechanism of action might be not potentiation of bladder contraction but rather preferential relief of urethral constriction. © 2014 Wiley Publishing Asia Pty Ltd.

  2. Putative β4-adrenoceptors in rat ventricle mediate increases in contractile force and cell Ca2+: comparison with atrial receptors and relationship to (−)-[3H]-CGP 12177 binding

    PubMed Central

    Sarsero, Doreen; Molenaar, Peter; Kaumann, Alberto J; Freestone, Nicholas S

    1999-01-01

    We identified putative β4-adrenoceptors by radioligand binding, measured increases in ventricular contractile force by (−)-CGP 12177 and (±)-cyanopindolol and demonstrated increased Ca2+ transients by (−)-CGP 12177 in rat cardiomyocytes.(−)-[3H]-CGP 12177 labelled 13–22 fmol mg−1 protein ventricular β1, β2-adrenoceptors (pKD ∼9.0) and 50–90 fmol mg−1 protein putative β4-adrenoceptors (pKD ∼7.3). The affinity values (pKi) for (β1,β2-) and putative β4-adrenoceptors, estimated from binding inhibition, were (−)-propranolol 8.4, 5.7; (−)-bupranolol 9.7, 5.8; (±)-cyanopindolol 10.0,7.4.In left ventricular papillary muscle, in the presence of 30 μM 3-isobutyl-1-methylxanthine, (−)-CGP 12177 and (±)-cyanopindolol caused positive inotropic effects, (pEC50, (−)-CGP 12177, 7.6; (±)-cyanopindolol, 7.0) which were antagonized by (−)-bupranolol (pKB 6.7–7.0) and (−)-CGP 20712A (pKB 6.3–6.6). The cardiostimulant effects of (−)-CGP 12177 in papillary muscle, left and right atrium were antagonized by (±)-cyanopindolol (pKP 7.0–7.4).(−)-CGP 12177 (1 μM) in the presence of 200 nM (−)-propranolol increased Ca2+ transient amplitude by 56% in atrial myocytes, but only caused a marginal increase in ventricular myocytes. In the presence of 1 μM 3-isobutyl-1-methylxanthine and 200 nM (−)-propranolol, 1 μM (−)-CGP 12177 caused a 73% increase in Ca2+ transient amplitude in ventricular myocytes. (−)-CGP 12177 elicited arrhythmic transients in some atrial and ventricular myocytes.Probably by preventing cyclic AMP hydrolysis, 3-isobutyl-1-methylxanthine facilitates the inotropic function of ventricular putative β4-adrenoceptors, suggesting coupling to Gs protein-adenylyl cyclase. The receptor-mediated increases in contractile force are related to increases of Ca2+ in atrial and ventricular myocytes. The agreement of binding affinities of agonists with cardiostimulant potencies is consistent with mediation

  3. Dexmedetomidine oromucosal gel for noise-associated acute anxiety and fear in dogs-a randomised, double-blind, placebo-controlled clinical study.

    PubMed

    Korpivaara, M; Laapas, K; Huhtinen, M; Schöning, B; Overall, K

    2017-04-08

    The aim of this randomised, double-blind, placebo-controlled, clinical-field study was to evaluate the effect of dexmedetomidine oromucosal gel at subsedative doses in alleviation of noise-associated acute anxiety and fear in dogs. On New Year's Eve, 182 dogs with a history of acute anxiety and fear associated with fireworks received treatment as needed up to five times: 89 dogs received dexmedetomidine and 93 dogs received placebo. For the primary efficacy variables, dog owners assessed the overall treatment effect as well as signs and extent of anxiety and fear. The overall treatment effect was statistically significant (P<0.0001). An excellent or good treatment effect was reported for a higher proportion of dogs treated with dexmedetomidine (64/89, 72 per cent) than those receiving placebo (34/93, 37 per cent). Additionally, dexmedetomidine-treated dogs expressed significantly (P<0.0314) fewer signs of fear and anxiety despite the noise of fireworks. No local tolerance or clinical safety concerns occurred during the study. This study demonstrated that oromucosal dexmedetomidine at subsedative doses alleviates noise-associated acute anxiety and fear in dogs. British Veterinary Association.

  4. The efficacy of dexmedetomidine-remifentanil versus dexmedetomidine-propofol in children undergoing flexible bronchoscopy

    PubMed Central

    Zhang, Hongquan; Fang, Baojun; Zhou, Wenjing

    2017-01-01

    Abstract Flexible bronchoscopy has been more and more used for diagnosis and management diseases of respiratory system in pediatrics. Previous studies have reported that remifentanil (RF) and propofol are safe and effective for flexible bronchoscopy in adults, however, there have no trials evaluate the efficacy of DEX-RF versus dexmedetomidine-propofol in children undergoing flexible bronchoscopy. We divided 123 children undergoing flexible bronchoscopy with DEX-RF or dexmedetomidine-propofol into 2 groups: Group DR (n = 63, DEX infusion at 1.0 μg kg−1 for 10 minutes, then adjusted to 0.5–0.7 μg kg−1 h−1; RF infusion at 1.0 μg kg−1 for 5 minutes, then adjusted to 0.05–0.2 μg kg−1 min−1), Group DP (n = 60, DEX infusion at 1.0 μg kg−1 for 10 minutes, then adjusted to 0.5–0.7 μg kg−1 h−1; propofol infusion at 10 μg kg−1 for 5 minutes, then adjusted to 0.05–0.1 μg kg−1 min−1). Ramsay sedation scale of the 2 groups was maintained at 3. Anesthesia onset time; total number of intraoperative patient movements; hemodynamics; total cumulative dose of DEX; amount of and time to first-dose rescue midazolam and lidocaine; postoperative recovery time; adverse events; and bronchoscopist satisfaction score were recorded. Anesthesia onset time was significantly shorter in DP (8.22 ± 2.48 vs 12.25 ± 6.43 minutes, respectively, for DP, DR, P = 0.015). The perioperative hemodynamic profile was more stable in DR than DP group. More children moved during flexible bronchoscopy in DP group (P = 0.009). Total dose of rescue midazolam and lidocaine was significantly higher in DR than in DP (P < 0.001). Similarly, the time to first dose of rescue midazolam and lidocaine was significantly longer in DP than in DR (P < 0.001). Total cumulative dose of DEX was more in DR than DP group (P < 0.001). The time to recovery for discharge from the postanesthesia care unit

  5. Dexmedetomidine, ketamine, and midazolam for oral rehabilitation: a case report.

    PubMed

    Kim, Bill W S; Peskin, Robert M

    2015-01-01

    Intravenous sedation is frequently provided by anesthesiologists for phobic patients undergoing elective dental treatment in outpatient settings. Propofol is one of the most commonly used anesthetic agents that can result in apnea and respiratory depression, thereby posing potential difficulties with perioperative airway management. Dexmedetomidine has been utilized successfully in intravenous sedation for a wide variety of procedures and holds potential as an alternative to propofol in outpatient dental settings. However, as a single agent, it may not provide adequate depth of sedation and analgesia for oral rehabilitation. In this case report we demonstrate an effective alternative intravenous deep-sedation technique for an adult phobic patient undergoing oral rehabilitation utilizing 3 agents in combination: dexmedetomidine, ketamine, and midazolam. This combination of agents may be especially useful for those patients with a history of substance abuse, where administration of opioids may be undesirable or contraindicated.

  6. Vasodilators and α-adrenoceptor antagonists in hypertension and heart failure

    PubMed Central

    Taylor, S. H.

    1981-01-01

    1 The mechanism of the increase in arteriolar resistance in hypertension and heart failure is differently derived. In hypertension, venous compliance is normal and the concentric narrowing of the arteriolar resistance vessels is `anatomical'; it is not due to increased stimulation or enhanced sensitivity of the vascular smooth muscle. In heart failure narrowing of both the arteriolar resistance and venous capacitance vessels derives predominantly from increased sympathoadrenal stimulation of α1-adrenoceptors in the vascular smooth muscle. 2 Vasodilator drugs which relax vascular smooth muscle differ widely in their site of activity. None are entirely specific for arteries, arterioles or veins, but they may be grouped for therapeutic convenience into those predominantly acting on arterioles (for example hydralazine) and those acting on veins (for example nitrates). 3 Control of the resting blood pressure in stable essential hypertension appears to be equally well achieved with non-specific arteriolar dilators (for example hydralazine, minoxidil, calcium antagonists) as those with specific α1-adrenoceptor blocking properties (for example prazosin, indoramin). Pressure surges due to dynamic exercise and mental stress are little influenced by either category of drug. In contrast, α-adrenoceptor antagonists appear to be capable of partly suppressing increase in ambulatory pressure and the pressor responses to isometric exercise and cold, particularly in patients pre-treated with β-blocking drugs. 4 In acute heart failure, non-selective α-blocking drugs (for example phentolamine) produce an equal reduction in left ventricular filling pressure but greater increase in cardiac output than vasodilator drugs with a more balanced relaxing effect on arterioles and venules. 5 In chronic heart failure, the little information available indicates that non-selective arteriolar dilatation is probably associated with a greater increase in cardiac output lesser reduction in left

  7. Comparative Evaluation of Remifentanil and Dexmedetomidine in General Anesthesia for Cesarean Delivery

    PubMed Central

    Li, Chengwen; Li, Yandong; Wang, Kun; Kong, Xiangang

    2015-01-01

    Background Use of remifentanil and dexmedetomidine in general anesthesia for cesarean section have been described. This study was designed to evaluate the effects of remifentanil and dexmedetomidine on maternal hemodynamics and bispectral index, and neonatal outcomes in elective caesarean delivery. Material/Methods Forty-four women undergoing elective cesarean delivery with ASA I or II and term or near-term singleton pregnancies were randomly assigned to receive remifentanil at a loading dose of 2 μg/kg over 10 min followed by a continuous infusion of 2 μg/kg/h until about 6 min before fetal delivery (Group REM), or dexmedetomidine at a loading dose of 0.4 μg/kg over 10 min followed by a continuous infusion of 0.4 μg/kg/h until about 6 min before fetal delivery (Group DEX). Maternal hemodynamics and BIS values were recorded. Neonatal effects were assessed using Apgar scores and umbilical cord blood gas analysis. Results Mean arterial pressure (MAP) increased after intubation in both groups, and the change magnitude of the MAP was higher in Group DEX (P<0.05). Patients in Group DEX had a lower BIS value at recovery and consumed less propofol during surgery (P<0.05). The incidences of neonatal resuscitation at 1 min were 81.8% in Group REM and 54.5% in Group DEX (P=0.052). There was no significant difference in either group in Apgar scores at 1 and 5 min and umbilical cord blood gas values. Conclusions Both remifentanil and dexmedetomidine are effective to blunt hemodynamic responses to intubation and also seem safe for neonates at the administrated doses, but remifentanil still has the potential to cause neonatal transient respiratory depression. PMID:26638888

  8. Does dexmedetomidine given as a premedication or intraoperatively reduce post-hospitalisation behaviour change in children? A study protocol for a randomised controlled trial in a tertiary paediatric hospital.

    PubMed

    Lee-Archer, Paul; McBride, Craig; Paterson, Rebecca; Reade, Michael; Regli-von Ungern-Sternberg, Britta; Long, Deborah

    2018-04-17

    It has been reported that post-hospitalisation behaviour change (PHBC) occurs in over 50% of children undergoing a general anaesthetic and manifests as behaviours such as sleep and eating disorders, defiance of authority, nightmares, enuresis and temper tantrums. The effect is usually short-lived (2-4 weeks); however, in 5-10% of children, these behaviours can last up to 12 months. The risk factors for developing PHBC include underlying anxiety in the child or parent, a previous bad hospital experience, emergence delirium and preschool age. A recent meta-analysis of alpha-2 agonists (including dexmedetomidine) found that they effectively reduce the incidence of emergence delirium but none of the studies looked at longer term outcomes, such as PHBC. Two-year-old to seven-year-old children requiring general anaesthesia for common day-case procedures will be randomly assigned to one of three groups: a dexmedetomidine pre medication group, an intraoperative dexmedetomidine group and a control group. Baseline anxiety levels of the parent will be recorded and the anxiety of the child during induction of anaesthesia will also be recorded using validated tools. The primary outcome will be negative behaviours after hospitalisation and these will be measured using the Post Hospitalisation Behaviour Questionnaire for Ambulatory Surgery and the Strengths and Difficulties Questionnaire. These questionnaires will be administered by a blinded researcher at days 3, 14 and 28 post surgery. Ethics approval has been granted by the Children's Health Queensland human research ethics committee (HREC/15/QRCH/248) and the University of Queensland human research ethics office (#2016001715). Any amendments to this protocol will be submitted to the ethics committees for approval. ANZCTR:12616000096459; Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly

  9. Evaluation of the advantageous anesthetic properties of dexmedetomidine used as hypotensive agent compared with nitroglycerin in orthognathic surgery.

    PubMed

    Rummasak, Duangdee; Apipan, Benjamas

    2014-12-01

    To evaluate the advantageous anesthetic properties, such as the decrease of intraoperative analgesic requirement, time to extubation and recovery, and early postoperative pain, of dexmedetomidine used as hypotensive agent compared with nitroglycerin in orthognathic surgery. The authors implemented a prospective, single-blinded, randomized clinical trial. The sample was composed of healthy patients who were admitted for bimaxillary osteotomies and were assigned to 1 of 2 groups by a computer-generated random number and blinded to the group. Dexmedetomidine or nitroglycerin was used as the hypotensive drug for each group. All patients underwent hypotensive anesthesia and surgery according to standard protocol. Intraoperative amount of fentanyl, time to eye opening, time to follow basic verbal commands, time to extubation, early postoperative pain scores, and analgesics were recorded. Compared means were analyzed using the unpaired Student t test. A 2-sided statistical test was used. A P value less than .05 was considered significant. The sample was composed of 40 participants. The intraoperative fentanyl requirement was significantly lower in the dexmedetomidine group than in the nitroglycerin group (168.75±56.29 and 222.50±96.12 μg, respectively; P=.037). Times to eye opening and following commands were considerably longer in the dexmedetomidine group, but the time to extubation showed no meaningful difference. Early postoperative pain after 30 and 60 minutes and the requirement for meperidine were not meaningfully different between the 2 groups. Dexmedetomidine, used as a hypotensive drug, has anesthetic benefits compared with nitroglycerin. Dexmedetomidine decreases the intraoperative fentanyl requirement and does not meaningfully change the time to extubation, early postoperative pain, and analgesic drug requirement. Copyright © 2014 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  10. Alpha-2 adrenergic agonists for the prevention of cardiac complications among adults undergoing surgery.

    PubMed

    Duncan, Dallas; Sankar, Ashwin; Beattie, W Scott; Wijeysundera, Duminda N

    2018-03-06

    The surgical stress response plays an important role on the pathogenesis of perioperative cardiac complications. Alpha-2 adrenergic agonists attenuate this response and may help prevent postoperative cardiac complications. To determine the efficacy and safety of α-2 adrenergic agonists for reducing mortality and cardiac complications in adults undergoing cardiac surgery and non-cardiac surgery. We searched CENTRAL (2017, Issue 4), MEDLINE (1950 to April Week 4, 2017), Embase (1980 to May 2017), the Science Citation Index, clinical trial registries, and reference lists of included articles. We included randomized controlled trials that compared α-2 adrenergic agonists (i.e. clonidine, dexmedetomidine or mivazerol) against placebo or non-α-2 adrenergic agonists. Included trials had to evaluate the efficacy and safety of α-2 adrenergic agonists for preventing perioperative mortality or cardiac complications (or both), or measure one or more relevant outcomes (i.e. death, myocardial infarction, heart failure, acute stroke, supraventricular tachyarrhythmia and myocardial ischaemia). Two authors independently assessed trial quality, extracted data and independently performed computer entry of abstracted data. We contacted study authors for additional information. Adverse event data were gathered from the trials. We evaluated included studies using the Cochrane 'Risk of bias' tool, and the quality of the evidence underlying pooled treatment effects using GRADE methodology. Given the clinical heterogeneity between cardiac and non-cardiac surgery, we analysed these subgroups separately. We expressed treatment effects as pooled risk ratios (RR) with 95% confidence intervals (CI). We included 47 trials with 17,039 participants. Of these studies, 24 trials only included participants undergoing cardiac surgery, 23 only included participants undergoing non-cardiac surgery and eight only included participants undergoing vascular surgery. The α-2 adrenergic agonist studied

  11. Retigabine diminishes the effects of acetylcholine, adrenaline and adrenergic agonists on the spontaneous activity of guinea pig smooth muscle strips in vitro.

    PubMed

    Apostolova, Elisaveta; Zagorchev, Plamen; Kokova, Vesela; Peychev, Lyudmil

    2017-03-01

    The aim of this study is to evaluate the effect of retigabine on the smooth muscle response to acetylcholine, adrenaline, α-and β-adrenoceptor agonists. We studied the change in the spontaneous smooth muscle contraction of guinea pig gastric corpus strips before and after 20-min treatment with 2μM retigabine. We also evaluated the effect of retigabine on the smooth muscle response to 10μM acetylcholine, 1 and 10μM adrenaline, 1μM methoxamine, 0.1μM p-iodoclonidine and 10μM isoproterenol. We observed a significant reduction in the effects of all studied mediators and agonists when they were added to organ baths in the presence of retigabine. Retigabine diminished the effect of acetylcholine on the spontaneous smooth muscle activity. The effect was fully antagonized by XE-991 (Kv7 channel blocker), which supports our hypothesis about the role of KCNQ channels in the registered changes. The increase in the contraction force after adding of 1μM adrenaline, methoxamine, and 0.1μM p-iodoclonidine was also significantly smaller in presence of retigabine. However, comparing the effect of 10μM adrenaline on the contractility before and after treatment with retigabine, we observed increased contractility when retigabine was present in the organ baths. A possible explanation for the observed diminished effects of mediators and receptor agonists is that the effect of retigabine on smooth muscle contractility is complex. The membrane hyperpolarization, the interaction between Kv7 channels and adrenoceptors, and the influence on signaling pathways may contribute to the summary smooth muscle response. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Effects of Lidocaine, Dexmedetomidine or Their Combination on the Minimum Alveolar Concentration of Sevoflurane in Dogs

    PubMed Central

    MORAN-MUÑOZ, Rafael; IBANCOVICHI, J. A.; Gutierrez-BLANCO, Eduardo; ACEVEDO-ARCIQUE, Carlos M.; Victoria MORA, J. Mauro; TENDILLO, Francisco J.; SANTOS-GONZALEZ, Martin; YAMASHITA, Kazuto

    2014-01-01

    ABSTRACT The aim of this study was to determine the effects of lidocaine (LIDO) and dexmedetomidine (DEX) or their combination (LIDO–DEX), administered by constant-rate infusion (CRI), on the minimum alveolar concentration (MAC) of sevoflurane in dogs. Seven healthy mongrel dogs were used with a 2-week washout interval between treatments in this study. Anesthesia was induced with propofol and maintained with sevoflurane in oxygen, and MAC of sevoflurane was determined after 90 min equilibration period in the dogs (SEV-MACBASAL). Then, sevoflurane MAC was determined again in the dogs after 45 min equilibration period of one of the following treatments: an intravenous loading dose of lidocaine 2 mg/kg followed by 6 mg/kg/hr CRI (SEV-MACLIDO); an intravenous loading dose of dexmedetomidine 2 µg/kg followed by 2 µg/kg/hr CRI (SEV-MACDEX); or their combination (SEV-MACLIDO-DEX). These SEV-MACs were determined in duplicate. Data were analyzed using ANOVA and post hoc Tuckey test when appropriate. The SEV-MACBASAL was 1.82 ± 0.06%, SEV-MACLIDO was 1.38 ± 0.08%, SEV-MACDEX was 1.22 ± 0.10%, and SEV-MACLIDO-DEX was 0.78 ± 0.06%. The CRI administration of lidocaine, dexmedetomidine and their combination produced a significant reduction in the MAC of sevoflurane by 26.1 ± 9.0% (P<0.0001), 43.7 ± 11.8% (P<0.0002) and 54.4 ± 9.8% (P<0.0001), respectively. The MAC reduction was significantly greater after the CRI combination of lidocaine and dexmedetomidine when compared with lidocaine CRI (P<0.0001) or dexmedetomidine CRI treatments (P<0.025). PMID:24572631

  13. Anaesthetic effects of alfaxalone administered intraperitoneally alone or combined with dexmedetomidine and fentanyl in the rat.

    PubMed

    Arenillas, Mario; Gomez de Segura, Ignacio A

    2018-01-01

    Alfaxalone is a neuroactive steroid used as a general anaesthetic in several species including dogs, cats, rabbits and ferrets. It has a wide margin of safety and a similar anaesthetic profile to propofol. To increase its aqueous solubility, a new formulation with cyclodextrins has been marketed recently. The objective of this study was to evaluate the anaesthetic effect of several doses of alfaxalone alone, considering differences between sexes, and alfaxalone combined with dexmedetomidine and fentanyl in the rat administered by the intraperitoneal route. A total of 40 Sprague Dawley rats, involved in three studies, were used. Firstly, 25, 35 and 45 mg kg -1 of alfaxalone alone were tested. In a second study, alfaxalone (25 mg kg -1 , females; 75 mg kg -1 , males) was combined with dexmedetomidine (0.05 mg kg -1 ). Finally, alfaxalone (20 mg kg -1 , females; 60 mg kg -1 , males) was combined with dexmedetomidine (0.05 mg kg -1 ) and fentanyl (0.1 mg kg -1 ). Times of onset and duration of anaesthesia, and analgesia, deemed as losing of withdrawal pedal reflex, were recorded. Alfaxalone alone produced a 2 - to 3-fold longer time of anaesthesia in females, although surgical anaesthesia was not achieved in either sex. The addition of dexmedetomidine and fentanyl to alfaxalone produced a similar time of analgesia as well as increased time of anaesthesia in both sexes. In conclusion, alfaxalone produces light anaesthesia in rats, and males required a higher dose. The combination with other sedatives or analgesics, such as dexmedetomidine or fentanyl, allows a more prolonged anaesthesia with analgesic effects, potentially suitable for invasive procedures.

  14. Bronchial thermoplasty: a novel treatment for severe asthma requiring monitored anesthesia care.

    PubMed

    Lee, Jamille A; Rowen, David W; Rose, David D

    2011-12-01

    Dexmedetomidine used in monitored anesthesia care produces a safe and effective technique well documented in research. We report the successful use of dexmedetomidine for sedation during bronchial thermoplasty, a new treatment for patients with severe persistent asthma refractory to inhaled corticosteroids and long-term beta-2 agonists.

  15. Pharmacokinetics of dexmedetomidine administered to patients with end-stage renal failure and secondary hyperparathyroidism undergoing general anaesthesia.

    PubMed

    Zhong, W; Zhang, Y; Zhang, M-Z; Huang, X-H; Li, Y; Li, R; Liu, Q-W

    2018-06-01

    The primary objective of this study was to compare the pharmacokinetics of dexmedetomidine in patients with end-stage renal failure and secondary hyperparathyroidism with those in normal individuals. Fifteen patients with end-stage renal failure and secondary hyperparathyroidism (Renal-failure Group) and 8 patients with normal renal and parathyroid gland function (Control Group) received intravenous 0.6 μg/kg dexmedetomidine for 10 minutes before anaesthesia induction. Arterial blood samples for plasma dexmedetomidine concentration analysis were drawn at regular intervals after the infusion was stopped. The pharmacokinetics were analysed using a nonlinear mixed-effect model with NONMEM software. The statistical significance of covariates was examined using the objective function (-2 log likelihood). In the forward inclusion and backward deletion, covariates (age, weight, sex, height, lean body mass [LBM], body surface area [BSA], body mass index [BMI], plasma albumin and grouping factor [renal failure or not]) were tested for significant effects on pharmacokinetic parameters. The validity of our population model was also evaluated using bootstrap simulations. The dexmedetomidine concentration-time curves fitted best with the principles of a two-compartmental pharmacokinetic model. No covariate of systemic clearance further improved the model. The final pharmacokinetic parameter values were as follows: V 1  = 60.6 L, V 2  = 222 L, Cl 1  = 0.825 L/min and Cl 2  = 4.48 L/min. There was no influence of age, weight, sex, height, LBM, BSA, BMI, plasma albumin and grouping factor (renal failure or not) on pharmacokinetic parameters. Although the plasma albumin concentrations (35.46 ± 4.13 vs 44.10 ± 1.12 mmol/L, respectively, P < .05) and dosage of propofol were significantly lower in the Renal-failure Group than in the Control Group (81.68 ± 18.08 vs 63.07 ± 13.45 μg/kg/min, respectively, P < .05), there were no differences in the

  16. Dexmedetomidine, Ketamine, and Midazolam for Oral Rehabilitation: A Case Report

    PubMed Central

    Kim, Bill W. S.; Peskin, Robert M.

    2015-01-01

    Intravenous sedation is frequently provided by anesthesiologists for phobic patients undergoing elective dental treatment in outpatient settings. Propofol is one of the most commonly used anesthetic agents that can result in apnea and respiratory depression, thereby posing potential difficulties with perioperative airway management. Dexmedetomidine has been utilized successfully in intravenous sedation for a wide variety of procedures and holds potential as an alternative to propofol in outpatient dental settings. However, as a single agent, it may not provide adequate depth of sedation and analgesia for oral rehabilitation. In this case report we demonstrate an effective alternative intravenous deep-sedation technique for an adult phobic patient undergoing oral rehabilitation utilizing 3 agents in combination: dexmedetomidine, ketamine, and midazolam. This combination of agents may be especially useful for those patients with a history of substance abuse, where administration of opioids may be undesirable or contraindicated. PMID:25849472

  17. Impaired structural and functional regeneration of skeletal muscles from β2-adrenoceptor knockout mice

    PubMed Central

    Silva, M T; Wensing, L A; Brum, P C; Câmara, N O; Miyabara, E H

    2014-01-01

    Aims β2-adrenergic stimulation causes beneficial effects on structure and function of regenerating muscles; thus, the β2-adrenoceptor may play an important role in the muscle regenerative process. Here, we investigated the role of the β2-adrenoceptor in skeletal muscle regeneration. Methods Tibialis anterior (TA) muscles from β2-adrenoceptor knockout (β2KO) mice were cryolesioned and analysed after 1, 3, 10 and 21 days. The role of β2-adrenoceptor on regenerating muscles was assessed through the analysis of morphological and contractile aspects, M1 and M2 macrophage profile, cAMP content, and activation of TGF-β signalling elements. Results Regenerating muscles from β2KO mice showed decreased calibre of regenerating myofibres and reduced muscle contractile function at 10 days when compared with those from wild type. The increase in cAMP content in muscles at 10 days post-cryolesion was attenuated in the absence of the β2-adrenoceptor. Furthermore, there was an increase in inflammation and in the number of macrophages in regenerating muscles lacking the β2-adrenoceptor at 3 and 10 days, a predominance of M1 macrophage phenotype, a decrease in TβR-I/Smad2/3 activation, and in the Smad4 expression at 3 days, while akirin1 expression increased at 10 days in muscles from β2KO mice when compared to those from wild type. Conclusions Our results suggest that the β2-adrenoceptor contributes to the regulation of the initial phases of muscle regeneration, especially in the control of macrophage recruitment in regenerating muscle through activation of TβR-I/Smad2/3 and reduction in akirin1 expression. These findings have implications for the future development of better therapeutic approaches to prevent or treat muscle injuries. PMID:24938737

  18. Isoproterenol Acts as a Biased Agonist of the Alpha-1A-Adrenoceptor that Selectively Activates the MAPK/ERK Pathway

    PubMed Central

    Copik, Alicja. J.; Baldys, Aleksander; Nguyen, Khanh; Sahdeo, Sunil; Ho, Hoangdung; Kosaka, Alan; Dietrich, Paul J.; Fitch, Bill; Raymond, John R.; Ford, Anthony P. D. W.; Button, Donald; Milla, Marcos E.

    2015-01-01

    The α1A-AR is thought to couple predominantly to the Gαq/PLC pathway and lead to phosphoinositide hydrolysis and calcium mobilization, although certain agonists acting at this receptor have been reported to trigger activation of arachidonic acid formation and MAPK pathways. For several G protein-coupled receptors (GPCRs) agonists can manifest a bias for activation of particular effector signaling output, i.e. not all agonists of a given GPCR generate responses through utilization of the same signaling cascade(s). Previous work with Gαq coupling-defective variants of α1A-AR, as well as a combination of Ca2+ channel blockers, uncovered cross-talk between α1A-AR and β2-AR that leads to potentiation of a Gαq-independent signaling cascade in response to α1A-AR activation. We hypothesized that molecules exist that act as biased agonists to selectively activate this pathway. In this report, isoproterenol (Iso), typically viewed as β-AR-selective agonist, was examined with respect to activation of α1A-AR. α1A-AR selective antagonists were used to specifically block Iso evoked signaling in different cellular backgrounds and confirm its action at α1A-AR. Iso induced signaling at α1A-AR was further interrogated by probing steps along the Gαq /PLC, Gαs and MAPK/ERK pathways. In HEK-293/EBNA cells transiently transduced with α1A-AR, and CHO_α1A-AR stable cells, Iso evoked low potency ERK activity as well as Ca2+ mobilization that could be blocked by α1A-AR selective antagonists. The kinetics of Iso induced Ca2+ transients differed from typical Gαq- mediated Ca2+ mobilization, lacking both the fast IP3R mediated response and the sustained phase of Ca2+ re-entry. Moreover, no inositol phosphate (IP) accumulation could be detected in either cell line after stimulation with Iso, but activation was accompanied by receptor internalization. Data are presented that indicate that Iso represents a novel type of α1A-AR partial agonist with signaling bias toward MAPK

  19. Dexmedetomidine infusion for analgesia and prevention of emergence agitation in children with obstructive sleep apnea syndrome undergoing tonsillectomy and adenoidectomy.

    PubMed

    Patel, Anuradha; Davidson, Melissa; Tran, Minh C J; Quraishi, Huma; Schoenberg, Catherine; Sant, Manasee; Lin, Albert; Sun, Xiuru

    2010-10-01

    Dexmedetomidine, a specific α(2) agonist, has an analgesic-sparing effect and reduces emergence agitation. We compared an intraoperative dexmedetomidine infusion with bolus fentanyl to reduce perioperative opioid use and decrease emergence agitation in children with obstructive sleep apnea syndrome undergoing adenotonsillectomy (T&A). One hundred twenty-two patients with obstructive sleep apnea syndrome undergoing T&A, ages 2 to 10 years, completed this prospective, randomized, U.S. Food and Drug Administration-approved study. After mask induction with sevoflurane, group D received IV dexmedetomidine 2 μg · kg(-1) over 10 minutes, followed by 0.7 μg · kg(-1) · h(-1), and group F received IV fentanyl bolus 1 μg · kg(-1). Anesthesia was maintained with sevoflurane, oxygen, and nitrous oxide. Fentanyl 0.5 to 1 μg · kg(-1) was given to subjects in both groups for an increase in heart rate or systolic blood pressure 30% above preincision values that continued for 5 minutes. Observers in the postanesthesia care unit (PACU) were blinded to treatment groups. Pain was evaluated using the objective pain score in the PACU on arrival, at 5 minutes, at 15 minutes, then every 15 minutes for 120 minutes. Emergence agitation was evaluated at the same intervals by 2 scales: the Pediatric Anesthesia Emergence Delirium scale and a 5-point scale described by Cole. Morphine (0.05 to 0.1 mg · kg(-1)) was given for pain (score >4) or severe agitation (score 4 or 5) lasting more than 5 minutes. In group D, 9.8% patients needed intraoperative rescue fentanyl in comparison with 36% in group F (P = 0.001). Mean systolic blood pressure and heart rate were significantly lower in group D (P < 0.05). Minimum alveolar concentration values were significantly different between the 2 groups (P = 0.015). The median objective pain score was 3 for group D and 5 for group F (P = 0.001). In group D, 10 (16.3%) patients required rescue morphine, in comparison with 29 (47.5%) in group F (P = 0

  20. Cardiovascular, respiratory, electrolyte and acid-base balance during continuous dexmedetomidine infusion in anesthetized dogs.

    PubMed

    Congdon, Jonathan M; Marquez, Megan; Niyom, Sirirat; Boscan, Pedro

    2013-09-01

    To evaluate the cardiovascular, respiratory, electrolyte and acid-base effects of a continuous infusion of dexmedetomidine during propofol-isoflurane anesthesia following premedication with dexmedetomidine. Prospective experimental study. Five adult male Walker Hound dogs 1-2 years of age averaging 25.4 ± 3.6 kg. Dogs were sedated with dexmedetomidine 10 μg kg(-1) IM, 78 ± 2.3 minutes (mean ± SD) before general anesthesia. Anesthesia was induced with propofol (2.5 ± 0.5 mg kg(-1) ) IV and maintained with 1.5% isoflurane. Thirty minutes later dexmedetomidine 0.5 μg kg(-1) IV was administered over 5 minutes followed by an infusion of 0.5 μg kg(-1)  hour(-1) . Cardiac output (CO), heart rate (HR), ECG, direct blood pressure, body temperature, respiratory parameters, acid-base and arterial blood gases and electrolytes were measured 30 and 60 minutes after the infusion started. Data were analyzed via multiple linear regression modeling of individual variables over time, compared to anesthetized baseline values. Data are presented as mean ± SD. No statistical difference from baseline for any parameter was measured at any time point. Baseline CO, HR and mean arterial blood pressure (MAP) before infusion were 3.11 ± 0.9 L minute(-1) , 78 ± 18 beats minute(-1) and 96 ± 10 mmHg, respectively. During infusion CO, HR and MAP were 3.20 ± 0.83 L minute(-1) , 78 ± 14 beats minute(-1) and 89 ± 16 mmHg, respectively. No differences were found in respiratory rates, PaO2 , PaCO2 , pH, base excess, bicarbonate, sodium, potassium, chloride, calcium or lactate measurements before or during infusion. Dexmedetomidine infusion using a loading dose of 0.5 μg kg(-1) IV followed by a constant rate infusion of 0.5 μg kg(-1)  hour(-1) does not cause any significant changes beyond those associated with an IM premedication dose of 10 μg kg(-1) , in propofol-isoflurane anesthetized dogs. IM dexmedetomidine given 108 ± 2

  1. Molecular cloning and functional expression of the guinea pig alpha(1a)-adrenoceptor.

    PubMed

    González-Espinosa, C; Romero-Avila, M T; Mora-Rodríguez, D M; González-Espinosa, D; García-Sáinz, J A

    2001-08-31

    In the present paper, the cloning and expression of the guinea pig alpha(1A)-adrenoceptor is presented. The nucleotide sequence had an open reading frame of 1401 bp that encoded a 466 amino-acid protein with an estimated molecular mass of approximately 51.5 kDa. When the clone was expressed in Cos-1 cells, specific high-affinity binding of [(3)H]prazosin and [(3)H]tamsulosin was observed. Chloroethylclonidine treatment of membranes slightly decreased the total binding with both radioligands. Binding competition experiments using [(3)H]tamsulosin showed the following potency order: (a) for agonists: oxymetazoline >epinephrine>norepinephrine>methoxamine, and (b) for antagonists: prazosin> or 5-methyl-urapidil=benoxathian>phentolamine>BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione). Photoaffinity labeling using [(125)I-aryl]azido-prazosin revealed a major broad band with a molecular mass between 70 and 80 kDa. The receptor was functional, as evidenced by an epinephrine-increased production of [(3)H]inositol phosphates that was blocked by prazosin.

  2. Adrenoceptor-Mediated Post- and Pre-Synaptic Regulations of the Reticulospinal Neurons in Rat Caudal Pontine Reticular Nucleus.

    PubMed

    Yang, Nian; Qiao, Qi-Cheng; Liu, Yu-Hui; Zhang, Ji-Qiang; Hu, Zhi-An; Zhang, Jun

    2016-12-01

    The central noradrenergic system participates in diverse nervous functions. Nevertheless, our knowledge of the action of adrenoceptors in motor regulation is still lacking. Intriguingly, reticulospinal neurons in the caudal pontine reticular nucleus (PnC) receive fairly dense noradrenergic innervation and play an important role in motor control. Here, after demonstrating the expression of α1- and α2-adrenoceptors in the PnC, we found that noradrenaline elicited a post-synaptic effect (inward or outward whole-cell current at -70 mV holding) on PnC reticulospinal neurons. The α1- and α2-adrenoceptors were co-expressed in individual PnC reticulospinal neurons to mediate an inward and an outward current component at -70 mV holding, respectively, which, when superposed, produced the overall post-synaptic effects of noradrenaline (NA). More importantly, the activation of post-synaptic α1- or α2-adrenoceptors indeed exerted opposing modulations (excitation vs. inhibition) on the firing activities of individual PnC reticulospinal neurons. Furthermore, the activation and inhibition of the Na + -permeable non-selective cationic conductance (NSCC) were demonstrated to be coupled to α1- and α2-adrenoceptors, respectively. Additionally, the activation of α2-adrenoceptors activated K + conductance. Pre-synaptically, the α2-adrenoceptors were expressed to attenuate the miniature excitatory postsynaptic current (mEPSC) in PnC reticulospinal neurons, but not to affect the miniature inhibitory postsynaptic current (mIPSC). Consistently, the evoked EPSC in PnC reticulospinal neurons was suppressed after the activation of pre-synaptic α2-adrenoceptors. Thus, the excitatory input and post-synaptic dynamics of PnC reticulospinal neurons are indeed intricately modulated by the activation of α1- and α2-adrenoceptors, through which motor control may be regulated in an adaptive manner by the central noradrenergic system.

  3. A case report of dexmedetomidine used to treat intractable pain and delirium in a tertiary palliative care unit.

    PubMed

    Hilliard, Neil; Brown, Stuart; Mitchinson, Steve

    2015-03-01

    This case report describes an end-stage cancer patient with intractable neuropathic pain and delirium who was successfully managed during the last 3 weeks of her life with a continuous subcutaneous infusion of dexmedetomidine. A 55-year-old woman with locally advanced cervical cancer and uncontrolled pelvic pain was admitted to a tertiary palliative care unit for pain management. As her disease progressed, the patient's pelvic pain intensified despite treatment with methadone, gabapentin, ketamine, and hydromorphone administered by continuous subcutaneous infusion plus frequent breakthrough doses of hydromorphone and sufentanil. A continuous subcutaneous infusion of dexmedetomidine was started and titrated to achieve pain relief. The patient's pain and delirium cleared. The treatment was successful in fulfilling the patient's goal of care: not to be deeply and continuously sedated, but to be rousable and of clear mind while still having good pain control. Dexmedetomidine is a potentially useful medication for the targeted treatment of intractable pain and delirium in the tertiary palliative care environment. Future research is required to compare dexmedetomidine infusion to standard treatment with midazolam infusion for treatment of intractable symptoms in the palliative care environment. © The Author(s) 2014.

  4. Involvement of alpha-adrenoceptors in myometrial responses in the pro-oestral rat.

    PubMed Central

    Acritopoulou-Fourcroy, S.; Marçais-Collado, H.

    1988-01-01

    1. Myometrial responses to different agents acting on adrenoceptors were examined in vivo in the pro-oestrous rat. Changes in spontaneous uterine mechanical activity were recorded isometrically and evaluated in terms of amplitude and duration of uterine contractions. 2. Phenylephrine (10 micrograms kg-1) markedly increased the amplitude and duration of contractions and 40 micrograms kg-1 gave rise to tetanic contractions. 3. Administration of either nicergoline (400 micrograms kg-1) or phentolamine (1000 micrograms kg-1) to phenylephrine-primed rat uterus reduced the strength of contractions and phentolamine abolished the phenylephrine-induced uterine contracture. 4. Following blockade of alpha 2-adrenoceptors by yohimbine (1000 micrograms kg-1) and beta-adrenoceptors by propranolol (2400 micrograms kg-1), a single injection of phenylephrine (100 micrograms kg-1) increased the amplitude of uterine contractions by 30%. 5. Noradrenaline reduced the amplitude of contractions and caused elevation of the baseline level. The response of myometrium to the combination of both propranolol and noradrenaline was the establishment of uterine contracture with subsequent increase of the duration of contractions. 6. These results clearly demonstrate the involvement of alpha-adrenoceptors in the myometrial activity of the rat in vivo during pro-oestrus. PMID:2832026

  5. Dexmedetomidine in Attenuation of Haemodynamic Response and Dose Sparing Effect on Opioid and Anaesthetic Agents in Patients undergoing Laparoscopic Cholecystectomy- A Randomized Study

    PubMed Central

    Bhagat, Nandlal; Karim, Habib Md Reazaul; Hajong, Ranendra; Bhattacharyya, Prithwis; Singh, Manorama

    2016-01-01

    Introduction Perioperative procedures are stressful and lead to haemodynamic instability with potentially devastating consequences. Dexmedetomidine is found to have many of the desired characteristics that are required in perioperative period. Aim To evaluate the ability of pre and intraoperative dexmedetomidine to attenuate stress induced haemodynamic responses, quantifying the anaesthetic agents sparing as well as its cost-effectiveness in patients undergoing laparoscopic cholecystectomy. Materials and Methods The present single blind randomized study was conducted with 120 ASA I and II consented patients who underwent laparoscopic cholecystectomy. Patients were randomly divided into 2 groups (i.e., group D and group N). Prior to induction, group D received 1 μg/kg of Dexmedetomidine and group N received Normal saline infusion over 20 minutes. Group D also received maintenance Dexmedetomidine intraoperatively. Bispectral index and minimum alveolar concentration monitoring was done in both the groups. Haemodynamic parameters were noted till 100 minutes post laryngoscopy. Opioid and anaesthetic agent consumptions were also noted and cost analysis was done. Medcalc–Version 12.5.0.0 software was used for statistics and p <0.05 was considered significant. Results Dexmedetomidine attenuated the stress induced haemodynamics responses and produced stable, relatively non fluctuating haemodynamics throughout. The Minimum Alveolar Concentration (MAC) requirement and the consumptions of Fentanyl and Isoflurane were significantly less in the Dexmedetomidine group (p<0.0001). However, despite anaesthetic dose sparing effect the anaesthetic technique was not cost-effective. Conclusion Dexmedetomidine is effective in attenuating haemodynamic responses in laparoscopic surgery and having dose sparing effect on Fentanyl, Propofol and Isoflurane. However, overall this technique is not cost-effective. PMID:28050479

  6. An ERβ agonist induces browning of subcutaneous abdominal fat pad in obese female mice.

    PubMed

    Miao, Yi-Fei; Su, Wen; Dai, Yu-Bing; Wu, Wan-Fu; Huang, Bo; Barros, Rodrigo P A; Nguyen, Hao; Maneix, Laure; Guan, You-Fei; Warner, Margaret; Gustafsson, Jan-Åke

    2016-12-06

    Estrogen, via estrogen receptor alpha (ERα), exerts several beneficial effects on metabolism and energy homeostasis by controlling size, enzymatic activity and hormonal content of adipose tissue. The actions of estrogen on sympathetic ganglia, which are key players in the browning process, are less well known. In the present study we show that ERβ influences browning of subcutaneous adipose tissue (SAT) via its actions both on sympathetic ganglia and on the SAT itself. A 3-day-treatment with a selective ERβ agonist, LY3201, induced browning of SAT in 1-year-old obese WT and ERα -/- female mice. Browning was associated with increased expression of ERβ in the nuclei of neurons in the sympathetic ganglia, increase in tyrosine hydroxylase in both nerve terminals in the SAT and sympathetic ganglia neurons and an increase of β3-adrenoceptor in the SAT. LY3201 had no effect on browning in young female or male mice. In the case of young females browning was already maximal while in males there was very little expression of ERβ in the SAT and very little expression of the β3-adrenoceptor. The increase in both sympathetic tone and responsiveness of adipocytes to catecholamines reveals a novel role for ERβ in controlling browning of adipose tissue.

  7. An ERβ agonist induces browning of subcutaneous abdominal fat pad in obese female mice

    PubMed Central

    Miao, Yi-fei; Su, Wen; Dai, Yu-bing; Wu, Wan-fu; Huang, Bo; Barros, Rodrigo P. A.; Nguyen, Hao; Maneix, Laure; Guan, You-fei; Warner, Margaret; Gustafsson, Jan-Åke

    2016-01-01

    Estrogen, via estrogen receptor alpha (ERα), exerts several beneficial effects on metabolism and energy homeostasis by controlling size, enzymatic activity and hormonal content of adipose tissue. The actions of estrogen on sympathetic ganglia, which are key players in the browning process, are less well known. In the present study we show that ERβ influences browning of subcutaneous adipose tissue (SAT) via its actions both on sympathetic ganglia and on the SAT itself. A 3-day-treatment with a selective ERβ agonist, LY3201, induced browning of SAT in 1-year-old obese WT and ERα−/− female mice. Browning was associated with increased expression of ERβ in the nuclei of neurons in the sympathetic ganglia, increase in tyrosine hydroxylase in both nerve terminals in the SAT and sympathetic ganglia neurons and an increase of β3-adrenoceptor in the SAT. LY3201 had no effect on browning in young female or male mice. In the case of young females browning was already maximal while in males there was very little expression of ERβ in the SAT and very little expression of the β3-adrenoceptor. The increase in both sympathetic tone and responsiveness of adipocytes to catecholamines reveals a novel role for ERβ in controlling browning of adipose tissue. PMID:27922125

  8. Intraoperative Sedation With Dexmedetomidine is Superior to Propofol for Elderly Patients Undergoing Hip Arthroplasty: A Prospective Randomized Controlled Study.

    PubMed

    Mei, Bin; Meng, Gaige; Xu, Guanghong; Cheng, Xinqi; Chen, Shishou; Zhang, Ye; Zhang, Ming; Liu, Xuesheng; Gu, Erwei

    2018-03-09

    Peripheral nerve block is a preferable method for elderly patients receiving hip arthroplasty. Sedation with dexmedetomidine may reduce postoperative delirium. The aim of this study was to investigate whether intraoperative sedation with dexmedetomidine, as a supplementary to peripheral nerve block for elderly patients receiving total hip arthroplasty, can decrease the prevalence of postoperative delirium. A prospective, randomized controlled study was conducted with patients 65 years of age or older who underwent total hip arthroplasty between June 2016 and June 2017. The patients were randomly assigned to receive a lumbosacral plexus plus T12 paravertebral block supplemented with propofol or dexmedetomidine for sedation. Incidence of postoperative delirium was the primary endpoint and was determined with the Confusion Assessment Method, and incidence of postoperative cognitive dysfunction was assessed with the Mini-Mental State Examination. The time of ambulation, discharge time, and complications over a 30-day post-surgery period were also recorded. 296 patients were randomly assigned to two groups. The patients sedated with dexmedetomidine had lower incidences of postoperative delirium and postoperative cognitive dysfunction and were out of bed and discharged sooner than the patients sedated with propofol. There was no difference in complications between the two groups. As a supplementary to peripheral nerve block, intraoperative sedation with dexmedetomidine could be associated with a lower incidence of POD, which may have benefits on reducing the incidence of early postoperative cognitive dysfunction and offering a better short-term recovery for elderly patients receiving hip arthroplasty.

  9. The effects of increasing doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs.

    PubMed

    Honkavaara, J M; Restitutti, F; Raekallio, M R; Kuusela, E K; Vainio, O M

    2011-08-01

    Different doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, with or without dexmedetomidine were compared in conscious dogs. Eight animals received either dexmedetomidine (10 μg/kg [D]), MK-467 (250 μg/kg [M250] or dexmedetomidine (10 μg/kg) with increasing doses of MK-467 (250 μg/kg [DM250], 500 μg/kg [DM500] and 750 μg/kg [DM750], respectively). Treatments were given intravenously (i.v.) in a randomized, crossover design with a 14-day washout period. Systemic hemodynamics and arterial blood gas analyses were recorded at baseline and at intervals up to 90 min after drugs administration. Dexmedetomidine alone decreased heart rate, cardiac index and tissue oxygen delivery and increased mean arterial pressure and systemic vascular resistance 5 min after administration. DM250 did not completely prevent these early effects, while DM750 induced a decrease in mean arterial pressure. With DM500, systemic hemodynamics remained stable throughout the observational period. MK-467 alone increased cardiac index and tissue oxygen delivery and had no deleterious adverse effects. No differences in arterial blood gases were observed between treatments that included dexmedetomidine. It was concluded that MK-467 attenuated or prevented dexmedetomidine's systemic hemodynamic effects in a dose-dependent manner when given simultaneously i.v. but had no effect on the pulmonary outcome in conscious dogs. A 50:1 dose ratio (MK-467:dexmedetomidine) induced the least alterations in cardiovascular function. © 2010 Blackwell Publishing Ltd.

  10. Thermal antinociception after dexmedetomidine administration in cats: a comparison between intramuscular and oral transmucosal administration.

    PubMed

    Slingsby, Louisa S; Taylor, Polly M; Monroe, Taylor

    2009-10-01

    Dexmedetomidine 40microg/kg was administered either intramuscularly (IM) or oral transmucosally (OTM) to 12 cats in a randomised cross-over study. Thermal nociceptive thresholds and visual analogue scale (VAS) sedation scores were obtained before and at regular intervals up to 24h after test drug administration. The summary measures of overall mean threshold, overall mean VAS sedation plus onset, offset and duration of analgesia were investigated using a univariate general linear model. There were no significant differences between treatment groups. Data are presented as mean+/-standard deviation: delta T mean increase over time (IM 6 degrees C+/-3 degrees C, OTM 6 degrees C+/-2 degrees C); overall mean VAS (IM 43+/-9 OTM 39+/-1); onset (IM 35+/-32 and OTM 30+/-40min); offset (IM 96+/-56 and OTM 138+/-135min); duration (IM 61+/-47 OTM 99+/-124min). Dexmedetomidine is well absorbed through the oral mucosa in cats since OTM and IM administration of dexmedetomidine 40microg/kg produced similar overall sedative and antinociceptive effects.

  11. Rational design, synthesis, biologic evaluation, and structure-activity relationship studies of novel 1-indanone alpha(1)-adrenoceptor antagonists.

    PubMed

    Li, Minyong; Xia, Lin

    2007-11-01

    In the present report, a novel series of 1-indanone alpha(1)-adrenoceptor antagonists were designed and synthesized based on 3D-pharmacophore model. Their in vitro alpha(1)-adrenoceptor antagonistic assay showed that three compounds (2a, 2m, and 2o) had similar or improved alpha(1)-adrenoceptor antagonistic activities relative to the positive control prazosin. Based on these results, a three-dimensional quantitative structure-activity relationship study was performed using a Self-Organizing Molecular Field Analysis method to provide insight for the future development of alpha(1)-adrenoceptor antagonists.

  12. Rescue Sedation With Intranasal Dexmedetomidine for Pediatric Ophthalmic Examination After Chloral Hydrate Failure: A Randomized, Controlled Trial.

    PubMed

    Gan, Xiaoliang; Lin, Haotian; Chen, Jingjing; Lin, Zhuoling; Lin, Yiquan; Chen, Weirong

    2016-06-01

    It is a challenge to rescue ophthalmology examinations performed in children in the sedation room after initial chloral hydrate failure. Intranasal dexmedetomidine can be used in rescue sedation in children undergoing computed tomography. The present study aimed to assess the efficacy and tolerability of intranasal dexmedetomidine use in children undergoing ophthalmic examination after chloral hydrate failure. Sixty uncooperative pediatric patients with cataract (aged 5-36 months; weight, 7-15 kg) presented for follow-up ophthalmic examination. Patients who experienced chloral hydrate failure were randomized to 1 of 2 groups to receive intranasal dexmedetomidine 1 or 2 μg/kg for rescue sedation. Each group contained 30 patients. The primary outcome was the rate of a successful ophthalmic examination. Secondary outcomes included sedation onset time, recovery time, duration of examination, discharge time, and adverse events, including percentage of heart rate reduction, respiratory depression, vomiting, and postsedative agitation. A successful ophthalmic examination was achieved in 93.3% (28/30) of patients in the 2-μg/kg dose group and in 66.7% (20/30) of patients in the 1-μg/kg dose group (P = 0.021). The onset time, recovery time, and discharge time did not significantly differ between the 2 groups. None of the patients required clinical intervention due to heart rate reduction, and none of the patients in either group experienced vomiting, respiratory depression, or agitation after the administration of dexmedetomidine. In children undergoing ophthalmic examination, intranasal dexmedetomidine can be administered in the sedation room for rescue sedation after chloral hydrate failure, with the 2-μg/kg dose being more efficacious than the 1-μg/kg dose, as measured by success rate. ClinicalTrials.gov identifier: NCT02077712. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

  13. Effectiveness of preoperative intranasal dexmedetomidine, compared with oral midazolam, for the prevention of emergence delirium in the pediatric patient undergoing general anesthesia: a systematic review.

    PubMed

    FitzSimons, James; Bonanno, Laura S; Pierce, Stephanie; Badeaux, Jennifer

    2017-07-01

    Emergence delirium is defined as a cognitive disturbance during emergence from general anesthesia resulting in hallucinations, delusions and confusion manifested by agitation, restlessness, involuntary physical movement and extreme flailing in bed. Postoperative emergence delirium develops in 12% to 18% of all children undergoing general anesthesia for surgery. This post-anesthetic phenomenon changes cognitive and psychomotor behavior, and puts pediatric patients and health care personnel at risk of injury. A newer drug, dexmedetomidine, is a selective alpha-2 agonist, which works in the brain and spinal cord that has sedative, analgesic and anxiolytic properties. Dexmedetomidine also has the ability to lower the overall anesthetic requirements by reducing sympathetic outflow in response to painful surgical stimulation. In current literature, there is not a systematic review that compares the effectiveness of preoperative intranasal dexmedetomidine administration against oral midazolam for the prevention of emergence delirium. The objective of this review was to identify the effectiveness of preoperative intranasal dexmedetomidine compared to oral midazolam for the prevention of emergence delirium in the pediatric patient undergoing general anesthesia. This review considered studies that included pediatric patients aged three to seven years, with an American Society of Anesthesiologists (ASA) classification of I or II, and undergoing general anesthesia for elective/ambulatory surgery. This review excluded studies that included patients who had special needs including: developmental delay, chronic pain issues, and/or any preexisting mental or physical health disorders which categorized them above an ASA II. This review considered studies that compared preoperative intranasal administration of dexmedetomidine with preoperative oral administration of midazolam for the prevention of emergence delirium. This review considered both experimental and non-experimental study

  14. 78 FR 33698 - New Animal Drugs; Dexmedetomidine; Lasalocid; Melengestrol; Monensin; and Tylosin; Correction

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-05

    ... 2013 that appeared in the Federal Register of April 30, 2013. FDA is correcting the approved strengths... correcting the approved strengths of dexmedetomidine hydrochloride injectable solution. This correction is...

  15. Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis.

    PubMed

    Grimsrud, K N; Ait-Oudhia, S; Durbin-Johnson, B P; Rocke, D M; Mama, K R; Rezende, M L; Stanley, S D; Jusko, W J

    2015-02-01

    The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2-adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half-maximal effect (IC50 ) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data. © 2014 John Wiley & Sons Ltd.

  16. Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis

    PubMed Central

    Grimsrud, K. N.; Ait-Oudhia, S.; Durbin-Johnson, B. P.; Rocke, D. M.; Mama, K. R.; Rezende, M. L.; Stanley, S. D.; Jusko, W. J.

    2014-01-01

    The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2-adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half-maximal effect (IC50) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data. PMID:25073816

  17. Comparison of Dexmedetomidine and Fentanyl as an Adjuvant to Ropivacaine for Postoperative Epidural Analgesia in Pediatric Orthopedic Surgery.

    PubMed

    Park, Sang Jun; Shin, Seokyung; Kim, Shin Hyung; Kim, Hyun Woo; Kim, Seung Hyun; Do, Hae Yoon; Choi, Yong Seon

    2017-05-01

    Opioids are commonly used as an epidural adjuvant to local anesthetics, but are associated with potentially serious side effects, such as respiratory depression. The aim of this study was to compare the efficacy and safety of dexmedetomidine with that of fentanyl as an adjuvant to epidural ropivacaine in pediatric orthopedic surgery. This study enrolled 60 children (3-12 years old) scheduled for orthopedic surgery of the lower extremities and lumbar epidural patient-controlled analgesia (PCA). Children received either dexmedetomidine (1 μg/kg) or fentanyl (1 μg/kg) along with 0.2% ropivacaine (0.2 mL/kg) via an epidural catheter at 30 minutes before the end of surgery. Postoperatively, the children were observed for ropivacaine consumption via epidural PCA, postoperative pain intensity, need for rescue analgesics, emergence agitation, and other adverse effects. The mean dose of bolus epidural ropivacaine was significantly lower within the first 6 h after surgery in the dexmedetomidine group, compared with the fentanyl group (0.029±0.030 mg/kg/h vs. 0.053±0.039 mg/kg/h, p=0.012). The median pain score at postoperative 6 h was also lower in the dexmedetomidine group, compared to the fentanyl group [0 (0-1.0) vs. 1.0 (0-3.0), p=0.039]. However, there was no difference in the need for rescue analgesia throughout the study period between groups. The use of dexmedetomidine as an epidural adjuvant had a significantly greater analgesic and local anesthetic-sparing effect, compared to fentanyl, in the early postoperative period in children undergoing major orthopedic lower extremity surgery. © Copyright: Yonsei University College of Medicine 2017

  18. Comparison of Dexmedetomidine and Fentanyl as an Adjuvant to Ropivacaine for Postoperative Epidural Analgesia in Pediatric Orthopedic Surgery

    PubMed Central

    Park, Sang Jun; Shin, Seokyung; Kim, Shin Hyung; Kim, Hyun Woo; Kim, Seung Hyun; Do, Hae Yoon

    2017-01-01

    Purpose Opioids are commonly used as an epidural adjuvant to local anesthetics, but are associated with potentially serious side effects, such as respiratory depression. The aim of this study was to compare the efficacy and safety of dexmedetomidine with that of fentanyl as an adjuvant to epidural ropivacaine in pediatric orthopedic surgery. Materials and Methods This study enrolled 60 children (3–12 years old) scheduled for orthopedic surgery of the lower extremities and lumbar epidural patient-controlled analgesia (PCA). Children received either dexmedetomidine (1 µg/kg) or fentanyl (1 µg/kg) along with 0.2% ropivacaine (0.2 mL/kg) via an epidural catheter at 30 minutes before the end of surgery. Postoperatively, the children were observed for ropivacaine consumption via epidural PCA, postoperative pain intensity, need for rescue analgesics, emergence agitation, and other adverse effects. Results The mean dose of bolus epidural ropivacaine was significantly lower within the first 6 h after surgery in the dexmedetomidine group, compared with the fentanyl group (0.029±0.030 mg/kg/h vs. 0.053±0.039 mg/kg/h, p=0.012). The median pain score at postoperative 6 h was also lower in the dexmedetomidine group, compared to the fentanyl group [0 (0–1.0) vs. 1.0 (0–3.0), p=0.039]. However, there was no difference in the need for rescue analgesia throughout the study period between groups. Conclusion The use of dexmedetomidine as an epidural adjuvant had a significantly greater analgesic and local anesthetic-sparing effect, compared to fentanyl, in the early postoperative period in children undergoing major orthopedic lower extremity surgery. PMID:28332374

  19. Efficacy of Dexmedetomidine as an Adjuvant to Local Anesthetic Agent in Scalp Block and Scalp Infiltration to Control Postcraniotomy Pain: A Double-Blind Randomized Trial.

    PubMed

    Vallapu, Shankar; Panda, Nidhi Bidyut; Samagh, Navneh; Bharti, Neerja

    2018-01-01

    Scalp infiltration and scalp block are being used to manage postcraniotomy pain. Dexmedetomidine has been successfully used as an adjuvant in regional anesthesia. The study was intended to compare whether addition of dexmedetomidine prolonged the duration of analgesia as well as to compare the two techniques. The primary objective was to assess whether addition of dexmedetomidine to bupivacaine prolonged the duration of analgesia. The secondary objective was to compare between scalp nerve block and scalp infiltration as techniques for pain relief. The randomized control study was conducted in a tertiary care center from November 2013 to October 2014. A total of 150 American Society of Anesthesiologists Physical Status I-II patients, aged 18-70 years undergoing elective craniotomy were included. Patients were randomized into three groups of 50 patients, i.e., Group BI (bupivacaine infiltration), Group BDI (bupivacaine and dexmedetomidine infiltration), and Group BDNB (bupivacaine and dexmedetomidine scalp nerve block). Patient's pain score, pain-free interval, rescue analgesic requirement, and hemodynamic and respiratory parameters were noted for 48 h. Patients were followed up at 1 and 3 months to assess postcraniotomy pain. Pain-free period was significantly longer in Group BDNB than Groups BDI and BI ( P < 0.0001) and pain control was better in dexmedetomidine containing groups than in bupivacaine group (BI) ( P < 0.0001). The rescue analgesic requirement was significantly lower in Group BDNB and Group BDI compared to Group BI. The addition of dexmedetomidine (1 μg/kg) to bupivacaine prolonged the pain-free period. Scalp nerve block is a superior technique than scalp infiltration.

  20. Involvement of α2-adrenoceptors in inhibitory and facilitatory pain modulation processes.

    PubMed

    Vo, L; Drummond, P D

    2016-03-01

    In healthy humans, high-frequency electrical stimulation (HFS) of the forearm not only produces hyperalgesia at the site of stimulation but also reduces sensitivity to pressure-pain on the ipsilateral side of the forehead. In addition, HFS augments the ipsilateral trigeminal nociceptive blink reflex and intensifies the ipsilateral component of conditioned pain modulation. The aim of this study was to determine whether α2-adrenoceptors mediate these ipsilateral nociceptive influences. The α2-adrenoceptor antagonist yohimbine was administered to 22 participants in a double-blind, placebo-controlled crossover study. In each session, thermal and mechanical sensitivity in the forearms and forehead was assessed before and after HFS. In addition, the combined effect of HFS and yohimbine on the nociceptive blink reflex and on conditioned pain modulation was explored. In this paradigm, the conditioning stimulus was cold pain in the ipsilateral or contralateral temple, and the test stimulus was electrically evoked pain in the forearm. Blood pressure and electrodermal activity increased for several hours after yohimbine administration, consistent with blockade of central α2-adrenoceptors. Yohimbine not only augmented the nociceptive blink reflex ipsilateral to HFS but also intensified the inhibitory influence of ipsilateral temple cooling on electrically evoked pain at the HFS-treated site in the forearm. Yohimbine had no consistent effect on primary or secondary hyperalgesia in the forearm or on pressure-pain in the ipsilateral forehead. These findings imply involvement of α2-adrenoceptors both in ipsilateral antinociceptive and pronociceptive pain modulation processes. However, a mechanism not involving α2-adrenoceptors appears to mediate analgesia in the ipsilateral forehead after HFS. © 2015 European Pain Federation - EFIC®

  1. Dexmedetomidine versus midazolam as adjuvants to intrathecal bupivacaine: A clinical comparison.

    PubMed

    Shukla, Usha; Prabhakar, Tallamraju; Malhotra, Kiran; Srivastava, Dheeraj

    2016-01-01

    Trials are being carried out to identify an adjuvant to intrathecal bupivacaine that preferably potentiates postoperative analgesia. This prospective, randomized, double-blind study was aimed to compare the onset and duration of sensory and motor block, postoperative analgesia and adverse effects of dexmedetomidine or midazolam given with 0.5% hyperbaric bupivacaine for spinal anesthesia. A total of 80 patients, scheduled for vaginal hysterectomies, were randomly allocated to Group D (n = 40) to receive intrathecally 3.0 mL 0.5% hyperbaric bupivacaine +5 ug dexmedetomidine in 0.5 mL of normal saline; and Group M (n = 40) to receive 3 mL of 0.5% hyperbaric bupivacaine +2 mg midazolam in 0.4 mL (5 mg/mL) +0.1 mL normal saline. The onset, duration of sensory and motor block, time to first postoperative analgesia and side effects were noted. Power and Sample size (PS) version 3.0.0.34 was used for power and sample size calculation. Statistical analysis was performed using Microsoft (MS) Office Excel software with the Student's t-test and Chi-square test (level of significance P = 0.05). Duration of sensory, motor blockade and time to the first requirement of analgesia were significantly higher in Group D. Postoperative visual analog scale was significantly less in Group D than Group M. Both groups were similar with respect to sedation, hemodynamic variables and side-effects. Intrathecal dexmedetomidine was better adjuvant than midazolam as it produces significantly longer duration of sensory block, reduced doses of postoperative analgesic agents with comparable side-effects.

  2. Phosphorylation-induced conformation of β2-adrenoceptor related to arrestin recruitment revealed by NMR.

    PubMed

    Shiraishi, Yutaro; Natsume, Mei; Kofuku, Yutaka; Imai, Shunsuke; Nakata, Kunio; Mizukoshi, Toshimi; Ueda, Takumi; Iwaï, Hideo; Shimada, Ichio

    2018-01-15

    The C-terminal region of G-protein-coupled receptors (GPCRs), stimulated by agonist binding, is phosphorylated by GPCR kinases, and the phosphorylated GPCRs bind to arrestin, leading to the cellular responses. To understand the mechanism underlying the formation of the phosphorylated GPCR-arrestin complex, we performed NMR analyses of the phosphorylated β 2 -adrenoceptor (β 2 AR) and the phosphorylated β 2 AR-β-arrestin 1 complex, in the lipid bilayers of nanodisc. Here we show that the phosphorylated C-terminal region adheres to either the intracellular side of the transmembrane region or lipids, and that the phosphorylation of the C-terminal region allosterically alters the conformation around M215 5.54 and M279 6.41 , located on transemembrane helices 5 and 6, respectively. In addition, we found that the conformation induced by the phosphorylation is similar to that corresponding to the β-arrestin-bound state. The phosphorylation-induced structures revealed in this study propose a conserved structural motif of GPCRs that enables β-arrestin to recognize dozens of GPCRs.

  3. Satisfaction and safety using dexmedetomidine or propofol sedation during endoscopic oesophageal procedures: A randomised controlled trial.

    PubMed

    Eberl, Susanne; Preckel, Benedikt; Bergman, Jacques J; van Dieren, Susan; Hollmann, Markus W

    2016-09-01

    Dexmedetomidine possesses anxiolytic and hypnotic properties without respiratory side-effects, making it theoretically an ideal sedative agent for endoscopic procedures. We aimed to compare satisfaction and safety among outpatients receiving sedation with dexmedetomidine or propofol for endoscopic oesophageal procedures. A randomised controlled study. Endoscopic intervention suite at the Academic Medical Centre in Amsterdam, Netherlands. Patients aged at least 18 years, and American Society of Anesthesiologists' physical status 1 to 3. Total 63 patients were randomised to receive either dexmedetomidine (D) or propofol (P). Pain was treated with alfentanil in both groups. The primary outcomes were patients' and endoscopists' satisfaction levels measured by validated questionnaires (1 = very dissatisfied; 7 = highly satisfied). A secondary outcome was safety, determined by blood pressure, heart rate and oxygen saturation during and after the procedure, and respiratory rate and noninvasive cardiac output during the procedure. Satisfaction of patients [median (IQR); group D, 5.0 (3.75 to 5.75) vs. group P, 6.25 (5.3 to 6.5)] and satisfaction of gastroenterologists [group D, 5.0 (4.4 to 5.8) vs. group P, 6.0 (5.4 to 6.0)] were lower in group D (both P < 0.001). More patients in group D would not recommend this form of sedation to one of their friends (group D, 15 of 32 vs. group P, 1 of 31; P < 0.001). Total 30 min after the procedure, heart rate [group D, 60 bpm (52 to 69) vs. group P, 70 bpm (60 to 81), P = 0.031] and SBP group D, 112 mmHg (92 to 132) vs. group P, 120 mmHg (108 to 132); P = 0.013] were significantly lower after dexmedetomidine sedation. There were no other differences in safety between groups. Compared with propofol, sedation with dexmedetomidine resulted in less satisfaction, and caused prolonged haemodynamic depression after endoscopic oesophageal procedures. ISRCTN Register (ISRCTN 68599804).

  4. Role of α1-adrenoceptor subtypes in the effects of methylenedioxy methamphetamine (MDMA) on body temperature in the mouse

    PubMed Central

    Bexis, S; Docherty, J R

    2007-01-01

    Background and purpose: We have investigated the ability of α1-adrenoceptor antagonists to affect the hyperthermia produced by methylenedioxy methamphetamine (MDMA) in conscious mice. Experimental approach: Mice were implanted with temperature probes under ether anaesthesia and allowed 2 weeks recovery. MDMA (20 mg kg−1) was administered subcutaneously 30 min after vehicle or test antagonist or combination of antagonists and effects on body temperature monitored. Key results: Following vehicle, MDMA produced a hyperthermia, reaching a maximum increase of 1.8 °C at 140 min. Prazosin (0.1 mg kg−1) revealed an early significant hypothermia to MDMA of −1.94 °C. The α1A-adrenoceptor antagonist RS 100329 (0.1 mg kg−1), or the α1D-adrenoceptor antagonist BMY 7378 (0.5 mg kg−1) given alone, did not reveal a hypothermia to MDMA, but the combination of the two antagonists revealed a significant hypothermia to MDMA. The putative α1B-adrenoceptor anatagonist cyclazosin (1 mg kg−1) also revealed a significant hypothermia to MDMA, but actions of cyclazosin at the other α1-adrenoceptor subtypes cannot be excluded. Conclusions and implications: More than one subtype of α1-adrenoceptor is involved in a component of the hyperthermic response to MDMA in mouse, probably both α1A- and α1D-adrenoceptors, and removal of this α1-adrenoceptor-mediated component reveals an initial hypothermia. PMID:18037913

  5. Inhibition by alpha- and beta-adrenoceptors of the twitch response to transmural stimulation in the guinea-pig vas deferens.

    PubMed

    Hedqvist, P; Von Euler, U S

    1976-11-01

    Noradrenaline as well as the indirectly acting amines tyramine and phenethylamine either enhance or inhibit the twitch response of the transmurally stimulated, isolated guine-pig vas deferens, thus partly confirming previous reports. In both cases enhancement is annulled by alpha-adrenoceptor blockers. The twitch inhibition caused by noradrenaline is abolished by alpha- + beta2-adrenoceptor blockers, but not by either blocker alone. The inhibition caused by the indirectly acting amines is largely abolished by alpha-adrenoceptor blockers. Clonidine strongly inhibits the twitch. This effect if promptly removed by phentolamine. After blockade of the neurally induced twitch by tetrodotoxin, noradrenaline and the indirectly acting amines have no effect or slightly enhance the twitch elicited by transmural stimulation of the smooth muscle. It is concluded that exogenous noradrenaline acts on postjunctional stimulatory alpha-adrenoceptors and on inhibitory alpha- and beta2-adrenoceptors, which are presumably prejunctional. In the unstimulated preparation contracted by acetylcholine, noradrenaline causes further contraction which is changed into relaxation after phentolamine. This relaxation is abolished by butoxamine, suggesting that noradrenaline may also act on inhibitory postjunctional beta2-adrenoceptors. The twitch-inhibiting effect of endogenous noradrenaline, released by nerve stimulation or by indirectly acting amines, appears to be primarily mediated by prejunctional alpha-adrenoceptors.

  6. Intranasal dexmedetomidine for sedation for pediatric computed tomography imaging.

    PubMed

    Mekitarian Filho, Eduardo; Robinson, Fay; de Carvalho, Werther Brunow; Gilio, Alfredo Elias; Mason, Keira P

    2015-05-01

    This prospective observational pilot study evaluated the aerosolized intranasal route for dexmedetomidine as a safe, effective, and efficient option for infant and pediatric sedation for computed tomography imaging. The mean time to sedation was 13.4 minutes, with excellent image quality, no failed sedations, or significant adverse events. Registered with ClinicalTrials.gov: NCT01900405. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Comparison of the efficacy and safety of sedation between dexmedetomidine-remifentanil and propofol-remifentanil during endoscopic submucosal dissection

    PubMed Central

    Kim, Namo; Yoo, Young-Chul; Lee, Sang Kil; Kim, Hyunzu; Ju, Hyang Mi; Min, Kyeong Tae

    2015-01-01

    AIM: To compare the efficacy and safety of sedation protocols for endoscopic submucosal dissection (ESD) between dexmedetomidine-remifentanil and propofol-remifentanil. METHODS: Fifty-nine patients scheduled for ESD were randomly allocated into a dexmedetomidine-remifentanil (DR) group or a propofol-remifentanil (PR) group. To control patient anxiety, dexmedetomidine or propofol was infused to maintain a score of 4-5 on the Modified Observer’s Assessment of Alertness/Sedation scale. Remifentanil was infused continuously at a rate of 6 μg/kg per hour in both groups. The ease of advancing the scope into the throat, gastric motility grading, and satisfaction of the endoscopist and patient were assessed. Hemodynamic variables and hypoxemic events were compared to evaluate patient safety. RESULTS: Demographic data were comparable between the groups. The hemodynamic variables and pulse oximetry values were stable during the procedure in both groups despite a lower heart rate in the DR group. No oxygen desaturation events occurred in either group. Although advancing the scope into the throat was easier in the PR group (“very easy” 24.1% vs 56.7%, P = 0.010), gastric motility was more suppressed in the DR group (“no + mild” 96.6% vs 73.3%, P = 0.013). The endoscopists felt that the procedure was more favorable in the DR group (“very good + good” 100% vs 86.7%, P = 0.042), whereas patient satisfaction scores were comparable between the groups. En bloc resection was performed 100% of the time in both groups, and the complete resection rate was 94.4% in the DR group and 100% in the PR group (P = 0.477). CONCLUSION: The efficacy and safety of dexmedetomidine and remifentanil were comparable to propofol and remifentanil during ESD. However, the endoscopists favored dexmedetomidine perhaps due to lower gastric motility. PMID:25834336

  8. Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling

    PubMed Central

    Kiriazis, Helen; Tugiono, Niquita; Xu, Qi; Gao, Xiao-Ming; Jennings, Nicole L; Ming, Ziqui; Su, Yidan; Klenowski, Paul; Summers, Roger J; Kaumann, Alberto; Molenaar, Peter; Du, Xiao-Jun

    2013-01-01

    BACKGROUND AND PURPOSE The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations. EXPERIMENTAL APPROACH C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg−1·day−1). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4–8 or 4–12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. CONCLUSIONS AND IMPLICATIONS β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure. PMID:23750586

  9. Post-operative analgesic effect of dexmedetomidine administration in wound infiltration for abdominal hysterectomy: A randomised control study

    PubMed Central

    Singh, Swati; Prasad, Chandrakant

    2017-01-01

    Background and Aims: Local infiltration of the surgical wound is one of the important components of multimodal analgesia for post-operative pain relief. This study determines the post-operative analgesic effect of addition of dexmedetomidine to bupivacaine for local infiltration of the surgical wound. Methods: Sixty women belonging to American Society of Anesthesiologists’ Grade 1 or 2 posted for abdominal hysterectomy were randomly allocated to Group I (control group) where patients received wound infiltration with 30 mL 0.25% bupivacaine at the end of surgery, or Group II, where patients received wound infiltration with 1.0 μg/kg dexmedetomidine diluted in 30 mL 0.25% bupivacaine. The primary objective of the study was to assess post-operative pain scores. Number of patients requiring rescue analgesia and total morphine consumption during 24 h after surgery were also recorded. Statistical significance for analgesic requirement was determined by one-way analysis of variance. Results: Pain scores were lower at rest for 12 h and on cough for 6 h in Group II (<0.01). All patients in Group I required supplemental morphine compared to only 3 patients in Group II (P < 0.003). Post-operative analgesia requirement was significantly less in patients receiving dexmedetomidine in wound infiltration compared to patients receiving bupivacaine alone (P < 0.001). Conclusions: Wound infiltration of dexmedetomidine with bupivacaine provides superior pain relief compared to bupivacaine alone. PMID:28655956

  10. Comparison of sedation and mechanical antinociception induced by intravenous administration of acepromazine and four dose rates of dexmedetomidine in donkeys.

    PubMed

    Lizarraga, Ignacio; Castillo-Alcala, Fernanda; Robinson, Lauren S

    2017-05-01

    To assess and compare the sedative and antinociceptive effects of four dosages of dexmedetomidine in donkeys. Randomized, controlled, crossover, Latin-square, blinded study. Six healthy, castrated, adult, standard donkeys. Dexmedetomidine (2, 3, 4 and 5 μg kg -1 ; D2, D3, D4 and D5), acepromazine (0.1 mg kg -1 ) and saline were administered intravenously to each donkey and a 1 week interval was allowed between successive trials on each animal. Sedation scores (SS) and head heights above ground (HHAG) were used to assess sedation and mechanical nociceptive threshold (MNT) testing to assess antinociception over 120 minutes post-treatment. Areas under the curve (AUC) for 0-30, 30-60 and 60-120 minutes were computed to compare the effect of treatments. SS-AUC 0-30 values were larger for D4 and D5, and SS-AUC 30-60 values were larger for D5 than for saline. All dexmedetomidine treatments produced lower HHAG-AUC 0-30 and HHAG-AUC 30-60 values, and acepromazine produced lower HHAG AUC 60-120 values than did saline. For MNT, D3, D4 and D5 increased AUC 0-30 and AUC 30-60 values compared with saline and also AUC 0-30 values compared with D2 and acepromazine. Smaller MNT-AUC 30-60 values were obtained with D2 than with D4 and D5, with D3 than with D5, and with acepromazine than with D4 and D5. Dexmedetomidine induced sedation and dosage-dependent mechanical antinociception. Larger dexmedetomidine dose rates were required to induce antinociception than sedation. Furthermore, the antinociception induced by dexmedetomidine was of shorter duration than its sedation. For minor painful procedures on standing donkeys, D5 may be clinically useful to provide sedation and analgesia. Copyright © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

  11. [(35)S]-GTPgammaS autoradiography reveals alpha(2) adrenoceptor-mediated G-protein activation in amygdala and lateral septum.

    PubMed

    Newman-Tancredi, A; Chaput, C; Touzard, M; Millan, M J

    2000-04-03

    alpha(2)-adrenoceptor-mediated G-protein activation was examined by [(35)S]-GTPgammaS autoradiography. In alpha(2)-adrenoceptor-rich regions (amygdala, lateral septum), noradrenaline stimulated [(35)S]-GTPgammaS binding. These actions were abolished by the selective alpha(2) antagonist, atipamezole. Conversely, in caudate nucleus, which expresses few alpha(2) receptors, noradrenaline-induced stimulation was not inhibited by atipamezole, suggesting that it is not mediated by alpha(2)-adrenoceptors.

  12. The expression of β3-adrenoceptors and their function in the human prostate.

    PubMed

    Suzuki, Takahisa; Otsuka, Atsushi; Matsumoto, Rikiya; Furuse, Hiroshi; Ozono, Seiichiro

    2016-02-01

    Little is known about β3-adrenoceptor (AR) expression and function in human prostate. We examined the expression and distribution of β-AR subtypes in normal prostate and benign prostatic hyperplasia (BPH) tissues, and investigated which selective β-AR subtype agonist was most involved in the relaxation of isolated human prostate strips. Messenger RNA (mRNA) expression for β1-, β2-, and β3 -ARs was investigated using reverse transcriptase-polymerase chain reactions (RT-PCR). Quantitative analysis of mRNA expression of β-AR subtypes between normal prostate and BPH tissues was performed using quantitative RT-PCR (qPCR). Distributions were examined by immunohistochemistry (IHC). Strips of human normal prostate or BPH were suspended in organ baths and exposed to isoproterenol, dobutamine, procaterol, and TRK-380 to investigate their relaxant effects on KCl-induced contractions, and their inhibitory effects on electrical field stimulation (EFS)-induced contractions. We confirmed the presence of mRNA for β1-, β2-, and β3-ARs both in normal prostate and in BPH tissues. For β3-AR, mRNA expression in BPH tissues was significantly higher than in normal prostate tissues, but there was no significant difference in β1- and β2-AR expression between normal and BPH tissues. IHC revealed differences in staining intensity between smooth muscle cells and glandular cells, with different proportions for different β-AR subtypes. Staining of β3-AR was particularly intense in smooth muscle cells as opposed to glandular cells. Isoproterenol and TRK-380 significantly decreased the tone of KCl-induced contractions of the normal prostate strips. The rank order of relaxant effects was isoproterenol > TRK-380 > procaterol > dobutamine. All selective β-AR agonists significantly decreased the amplitude of EFS-induced contractions of the normal prostate strips. The rank order of inhibitory effects was isoproterenol > dobutamine >TRK-380 > procaterol. In BPH strips, all selective

  13. Modulation of intracellular Ca2+ via L-type calcium channels in heart cells by the autoantibody directed against the second extracellular loop of the alpha1-adrenoceptors.

    PubMed

    Bkaily, Ghassan; El-Bizri, Nesrine; Bui, Michel; Sukarieh, Rami; Jacques, Danielle; Fu, Michael L X

    2003-03-01

    The effects of methoxamine, a selective alpha1-adrenergic receptor agonist, and the autoantibody directed against the second extracellular loop of alpha1-adrenoceptors were studied on intracellular free Ca2+ levels using confocal microscopy and ionic currents using the whole-cell patch clamp technique in single cells of 10-day-old embryonic chick and 20-week-old fetal human hearts. We observed that like methoxamine, the autoantibody directed against the second extracellular loop of alpha1-adrenoreceptors significantly increased the L-type calcium current (I(Ca(L))) but had no effect on the T-type calcium current (I(Ca(T))), the delayed outward potassium current, or the fast sodium current. This effect of the autoantibody was prevented by a prestimulation of the receptors with methoxamine and vice versa. Moreover, treating the cells with prazosin, a selective alpha1-adrenergic receptor antagonist blocked the methoxamine and the autoantibody-induced increase in I(Ca(L)), respectively. In absence of prazosin, both methoxamine and the autoantibody showed a substantial enhancement in the frequency of cell contraction and that of the concomitant cytosolic and nuclear free Ca2+ variations. The subsequent addition of nifedipine, a specific L-type Ca2+ channel blocker, reversed not only the methoxamine or the autoantibody-induced effect but also completely abolished cell contraction. These results demonstrated that functional alpha1-adrenoceptors exist in both 10-day-old embryonic chick and 20-week-old human fetal hearts and that the autoantibody directed against the second extracellular loop of this type of receptors plays an important role in stimulating their activity via activation of L-type calcium channels. This loop seems to have a functional significance by being the target of alpha1-receptor agonists like methoxamine.

  14. Effect and placental transfer of dexmedetomidine during caesarean section under epidural anaesthesia

    PubMed Central

    Wang, Changsheng; Liu, Shijiang; Han, Chuanbao; Yu, Min; Hu, Youli; Liu, Cunming

    2017-01-01

    Objective To investigate the neonatal effect and placental transfer of dexmedetomidine during caesarean section under epidural anaesthesia. Methods Forty parturients with a single newborn who were scheduled for caesarean section were enrolled. Patients received 0.5 µg/kg dexmedetomidine 10 min after epidural anaesthesia, followed by 0.5 µg/kg/h until abdominal closure (Dex group) or infusion of normal saline (NS group). Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were monitored before infusion (T0), 10 min after infusion (T1), at delivery (T2), and at the end of the operation (T3). Umbilical vein and artery blood was collected. Apgar scores were evaluated at 1 and 5 min after delivery. Results SBP, DBP, and HR in the Dex group were decreased at T3 compared with T0 (116 ± 10.4 vs 111 ± 9.2 mmHg, 74 ± 6.7 vs 66 ± 7.9 mmHg, 91 ± 12.1 vs 71 ± 8.4 beats/min, respectively, P < 0.05). HR was lower at T1, T2, and T3 in the Dex group compared with the NS group (P < 0.05). There were no significant differences in blood gases and Apgar scores between the groups (P > 0.05). Conclusion Dexmedetomidine during caesarean section under epidural anaesthesia is beneficial to parturients. The placental transfer rate is 0.68. PMID:28449631

  15. Inhibition of muscarinic receptor-induced inositol phospholipid hydrolysis by caffeine, beta-adrenoceptors and protein kinase C in intestinal smooth muscle.

    PubMed Central

    Prestwich, S A; Bolton, T B

    1995-01-01

    1. The effects of caffeine, isoprenaline, dibutyryl cyclic AMP, isobutylmethylxanthine (IBMX), 12-O-tetradecanoylphorbol-13-acetate (TPA) or 1-oleoyl-2-acetylglycerol (OAG), (protein kinase C (PKC) activators), 2-methoxy verapamil (D600), thapsigargin and ryanodine on muscarinic acetylcholine receptor (AChR)-stimulated inositol phospholipid hydrolysis were studied in smooth muscle fragments from the longitudinal layer of the small intestine of the guinea-pig. 2. Incubation of the fragments with the muscarinic agonist, carbachol (CCh) (100 microM) resulted in rapid increases in the levels of all the inositol phosphate isomers with maximal increases in the [3H]-inositol (1,4,5) trisphosphate ([3H]-Ins(1,4,5)P3) isomer occurring 10 s following incubation. 3. The beta-adrenoceptor agonist, isoprenaline (10 microM) and dibutyryl cyclic AMP (10 microM), a membrane permeant analogue of cyclic AMP both reduced the CCh stimulation, but not the basal levels of [3H]-inositol phosphates. This inhibition by dibutyryl cyclic AMP was enhanced in the presence of the phosphodiesterase inhibitor, IBMX. CCh inhibited the isoprenaline-induced increases in the levels of cyclic AMP and this was via a pertussi toxin (PTX)-sensitive G-protein mechanism. 4. TPA (1 microM) and OAG (100 microM) a 1,2-diacylglycerol (DAG) analogue both reduced the CCh-induced increases in [3H]-inositol phosphates levels but neither affected basal values nor the basal levels of cyclic AMP. 5. D600 (10 microM), which blocks voltage-dependent Ca2+ channels, also reduced the CCh-stimulated levels of [3H]-inositol phosphates suggesting that some of the agonist-induced increases are due to a potentiating effect of Ca2+ entering the cell. 6. Caffeine (0.5-30 mM) significantly inhibited both the basal and CCh-induced increases in all the [3H]-inositol phosphate isomers. Its inhibitory action was not due to increases in cyclic AMP since caffeine had no effect on the levels of cyclic AMP at concentrations up to 30 m

  16. Dexmedetomidine as an adjuvant to 0.5% ropivacaine in ultrasound-guided axillary brachial plexus block.

    PubMed

    Koraki, E; Stachtari, C; Kapsokalyvas, I; Stergiouda, Z; Katsanevaki, A; Trikoupi, A

    2018-06-01

    The aim of this study was to elucidate the effect of dexmedetomidine added to ropivacaine on the onset and duration of sensory and motor block and duration of analgesia of ultrasound-guided axillary brachial plexus block. Thirty-seven ASA physical status I-II patients with elective forearm and hand surgery under ultrasound-guided axillary brachial plexus block were randomly divided into 2 groups. Patients in ropivacaine-dexmedetomidine group (group RD, n = 19) received 15 mL of 0.5% ropivacaine with 100 μg (1 mL) dexmedetomidine, and patients in ropivacaine group (group R, n = 18) received 15 mL of 0.5% ropivacaine with 1 mL of normal saline. Onset time and duration of sensory and motor block and duration of analgesia were assessed. Duration of sensory block (U-value = 35, P < .001), duration of motor block (P = .001) and duration of analgesia (P < .001) were extended in group RD compared to group R. Onset time of sensory block in group RD was significantly faster than in group R (U-value = 65.5, P = .001). Onset time of motor block showed no significant difference between the 2 groups (U-value = 116.5, P = .096). Adverse reactions were reported only in group RD (bradycardia in 2 and hypotension in 3 patients). Our study indicated that dexmedetomidine 100 μg as adjuvant on ultrasound-guided axillary plexus block significantly prolonged the duration of sensory block and analgesia, as well as accelerated the time to onset of sensory block. These results should be weighed against the increased risks of motor block prolongation, transient bradycardia and hypotension and allow for attentive optimism, only if prolonged clinical trials provide a definitive answer. © 2017 John Wiley & Sons Ltd.

  17. 78 FR 25182 - New Animal Drugs; Dexmedetomidine; Lasalocid; Melengestrol; Monensin; and Tylosin

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-30

    ... [Docket No. FDA-2013-N-0002] New Animal Drugs; Dexmedetomidine; Lasalocid; Melengestrol; Monensin; and... Food and Drug Administration (FDA) is amending the animal drug regulations to reflect approval actions for new animal drug applications and abbreviated new animal drug applications during March 2013. FDA...

  18. Anticholinergic premedication to prevent bradycardia in combined spinal anesthesia and dexmedetomidine sedation: a randomized, double-blind, placebo-controlled study.

    PubMed

    Ahn, Eun Jin; Park, Jun Ha; Kim, Hyo Jin; Kim, Kyung Woo; Choi, Hey Ran; Bang, Si Ra

    2016-12-01

    When dexmedetomidine is used in patients undergoing spinal anesthesia, high incidence of bradycardia in response to parasympathetic activation is reported. Therefore, we aimed to evaluate the effectiveness of atropine premedication for preventing the incidence of bradycardia and the hemodynamic effect on patients undergoing spinal anesthesia with sedation by dexmedetomidine. Randomized, double-blind, placebo-controlled study. Operating room. One hundred fourteen patients (age range, 2-65 years; American Society of Anesthesiology class I-II) participated in this study, willing to be sedated and to undergo spinal anesthesia. The patients were divided into 2 groups: group A and group C. After performing spinal anesthesia, dexmedetomidine was infused at a loading dose of 0.6 μg/kg for 10 minutes, followed by an infusion at 0.25 μg/(kg h). Simultaneously with the loading dose of dexmedetomidine, patients in group A received an intravenous bolus of 0.5 mg atropine, whereas patients in group C received an intravenous normal saline bolus. Data on administration of atropine and ephedrine were collected. Hemodynamic data including heart rate, systolic blood pressure, diastolic blood pressure (DBP), and mean blood pressure (MBP) were also recorded. The incidence of bradycardia requiring atropine treatment was significantly higher in group C than group A (P=.035). However, the incidence of hypotension needing ephedrine treatment showed no significant difference between the 2 groups (P=.7). Systolic blood pressure and heart rate showed no significant differences between the 2 groups (P=.138 and .464, respectively). However, group A showed significant increases in DBP and MBP, and group C did not (P=.014 and .008, respectively). Prophylactic atropine reduces the incidence of bradycardia in patients undergoing spinal anesthesia with dexmedetomidine sedation. However, DBP and MBP showed significant increases in patients when prophylactic atropine was administrated. Therefore

  19. Pediatric awake craniotomy for seizure focus resection with dexmedetomidine sedation-a case report.

    PubMed

    Sheshadri, Veena; Chandramouli, B A

    2016-08-01

    Resection of lesions near the eloquent cortex of brain necessitates awake craniotomy to reduce the risk of permanent neurologic deficits during surgery. There are limited reports of anesthetic management of awake craniotomy in pediatric patients. This report is on use of dexmedetomidine sedation for awake craniotomy in a 11-year-old child, without any airway adjuncts throughout the procedure. Dexmedetomidine infusion administered at a dosage of 0.2 to 0.7μg kg(-1) h(-1) provided adequate sedation for the entire procedure. There were no untoward incidents or any interference with electrocorticography, intraoperative stimulation, and functional mapping. Adequate preoperative visits and counseling of patient and parents regarding course and nature of events along with well-planned intraoperative management are of utmost importance in a pediatric age group for successful intraoperative awake craniotomy. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Influence of the low thyroid state in diabetes mellitus on cardiac function and inotropic responsiveness to alpha 1-adrenoceptor stimulation: comparison with the role of hypothyroidism alone.

    PubMed

    Beenen, O H; Pfaffendorf, M; van Zwieten, P A

    1996-10-01

    The hypothyroid state accompanying diabetes mellitus has been suggested to be partly responsible for the diabetes-induced metabolic, hemodynamic, and pharmacological cardiovascular changes. We assessed the effectivity of streptozotocin (STZ) to induce diabetes mellitus and a hypothyroid state. Furthermore, we investigated the influence of diabetes and hypothyrodism on cardiac function and the inotropic responsiveness to the alpha 1-adrenoceptor agonist cirazoline in isolated perfused hearts. Fasted or nonfasted Wistar rats were made diabetic with STZ 20, 40 or 60 mg/kg intravenously (i.v.). Another group was made hypothyroid by addition of 6-n-propyl-2-thiouracil (PTU) to their drinking water. Rats receiving PTU became hypothyroid, whereas rats receiving STZ became simultaneously diabetic and hypothyroid. Basal functional parameters obtained in isolated perfused hearts were not influenced by diabetes, whereas maximal contractility was reduced in hearts obtained from hypothyroid animals. Cardiac inotropic responses to cirazoline were increased in diabetic rats, whereas responses in hypothyroid rats were not different from those in hearts obtained from control animals. Although diabetes mellitus and hypothyroidism are associated with various similar metabolic and haemodynamic parameters, the increased inotropic response to alpha 1-adrenoceptor stimulation as observed in isolated perfused hearts of diabetic rats cannot be explained by the decrease in serum thyroxine levels.

  1. Involvement of β3-adrenoceptors in the inhibitory control of cholinergic activity in human bladder: Direct evidence by [(3)H]-acetylcholine release experiments in the isolated detrusor.

    PubMed

    D' Agostino, Gianluigi; Maria Condino, Anna; Calvi, Paolo

    2015-07-05

    Bladder overactivity (OAB) is a multifactorial bladder disorder that requires therapeutics superior to the current pharmacological treatment with muscarinic antagonists. β3-adrenoceptor (β3-ADR) agonists represent a novel promising approach that differently addresses the parasympathetic pathway, but the clinical efficacy of these drugs has not been fully elucidated to date. Therefore, we aimed to study the pharmacological mechanisms activated by β3-ADR agonists at muscular and neural sites in the isolated human bladder. Detrusor smooth muscle strips obtained from male patients undergoing total cystectomy were labelled with tritiated choline and stimulated with electrical field stimulation (EFS). EFS produced smooth muscle contraction and simultaneous acetylcholine ([(3)H]-ACh) release, which mostly reflects the neural origin of acetylcholine. Isoprenaline (INA), BRL37344 and mirabegron inhibited the EFS-evoked contraction and [(3)H]-ACh release in a concentration-dependent manner, yielding concentration-response curves (CRCs) that were shifted to the right by the selective β3-ADR antagonists L-748,337 and SR59230A. Based on the agonist potency estimates (pEC50) and apparent affinities (pKb) of antagonists evaluated from the CRCs of agonists, our data confirm the occurrence of β3-ADRs at muscle sites. Moreover, our data are consistent with the presence of inhibitory β3-ADRs that are functionally expressed at the neural site. Taken together, these findings elucidate the mechanisms activated by β3-ADR agonists because neural β3-ADRs participate in the inhibition of detrusor motor drive by reducing the amount of acetylcholine involved in the cholinergic pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. The Effects of Short-Term Propofol and Dexmedetomidine on Lung Mechanics, Histology, and Biological Markers in Experimental Obesity.

    PubMed

    Heil, Luciana Boavista Barros; Santos, Cíntia L; Santos, Raquel S; Samary, Cynthia S; Cavalcanti, Vinicius C M; Araújo, Mariana M P N; Poggio, Hananda; Maia, Lígia de A; Trevenzoli, Isis Hara; Pelosi, Paolo; Fernandes, Fatima C; Villela, Nivaldo R; Silva, Pedro L; Rocco, Patricia R M

    2016-04-01

    Administering anesthetics to the obese population requires caution because of a variety of reasons including possible interactions with the inflammatory process observed in obese patients. Propofol and dexmedetomidine have protective effects on pulmonary function and are widely used in short- and long-term sedation, particularly in intensive care unit settings in lean and obese subjects. However, the functional and biological effects of these drugs in obesity require further elucidation. In a model of diet-induced obesity, we compared the short-term effects of dexmedetomidine versus propofol on lung mechanics and histology, as well as biological markers of inflammation and oxidative stress modulation in obesity. Wistar rats (n = 56) were randomly fed a standard diet (lean) or experimental diet (obese) for 12 weeks. After this period, obese animals received sodium thiopental intraperitoneally and were randomly allocated into 4 subgroups: (1) nonventilated (n = 4) for molecular biology analysis only (control); (2) sodium thiopental (n = 8); (3) propofol (n = 8); and (4) dexmedetomidine (n = 8), which received continuous IV administration of the corresponding agents and were mechanically ventilated (tidal volume = 6 mL/kg body weight, fraction of inspired oxygen = 0.4, positive end-expiratory pressure = 3 cm H2O) for 1 hour. Compared with lean animals, obese rats did not present increased body weight but had higher total body and trunk fat percentages, airway resistance, and interleukin-6 levels in the lung tissue (P = 0.02, P = 0.0027, and P = 0.01, respectively). In obese rats, propofol, but not dexmedetomidine, yielded increased airway resistance, bronchoconstriction index (P = 0.016, P = 0.02, respectively), tumor necrosis factor-α, and interleukin-6 levels, as well as lower levels of nuclear factor-erythroid 2-related factor-2 and glutathione peroxidase (P = 0.001, Bonferroni-corrected t test). In this model of diet-induced obesity, a 1-hour propofol infusion

  3. α-Adrenoceptor blockade modifies neurally induced atrial arrhythmias

    PubMed Central

    Richer, Louis-Philippe; Vinet, Alain; Kus, Teresa; Cardinal, René; Ardell, Jeffrey L.; Armour, John Andrew

    2008-01-01

    Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by α-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (α1-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (α2-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined α-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by α1,2-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal α-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that α-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system. PMID:18716036

  4. Alpha-adrenoceptor blockade modifies neurally induced atrial arrhythmias.

    PubMed

    Richer, Louis-Philippe; Vinet, Alain; Kus, Teresa; Cardinal, René; Ardell, Jeffrey L; Armour, John Andrew

    2008-10-01

    Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by alpha-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (alpha(1)-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (alpha(2)-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined alpha-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by alpha(1,2)-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal alpha-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that alpha-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system.

  5. Guinea pig hepatocyte alpha 1A-adrenoceptors: characterization, signal transduction and regulation.

    PubMed

    García-Sáinz, J A; Romero-Avila, T; Olivares-Reyes, J A; Macías-Silva, M

    1992-11-02

    Activation of guinea pig hepatocyte alpha 1-adrenoceptors increases phosphatidylinositol (PI) labeling, [3H]inositol phosphate production and phosphorylase activity. These adrenergic actions were not altered by pretreatment with chlorethylclonidine but were blocked by 5-methyl urapidil and prazosin (the former being 3- to 10-fold more potent than the latter), indicating that alpha 1A-adrenoceptors were involved. When the cells were incubated in buffer without calcium and containing EGTA, the alpha 1A-adrenergic stimulation of PI labeling was diminished but not abolished and that of phosphorylase was not affected. The alpha 1A-adrenergic effects were insensitive to pertussis toxin treatment. Phorbol myristate acetate inhibited the alpha 1A-adrenergic actions, although at relatively large concentrations, and also those of other agents such as angiotensin II and NaF. Our data clearly indicate that guinea pig hepatocytes express alpha 1A-adrenoceptors whose activation stimulates phosphoinositide turnover, via a pertussis toxin-insensitive process; the alpha 1A-adrenergic effects were at least partially independent of extracellular calcium.

  6. Alpha 2-adrenoceptors and endothelium-dependent relaxation in canine large arteries.

    PubMed Central

    Angus, J. A.; Cocks, T. M.; Satoh, K.

    1986-01-01

    Ring preparations from the carotid, coronary, renal, mesenteric and femoral arteries of the dog were precontracted with the thromboxane mimetic U46619, after ensuring that the resting conditions were comparable from the Laplace relationship. In the presence of prazosin (1 microM) and propranolol (3 microM), noradrenaline (NA) relaxed the arteries in the order coronary greater than carotid greater than femoral greater than renal = mesenteric. When maximum relaxation to nitroglycerin (10 microM) was taken to be 100% the maximum relaxation to noradrenaline in each artery was: coronary 70%; carotid 34%; femoral 19%; renal 7% and mesenteric 2%. In endothelium-intact arteries UK14304 mimicked the relaxation responses to NA and idazoxan shifted the curves to both agonists to the right, consistent with an alpha 2-adrenoceptor classification. Substance P relaxed the arteries in the same order as for NA but showed higher efficacy i.e.: coronary 100%; carotid 80%; femoral 71% renal 49%; and mesenteric 41%. Removal of the endothelium abolished the relaxation to NA. We conclude that endothelium-dependent relaxation to NA and substance P varies greatly across 5 large arteries of the dog. This may indicate that endothelium-derived relaxing factor (EDRF) release is site-dependent or that the efficacy of EDRF on smooth muscle varies; being greatest in the coronary and weakest in the renal and mesenteric arteries. PMID:2427147

  7. Novel Small Airway Bronchodilator Responses to Rosiglitazone in Mouse Lung Slices

    PubMed Central

    Bai, Yan; Donovan, Chantal; Esposito, James G.; Tan, Xiahui; Sanderson, Michael J.

    2014-01-01

    There is a need to identify novel agents that elicit small airway relaxation when β2-adrenoceptor agonists become ineffective in difficult-to-treat asthma. Because chronic treatment with the synthetic peroxisome proliferator activated receptor (PPAR)γ agonist rosiglitazone (RGZ) inhibits airway hyperresponsiveness in mouse models of allergic airways disease, we tested the hypothesis that RGZ causes acute airway relaxation by measuring changes in small airway size in mouse lung slices. Whereas the β-adrenoceptor agonists albuterol (ALB) and isoproterenol induced partial airway relaxation, RGZ reversed submaximal and maximal contraction to methacholine (MCh) and was similarly effective after precontraction with serotonin or endothelin-1. Concentration-dependent relaxation to RGZ was not altered by the β-adrenoceptor antagonist propranolol and was enhanced by ALB. RGZ-induced relaxation was mimicked by other synthetic PPARγ agonists but not by the putative endogenous agonist 15-deoxy-PGJ2 and was not prevented by the PPARγ antagonist GW9662. To induce airway relaxation, RGZ inhibited the amplitude and frequency of MCh-induced Ca2+ oscillations of airway smooth muscle cells (ASMCs). In addition, RGZ reduced MCh-induced Ca2+ sensitivity of the ASMCs. Collectively, these findings demonstrate that acute bronchodilator responses induced by RGZ are PPARγ independent, additive with ALB, and occur by the inhibition of ASMC Ca2+ signaling and Ca2+ sensitivity. Because RGZ continues to elicit relaxation when β-adrenoceptor agonists have a limited effect, RGZ or related compounds may have potential as bronchodilators for the treatment of difficult asthma. PMID:24188042

  8. A prospective, randomized, double-blind trial of intranasal dexmedetomidine and oral chloral hydrate for sedated auditory brainstem response (ABR) testing.

    PubMed

    Reynolds, Jason; Rogers, Amber; Medellin, Eduardo; Guzman, Jonathan A; Watcha, Mehernoor F

    2016-03-01

    Dexmedetomidine is increasingly used by various routes for pediatric sedation. However, there are few randomized controlled trials comparing the efficacy of dexmedetomidine to other commonly used sedatives. To compare the efficacy of sedation with intranasal dexmedetomidine to oral chloral hydrate for auditory brainstem response (ABR) testing. In this double-blind, double-dummy study, children undergoing ABR testing were randomized to receive intranasal dexmedetomidine 3 mcg · kg(-1) plus oral placebo (Group IN DEX) or oral chloral hydrate 50 mg · kg(-1) plus intranasal saline placebo (Group CH). We recorded demographic data, times from sedative administration to start and completion of testing, quality of sedation, occurrence of predefined adverse events, discharge times, and return to baseline activity on the day of testing. Testing completion rates with a single dose of medication were higher in the IN DEX group (89% vs 66% for CH, odds ratio with 95% confidence intervals 4.04 [1.3-12.6], P = 0.018). The median [95% CI)] time to successful testing start was shorter (25 [20-29] min vs 30 [20-49] min for IN DEX and CH, respectively, log rank test P = 0.02) and the proportion of children whose parents reported a return to baseline activity on the day of testing was greater for the IN DEX than the CH group (89% vs 64%, OR [95% CI] 4.71 [1.34-16.6], P = 0.02). There were no major adverse events in either group and no significant differences in the incidence of minor events. Intranasal dexmedetomidine is an effective alternative to oral chloral hydrate sedation for ABR testing, with the advantages of a higher incidence of testing completion with a single dose, shorter time to desired sedation level, and with significantly more patients reported to return to baseline activity on the same day. © 2016 John Wiley & Sons Ltd.

  9. Tramadol vs dexmedetomidine for emergence agitation control in pediatric patients undergoing adenotonsillectomy with sevoflurane anesthesia: prospective randomized controlled clinical study.

    PubMed

    Bedirli, Nurdan; Akçabay, Mehmet; Emik, Ulku

    2017-03-11

    This study was designed to compare the efficacy of an intraoperative single dose administration of tramadol and dexmedetomidine on hemodynamics and postoperative recovery profile including pain, sedation, emerge reactions in pediatric patients undergoing adenotonsillectomy with sevoflurane anesthesia. Seventy-seven patient, aged 2-12, undergoing adenotonsillectomy with sevoflurane anesthesia was enrolled in this study. Patients were randomly assigned to receive either intravenous 2 mg/kg tramadol (Group T; n = 39) or 1 μg/kg dexmedetomidine (Group D; n = 38) after intubation. Heart rates (HR), mean arterial pressure (MAP) were recorded before induction, at induction and every 5 min after induction. Observational pain scores (OPS), pediatric anesthesia emergence delirium (PAED) scores, percentage of patients with OPS ≥ 4 or PAED scale items 4 or 5 with an intensity of 3 or 4, and Ramsay sedation scores (RSS) were recorded on arrival to the postoperative care unit (PACU) and at 5, 10, 15, 30, 45, 60 min. Extubation time and time to reach Alderete score > 9 were recorded. Dexmedetomidine significantly decreased the HR and MAP 10 and 15 min after induction; increased the RSS 15, 30 and 45 min after arrival to PACU. OPS and PAED scores and percentage of patients with OPS ≥ 4 or PAED scale items 4 or 5 with an intensity of 3 or 4 in both groups did not show any significant difference. Extubation time and time to have Alderete score > 9 was significantly longer in Group D. Both tramadol and dexmedetomidine were effective for controlling pain and emergence agitation. When compared with tramadol intraoperative hypotension, bradycardia and prolonged sedation were problems related with dexmedetomidine administration. Retrospectively registered, registration number: ISRCTN89326952 registration date: 14.07.2016.

  10. Inward rectifier K+ channel and T-type Ca2+ channel contribute to enhancement of GABAergic transmission induced by β1-adrenoceptor in the prefrontal cortex.

    PubMed

    Luo, Fei; Zheng, Jian; Sun, Xuan; Tang, Hua

    2017-02-01

    The functions of prefrontal cortex (PFC) are sensitive to norepinephrine (NE). Endogenously released NE influences synaptic transmission through activation of different subtypes of adrenergic receptors in PFC including α 1 , α 2 , β 1 or β 2 -adrenoceptor. Our recent study has revealed that β 1 -adrenoceptor (β 1 -AR) activation modulates glutamatergic transmission in the PFC, whereas the roles of β 1 -AR in GABAergic transmission are elusive. In the current study, we probed the effects of the β 1 -AR agonist dobutamine (Dobu) on GABAergic transmission onto pyramidal neurons in the PFC of juvenile rats. Dobu increased both the frequency and amplitude of miniature IPSCs (mIPSCs). Ca 2+ influx through T-type voltage-gated Ca 2+ channel was required for Dobu-enhanced mIPSC frequency. We also found that Dobu facilitated GABA release probability and the number of releasable vesicles through regulating T-type Ca 2+ channel. Dobu depolarized GABAergic fast-spiking (FS) interneurons with no effects on the firing rate of action potentials (APs) of interneurons. Dobu-induced depolarization of FS interneurons required inward rectifier K + channel (Kir). Our results suggest that Dobu increase GABA release via inhibition of Kir, which further depolarizes FS interneurons resulting in Ca 2+ influx via T-type Ca 2+ channel. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Postoperative Analgesia with Intravenous Paracetamol and Dexmedetomidine in Laparoscopic Cholecystectomy Surgeries: A Prospective Randomized Comparative Study

    PubMed Central

    Sharma, Ridhima; Gupta, Raghav; Choudhary, Ripon; Singh Bajwa, Sukhminder Jit

    2017-01-01

    Background and Aim: Therapeutic use of nonopioid analgesic such as paracetamol (PCM) is an alternative to opioids, so to avoid the established side effects associated with opioids, PCM is commonly used due to its analgesic and antipyretic effects. Recently, dexmedetomidine has also emerged on the anesthesia front with a potential role of providing postoperative analgesia. The present study was conducted to compare and assess the quality and duration of analgesia with PCM and dexmedetomidine using visual analog scale (VAS). Methods: One hundred patients between the age of 18 and 60 years of the American Society of Anesthesiologists grade I and II undergoing laparoscopic cholecystectomy surgery were randomly allocated into two groups (n = 50). Each patient received either 1 g intravenous PCM, in 100 ml solution before incision (Group I), or i.v. dexmedetomidine 1 μg/kg as bolus over 10 min followed by infusion of 0.5 μg/kg/h (Group II). Postoperatively, the following parameters were observed: quality and duration of analgesia, hemodynamic parameters, time to the first dose of rescue analgesia, sedation, and any postoperative complication or side effects. Statistical analysis was carried out using an unpaired t-test for quantitative parameters and nonparametric data using Wilcoxon signed-rank test and Mann–Whitney U-test. Qualitative data were analyzed using Chi-square or Fishers' exact test. Results: Postoperative analgesic requirement significantly decreased (P = 0.001), with a lower score on VAS, better patient satisfaction scores, and Ramsay Sedation Score ranges from 3 to 5 (62%) in Group I. The incidence of nausea and vomiting, hypotension, and bradycardia was comparable in both the groups except shivering, which was found significantly less in Group II. Conclusion: Incorporation of dexmedetomidine as a part of multimodal analgesia provides better hemodynamic profile, analgesic, sedative, and amnesic properties along with negligible serious adverse effects

  12. Selective inhibition of alpha1B-adrenergic receptor expression and function using a phosphorothioate antisense oligodeoxynucleotide.

    PubMed

    Gonzalez-Cabrera, P J; Iversen, P L; Liu, M F; Scofield, M A; Jeffries, W B

    1998-06-01

    To investigate alpha1B-adrenoceptor function, we developed a phosphorothioate antisense oligodeoxynucleotide (AO) to inhibit the expression of the alpha1B-adrenoceptor subtype in DDT1 MF2 cells. We measured the cellular uptake of the AO and its effect on alpha1B-adrenoceptor mRNA expression, protein density, and coupling to phospholipase C. Cells treated with either a control oligodeoxynucleotide (CO) or medium alone served as control groups. Confocal microscopy demonstrated that DDT1 MF2 cells internalized carboxyfluorescein-labeled (FAM) AO within 30 min. Analysis of cellular lysates showed that approximately 50% of the intracellular FAM-AO was present as an intact 18-mer for up to 48 hr. Incubation of cells with AO for 48 hr decreased alpha1B-adrenoceptor density ([3H]prazosin Bmax) versus control groups by 12% (1 microM AO) and 72% (10 microM AO). In time course experiments, AO (10 microM) reduced alpha1B-adrenoceptor density by 28, 64, and 68% versus controls after 24, 48, and 72 hr of exposure, respectively. alpha1B-Adrenoceptor mRNA concentration (measured by RT-PCR) was reduced by 25% in cells treated for 48 hr with 10 microM AO versus controls. AO pretreatment (10 microM, 48 hr) reduced the maximum response to agonist-stimulated [3H]inositol phosphate accumulation. The maximal response of the full agonist norepinephrine was reduced by 30% after AO treatment, and by 73% for the partial agonist naphazoline. In contrast, AO did not affect histamine-stimulated total [3H]inositol phosphate accumulation. Thus, AO effectively reduced alpha1B-adrenoceptor subtype expression and function in vitro, suggesting a potential to selectively inhibit alpha1B-adrenoceptor function in vivo.

  13. A comparison of single-dose dexmedetomidine or propofol on the incidence of emergence delirium in children undergoing general anaesthesia for magnetic resonance imaging.

    PubMed

    Bong, C L; Lim, E; Allen, J C; Choo, W L H; Siow, Y N; Teo, P B Y; Tan, J S K

    2015-04-01

    Emergence delirium is a significant problem in children regaining consciousness following general anaesthesia. We compared the emergence characteristics of 120 patients randomly assigned to receive a single intravenous dose of dexmedetomidine 0.3 μg.kg(-1) , propofol 1 mg.kg(-1) , or 10 ml saline 0.9% before emerging from general anaesthesia following a magnetic resonance imaging scan. Emergence delirium was diagnosed as a score of 10 or more on the Paediatric Anaesthesia Emergence Delirium scale. The incidence of emergence delirium was 42.5% in the dexmedetomidine group, 33.3% in the propofol group and 41.5% in the saline group (p = 0.671). Three patients in the dexmedetomidine group, none in the propofol group and two in the saline group required pharmacological intervention for emergence delirium (p = 0.202). Administration of neither dexmedetomidine nor propofol significantly reduced the incidence, or severity, of emergence delirium. The only significant predictor for emergence delirium was the time taken to awaken from general anaesthesia, with every minute increase in wake-up time reducing the odds of emergence delirium by 7%. © 2014 The Association of Anaesthetists of Great Britain and Ireland.

  14. The antagonistic effect of antipsychotic drugs on a HEK293 cell line stably expressing human alpha1A1-adrenoceptors.

    PubMed

    Nourian, Zahra; Mulvany, Michael J; Nielsen, Karsten Bork; Pickering, Darryl S; Kristensen, Torsten

    2008-10-31

    Antipsychotic drugs often cause orthostatic hypotension, probably through antagonist action on resistance vessel alpha(1A)-adrenoceptors. Here we have tested this possibility directly using cells transfected with a relevant human alpha(1A)-adrenoceptor splice variant. To determine a splice variant which was relevant, we used quantitative real-time polymerase chain reaction (qPCR) to determine the prevalence in human subcutaneous small arteries of three of the five splice variants ADRA1A_v1-5, which encode functional protein: alpha(1A1)-, alpha(1A3)-, alpha(1A4)-adrenoceptors. Our statistical analysis showed higher transcription levels of alpha(1A1)- than of alpha(1A3)- and alpha(1A4)-adrenoceptors (1.6 and 5.8 times, respectively). We therefore chose to study the alpha(1A1)-adrenoceptor, and the cDNA encoding it was transfected into the Flp-In-293 (modified from HEK-293) cell line to produce a cell line stably expressing a functional form of this splice variant. The expression of recombinant alpha(1A1)-adrenoceptor subtype was confirmed by Western immunoblot analysis, and its functionality demonstrated using a Fura-2 assay by a rise in intracellular calcium concentration ([Ca(2+)](i)) when challenged with phenylephrine (EC(50)=1.61x10(-8) M). From Schild analysis, prazosin, sertindole, risperidone, and haloperidol caused a concentration-dependent, rightward shift of the cumulative concentration-response curves for phenylephrine in cells expressing human recombinant alpha(1A1)-adrenoceptors to yield pK(B) values of 8.40, 8.05, 8.26 and 7.38, respectively. In [7-methoxy-(3)H]-prazosin binding experiments, high expression was seen (B(max)=48.5+/-16.7 pmol/mg protein, +/-S.E.M.) along with high affinity binding to a single site (K(d)=0.210+/-0.034 nM). The pharmacological profiles of recombinant human alpha(1A1)-adrenoceptors in competition binding studies confirmed much higher antagonist affinity of sertindole and risperidone than haloperidol for these receptors. In

  15. Structure-bias relationships for fenoterol stereoisomers in six molecular and cellular assays at the β2-adrenoceptor.

    PubMed

    Reinartz, Michael T; Kälble, Solveig; Littmann, Timo; Ozawa, Takeaki; Dove, Stefan; Kaever, Volkhard; Wainer, Irving W; Seifert, Roland

    2015-01-01

    Functional selectivity is well established as an underlying concept of ligand-specific signaling via G protein-coupled receptors (GPCRs). Functionally, selective drugs could show greater therapeutic efficacy and fewer adverse effects. Dual coupling of the β2-adrenoceptor (β2AR) triggers a signal transduction via Gsα and Giα proteins. Here, we examined 12 fenoterol stereoisomers in six molecular and cellular assays. Using β2AR-Gsα and β2AR-Giα fusion proteins, (R,S')- and (S,S')-isomers of 4'-methoxy-1-naphthyl-fenoterol were identified as biased ligands with preference for Gs. G protein-independent signaling via β-arrestin-2 was disfavored by these ligands. Isolated human neutrophils constituted an ex vivo model of β2AR signaling and demonstrated functional selectivity through the dissociation of cAMP accumulation and the inhibition of formyl peptide-stimulated production of reactive oxygen species. Ligand bias was calculated using an operational model of agonism and revealed that the fenoterol scaffold constitutes a promising lead structure for the development of Gs-biased β2AR agonists.

  16. Characterization of adrenergic receptors of the cat iris and nictitating membrane.

    PubMed

    Koss, M C; Hey, J A; Gherezghiher, T

    1990-01-01

    Graded pupillary dilations and nictitating membrane (NM) contractions were elicited in anesthetized cats by electrical stimulation of the preganglionic sympathetic nerve or by i.a. administration of norepinephrine (NE) or phenylephrine into the carotid artery. Pupil and NM responses were measured simultaneously from the same side. Alpha-adrenoceptor antagonists were administered intravenously. All of the alpha 1-adrenoceptor blockers tested produced a dose-related reduction of NM responses to both neural and agonist activation; the potency rank order was prazosin greater than WB-4101 greater than phentolamine greater than phenoxybenzamine (PBZ). In contrast, responses of the iris dilator were antagonized only by WB-4101 and PBZ. The iris was almost totally refractory to doses of prazosin and phentolamine that blocked NM responses by more than 75% of control. Neither alpha 2- nor beta-adrenoceptor antagonism produced significant inhibition of neural or agonist activation of either organ (with the exception of high doses of yohimbine on the NM). These results suggest that the postjunctional adrenoceptors of the NM are exclusively of the alpha 1-adrenoceptor subtype. In contrast, those of the iris dilator muscle cannot be easily classified pharmacologically as either alpha 1 or alpha 2-adrenoceptors.

  17. Effects of ketamine, dexmedetomidine and propofol anesthesia on emotional memory consolidation in rats: Consequences for the development of post-traumatic stress disorder.

    PubMed

    Morena, Maria; Berardi, Andrea; Peloso, Andrea; Valeri, Daniela; Palmery, Maura; Trezza, Viviana; Schelling, Gustav; Campolongo, Patrizia

    2017-06-30

    Intensive Care Unit (ICU) or emergency care patients, exposed to traumatic events, are at increased risk for Post-Traumatic Stress Disorder (PTSD) development. Commonly used sedative/anesthetic agents can interfere with the mechanisms of memory formation, exacerbating or attenuating the memory for the traumatic event, and subsequently promote or reduce the risk of PTSD development. Here, we evaluated the effects of ketamine, dexmedetomidine and propofol on fear memory consolidation and subsequent cognitive and emotional alterations related to traumatic stress exposure. Immediately following an inhibitory avoidance training, rats were intraperitoneally injected with ketamine (100-125mg/kg), dexmedetomidine (0.3-0.4mg/kg) or their vehicle and tested for 48h memory retention. Furthermore, the effects of ketamine (125mg/kg), dexmedetomidine (0.4mg/kg), propofol (300mg/kg) or their vehicle on long-term memory and social interaction were evaluated two weeks after drug injection in a rat PTSD model. Ketamine anesthesia increased memory retention without altering the traumatic memory strength in the PTSD model. However, ketamine induced a long-term reduction of social behavior. Conversely, dexmedetomidine markedly impaired memory retention, without affecting long-lasting cognitive or emotional behaviors in the PTSD model. We have previously shown that propofol anesthesia enhanced 48h memory retention. Here, we found that propofol induced an enduring traumatic memory enhancement and anxiogenic effects in the PTSD model. These findings provide new evidence for clinical studies showing that the use of ketamine or propofol anesthesia in emergency care and ICU might be more likely to promote the development of PTSD, while dexmedetomidine might have prophylactic effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. The subtype of alpha-adrenoceptor involved in the neural control of renal tubular sodium reabsorption in the rabbit.

    PubMed Central

    Hesse, I F; Johns, E J

    1984-01-01

    A study was undertaken in pentobarbitone anaesthetized rabbits, undergoing a saline diuresis, to determine the subtype of alpha-adrenoceptor mediating renal tubular sodium reabsorption. Stimulation of the renal nerves at low rates, to cause an 11% fall in renal blood flow, did not change glomerular filtration rate but significantly reduced urine flow rate, and absolute and fractional sodium excretions by approximately 40%. These responses were reproducible in different groups of animals and with time. Renal nerve stimulation during an intra-renal arterial infusion of prazosin, to block alpha 1-adrenoceptors, had no effect on the renal haemodynamic response but completely abolished the reductions in urine flow rate, and absolute and fractional sodium excretion. During intra-renal arterial infusion of yohimbine, to block renal alpha 2-adrenoceptors, stimulation of the renal nerves to cause similar renal haemodynamic changes resulted in significantly larger reductions in urine flow rate, and absolute and fractional sodium excretion of about 52-58%. These results indicate that in the rabbit alpha 1-adrenoceptors are present on the renal tubules, which mediate the increase in sodium reabsorption caused by renal nerve stimulation. They further suggest the presence of presynaptic alpha 2-adrenoceptors on those nerves innervating the renal tubules. PMID:6086915

  19. A comparative study of clonidine and dexmedetomidine as an adjunct to bupivacaine in supraclavicular brachial plexus block.

    PubMed

    Tripathi, Archana; Sharma, Khushboo; Somvanshi, Mukesh; Samal, Rajib Lochan

    2016-01-01

    Various additives are mixed with local anesthetic agents to increase the quality of block in regional anesthesia. We compared clonidine and dexmedetomidine as an adjunct to bupivacaine in supraclavicular brachial plexus block with respect to the onset and duration of sensory and motor block and duration of analgesia. Sixty American Society of Anesthesiologists Grades I and II patients scheduled for various orthopedic surgeries of the upper limb under supraclavicular brachial plexus block were divided into two equal groups in a randomized, double-blind manner. Patients were assigned randomly to one of the two groups. In Group C (n = 30), 39 ml of 0.25% bupivacaine plus 1 ml (1 μg/kg) clonidine and in Group D (n = 30), 39 ml of 0.25% bupivacaine plus 1 ml (1 μg/kg) dexmedetomidine were given. The onset and duration of sensory and motor block, duration of analgesia, and quality of anesthesia were studied in both the groups. There was no statistically significant difference in the onset of sensory and motor block in both the groups. The durations of sensory and motor block were 316.67 ± 45.21 and 372.67 ± 44.48 min, respectively, in Group C, whereas they were 502.67 ± 43.78 and 557.67 ± 38.83 min, respectively, in Group D. The duration of analgesia was 349.33 ± 42.91 min, significantly less in Group C compared to 525.33 ± 42.89 min in Group D (P < 0.001). The quality of anesthesia was significantly better in dexmedetomidine group compared to clonidine group (P < 0.001). The addition of dexmedetomidine prolongs the durations of sensory and motor block and duration of analgesia and improves the quality of anesthesia as compared with clonidine when injected with bupivacaine in supraclavicular brachial plexus block.

  20. Contribution of beta 1- and beta 2-adrenoceptors of human atrium and ventricle to the effects of noradrenaline and adrenaline as assessed with (-)-atenolol.

    PubMed Central

    Lemoine, H.; Schönell, H.; Kaumann, A. J.

    1988-01-01

    1. (-)-Atenolol was used as a tool to assess the function of beta 1- and beta 2-adrenoceptors in human heart. Right atrial and left ventricular preparations from patients undergoing open heart surgery were set up to contract isometrically. Membrane particles were prepared for beta-adrenoceptor labelling with [3H]-(-)-bupranolol and adenylate cyclase assays. 2. The positive inotropic effects of (-)-noradrenaline were antagonized to a similar extent by (-)-atenolol in atrial and ventricular preparations. (-)-Atenolol consistently antagonized the effects of (-)-adrenaline to a lesser extent than those of (-)-noradrenaline in atrial preparations. In ventricular preparations (-)-atenolol antagonized the effects of low concentrations of (-)-adrenaline to a lesser extent than those of high concentrations. 3. pKB values (M) of (-)-atenolol, estimated with non-linear analysis from the blockade of the positive inotropic effects of the catecholamines, were 7.4 for beta 1-adrenoceptors and 6.0 for beta 2-adrenoceptors. 4. (-)-Atenolol inhibited the binding of [3H]-(-)-bupranolol to ventricular beta 1-adrenoceptors with a pKD (M) of 5.9 and to ventricular beta 2-adrenoceptors with a pKD of 4.6. 5. (-)-Atenolol inhibited the catecholamine-induced adenylate cyclase stimulation in the atrium and ventricle with pKB values of 5.8-6.4 for beta 1- and pKB values of 4.7-5.7 for beta 2-adrenoceptors. The binding and cyclase assays suggest a partial affinity loss for (-)-atenolol inherent to membrane preparations. 6. beta 1-Adrenoceptors mediate the maximum positive inotropic effects of (-)-noradrenaline in both the atrium and ventricle of man. beta 2-Adrenoceptors appear to be capable of mediating maximal positive inotropic effects of (-)-adrenaline in atrium. In contrast, ventricular beta 2-adrenoceptors mediated only submaximal effects of (-)-adrenaline. PMID:2851354

  1. Beta-2 adrenoceptor genotype and progress in term and late preterm active labor

    PubMed Central

    MILLER, Russell S.; SMILEY, Richard M.; DANIEL, Danette; WENG, Chunhua; EMALA, Charles W.; BLOUIN, Jean-Louis; FLOOD, Pamela D.

    2011-01-01

    OBJECTIVE To evaluate whether beta-2 adrenoceptor genotype at a functional polymorphic site encoding for amino acid residue 16 influences rate of cervical dilatation in term and late preterm active labor. STUDY DESIGN Subjects that underwent vaginal delivery at 34 or greater weeks gestational age between May, 2006, and August, 2007, were identified. Each subject had provided venous blood from which DNA was extracted for beta-2 adrenoceptor genotyping. Digital cervical examinations with paired examination times were collected from intrapartum records. Rate of cervical dilatation in active labor was determined using linear regression and rates were compared between genotype groups. RESULTS Among 401 subjects with satisfactory genotype and intrapartum data, overall rate of active labor was 0.76+/−0.01 cm/hr. When labor was compared by genotype, homozygous Arg/Arg16 subjects progressed at a slower rate (0.64+/−0.03 cm/hr) than all other pooled genotypes (0.8+/−0.02 cm/hr). CONCLUSION Homozygous beta-2 adrenoceptor genotype encoding for Arg/Arg16 was associated with slower progress in active labor. PMID:21600547

  2. Effect of dexmedetomidine on preventing agitation and delirium after microvascular free flap surgery: a randomized, double-blind, control study.

    PubMed

    Yang, Xudong; Li, Zhenzhen; Gao, Chunyan; Liu, Ruichang

    2015-06-01

    To determine whether dexmedetomidine sedation in the postanesthesia care unit (PACU) could decrease agitation and delirium after free flap surgery. Eighty patients were randomly divided into 2 groups. In the experimental group, dexmedetomidine was given at an hourly infusion rate of 0.5 μg/kg for 1 hour before the operation was completed and continued in the PACU at 0.2 to 0.7 μg/kg continuously until the next morning. In the control group, normal saline was given during the same periods. Patients in the 2 groups received sufentanil and midazolam for sedation and pain relief when necessary. Agitation was monitored with the Riker Sedation-Agitation Scale in the PACU and delirium was monitored with the Confusion Assessment Method for the Intensive Care Unit for 5 days postoperatively. The overall incidence of agitation was similar between the 2 groups. However, when the influence of patient shifting was excluded, the incidence of agitation in the dexmedetomidine group was apparently lower than that in the control group (10.3 vs 30%; P = .029). No difference was found in the occurrence of delirium between the experimental and control groups (5.1 vs 12.5%; P = .432). Dexmedetomidine does not change the overall incidence of agitation after free flap surgery; however, it does decrease agitation after PACU admission. It does not prevent delirium within 5 days postoperatively. Copyright © 2015 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

  3. Cetamolol: a new cardioselective beta-adrenoceptor blocking agent without membrane-stabilizing activity.

    PubMed

    Beaulieu, G; Jaramillo, J; Cummings, J R

    1984-03-01

    Cetamolol, a new beta-adrenoceptor blocker with partial agonist activity and cardioselectivity, was studied in vivo to determine its membrane-stabilizing effects. Comparisons were carried out with atenolol, pindolol, practolol, propranolol, timolol, dexpropranolol, lidocaine, and procaine. The following results indicated that cetamolol lacked membrane-stabilizing activity: (i) failure to cause local anesthesia on the rabbit cornea and motor nerve of the rat tail; (ii) ineffectiveness in reversing ventricular arrhythmias induced by coronary artery litigation in dogs; (iii) failure to reduce cardiac automaticity in catecholamine-depleted dogs as determined by the rate of a subatrial rhythm during ventricular (vagal) escape; and (iv) lack of a significant increase in atrioventricular conduction time in vagotomized or atropinized dogs in contrast to the effect in normal dogs indicating a reflex effect of cetamolol. Other results include a restoration of sinus rhythm in dogs with ventricular tachycardia induced by ouabain, and a dose-related decline in the force of cardiac contraction in anesthetized dogs at doses from 3 to 15 mg/kg, which occurred after an initial increase in force owing to intrinsic sympathomimetic activity. Although the mechanisms for the latter two effects are not clear at this time, explanations other than membrane-stabilizing activity have been considered in view of the other findings. It is concluded that cetamolol lacks membrane-stabilizing activity even at inordinately high doses.

  4. Effect of dexmedetomidine on intraocular pressure in patients undergoing robot-assisted laparoscopic radical prostatectomy under total intravenous anesthesia: A randomized, double blinded placebo controlled clinical trial.

    PubMed

    Kitamura, Sakiko; Takechi, Kenichi; Nishihara, Tasuku; Konishi, Amane; Takasaki, Yasushi; Yorozuya, Toshihiro

    2018-06-05

    To study the effects of intraoperative dexmedetomidine on the intraocular pressure (IOP) in patients undergoing robot-assisted laparoscopic radical prostatectomy (RALRP) under propofol-remifentanil anesthesia. Double-blind, randomized controlled trial. Operating room. Forty consenting male patients aged ≥20 to <80 years with American Society of Anesthesiologists physical status classes I and II. The patients were randomly assigned to either dexmedetomidine (DEX) (n = 20) or control (n = 20) group. Anesthesia was induced and maintained using propofol, remifentanil, and rocuronium. In the dexmedetomidine group, dexmedetomidine was administered at 0.4 μg/kg/h immediately after anesthesia induction until the end of the surgery, whereas normal saline was administered as placebo in the control group. IOP was measured using a rebound tonometer. Time points of measuring IOP were as follows: T1: before anesthesia induction, T2: 5 min after intubation, T3: 60 min after placing patient in the Trendelenburg position, T4: 120 min after placing patient in the Trendelenburg position, T5: 180 min after placing patient in the Trendelenburg position, T6: 5 min after placing patient in a horizontal position, T7: 5 min after extubation, and T8: 30 min after extubation. A linear mixed model analysis demonstrated a significant intergroup difference in IOP over time and during pneumoperitoneum in the steep Trendelenburg position. IOP at T5 was significantly lower in the dexmedetomidine group than in the control group even after post-hoc analysis in the steep Trendelenburg position periods with Bonferroni correction. Dexmedetomidine combined with propofol decreases IOP in the steep Trendelenburg position during RALRP. Copyright © 2018 Elsevier Inc. All rights reserved.

  5. Comparison of dexmedetomidine and chloral hydrate sedation for transthoracic echocardiography in infants and toddlers: a randomized clinical trial.

    PubMed

    Miller, Jeff; Xue, Bin; Hossain, Md; Zhang, Ma-Zhong; Loepke, Andreas; Kurth, Dean

    2016-03-01

    Procedural sedation using chloral hydrate is used in many institutions to improve the quality of transthoracic echocardiograms (TTE) in infants and young children. Chloral hydrate has limited availability in some countries, creating the need for alternative effective sedatives. The aim of our study was to compare the effectiveness of two doses of intranasal dexmedetomidine vs oral chloral hydrate sedation for transthoracic echocardiography. This is a randomized, prospective study of 150 children under the age of 3 years with known or suspected congenital heart disease scheduled for transthoracic echocardiography with sedation. Group CH received oral chloral hydrate 70 mg · kg(-1), group DEX2 received 2 μg · kg(-1) intranasal dexmedetomidine, and group DEX3 received 3 μg · kg(-1) intranasal dexmedetomidine. Acceptance of drug administration, sedation onset and duration, heart rate, and oxygen saturation, sonographer and parent satisfaction were recorded. All patients were successfully sedated for TTE. A second sedative dose (rescue) for failed single-dose sedation was required for 4% of patients after CH, none of the patients after DEX2, and 4% of patients after DEX3. Patients in group CH had an average heart rate decline of 22% during sedation, while group DEX2 decreased 27%, and group DEX3 23% (P = 0.2180). Mean time from administration of the sedative to final patient discharge was 96 min after CH, 83 min after DEX2, and 94 min after DEX3 (P = 0.1826). Intranasal dexmedetomidine 2 and 3 μg · kg(-1) were found to be as effective for TTE sedation as oral chloral hydrate with similar sedation onset and recovery time and heart rate changes in this study population. © 2015 John Wiley & Sons Ltd.

  6. Comparative analysis of efficacy of lignocaine 1.5 mg/kg and two different doses of dexmedetomidine (0.5 μg/kg and 1 μg/kg) in attenuating the hemodynamic pressure response to laryngoscopy and intubation

    PubMed Central

    Gulabani, Michell; Gurha, Pavan; Dass, Prashant; Kulshreshtha, Nishi

    2015-01-01

    Context: Laryngoscopy and intubation cause an intense reflex increase in heart rate, blood pressure, due to an increased sympathoadrenal pressor response. Lignoocaine has shown blunting of pressor response to intubation. Dexmedetomidine has sympatholytic effects. Aims: To the best of our knowledge there is no study comparing the efficacy of lignocaine with two different doses of dexmedetomidine for attenuating the pressor response. With this idea, we planned to conduct the present study. Materials and Methods: After approval by the Hospital Ethics committee, 90 consenting adults aged 18-65 years of age of either sex of non-hypertensive ASA Grade I or II were randomly allocated into three groups. Group D1- IV Dexmedetomidine 0.5μg/kg over 10 minutes Group D2- IV Dexmedetomidine 1μg/kg over 10 minutes Group X- IV Lignocaine 1.5mg/kg in 10 ml normal saline Statistical Analysis Used: ANOVA and Student's t test used for analysis. Results: Dexmedetomidine 1µg/kg was more effective than 0.5µg/kg and lignocaine 1.5mg/kg in attenuating the pressor response. Conclusions: We conclude that dexmedetomidine 1μg/kg adequately attenuates the hemodynamic response to laryngoscopy and endotracheal intubation when compared with dexmedetomidine 0.5μg/kg and lignocaine 1.5mg/kg. PMID:25886414

  7. Reduction in the incidence of shivering with perioperative dexmedetomidine: A randomized prospective study

    PubMed Central

    Bajwa, Sukhminder Jit Singh; Gupta, Sachin; Kaur, Jasbir; Singh, Amarjit; Parmar, SS

    2012-01-01

    Background and Aims: Shivering is distressing to the patient and discomforting to the attending anesthesiologist, with a varying degree of success. Various drugs and regimens have been employed to abolish the occurrence of shivering. The present study aims to explore the effectiveness of dexmedetomidine in suppressing the postanesthetic shivering in patients undergoing general anesthesia. Materials and Methods: The present study was carried out on 80 patients, in American Society of Anesthesiologists I and II, aged 22–59 years, who underwent general anesthesia for laparoscopic surgical procedures. Patients were allocated randomly into two groups: group N (n = 40) and group D (n = 40). Group D were administered 1 μg/kg of dexmedetomidine intravenously, while group N received similar volume of saline during peri-op period. Cardiorespiratory parameters were observed and recorded during the preop, intraop, and postop periods. Any incidence of postop shivering was observed and recorded as per 4 point scale. Side effects were also observed, recorded, and treated symptomatically. Statistical analysis was carried out using statistical package for social sciences (SPSS) version 15.0 for windows and employing ANOVA and chi-square test with post-hoc comparisons with Bonferroni's correction. Results: The two groups were comparable regarding demographic profile (P > 0.05). Incidence of shivering in group N was 42.5%, which was statistically highly significant (P = 0.014). Heart rate and mean arterial pressure also showed significant variation clinically and statistically in group D patients during the postop period (P = 0.008 and 0.012). A high incidence of sedation (P = 0.000) and dry mouth (P = 0.000) was observed in group D, whereas the incidence of nausea and vomiting was higher in group N (P = 0.011 and 0.034). Conclusions: Dexmedetomidine seems to possess antishivering properties and was found to reduce the occurrence of shivering in patients undergoing general

  8. The effects of lower than conventional doses of oral nadolol on relative beta 1/beta 2-adrenoceptor blockade.

    PubMed

    Wheeldon, N M; McDevitt, D G; Lipworth, B J

    1994-08-01

    1. The aim of the present study was to evaluate the relative beta 1/beta 2 antagonist selectivity of the beta-adrenoceptor blocker nadolol, in lower than conventional clinical doses. 2. Eight normal volunteers received single oral doses of either placebo (PL), nadolol 5 mg (N5), 20 mg (N20) or 80 mg (N80) in a single-blind, randomised crossover design. beta 1-adrenoceptor antagonism was assessed by attenuation of exercise tachycardia, and beta 2-adrenoceptor blockade by effects on salbutamol-induced chronotropic, hypokalaemic and finger tremor responses. The relative percentage attenuation of beta 2 and beta 1-mediated responses was calculated and expressed as beta 2:beta 1 selectivity ratios. 3. Nadolol produced dose-related reductions in exercise tachycardia in keeping with increasing beta 1-adrenoceptor blockade; mean % reduction (95% CI) compared with placebo: N5 10.7 (6.6 to 14.8), N20 21.4 (17.3 to 25.4), N80 38.9 (34.8 to 42.9). However, even the lowest dose of nadolol (5 mg) produced almost complete blunting of beta 2-mediated effects and significantly increase exercise hyperkalaemia; peak exercise hyperkalaemia (mmol l-1) (means and 95% CI): PL 4.88 (4.68 to 5.07), N5 5.36 (5.17 to 5.55), N20 5.48 (5.28 to 5.67), N80 5.42 (5.22 to 5.61). beta 2:beta 1 selectivity ratios significantly increased as the dose of nadolol was reduced. 4. These data suggest that whereas in the clinical dose range nadolol behaves as a non-selective beta-adrenoceptor antagonist, as the dose is reduced this drug demonstrates an increasing degree of selectivity for the beta 2-adrenoceptor.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Functional β2-adrenoceptors in rat left atria: effect of foot-shock stress.

    PubMed

    Moura, André Luiz de; Hyslop, Stephen; Grassi-Kassisse, Dora M; Spadari, Regina C

    2017-09-01

    Altered sensitivity to the chronotropic effect of catecholamines and a reduction in the β 1 /β 2 -adrenoceptor ratio have previously been reported in right atria of stressed rats, human failing heart, and aging. In this report, we investigated whether left atrial inotropism was affected by foot-shock stress. Male rats were submitted to 3 foot-shock sessions and the left atrial inotropic response, adenylyl cyclase activity, and β-adrenoceptor expression were investigated. Left atria of stressed rats were supersensitive to isoprenaline when compared with control rats and this effect was abolished by ICI118,551, a selective β 2 -receptor antagonist. Schild plot slopes for the antagonism between CGP20712A (a selective β 1 -receptor antagonist) and isoprenaline differed from unity in atria of stressed but not control rats. Atrial sensitivity to norepinephrine, as well as basal and forskolin- or isoprenaline-stimulated adenylyl cyclase activities were not altered by stress. The effect of isoprenaline on adenylyl cyclase stimulation was partially blocked by ICI118,551 in atrial membranes of stressed rats. These findings indicate that foot-shock stress equally affects inotropism and chronotropism and that β 2 -adrenoceptor upregulation contributes to the enhanced inotropic response to isoprenaline.

  10. Effect of dexmedetomidine constant rate infusion on the bispectral index during alfaxalone anaesthesia in dogs.

    PubMed

    Navarrete, Rocio; Quirós-Carmona, Setefilla; Granados, María Del M; Gómez-Villamandos, Rafael J; Domínguez, Juan M; Férnandez-Sarmiento, José A; Muñoz-Rascón, Pilar; Funes, Francisco J; Morgaz, Juan

    2016-07-01

    To assess the effect of two rates of infusion of dexmedetomidine on the bispectral index (BIS) in dogs anaesthetized with alfaxalone constant rate infusion (CRI). Prospective, randomized, 'blinded' experimental study. Six healthy Beagles (three females and three males). Dogs received as premedication saline (group D0), 1 μg kg(-1) (group D1) or 2 μg kg(-1) (group D2) dexmedetomidine, intravenously (IV). Anaesthesia was induced with alfaxalone (6 mg kg(-1) to effect IV) and maintained with alfaxalone at 0.07 mg kg(-1)  minute(-1) and a CRI of saline (D0) or dexmedetomidine 0.5 μg kg(-1)  hour(-1) (D1) or 1 μg kg(-1)  hour(-1) (D2) for 90 minutes. BIS, electromyography (EMG), signal quality index (SQI) and suppression ratio (SR) were measured at 10 minute intervals and the median values were calculated. Nociceptive stimuli were applied every 30 minutes and BIS and cardiorespiratory values were compared before and after stimuli. Cardiorespiratory parameters were recorded throughout the study. BIS and EMG values differed significantly among groups, being lower in D2 (71 ± 8) than in D0 (85 ± 10) and D1 (84 ± 9). SQI was always over 90% and SR was zero throughout all the treatments. There were no significant differences between pre- and post-stimulus values of BIS, EMG and SQI for any treatment, although in D0 and D1, heart rate, respiratory rate and arterial pressures increased significantly after the nociceptive stimulus. Administration of dexmedetomidine (2 μg kg(-1)  + CRI 1 μg kg(-1)  hour(-1) ) decreases the BIS values and avoids the autonomic responses of a nociceptive stimulus during alfaxalone anaesthesia at 0.07 mg kg(-1)  minute(-1) in dogs. However, further studies are needed to verify whether this combination produces an adequate degree of hypnosis under surgical situations. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  11. Molecular mechanism of emotional stress-induced and catecholamine-induced heart attack.

    PubMed

    Ueyama, Takashi; Senba, Emiko; Kasamatsu, Ken; Hano, Takuzo; Yamamoto, Katsuhiro; Nishio, Ichiro; Tsuruo, Yoshihiro; Yoshida, Ken-ichi

    2003-01-01

    Emotional or physical stress triggers 'tako-tsubo' cardiomyopathy or 'transient left ventricular apical ballooning', but the pathogenesis is unclear. In response to the immobilization stress of rats, a useful model of emotional stress, rapid activation of p44/p42 mitogen-activated protein kinase was observed in the heart, followed by a transient upregulation of immediate early genes in the smooth muscle cells of coronary arteries, the endothelial cells and the myocardium. Heat shock protein 70 was induced in the aortic and coronary arterial smooth muscle cells and in the myocardium. Natriuretic peptide genes were also upregulated in the myocardium. Sequential gene expression can be considered as an adaptive response to emotional stress. Blocking of both alpha-adrenoceptors and beta-adrenoceptors eliminated the upregulation of immediate early genes induced by stress, while alpha-agonists and beta-agonists upregulated immediate early genes in the perfused heart. Activation of alpha-adrenoceptors and beta-adrenoceptors is the primary trigger of emotional stress-induced molecular changes in the heart.

  12. Interactions of nitric oxide with α2 -adrenoceptors within the locus coeruleus underlie the facilitation of inhibitory avoidance memory by agmatine.

    PubMed

    Shelkar, Gajanan P; Gakare, Sukanya G; Chakraborty, Suwarna; Dravid, Shashank M; Ugale, Rajesh R

    2016-09-01

    Agmatine, a putative neurotransmitter, plays a vital role in learning and memory. Although it is considered an endogenous ligand of imidazoline receptors, agmatine exhibits high affinity for α-adrenoceptors, NOS and NMDA receptors. These substrates within the locus coeruleus (LC) are critically involved in learning and memory processes. The hippocampus and LC of male Wistar rat were stereotaxically cannulated for injection. Effects of agmatine, given i.p. or intra-LC, on acquisition, consolidation and retrieval of inhibitory avoidance (IA) memory were measured. The NO donor S-nitrosoglutathione, non-specific (L-NAME) and specific NOS inhibitors (L-NIL, 7-NI, L-NIO), the α2 -adrenoceptor antagonist (yohimbine) or the corresponding agonist (clonidine) were injected intra-LC before agmatine. Intra-hippocampal injections of the NMDA antagonist, MK-801 (dizocilpine), were used to modify the memory enhancing effects of agmatine, SNG and yohimbine. Expression of tyrosine hydroxylase (TH) and eNOS in the LC was assessed immunohistochemically. Agmatine (intra-LC or i.p.) facilitated memory retrieval in the IA test. S-nitrosoglutathione potentiated, while L-NAME and L-NIO decreased, these effects of agmatine. L-NIL and 7-NI did not alter the effects of agmatine. Yohimbine potentiated, whereas clonidine attenuated, effects of agmatine within the LC. The effects of agmatine, S-nitrosoglutathione and yohimbine were blocked by intra-hippocampal MK-801. Agmatine increased the population of TH- and eNOS-immunoreactive elements in the LC. The facilitation of memory retrieval in the IA test by agmatine is probably mediated by interactions between eNOS, NO and noradrenergic pathways in the LC. © 2016 The British Pharmacological Society.

  13. A Comparison of Dexmedetomidine and Clonidine in Attenuating the Hemodynamic Responses at Various Surgical Stages in Patients Undergoing Elective Transnasal Transsphenoidal Resection of Pituitary Tumors

    PubMed Central

    Jan, Summaira; Ali, Zulfiqar; Nisar, Yasir; Naqash, Imtiaz Ahmad; Zahoor, Syed Amer; Langoo, Shabir Ahmad; Azhar, Khan

    2017-01-01

    Background: Transsphenoidal approach to pituitary tumors is a commonly performed procedure with the advantage of a rapid midline access to the sella with minimal complications. It may be associated with wide fluctuations in hemodynamic parameters due to intense noxious stimulus at various stages of the surgery. As duration of the surgery is short and the patients have nasal packs, it is prudent to use an anesthestic technique with an early predictable recovery. Materials and Methods: A total of 60 patients of either sex between 18 and 65 years of age, belonging to the American Society of Anesthesiologists I and II who were undergoing elective transnasal transsphenoidal pituitary surgery were chosen for this study. Patients were randomly allocated into two groups, Group C (clonidine) and Group D (dexmedetomidine), with each group consisting of 30 patients. Patients in Group C received 200 μg tablet of clonidine and those in Group D received a pantoprazole tablet as placebo at the same time. Patients in the Group D received an intravenous infusion of dexmedetomidine diluted in 50 ml saline (200 μg in 50 ml saline) 10 min before induction and patients in Group C received 0.9% normal saline (50 ml) as placebo. The hemodynamic variables (heart rate, mean arterial pressure) were noted at various stages of the surgery. Statistical analysis of the data was performed. Results: A total of 60 patients were recruited. The mean age, sex, weight and duration of surgery among the two groups were comparable (P > 0.05). Both dexmedetomidine and clonidine failed to blunt the increase in hemodynamic responses (heart rate and blood pressure) during intubation, nasal packing, speculum insertion and extubation. However when the hemodynamic response was compared between the patients receiving dexmedetomidine and clonidine it was seen that patients who received dexmedetomidine had a lesser increase in heart rate and blood pressure (P < 0.05) when compared to clonidine. Conclusions: A

  14. A Comparison of Dexmedetomidine and Clonidine in Attenuating the Hemodynamic Responses at Various Surgical Stages in Patients Undergoing Elective Transnasal Transsphenoidal Resection of Pituitary Tumors.

    PubMed

    Jan, Summaira; Ali, Zulfiqar; Nisar, Yasir; Naqash, Imtiaz Ahmad; Zahoor, Syed Amer; Langoo, Shabir Ahmad; Azhar, Khan

    2017-01-01

    Transsphenoidal approach to pituitary tumors is a commonly performed procedure with the advantage of a rapid midline access to the sella with minimal complications. It may be associated with wide fluctuations in hemodynamic parameters due to intense noxious stimulus at various stages of the surgery. As duration of the surgery is short and the patients have nasal packs, it is prudent to use an anesthestic technique with an early predictable recovery. A total of 60 patients of either sex between 18 and 65 years of age, belonging to the American Society of Anesthesiologists I and II who were undergoing elective transnasal transsphenoidal pituitary surgery were chosen for this study. Patients were randomly allocated into two groups, Group C (clonidine) and Group D (dexmedetomidine), with each group consisting of 30 patients. Patients in Group C received 200 μg tablet of clonidine and those in Group D received a pantoprazole tablet as placebo at the same time. Patients in the Group D received an intravenous infusion of dexmedetomidine diluted in 50 ml saline (200 μg in 50 ml saline) 10 min before induction and patients in Group C received 0.9% normal saline (50 ml) as placebo. The hemodynamic variables (heart rate, mean arterial pressure) were noted at various stages of the surgery. Statistical analysis of the data was performed. A total of 60 patients were recruited. The mean age, sex, weight and duration of surgery among the two groups were comparable ( P > 0.05). Both dexmedetomidine and clonidine failed to blunt the increase in hemodynamic responses (heart rate and blood pressure) during intubation, nasal packing, speculum insertion and extubation. However when the hemodynamic response was compared between the patients receiving dexmedetomidine and clonidine it was seen that patients who received dexmedetomidine had a lesser increase in heart rate and blood pressure ( P < 0.05) when compared to clonidine. A continuous intravenous infusion of dexmedetomidine as

  15. Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis by possible reduction of NLRP3 activation and up-regulation of NET expression.

    PubMed

    Li, Yong; Pan, Yiyuan; Gao, Lin; Lu, Guotao; Zhang, Jingzhu; Xie, Xiaochun; Tong, Zhihui; Li, Baiqiang; Li, Gang; Li, Weiqin

    2018-01-22

    Previous studies have shown that acute inflammation is associated with increased sympathetic activity, which in turn increases the inflammatory response and leads to organ damage. The present study aimed to investigate whether dexmedetomidine administration during acute pancreatitis (AP) lessens pancreatic pathological and functional injury and the inflammatory response, and to explore the underlying mechanisms. Mild pancreatitis was induced in mice with caerulein, and severe pancreatitis was induced with caerulein plus lipopolysaccharide (LPS). After pancreatitis induction, dexmedetomidine at 10 or 20 μg/kg was injected via the tail vein. Pancreatic pathological and functional injury was assessed by histology and serum levels of amylase and lipase, respectively. The inflammatory response was evaluated by determining serum levels of inflammatory factors. The expression of myeloperoxidase (MPO) was examined by immunohistochemistry. The expression of norepinephrine transporter (NET), NLRP3, pro-IL-1β, and interleukin (IL)-1β in pancreatic tissue was detected by Western blot and real-time PCR. Dexmedetomidine at 20 μg/kg significantly attenuated pancreatic pathological injury, reduced serum levels of amylase, lipase, IL-1β, IL-6, and tumor necrosis factor (TNF)-α, and decreased the expression of MPO in pancreatic tissue in both mouse models of pancreatitis. In addition, dexmedetomidine at 20 μg/kg significantly down-regulated the expression of NLRP3, pro-IL-1β, and IL-1β in pancreatic tissue, but up-regulated the expression of NET in both mouse models. Dexmedetomidine attenuates pancreatic injury and inflammatory response in mice with pancreatitis possibly by reducing NLRP3 activation and up-regulating NET expression. Copyright © 2018 Elsevier Inc. All rights reserved.

  16. Anesthetic approach to high-risk patients and prolonged awake craniotomy using dexmedetomidine and scalp block.

    PubMed

    Garavaglia, Marco M; Das, Sunit; Cusimano, Michael D; Crescini, Charmagne; Mazer, C David; Hare, Gregory M T; Rigamonti, Andrea

    2014-07-01

    Awake craniotomy with intraoperative speech or motor testing is relatively contraindicated in cases requiring prolonged operative times and in patients with severe medical comorbidities including anxiety, anticipated difficult airway, obesity, large tumors, and intracranial hypertension. The anesthetic management of neurosurgical patients who possess these contraindications but would be optimally treated by an awake procedure remains unclear. We describe a new anesthetic approach for awake craniotomy that did not require any airway manipulation, utilizing a bupivacaine-based scalp nerve block, and dexmedetomidine as the primary hypnotic-sedative agent. Using this technique, we provided optimal operative conditions to perform awake craniotomy facilitating safe tumor resection, while utilizing intraoperative electrocorticography for motor and speech mapping in a cohort of 10 patients at a high risk for airway compromise and complications associated with patient comorbidities. All patients underwent successful awake craniotomy, intraoperative mapping, and tumor resection with adequate sedation for up to 9 hours (median 3.5 h, range 3 to 9 h) without any loss of neurological function, airway competency, or the need to provide any active rescue airway management. We report 4 of these cases that highlight our experience: 1 case required prolonged surgery because of the complexity of tumor resection and 3 patients had important medical comorbidities and/or relative contraindication for an awake procedure. Dexmedetomidine, with concurrent scalp block, is an effective and safe anesthetic approach for awake craniotomy. Dexmedetomidine facilitates the extension procedure complexity and duration in patients who might traditionally not be considered to be candidates for this procedure.

  17. Agonist-induced glycogenolysis in rabbit retinal slices and cultures.

    PubMed Central

    Ghazi, H.; Osborne, N. N.

    1989-01-01

    1. The effects of different putative retinal transmitters and/or modulators on glycogenolysis in rabbit retinal slices and in retinal Müller cell cultures were examined. 2. Incubation of rabbit retinal slices or primary retinal cultures (either 3-5 day-old or 25-30 day-old) in a buffer solution containing [3H]-glucose resulted in the accumulation of newly synthesized [3H]-glycogen. 3. Noradrenaline (NA), isoprenaline, vasoactive intestinal peptide (VIP), 5-hydroxytryptamine (5-HT) and 8-hydroxy-dipropylaminetetralin (8-OH-DPAT) stimulated the hydrolysis of this newly formed 3H-polymer. The potency order of maximal stimulations was: VIP greater than NA greater than isoprenaline greater than 5-HT greater than 8-OH-DPAT. 4. The putative retinal transmitters, dopamine, gamma-aminobutyric acid (GABA), glycine and taurine and the muscarinic agonist carbachol (CCh) had no effect on [3H]-glycogen content. 5. The glycogenolytic effects of NA/isoprenaline and 5-HT/8-OH-DPAT appear to be mediated by beta-adrenoceptors and 5-HT1 receptors (possibly 5-HT1A), respectively while the VIP-induced response involved another receptor subtype. 6. Agonists which mediated [3H]-glycogen hydrolysis also stimulated an increase in adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation. Both responses are blocked to a similar extent by the same antagonists and so are probably mediated via the same receptor subtypes. Moreover, dibutyryl cyclic AMP (db cyclic AMP) promoted tritiated glycogen breakdown in the three retinal preparations. 7. Not all receptors linked to cyclic AMP production however promote glycogenolysis. Dopamine and apomorphine stimulated cyclic AMP formation via D1-receptors without influencing glycogenolysis. These receptors are exclusively associated with neurones. PMID:2568145

  18. Blockade of beta-adrenoceptors enhances cAMP signal transduction in vivo

    NASA Technical Reports Server (NTRS)

    Whalen, E. J.; Johnson, A. K.; Lewis, S. J.

    1998-01-01

    The aim of this study was to determine whether the blockade of beta-adrenoceptors would enhance cAMP-mediated signal transduction processes in vivo. The administration of the membrane permeable cAMP analogue, 8-(4-chlorophenylthiol)-cAMP (8-CPT-cAMP, 10 micromol/kg, i.v.) produced an increase in heart rate (+27 +/- 2%, P < 0.05), a fall in mean arterial blood pressure (-21 +/- 3%, P < 0.05) and falls in hindquarter (-12 +/- 3%, P < 0.05) and mesenteric (-32 +/- 3%, P < 0.05) vascular resistances in pentobarbital-anesthetized rats. The beta-adrenoceptor antagonist, propranolol (1 mg/kg, i.v.) lowered heart rate (-12 +/- 3%, P < 0.05) but did not affect mean arterial blood pressure or vascular resistances. The tachycardia, hypotension and vasodilation produced by 8-CPT-cAMP were exaggerated after administration of propranolol (P < 0.05 for all comparisons). The nitric oxide-donor, sodium nitroprusside (2 microg/kg, i.v.), produced falls in mean arterial blood pressure and vascular resistances of similar magnitude to those produced by 8-CPT-cAMP. These sodium nitroprusside-induced responses were unaffected by propranolol (P < 0.05 for all comparisons). Sodium nitroprusside also produced a minor increase in heart rate (+5 +/- 1%, P < 0.05) which was abolished by propranolol. These findings suggest that 8-CPT-cAMP directly increases heart rate and that blockade of beta-adrenoceptors enhances the potency of cAMP within the heart and vasculature.

  19. The beta-adrenergic agonist salbutamol modulates neuromuscular junction formation in zebrafish models of human myasthenic syndromes.

    PubMed

    McMacken, Grace; Cox, Dan; Roos, Andreas; Müller, Juliane; Whittaker, Roger; Lochmüller, Hanns

    2018-05-01

    Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of disorders, termed congenital myasthenic syndromes (CMS). Therapies acting on the sympathetic nervous system, including the selective β2 adrenergic agonist salbutamol and the α and β adrenergic agonist ephedrine, have become standard treatment for several types of CMS. However, the mechanism of the therapeutic effect of sympathomimetics in these disorders is not understood. Here, we examined the effect of salbutamol on NMJ development using zebrafish with deficiency of the key postsynaptic proteins Dok-7 and MuSK. Treatment with salbutamol reduced motility defects in zebrafish embryos and larvae. In addition, salbutamol lead to morphological improvement of postsynaptic acetycholine receptor (AChR) clustering and size of synaptic contacts in Dok-7-deficient zebrafish. In MuSK-deficient zebrafish, salbutamol treatment reduced motor axon pathfinding defects and partially restored the formation of aneural prepatterned AChRs. In addition, the effects of salbutamol treatment were prevented by pre-treatment with a selective β2 antagonist. Treatment with the cyclic adenosine monophosphate (cAMP) activator forskolin, replicated the effects of salbutamol treatment. These results suggest that sympathomimetics exert a direct effect on neuromuscular synaptogenesis and do so via β2 adrenoceptors and via a cAMP-dependent pathway.

  20. The beta-adrenergic agonist salbutamol modulates neuromuscular junction formation in zebrafish models of human myasthenic syndromes

    PubMed Central

    McMacken, Grace; Cox, Dan; Roos, Andreas; Müller, Juliane; Whittaker, Roger; Lochmüller, Hanns

    2018-01-01

    Abstract Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of disorders, termed congenital myasthenic syndromes (CMS). Therapies acting on the sympathetic nervous system, including the selective β2 adrenergic agonist salbutamol and the α and β adrenergic agonist ephedrine, have become standard treatment for several types of CMS. However, the mechanism of the therapeutic effect of sympathomimetics in these disorders is not understood. Here, we examined the effect of salbutamol on NMJ development using zebrafish with deficiency of the key postsynaptic proteins Dok-7 and MuSK. Treatment with salbutamol reduced motility defects in zebrafish embryos and larvae. In addition, salbutamol lead to morphological improvement of postsynaptic acetycholine receptor (AChR) clustering and size of synaptic contacts in Dok-7-deficient zebrafish. In MuSK-deficient zebrafish, salbutamol treatment reduced motor axon pathfinding defects and partially restored the formation of aneural prepatterned AChRs. In addition, the effects of salbutamol treatment were prevented by pre-treatment with a selective β2 antagonist. Treatment with the cyclic adenosine monophosphate (cAMP) activator forskolin, replicated the effects of salbutamol treatment. These results suggest that sympathomimetics exert a direct effect on neuromuscular synaptogenesis and do so via β2 adrenoceptors and via a cAMP-dependent pathway. PMID:29462491

  1. Effects of age and hypertension on α1-adrenoceptors in the major source arteries of the rat bladder and penis.

    PubMed

    Yono, Makoto; Tanaka, Takanori; Tsuji, Shigeki; Irie, Shin; Sakata, Yukikuni; Otani, Masayuki; Yoshida, Masaki; Latifpour, Jamshid

    2011-11-16

    α(1)-Adrenoceptors regulate blood pressure, regional vascular resistance and tissue blood flow. As aging and hypertension may impact pelvic arterial blood flow resulting in bladder and penile dysfunction, we investigated effects of age and hypertension on α(1)-adrenoceptors in the major source arteries of the rat bladder and penis. Using radioligand receptor binding, real-time reverse transcription-polymerase chain reaction (RT-PCR) and fluorescent microsphere infusion techniques, we compared 3 and 22-month-old male Fischer rats, and male normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Twenty-two-month-old rats and SHRs had significantly higher total α(1)-adrenoceptor density in the internal iliac artery and lower blood flow to the bladder and penis than 3-month-old and WKY rats, respectively. RT-PCR data showed an age and hypertension related increase in the expression of α(1B)-adrenoceptor mRNA in the internal iliac, vesical and internal pudendal arteries and a switch from α(1A) predominance in 3-month-old and WKY rats to α(1B)>α(1A) in 22-month-old rats and SHRs. Our data indicate the presence of age and hypertension related alterations in vascular α(1)-adrenoceptor subtype distribution and in blood flow to the rat bladder and penis. These findings suggest that pharmacological blockade of the vascular α(1B)-adrenoceptor, which could increase pelvic blood flow, may contribute to the improvement of bladder and penile dysfunctions in animal models for aging and hypertension. Copyright © 2011 Elsevier B.V. All rights reserved.

  2. Effect of perineural dexmedetomidine on the quality of supraclavicular brachial plexus block with 0.5% ropivacaine and its interaction with general anaesthesia.

    PubMed

    Gurajala, Indira; Thipparampall, Anil Kumar; Durga, Padmaja; Gopinath, R

    2015-02-01

    The effect of perineural dexmedetomidine on the time to onset, quality and duration of motor block with ropivacaine has been equivocal and its interaction with general anaesthesia (GA) has not been reported. We assessed the influence of dexmedetomidine added to 0.5% ropivacaine on the characteristics of supraclavicular brachial plexus block and its interaction with GA. In a randomised, double blind study, 36 patients scheduled for orthopaedic surgery on the upper limb under supraclavicular block and GA were divided into either R group (35 ml of 0.5% ropivacaine with 0.5 ml of normal saline [n - 18]) or RD group (35 mL of 0.5% ropivacaine with 50 μg dexmedetomidine [n - 18]). The onset time and duration of motor and sensory blockade were noted. The requirement of general anaesthetics was recorded. Both the groups were comparable in demographic characteristics. The time of onset of sensory block was not significantly different. The proportion of patients who achieved complete motor blockade was more in the RD group. The onset of motor block was earlier in group RD than group R (P < 0.05). The durations of analgesia, sensory and motor blockade were significantly prolonged in group RD (P < 0.00). The requirement of entropy guided anaesthetic agents was not different in both groups. The addition of dexmedetomidine to 0.5% ropivacaine improved the time of onset, quality and duration of supraclavicular brachial plexus block but did not decrease the requirement of anaesthetic agents during GA.

  3. Dexmedetomidine in a surgically inserted catheter for transversus abdominis plane block in donor hepatectomy: A prospective randomized controlled study.

    PubMed

    Aboelela, Mohamed Adel; Kandeel, Al-Refaey; Elsayed, Usama; Elmorshedi, Mohamed; Elsarraf, Waleed; Elsayed, Eman; Elgawalby, Ahmed; Sultan, Ahmed Mohamed; Wahab, Mohamed Abdel; Yassen, Amr

    2018-01-01

    Transversus abdominis plane (TAP) block is a promising technique for analgesia after abdominal surgery. This prospective, randomized controlled trial assessed the effect of adding dexmedetomidine to bupivacaine in TAP block for donor hepatectomy. We hypothesized that this would improve postoperative morphine consumption and reduce analgesia related complication and inflammation. A total of 50 donor hepatectomy were enrolled in this study. Patients divided into two equal groups according to drugs used for TAP block. Group (B) received 20 ml of bupivacaine hydrochloride 0.25%, Group (BD) received 20 ml of bupivacaine hydrochloride 0.25% and 0.3 μg/kg dexmedetomidine, on both sides at the end of surgery and every 8 h for 48 h at right side only through inserted catheter. Primary outcome objective was morphine consumption at first 72 h. Secondary outcome objectives were morphine requirement, numbers of intake, time to first intake, pain score numerical analog scale (NAS), postoperative analgesia related complications, recovery of intestinal motility, and inflammatory markers. Data were analyzed, rescue morphine analgesia was significantly lower in (BD) group compared with (B) groups as considering total morphine consumption (B 4 ± 1.9, BD 1.5 ± 0.5, P = 0.03), numbers of morphine intake ( P = 0.04), morphine requirement ( P = 0.03), and first time of analgesia intake ( P = 0.04). NAS was significantly lower in group (BD) compared with group (B) group in the first 12 h (NAS 0 - P = 0.001, NAS 1 - P = 0.03). Adding dexmedetomidine improved gut motility, first oral intake without detectable anti-inflammatory effect. Adding dexmedetomidine to bupivacine in a surgically inserted catheter for TAP block in donor hepatectomy reduced morphine consumption without detectable anti-inflammatory effect.

  4. [Efficiency of bupivacaine and association with dexmedetomidine in transversus abdominis plane block ultrasound guided in postoperative pain of abdominal surgery].

    PubMed

    Aksu, Recep; Patmano, Gülçin; Biçer, Cihangir; Emek, Ertan; Çoruh, Aliye Esmaoğlu

    We aimed to evaluate the effect of bupivacaine and dexmedetomidine added to bupivacaine used in tranversus abdominis plane (TAP) block on postoperative pain and patient satisfaction in patients undergoing lower abdominal surgery. Patients submitted to lower abdominal surgery were enrolled in the study. After anesthesia induction, ultrasound guided TAP block was performed. TAP block was obtained with 21mL 0.9% saline in Group C (n=31), 20mL 0.5% bupivacaine+1mL saline in Group B (n=31), and 20mL 0.5% bupivacaine+1mL dexmedetomidine (100μg) in Group BD (n=31). Visual analog scale scores were lower in Group BD compared to Group C, at all time points (p<0.05); it was lower in group BD than in group B at 10-24h. In Group B, it was lower than Group C at 2-8h (p<0.05). Total morphine consumption was lower in Group BD compared to other groups and lower in group B than in the controls (p<0.001). Patient satisfaction was higher in Group BD than in other groups and was higher in both study groups than in the controls (p<0.001). Nausea-vomiting scores, antiemetic requirement, or additional analgesic administration were not significant among groups (p>0.05). The addition of dexmedetomidine to bupivacaine on TAP block decreased postoperative pain scores and morphine consumption; it also increased patient satisfaction in patients undergoing lower abdominal surgery. Dexmedetomidine did not have any effect on nausea and vomiting score and antiemetic requirement. Copyright © 2017 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  5. alpha-Adrenoceptor and opioid receptor modulation of clonidine-induced antinociception.

    PubMed Central

    Sierralta, F.; Naquira, D.; Pinardi, G.; Miranda, H. F.

    1996-01-01

    1. The antinociceptive action of clonidine (Clon) and the interactions with alpha 1, alpha 2 adrenoceptor and opioid receptor antagonists was evaluated in mice by use of chemical algesiometric test (acetic acid writhing test). 2. Clon produced a dose-dependent antinociceptive action and the ED50 for intracerebroventricular (i.c.v.) was lower than for intraperitoneal (i.p.) administration (1 ng kg-1 vs 300 ng kg-1). The parallelism of the dose-response curves indicates activation of a common receptor subtype. 3. Systemic administration of prazosin and terazosin displayed antinociceptive activity. Pretreatment with prazosin produced a dual action: i.c.v. Clon effect did not change, and i.p. Clon effect was enhanced. Yohimbine i.c.v. or i.p. did not induce antinonciception, but antagonized Clon-induced activity. These results suggest that alpha 1- and alpha 2-adrenoceptors, either located at the pre- and/or post-synaptic level, are involved in the control of spinal antinociception. 4. Naloxone (NX) and naltrexone (NTX) induced antinociceptive effects at low doses (microgram kg-1 range) and a lower antinociceptive effect at higher doses (mg kg-1 range). Low doses of NX or NTX antagonized Clon antinociception, possibly in relation to a preferential mu opioid receptor antagonism. In contrast, high doses of NX or NTX increased the antinociceptive activity of Clon, which could be due to an enhanced inhibition of the release of substance P. 5. The results obtained in the present work suggest the involvement of alpha 1-, alpha 2-adrenoceptor and opioid receptors in the modulation of the antinociceptive activity of clonidine, which seems to be exerted either at spinal and/or supraspinal level. PMID:8894177

  6. alpha-Adrenoceptor and opioid receptor modulation of clonidine-induced antinociception.

    PubMed

    Sierralta, F; Naquira, D; Pinardi, G; Miranda, H F

    1996-10-01

    1. The antinociceptive action of clonidine (Clon) and the interactions with alpha 1, alpha 2 adrenoceptor and opioid receptor antagonists was evaluated in mice by use of chemical algesiometric test (acetic acid writhing test). 2. Clon produced a dose-dependent antinociceptive action and the ED50 for intracerebroventricular (i.c.v.) was lower than for intraperitoneal (i.p.) administration (1 ng kg-1 vs 300 ng kg-1). The parallelism of the dose-response curves indicates activation of a common receptor subtype. 3. Systemic administration of prazosin and terazosin displayed antinociceptive activity. Pretreatment with prazosin produced a dual action: i.c.v. Clon effect did not change, and i.p. Clon effect was enhanced. Yohimbine i.c.v. or i.p. did not induce antinonciception, but antagonized Clon-induced activity. These results suggest that alpha 1- and alpha 2-adrenoceptors, either located at the pre- and/or post-synaptic level, are involved in the control of spinal antinociception. 4. Naloxone (NX) and naltrexone (NTX) induced antinociceptive effects at low doses (microgram kg-1 range) and a lower antinociceptive effect at higher doses (mg kg-1 range). Low doses of NX or NTX antagonized Clon antinociception, possibly in relation to a preferential mu opioid receptor antagonism. In contrast, high doses of NX or NTX increased the antinociceptive activity of Clon, which could be due to an enhanced inhibition of the release of substance P. 5. The results obtained in the present work suggest the involvement of alpha 1-, alpha 2-adrenoceptor and opioid receptors in the modulation of the antinociceptive activity of clonidine, which seems to be exerted either at spinal and/or supraspinal level.

  7. Interactions of nitric oxide with α2‐adrenoceptors within the locus coeruleus underlie the facilitation of inhibitory avoidance memory by agmatine

    PubMed Central

    Shelkar, Gajanan P; Gakare, Sukanya G; Chakraborty, Suwarna; Dravid, Shashank M

    2016-01-01

    Background and Purpose Agmatine, a putative neurotransmitter, plays a vital role in learning and memory. Although it is considered an endogenous ligand of imidazoline receptors, agmatine exhibits high affinity for α‐adrenoceptors, NOS and NMDA receptors. These substrates within the locus coeruleus (LC) are critically involved in learning and memory processes. Experimental Approach The hippocampus and LC of male Wistar rat were stereotaxically cannulated for injection. Effects of agmatine, given i.p. or intra‐LC, on acquisition, consolidation and retrieval of inhibitory avoidance (IA) memory were measured. The NO donor S‐nitrosoglutathione, non‐specific (L‐NAME) and specific NOS inhibitors (L‐NIL, 7‐NI, L‐NIO), the α2‐adrenoceptor antagonist (yohimbine) or the corresponding agonist (clonidine) were injected intra‐LC before agmatine. Intra‐hippocampal injections of the NMDA antagonist, MK‐801 (dizocilpine), were used to modify the memory enhancing effects of agmatine, SNG and yohimbine. Expression of tyrosine hydroxylase (TH) and eNOS in the LC was assessed immunohistochemically. Key Results Agmatine (intra‐LC or i.p.) facilitated memory retrieval in the IA test. S‐nitrosoglutathione potentiated, while L‐NAME and L‐NIO decreased, these effects of agmatine. L‐NIL and 7‐NI did not alter the effects of agmatine. Yohimbine potentiated, whereas clonidine attenuated, effects of agmatine within the LC. The effects of agmatine, S‐nitrosoglutathione and yohimbine were blocked by intra‐hippocampal MK‐801. Agmatine increased the population of TH‐ and eNOS‐immunoreactive elements in the LC. Conclusions and Implications The facilitation of memory retrieval in the IA test by agmatine is probably mediated by interactions between eNOS, NO and noradrenergic pathways in the LC. PMID:27273730

  8. Dexmedetomidine-based intravenous anesthesia of a pediatric patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency: A case report.

    PubMed

    Takahashi, Nanae; Ogawa, Takashi; Wajima, Zen'ichiro; Omi, Akibumi

    2017-05-01

    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, resulting in deficits in nicotinamide adenine dinucleotide phosphate production, an important intracellular antioxidant enzyme. G6PD-deficient subjects present with a susceptibility of erythrocytes to oxidative stress and hemolysis, and should avoid drugs or stressors that have oxidative actions. Dexmedetomidine is an anesthetic agent with antioxidant actions. A 5-year-old boy with G6PD deficiency. The patient was diagnosed with G6PD deficiency at birth. His red blood cell levels were indicating Class II G6PD activity by the World Health Organization (WHO) classification, but had no history of hemolytic anemia. Because of the patient's anxiety and hyperactivity prior to an operation for upper labial frenum resection, we performed perioperative management using intravenous sedation with dexmedetomidine, which provides upper airway patency and has an antioxidant action. There was no abnormal breathing observed during anesthesia, and arousal was smooth with stable hemodynamics. The patient had no symptoms of hemolytic anemia up to 1 week postsurgery. Antioxidant sedatives such as dexmedetomidine may be useful for reducing the risk of hemolysis after surgery in infant G6PD deficiency cases.

  9. An investigation into the selectivity of a novel series of benzoquinolizines for alpha 2-adrenoceptors in vivo.

    PubMed Central

    Paciorek, P. M.; Pierce, V.; Shepperson, N. B.; Waterfall, J. F.

    1984-01-01

    The potencies and selectivities of a novel series of benzoquinolizines for the alpha 2-adrenoceptor have been investigated in the rat in comparison with yohimbine and indoramin. Peripheral postjunctional alpha 2- and alpha 1-adrenoceptor blockade was measured as the reversal of B-HT 933 and methoxamine-induced pressor responses, respectively, in the pithed rat. Peripheral prejunctional alpha 2-adrenoceptor blockade was measured as the reversal of B-HT 933-induced inhibition of an electrically evoked tachycardia in the pithed rat. Central alpha 2-adrenoceptor blockade was measured as a reversal of the hypotension induced in anaesthetized rats by central (i.c.v.) administration of clonidine. Wy 25309, Wy 26392, Wy 26703 and yohimbine (0.3-3 mg kg-1 i.v.) evoked dose-dependent shifts to the right of the dose-response curves to B-HT 933 whilst having minimal effects on the methoxamine dose-response curve. The selectivity for alpha 2-adrenoceptors increased with the dose of antagonist administered. In general, the order of selectivity was Wy 25309 greater than Wy 26392 greater than Wy 26703 greater than yohimbine. Indoramin (1 mg kg-1 i.v.) shifted the methoxamine pressor dose-response curve to the right without affecting the B-HT 933 dose-response curves, confirming its selective alpha 1-antagonist activity. Peripheral administration of all three benzoquinolizines (1-100 micrograms kg-1 i.v.) led to a dose-dependent reversal of the hypotension evoked by central administration of clonidine (500 ng i.c.v.). The reversal was incomplete, higher doses causing a further decrease in blood pressure. (ABSTRACT TRUNCATED AT 250 WORDS) PMID:6329385

  10. Mild prenatal protein malnutrition increases alpha 2C-adrenoceptor expression in the rat cerebral cortex during postnatal life.

    PubMed

    Sierralta, Walter; Hernández, Alejandro; Valladares, Luis; Pérez, Hernán; Mondaca, Mauricio; Soto-Moyano, Rubén

    2006-05-15

    Mild reduction in the protein content in the diet of pregnant rats from 25 to 8% casein, calorically compensated by carbohydrates, does not alter body and brain weights of rat pups at birth, but results in significant changes of the concentration and release of cortical noradrenaline during postnatal life, together with impaired long-term potentiation and memory formation. Since some central noradrenergic receptors are critically involved in neuroplasticity, the present study evaluated, by utilizing immunohistochemical methods, the effect of mild prenatal protein malnutrition on the alpha 2C-adrenoceptor expression in the frontal and occipital cortices of 8- and 60-day-old rats. At day 8 of postnatal age, prenatally malnourished rats exhibited a three-fold increase of alpha 2C-adrenoceptor expression in both the frontal and the occipital cortices, as compared to well-nourished controls. At 60 days of age, prenatally malnourished rats showed normal expression levels scores of alpha 2C-adrenoceptor in the neocortex. Results suggest that overexpression of neocortical alpha 2C-adrenoceptors during early postnatal life, subsequent to mild prenatal protein malnutrition, could in part be responsible for neural and behavioral disturbances showing prenatally malnourished animals during the postnatal life.

  11. Efficacy and safety of dexmedetomidine infusion for patients undergoing awake craniotomy: An observational study.

    PubMed

    Mahajan, Charu; Rath, Girija Prasad; Singh, Gyaninder Pal; Mishra, Nitasha; Sokhal, Suman; Bithal, Parmod Kumar

    2018-01-01

    The goal of awake craniotomy is to maintain adequate sedation, analgesia, respiratory, and hemodynamic stability and also to provide a cooperative patient for neurologic testing. An observational study carried out to evaluate the efficacy of dexmedetomidine sedation for awake craniotomy. Adult patients with age >18 year who underwent awake craniotomy for intracranial tumor surgery were enrolled. Those who were uncooperative and had difficult airway were excluded from the study. In the operating room, the patients received a bolus dose of dexmedetomidine 1 μg/kg followed by an infusion of 0.2-0.7 μg/kg/h (bispectral index target 60-80). Once the patients were sedated, scalp block was given with bupivacaine 0.25%. The data on hemodynamics at various stages of the procedure, intraoperative complications, total amount of fentanyl used, intravenous fluids required, blood loss and transfusion, duration of surgery, Intensive Care Unit (ICU), and hospital stay were collected. The patients were assessed for Glasgow outcome scale (GOS) score and patient satisfaction score (PSS). A total of 27 patients underwent awake craniotomy during a period of 2 years. Most common intraoperative complication was seizures; observed in five patients (18.5%). None of these patients experienced any episode of desaturation. Two patients had tight brain for which propofol boluses were administered. The average fentanyl consumption was 161.5 ± 85.0 μg. The duration of surgery, ICU, and hospital stays were 231.5 ± 90.5 min, 14.5 ± 3.5 h, and 4.7 ± 1.5 days, respectively. The overall PSS was 8 and GOS was good in all the patients. The use of dexmedetomidine infusion with regional scalp block in patients undergoing awake craniotomy is safe and efficacious. The absence of major complications and higher PSS makes it close to an ideal agent for craniotomy in awake state.

  12. Combination of Continuous Dexmedetomidine Infusion with Titrated Ultra-Low-Dose Propofol-Fentanyl for an Awake Craniotomy

    PubMed Central

    Das, Samaresh; Al-Mashani, Ali; Suri, Neelam; Salhotra, Neeraj; Chatterjee, Nilay

    2016-01-01

    An awake craniotomy is a continuously evolving technique used for the resection of brain tumours from the eloquent cortex. We report a 29-year-old male patient who presented to the Khoula Hospital, Muscat, Oman, in 2016 with a two month history of headaches and convulsions due to a space-occupying brain lesion in close proximity with the left motor cortex. An awake craniotomy was conducted using a scalp block, continuous dexmedetomidine infusion and a titrated ultra-low-dose of propofolfentanyl. The patient remained comfortable throughout the procedure and the intraoperative neuropsychological tests, brain mapping and tumour resection were successful. This case report suggests that dexmedetomidine in combination with titrated ultra-low-dose propofolfentanyl are effective options during an awake craniotomy, ensuring optimum sedation, minimal disinhibition and a rapid recovery. To the best of the authors’ knowledge, this is the first awake craniotomy conducted successfully in Oman. PMID:27606116

  13. Comparison of Two Different Intranasal Doses of Dexmedetomidine in Children for Magnetic Resonance Imaging Sedation.

    PubMed

    Tug, Aslihan; Hanci, Ayse; Turk, Hacer Sebnem; Aybey, Ferda; Isil, Canan Tulay; Sayin, Pinar; Oba, Sibel

    2015-12-01

    Anaesthetic agents used for magnetic resonance imaging (MRI) in paediatric patients should cause few adverse effects and allow fast anaesthetic induction and recovery. The administration route is also important and should be minimally invasive. In this study, we aimed to compare two different doses of intranasal dexmedetomidine applied to children for MRI sedation. Sixty patients between 1 and 10 years of age with American Society of Anesthesiologists Physical Status classification I or II who were scheduled for MRI were recruited into this prospective, randomized, double-blind study. Intranasal dexmedetomidine was administered at doses of 3 µg kg(-1) (Group 1) and 4 µg kg(-1) (Group 2) before imaging. Heart rate (HR), peripheral oxygen saturation, respiratory rate and Ramsay Sedation Scale (RSS) scores were recorded before the anaesthetic induction of sedation and every 10 min until discharge. If intranasal sedation failed, an intravenous cannula was placed and propofol was applied as a rescue anaesthetic. Bispectral Index (BIS) scores were also recorded before and after MRI. We recorded onset time of sedation, mood at separation from parents (defined as parental separation score), imaging quality, MRI duration, rescue anaesthetic requirement, total duration of sedation, recovery duration, parents' satisfaction and adverse effects. The results related to age, weight and adverse effects were not statistically different between the groups. The parental separation score was significantly higher in Group 2 (P = 0.003). Rescue anaesthetic requirement was significantly higher in Group 1 (P = 0.002). The results related to recovery duration, MRI duration, parents' satisfaction, onset time of sedation and total duration of sedation were not statistically different. HR was significantly lower in all time intervals compared with basal values in both groups. In Group 2, RSS scores were significantly higher in the 30th, 40th and 50th min. The BIS scores in Group 2 were

  14. The influence of norepinephrine and phenylephrine on cerebral perfusion and oxygenation during propofol-remifentanil and propofol-remifentanil-dexmedetomidine anaesthesia in piglets.

    PubMed

    Mikkelsen, Mai Louise Grandsgaard; Ambrus, Rikard; Rasmussen, Rune; Miles, James Edward; Poulsen, Helle Harding; Moltke, Finn Borgbjerg; Eriksen, Thomas

    2018-02-08

    Vasopressors are frequently used to increase blood pressure in order to ensure sufficient cerebral perfusion and oxygenation (CPO) during hypotensive periods in anaesthetized patients. Efficacy depends both on the vasopressor and anaesthetic protocol used. Propofol-remifentanil total intravenous anaesthesia (TIVA) is common in human anaesthesia, and dexmedetomidine is increasingly used as adjuvant to facilitate better haemodynamic stability and analgesia. Little is known of its interaction with vasopressors and subsequent effects on CPO. This study investigates the CPO response to infusions of norepinephrine and phenylephrine in piglets during propofol-remifentanil and propofol-remifentanil-dexmedetomidine anaesthesia. Sixteen healthy female piglets (25-34 kg) were randomly allocated into a two-arm parallel group design with either normal blood pressure (NBP) or induced low blood pressure (LBP). Anaesthesia was induced with propofol without premedication and maintained with propofol-remifentanil TIVA, and finally supplemented with continuous infusion of dexmedetomidine. Norepinephrine and phenylephrine were infused in consecutive intervention periods before and after addition of dexmedetomidine. Cerebral perfusion measured by laser speckle contrast imaging was related to cerebral oxygenation as measured by an intracerebral Licox probe (partial pressure of oxygen) and transcranial near infrared spectroscopy technology (NIRS) (cerebral oxygen saturation). During propofol-remifentanil anaesthesia, increases in blood pressure by norepinephrine and phenylephrine did not change cerebral perfusion significantly, but cerebral partial pressure of oxygen (Licox) increased following vasopressors in both groups and increases following norepinephrine were significant (NBP: P = 0.04, LBP: P = 0.02). In contrast, cerebral oxygen saturation (NIRS) fell significantly in NBP following phenylephrine (P = 0.003), and following both norepinephrine (P = 0.02) and phenylephrine

  15. Effects of Dexmedetomidine on motor- and somatosensory-evoked potentials in patients with thoracic spinal cord tumor: a randomized controlled trial.

    PubMed

    Li, Yan; Meng, Lingzhong; Peng, Yuming; Qiao, Hui; Guo, Lanjun; Han, Ruquan; Gelb, Adrian W

    2016-08-02

    We hypothesized that the addition of dexmedetomidine in a clinically relevant dose to propofol-remifentanil anesthesia regimen does not exert an adverse effect on motor-evoked potentials (MEP) and somatosensory-evoked potentials (SSEP) in adult patients undergoing thoracic spinal cord tumor resection. Seventy-one adult patients were randomized into three groups. Propofol group (n = 25): propofol-remifentanil regimenand the dosage was adjusted to maintain the bispectral index (BIS) between 40 and 50. DP adjusted group (n = 23): Dexmedetomidine (0.5 μg/kg loading dose infused over 10 min followed by a constant infusion of 0.5 μg/kg/h) was added to the propofol-remifentanil regimen and propofol was adjusted to maintain BIS between 40 and 50. DP unadjusted group (n = 23): Dexmedetomidine (administer as DP adjusted group) was added to the propofol-remifentanil regimen and propofol was not adjusted. All patients received MEP, SSEP and BIS monitoring. There were no significant changes in the amplitude and latency of MEP and SSEP among different groups (P > 0.05). The estimated propofol plasma concentration in DP adjusted group (2.7 ± 0.3 μg/ml) was significantly lower than in propofol group (3.1 ± 0.2 μg/ml) and DP unadjusted group (3.1 ± 0.2 μg/ml) (P = 0.000). BIS in DP unadjusted group (35 ± 5) was significantly lower than in propofol group (44 ± 3) (P = 0.000). The addition of dexmedetomidine to propofol-remifentanil regimen does not exert an adverse effect on MEP and SSEP monitoring in adult patients undergoing thoracic spinal cord tumor resection. The study was registered with the Chinese Clinical Trial Registry on January 31st, 2014. The reference number was ChiCTR-TRC-14004229.

  16. Dexmedetomidine acts as an oxidative damage prophylactic in rats exposed to ionizing radiation.

    PubMed

    Kutanis, Dilek; Erturk, Engin; Besir, Ahmet; Demirci, Yucel; Kayir, Selcuk; Akdogan, Ali; Vanizor Kural, Birgul; Bahat, Zumrut; Canyilmaz, Emine; Kara, Hanife

    2016-11-01

    To investigate the effects of dexmedetomidine on oxidative injury caused by ionizing radiation. Randomized controlled experimental study. Department of radiation oncology and research laboratory of an academic hospital. Twenty-eight rats were randomized to 4 groups (n=7 per group). Group S rats were administered physiologic serum; group SR rats were administered physiologic serum and 10 Gy external ionizing radiation. Groups D100 and D200 were administered 100 and 200 μg/kg dexmedetomidine intraperitoneally, respectively, 45 minutes before ionizing radiation. Liver, kidney, lung, and thyroid tissue and serum levels of antioxidant enzymes (glutathione peroxidase [GPX], superoxide dismutase, and catalase) and oxidative metabolites (advanced oxidation protein products, malondialdehyde, and nitrate/nitrite, and serum ischemia-modified albumin) were measured 6 hours postprocedure. In group SR, IR decreased antioxidant enzyme levels and increased oxidative metabolite levels (P<.05). In plasma, antioxidant enzyme levels were higher and oxidative metabolite levels were lower in groups D100 and D200 than in group SR (P<.01). In tissues, hepatic and lung GPX levels were higher in groups D100 and D200 than in group SR (P<.001). Renal and thyroid GPX levels were higher in D200 than in group SR (P<.01). Thyroid superoxide dismutase levels were higher in groups D100 and D200 than in group SR (P<.01). Renal, lung, and thyroid catalase levels were higher in group D200 than in group SR (P<.01). Hepatic, renal, and lung advanced oxidation protein products and malondialdehyde levels were lower in groups D100 and D200 than in group SR (P<.01). Hepatic, renal, and lung nitrate/nitrite levels were lower in group D200 than in group SR (P<.05). Dexmedetomidine preserves the antioxidant enzyme levels and reduces toxic oxidant metabolites. Therefore, it can provide protection from oxidative injury caused by ionizing radiation. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Marine Bivalve Cellular Responses to Beta Blocker Exposures

    EPA Science Inventory

    β blockers are prescription drugs used for medical treatment of hypertension and arrhythmias. They prevent binding of agonists such as catecholamines to β adrenoceptors. In the absence of agonist induced activation of the receptor, adenylate cyclase is not activated whi...

  18. Comparison of alpha 1A- and alpha 1B-adrenoceptor coupling to inositol phosphate formation in rat kidney.

    PubMed

    Büscher, R; Erdbrügger, W; Philipp, T; Brodde, O E; Michel, M C

    1994-12-01

    We have compared the coupling mechanisms of rat renal alpha 1A- and alpha 1B-like adrenoceptors to inositol phosphate formation. The experiments were performed in parallel in native renal tissue preparations and in those where alpha 1B-adrenoceptors had been inactivated by treatment with 10 mumol/l chloroethylclonidine for 30 min at 37 degrees C; renal slices were used in most experiments but isolated renal cells were also used in some cases. The Ca2+ chelating agent, EGTA (5 mmol/l), reduced noradrenaline-stimulated inositol phosphate formation in native but enhanced it in chloroethylclonidine-treated renal slices. The inhibitory effect of EGTA was not mimicked by 100 nmol/l nifedipine. Inactivation of 87% of cellular Gi by 16-20 h treatment with 500 ng/ml pertussis toxin did not significantly affect noradrenaline-stimulated inositol phosphate formation in isolated renal cells but abolished the inhibitory effect of chloroethylclonidine. The adenylate cyclase activator, forskolin (20 mumol/l), inhibited noradrenaline-stimulated inositol phosphate formation in native and chloroethylclonidine-treated slices, and the inhibitory effects of chloroethylclonidine treatment and forskolin were additive. We conclude that in rat kidney inositol phosphate formation via alpha 1B-like adrenoceptors may involve the influx of extracellular Ca2+ and a pertussis toxin-sensitive G-protein but is insensitive to inhibition by forskolin. In contrast alpha 1A-like adrenoceptor-mediated inositol phosphate formation does not require the presence of extracellular Ca2+ or of Gi and is sensitive to inhibition by forskolin. In comparison to published data from other model systems we further conclude that the signaling mechanisms of alpha 1-adrenoceptor subtypes may depend on their cellular environment.

  19. The effects of catecholamines and adrenoceptor blocking drugs on the canine peripheral lymph flow.

    PubMed Central

    De Micheli, P; Glässer, A H

    1975-01-01

    Blood flow through the femoral artery, lymph flow in a lymphatic vessel in the femoral triangle and metatarsal distal venous pressure were measured simultaneously in a canine moving hind limb. 2. Low intra-arterial doses of adrenaline and noradrenaline increased lymph flow even in the presence of marked arterial vasoconstriction. In contrast, isoprenaline increased arterial blood flow without affecting lymph flow rate. 3. Phenoxybenzamine, dihydroergotoxine, and nicergoline did not inhibit the lymphatic flow increase induced by adrenaline at doses active on arterial or venous vascular alpha-adrenoceptors. 4. Propranolol given intra-arterially into animals pretreated with alpha-adrenoceptor blocking agents restored the vasoconstrictor effect of adrenaline (reversal of adrenaline reversal). PMID:238702

  20. TASK-3 knockout mice exhibit exaggerated nocturnal activity, impairments in cognitive functions, and reduced sensitivity to inhalation anesthetics.

    PubMed

    Linden, Anni-Maija; Sandu, Cristina; Aller, M Isabel; Vekovischeva, Olga Y; Rosenberg, Per H; Wisden, William; Korpi, Esa R

    2007-12-01

    The TASK-3 channel is an acid-sensitive two-pore-domain K+ channel, widely expressed in the brain and probably involved in regulating numerous neuronal populations. Here, we characterized the behavioral and pharmacological phenotypes of TASK-3 knockout (KO) mice. Circadian locomotor activity measurements revealed that the nocturnal activity of the TASK-3 KO mice was increased by 38% (P < 0.01) compared with wild-type littermate controls, light phase activity being similar. Although TASK-3 channels are abundant in cerebellar granule cells, the KO mice performed as well as the wild-type mice in walking on a rotating rod or along a 1.2-cm-diameter beam. However, they fell more frequently from a narrower 0.8-cm beam. The KO mice showed impaired working memory in the spontaneous alternation task, with the alternation percentage being 62 +/- 3% for the wild-type mice and 48 +/- 4% (P < 0.05) for the KO mice. Likewise, during training for the Morris water-maze spatial memory task, the KO mice were slower to find the hidden platform, and in the probe trial, the female KO mice visited fewer times the platform quadrant than the male KO and wild-type mice. In pharmacological tests, the TASK-3 KO mice showed reduced sensitivity to the inhalation anesthetic halothane and the cannabinoid receptor agonist WIN55212-2 mesylate [(R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] but unaltered responses to the alpha2 adrenoceptor agonist dexmedetomidine, the i.v. anesthetic propofol, the opioid receptor agonist morphine, and the local anesthetic lidocaine. Overall, our results suggest important contributions of TASK-3 channels in the neuronal circuits regulating circadian rhythms, cognitive functions, and mediating specific pharmacological effects.

  1. Dexmedetomidine and propofol sedation requirements in an autistic rat model.

    PubMed

    Elmorsy, Soha A; Soliman, Ghada F; Rashed, Laila A; Elgendy, Hamed

    2018-05-30

    Autism is a challenging neurodevelopmental disorder. Previous clinical observations suggest altered sedation requirements for autistic children. Our study aimed to test this observation experimentally with an animal model and, to explore its possible mechanisms. Eight adult pregnant female Sprague Dawley rats were randomly selected into two groups. Four were injected with intraperitoneal sodium valproate on the gestational day 12 and four were injected with normal saline. On post-natal day 28 the newborn male rats were subjected to an open field test to confirm autistic features. Each rat was injected intraperitoneally with a single dose of propofol (50 mg/kg) or dexmedetomidine (0.2 mg/kg). Times to Loss of Righting Reflex (LORR) and to Return of Righting Reflex (RORR) were recorded. On the next day, all rats were re-sedated and their EEGs were recorded. The rats were sacrificed and hippocampal GABAA and glutamate NMDA receptor gene expression were assessed. Autistic rats showed significantly longer time to LORR and a shorter time to RORR compared to controls (Median time to LORR: 12.0 versus 5.0 for dexmedetomidine and 22.0 and 8.0 for propofol; p < 0.05). EEG showed a low frequency, high amplitude wave pattern two minutes after LORR in control rats. Autistic rats showed a high frequency, low amplitude awake pattern. Hippocampal GABAA receptor gene expression was significantly less in autistic rats and NMDA gene expression was greater. This study in rat supports the clinical observations of increased anesthetic sedative requirements in autistic children and proposes a mechanism for it.

  2. A PET Tracer for Brain α2C Adrenoceptors, (11)C-ORM-13070: Radiosynthesis and Preclinical Evaluation in Rats and Knockout Mice.

    PubMed

    Arponen, Eveliina; Helin, Semi; Marjamäki, Päivi; Grönroos, Tove; Holm, Patrik; Löyttyniemi, Eliisa; Någren, Kjell; Scheinin, Mika; Haaparanta-Solin, Merja; Sallinen, Jukka; Solin, Olof

    2014-07-01

    We report the development of a PET tracer for α2C adrenoceptor imaging and its preliminary preclinical evaluation. α2C adrenoceptors in the human brain may be involved in various neuropsychiatric disorders, such as depression, schizophrenia, and neurodegenerative diseases. PET tracers are needed for imaging of this receptor system in vivo. High-specific-activity (11)C-ORM-13070 (1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-4-(3-(11)C-methoxymethylpyridin-2-yl)-piperazine) was synthesized by (11)C-methylation of O-desmethyl-ORM-13070 with (11)C-methyl triflate, which was prepared from cyclotron-produced (11)C-methane via (11)C-methyl iodide. Rats and mice were investigated in vivo with PET and ex vivo with autoradiography. The specificity of (11)C-ORM-13070 binding to α2 adrenoceptors was demonstrated in rats pretreated with atipamezole, an α2 adrenoceptor antagonist. The α2C adrenoceptor selectivity of the tracer was determined by comparing tracer binding in wild-type and α2A- and α2AC adrenoceptor knockout (KO) mice. (11)C-ORM-13070 and its radioactive metabolites in rat plasma and brain tissue were analyzed with radio-high-performance liquid chromatography and mass spectroscopy. Human radiation dose estimates were extrapolated from rat biodistribution data. The radiochemical yield, calculated from initial cyclotron-produced (11)C-methane, was 9.6% ± 2.7% (decay-corrected to end of bombardment). The specific activity of the product was 640 ± 390 GBq/μmol (decay-corrected to end of synthesis). The radiochemical purity exceeded 99% in all syntheses. The highest levels of tracer binding were observed in the striatum and olfactory tubercle of rats and control and α2A KO mice-that is, in the brain regions known to contain the highest densities of α2C adrenoceptors. In rats pretreated with atipamezole and in α2AC KO mice, (11)C tracer binding in the striatum and olfactory tubercle was low, similar to that of the frontal cortex and thalamus, regions

  3. Detection of receptor ligands by monitoring selective stabilization of a Renilla luciferase-tagged, constitutively active mutant, G-protein-coupled receptor

    PubMed Central

    Ramsay, Douglas; Bevan, Nicola; Rees, Stephen; Milligan, Graeme

    2001-01-01

    The wild-type β2-adrenoceptor and a constitutively active mutant of this receptor were C-terminally tagged with luciferase from the sea pansy Renilla reniformis. C-terminal addition of Renilla luciferase did not substantially alter the levels of expression of either form of the receptor, the elevated constitutive activity of the mutant β2-adrenoceptor nor the capacity of isoprenaline to elevate cyclic AMP levels in intact cells expressing these constructs. Treatment of cells expressing constitutively active mutant β2-adrenoceptor-Renilla luciferase with antagonist/inverse agonist ligands resulted in upregulation of levels of this polypeptide which could be monitored by the elevated luciferase activity. The pEC50 for ligand-induced luciferase upregulation and ligand affinity to bind the receptor were highly correlated. Similar upregulation could be observed following sustained treatment with agonist ligands. These effects were only observed at a constitutively active mutant of the β2-adrenoceptor. Co-expression of the wild-type β2-adrenoceptor C-terminally tagged with the luciferase from Photinus pyralis did not result in ligand-induced upregulation of the levels of activity of this luciferase. Co-expression of the constitutively active mutant β2-adrenoceptor-Renilla luciferase and an equivalent mutant of the α1b-adrenoceptor C-terminally tagged with green fluorescent protein allowed pharmacological selectivity of adrenoceptor antagonists to be demonstrated. This approach offers a sensitive and convenient means, which is amenable to high throughput analysis, to monitor ligand binding to a constitutively active mutant receptor. As no prior knowledge of receptor ligands is required this approach may be suitable to identify ligands at orphan G protein-coupled receptors. PMID:11350868

  4. Dexmedetomidine Protects PC12 Cells from Lidocaine-Induced Cytotoxicity Through Downregulation of COL3A1 Mediated by miR-let-7b.

    PubMed

    Wang, Qiong; She, Yingjun; Bi, Xiaobao; Zhao, Baisong; Ruan, Xiangcai; Tan, Yonghong

    2017-07-01

    Safety concerns of some local anesthetics, such as lidocaine, have been raised in recent years due to potential neurological impairment. Dexmedetomidine may protect humans from neurotoxicity, and miR-let-7b is activated by nerve injury; however, the roles of miR-let-7b and its target gene in lidocaine-induced cytotoxicity are not well known. Through bioinformatics and a luciferase reporter assay, COL3A1 was suggested as a direct target gene of miR-let-7b. Here, we confirmed by measuring mRNA and protein levels that miR-let-7b was downregulated and COL3A1 was upregulated in lidocaine-treated cells, an observation that was reversed by dexmedetomidine. Similar to miR-let-7b mimics or knockdown of COL3A1, dexmedetomidine treatment reduced the expression of COL3A1, suppressed cell apoptosis and cell migration/invasion ability, and induced cell cycle progression and cell proliferation in PC12 cells, effects that were reversed by the miR-let-7b inhibitor. Meanwhile, proteins involved in cell apoptosis, such as Bcl2 and caspase 3, were impacted as well. Taken together, dexmedetomidine may protect PC12 cells from lidocaine-induced cytotoxicity through miR-let-7b and COL3A1, while also increasing Bcl2 and inhibiting caspase 3. Therefore, miR-let-7b and COL3A1 might play critical roles in neuronal injury, and they are potential therapeutic targets.

  5. Effects of Synephrine and B-Phenethylamine on Human a-Adrenoceptor Subtypes

    USDA-ARS?s Scientific Manuscript database

    Synephrine and B-phenethylamine are structurally related to ephedrine. In this study, the effects of synephrine and B-phenethylamine are investigated on a-adrenoceptor (a-AR) subtypes expressed in human embroyonic kidney (HEK293) or Chinese hamster ovary (CHO) cells, and compared to that of 1R,2S-no...

  6. Modification of certain pharmacological effects of ethanol by lipophilic alpha-1 adrenergic agonists

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Menon, M.K.; Dinovo, E.C.; Haddox, V.G.

    The influence of four centrally-acting alpha-1 adrenoceptor agonists, namely, 2(2-chloro-5-trifluoromethylphenylimino) imidazolidine (St 587), cirazoline, (-) 1,2,3,4-tetrahydro-8-methoxy-5-methylthio-2-naphthalenamine ((-)SKF 89748A) and 2-(2-methylindazol-4-imino)imidazolidine (Sgd 101/75) on the pharmacological effects of ethanol was investigated. All four drugs reduced the duration of ethanol-induced hypnosis in C57B1/6 mice, this effect being proportional to their relative potencies to exert central alpha-1 agonism. In prazosin-pretreated mice, St 587 failed to reduce the hypnotic effect of ethanol, which provided strong evidence for the role of alpha-1 agonism for the hypnosis reducing effect of St 587. Hyperactivity induced in C57B1/6 mice by a subhypnotic dose of ethanol and St 587more » was reported earlier. In the present study, St 587, cirazoline and (-)SKF 89748A produced similar response, but no correlation between this effect and ethanol hypnosis blockade could be established. 19 references, 8 figures, 2 tables.« less

  7. Optimal dose of perineural dexmedetomidine for interscalene brachial plexus block to control postoperative pain in patients undergoing arthroscopic shoulder surgery: A prospective, double-blind, randomized controlled study.

    PubMed

    Jung, Hong Soo; Seo, Kwon Hui; Kang, Jae Hyuk; Jeong, Jin-Young; Kim, Yong-Shin; Han, Na-Re

    2018-04-01

    Adjuvant perineural dexmedetomidine can be used to prolong the analgesic effect of interscalene brachial plexus block (ISB). We investigated the optimal dose of dexmedetomidine in ISB for postoperative analgesia in patients undergoing arthroscopic shoulder surgery. One hundred patients scheduled for elective shoulder arthroscopic surgery were enrolled in this randomized, double-blind study. Ultrasound-guided ISB was performed before general anesthesia using 22 mL of ropivacaine 0.5% combined with 1, 1.5, or 2 μg/kg of dexmedetomidine (group D1, D2, and D3, respectively) or with normal saline as a control (group R, n = 25 per group). The primary outcome was the duration of analgesia (DOA), numeric pain rating scale (NRS), and consumption of additional analgesics during 36 h after ISB. Secondary outcome included durations of motor and sensory block (DOM and DOS), hemodynamic variables and sedation and dyspnea scores. Ninety-seven patients completed the study. The DOS, DOM, and DOA were significantly longer in the dexmedetomidine groups than in group R. The DOA was significantly longer in group D3 than in groups D1 (P = .026) and D2 (P = .039). The DOA was 808.13 ± 179.97, 1032.60 ± 288.14, 1042.04 ± 188.13, and 1223.96 ± 238.06 min in groups R, D1, D2, and D3, respectively. The NRS score was significantly higher in group R than in the dexmedetomidine groups 12 h after ISB (P < .001) and significantly lower in group D3 than in the other groups 18 h after ISB (P = .02). The incidence of hypotension was higher in groups D2 and D3 than in group R during surgery (P = .008 and P = .011, respectively). There were no significant differences in consumption of rescue analgesics, sedation, and dyspnea scores between the study groups. Perineural dexmedetomidine 2 μg/kg could be the optimal dose in ISB for arthroscopic shoulder surgery in that it provides an adequate DOA. However, this dose was associated with

  8. Agonist-induced modulation of inverse agonist efficacy at the beta 2-adrenergic receptor.

    PubMed

    Chidiac, P; Nouet, S; Bouvier, M

    1996-09-01

    Sustained stimulation of several G protein-coupled receptors is known to lead to a reduction in the signaling efficacy. This phenomenon, named agonist-induced desensitization, has been best studied for the beta 2-adrenergic receptor (AR) and is characterized by a decreased efficacy of beta-adrenergic agonists to stimulate the adenylyl cyclase activity. Recently, several beta-adrenergic ligands were found to inhibit the spontaneous agonist-independent activity of the beta 2AR. These compounds, termed inverse agonists, have different inhibitory efficacies, ranging from almost neutral antagonists to full inverse agonists. The current study was undertaken to determine whether, as is the case for agonists, desensitization can affect the efficacies of inverse agonists. Agonist-promoted desensitization of the human beta 2AR expressed in Sf9 cells potentiated the inhibitory actions of the inverse agonists, with the extent of the potentiation being inversely proportional to their intrinsic activity. For example, desensitization increased the inhibitory action of the weak inverse agonist labetalol by 29%, whereas inhibition of the spontaneous activity by the strong inverse agonist timolol was not enhanced by the desensitizing stimuli. Interestingly, dichloroisoproterenol acted stochastically as either a weak partial agonist or a weak inverse agonist in control conditions but always behaved as an inverse agonist after desensitization. These data demonstrate that like for agonists, the efficacies of inverse agonists can be modulated by a desensitizing treatment. Also, the data show that the initial state of the receptor can determine whether a ligand behaves as a partial agonist or an inverse agonist.

  9. Analgesic and sedative effects of intranasal dexmedetomidine in third molar surgery under local anaesthesia.

    PubMed

    Cheung, C W; Ng, K F J; Liu, J; Yuen, M Y V; Ho, M H A; Irwin, M G

    2011-09-01

    Dexmedetomidine (DEX) is an alpha 2-adrenoreceptor agonist, which induces sedation and analgesia. This study aimed to determine whether intranasal DEX offered perioperative sedation and better postoperative analgesia. Patients having unilateral third molar surgery under local anaesthesia were recruited and allocated to receive either intranasal DEX 1 µg kg(-1) (Group D) or same volume of saline (Group P) 45 min before surgery. Patient-controlled sedation with propofol was offered as a rescue sedative. Perioperative sedation, postoperative pain relief and analgesic consumption, vital signs, adverse events, postoperative recovery, and satisfaction in sedation and analgesia were assessed. Thirty patients from each group were studied. Areas under curve (AUC) of postoperative numerical rating scale (NRS) pain scores 1-12 h at rest and during mouth opening were significantly lower in Group D (P=0.003 and 0.009, respectively). AUC BIS values and OAA/S sedation scores were significantly lower before surgery and at the recovery area (all P<0.01) with significantly less intra-operative propofol used in group D (P<0.01). In group D, heart rate was significantly lower at recovery period (P=0.005) while systolic blood pressure in different periods of the study (all P<0.01), but the decreases did not require treatment. More patients from placebo group experienced dizziness (P=0.026) but no serious adverse event was found. No difference was found in postoperative psychomotor recovery and satisfaction in pain relief and sedation. Patients receiving intranasal DEX for unilateral third molar surgery with local anaesthesia were more sedated perioperatively with better postoperative pain relief. No delay in psychomotor recovery was seen.

  10. Hemodynamic responses to dexmedetomidine in critically injured intubated pediatric burned patients: a preliminary study.

    PubMed

    Shank, Erik S; Sheridan, Robert L; Ryan, Colleen M; Keaney, Timothy J; Martyn, J A Jeevendra

    2013-01-01

    Because of ineffectiveness and tolerance to benzodiazepines and opioids developing with time, drugs acting via other receptor systems (eg, α-2 agonists) have been advocated in burn patients to improve sedation and analgesia. This study in severely burned pediatric subjects examined the hemodynamic consequences of dexmedetomidine (Dex) administration. Eight intubated patients with ≥20 to 79% TBSA burns were studied between 7 and 35 days after injury. After baseline measurements of mean arterial blood pressure and heart rhythm were taken, each patient received a 1.0 µg/kg bolus of Dex followed by an ascending dose infusion protocol (0.7-2.5 µg/kg/hr), with each dose administered for 15 minutes. There was significant hypotension (27±7.5%, average drop in mean arterial pressure [MAP] ± SD), and a decrease in heart rate (HR; 19% ± 7, average drop in HR ± SD). The average HR decreased from 146 beats per minute to 120. No bradycardia (HR < 60) or heart blocks were observed. In three patients, the MAP decreased to <50mm Hg with the bolus dose of Dex. Of the remaining five patients, three patients completed the study receiving the highest infusion dose of Dex (2.5 µg/kg/hr), whereas in 2 patients the infusion part of the study was begun, but the study was stopped due to persistent hypotension (MAP < 50mm Hg). These observations indicate that a bolus dose of Dex (1.0 µg/kg for 10 minutes) and high infusion rates may require fluid resuscitation or vasopressor support to maintain normotension in critically injured pediatric burn patients.

  11. [Effect of dexmedetomidine on perfusion of free flaps transferred to head and neck].

    PubMed

    Dobrodeev, A S; Rabinovich, S A; Malykhina, I F

    The paper presents the impact of perioperative care on feasibility of free fibula flap transfer for facial reconstruction. Flaps vitality was measured by means of somatic oximetry in 85 patients aged 20-74 years receiving reconstruction procedures in midfacial and lower facial areas. The patients were divided in three groups according to sedation agent used postoperatively. It has been demonstrated that dexmedetomidine postoperative sedation significantly improved free fibula flaps perfusion compared to propofol sedation.

  12. Efficacy and safety of dexmedetomidine infusion for patients undergoing awake craniotomy: An observational study

    PubMed Central

    Mahajan, Charu; Rath, Girija Prasad; Singh, Gyaninder Pal; Mishra, Nitasha; Sokhal, Suman; Bithal, Parmod Kumar

    2018-01-01

    Background: The goal of awake craniotomy is to maintain adequate sedation, analgesia, respiratory, and hemodynamic stability and also to provide a cooperative patient for neurologic testing. An observational study carried out to evaluate the efficacy of dexmedetomidine sedation for awake craniotomy. Materials and Methods: Adult patients with age >18 year who underwent awake craniotomy for intracranial tumor surgery were enrolled. Those who were uncooperative and had difficult airway were excluded from the study. In the operating room, the patients received a bolus dose of dexmedetomidine 1 μg/kg followed by an infusion of 0.2–0.7 μg/kg/h (bispectral index target 60–80). Once the patients were sedated, scalp block was given with bupivacaine 0.25%. The data on hemodynamics at various stages of the procedure, intraoperative complications, total amount of fentanyl used, intravenous fluids required, blood loss and transfusion, duration of surgery, Intensive Care Unit (ICU), and hospital stay were collected. The patients were assessed for Glasgow outcome scale (GOS) score and patient satisfaction score (PSS). Results: A total of 27 patients underwent awake craniotomy during a period of 2 years. Most common intraoperative complication was seizures; observed in five patients (18.5%). None of these patients experienced any episode of desaturation. Two patients had tight brain for which propofol boluses were administered. The average fentanyl consumption was 161.5 ± 85.0 μg. The duration of surgery, ICU, and hospital stays were 231.5 ± 90.5 min, 14.5 ± 3.5 h, and 4.7 ± 1.5 days, respectively. The overall PSS was 8 and GOS was good in all the patients. Conclusion: The use of dexmedetomidine infusion with regional scalp block in patients undergoing awake craniotomy is safe and efficacious. The absence of major complications and higher PSS makes it close to an ideal agent for craniotomy in awake state. PMID:29628833

  13. Metabolic benefits of 1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one: a non-selective α-adrenoceptor antagonist.

    PubMed

    Kotańska, Magdalena; Kulig, Katarzyna; Marcinkowska, Monika; Bednarski, Marek; Malawska, Katarzyna; Zaręba, Paula

    2018-05-01

    Previous studies have shown that several components of the metabolic syndrome, such as hypertension, obesity or imbalanced lipid and carbohydrate homeostasis, are associated with the sympathetic nervous system overactivity. Therefore, the inhibition of the adrenergic nervous system seems to be a reasonable and appropriate therapeutic approach for the treatment of metabolic disturbances. It has been suggested that non-selective adrenoceptor antagonists could be particularly beneficial, since α 1 -adrenoceptor antagonists can improve disrupted lipid and carbohydrate profiles, while the inhibition of the α 2 -adrenoceptor may contribute to body weight reduction. The aim of the present study was to investigate the metabolic benefits deriving from administration of a non-selective α-adrenoceptor antagonist from the group of pyrrolidin-2-one derivatives. The aim of the present study was to investigate the potential metabolic benefits deriving from chronic administration of a non-selective α-adrenoceptor antagonist, from the group of pyrrolidin-2-one derivatives. The α 1 - and α 2 -adrenoreceptor affinities of the tested compound-1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one had been investigated previously by means of the radioligand binding assay. In the present study, we extended the pharmacological profile characteristics of the selected molecule by additional intrinistic activity assays. Next, we investigated the influence of the tested compound on body weight, hyperglycemia, hypertriglyceridemia, blood pressure in the animal model of obesity induced by a high-fat diet, and additionally we measured the spontaneous activity and body temperature. The intrinistic activity studies revealed that the tested compound is a potent, non-selective antagonist of α 1B and α 2A -adrenoceptors. After the chronic administration of the tested compound, we observed reduced level of triglycerides and glucose in the rat plasma. Interestingly, the tested did not reduce

  14. Trek2a regulates gnrh3 expression under control of melatonin receptor Mt1 and α2-adrenoceptor.

    PubMed

    Loganathan, Kavinash; Moriya, Shogo; Parhar, Ishwar S

    2018-02-12

    Gonadotrophin-releasing hormone (GnRH) expression is associated with the two-pore domain potassium ion (K + ) channel-related K + (TREK) channel trek2a expression and melatonin levels. We aimed to investigate correlation of trek2a expression with gnrh3 expression, and regulatory mechanisms of trek2a expression by the melatonin receptor Mt1 and α 2 -adrenoceptor which are regulated by melatonin. trek2a specific siRNA, Mt1 antagonist luzindole and α 2 -adrenoceptor antagonist prazosin were administered into the adult zebrafish brain and gene expressions were examined by real-time PCR. trek2a specific siRNA administration significantly reduced expression levels of trek2a, gnrh3 and mt1. Luzindole administration suppressed trek2a and gnrh3 expressions. Prazosin administration reduced trek2a and gnrh3 expressions. It is suggested that Trek2a regulates gnrh3 expression under the control of Mt1 and α 2 -adrenoceptor. Copyright © 2018 Elsevier Inc. All rights reserved.

  15. Functional β-Adrenoceptors Are Important for Early Muscle Regeneration in Mice through Effects on Myoblast Proliferation and Differentiation

    PubMed Central

    Church, Jarrod E.; Trieu, Jennifer; Sheorey, Radhika; Chee, Annabel Y. -M.; Naim, Timur; Baum, Dale M.; Ryall, James G.; Gregorevic, Paul; Lynch, Gordon S.

    2014-01-01

    Muscles can be injured in different ways and the trauma and subsequent loss of function and physical capacity can impact significantly on the lives of patients through physical impairments and compromised quality of life. The relative success of muscle repair after injury will largely determine the extent of functional recovery. Unfortunately, regenerative processes are often slow and incomplete, and so developing novel strategies to enhance muscle regeneration is important. While the capacity to enhance muscle repair by stimulating β2-adrenoceptors (β-ARs) using β2-AR agonists (β2-agonists) has been demonstrated previously, the exact role β-ARs play in regulating the regenerative process remains unclear. To investigate β-AR-mediated signaling in muscle regeneration after myotoxic damage, we examined the regenerative capacity of tibialis anterior and extensor digitorum longus muscles from mice lacking either β1-AR (β1-KO) and/or β2-ARs (β2-KO), testing the hypothesis that muscles from mice lacking the β2-AR would exhibit impaired functional regeneration after damage compared with muscles from β1-KO or β1/β2-AR null (β1/β2-KO) KO mice. At 7 days post-injury, regenerating muscles from β1/β2-KO mice produced less force than those of controls but muscles from β1-KO or β2-KO mice did not exhibit any delay in functional restoration. Compared with controls, β1/β2-KO mice exhibited an enhanced inflammatory response to injury, which delayed early muscle regeneration, but an enhanced myoblast proliferation later during regeneration ensured a similar functional recovery (to controls) by 14 days post-injury. This apparent redundancy in the β-AR signaling pathway was unexpected and may have important implications for manipulating β-AR signaling to improve the rate, extent and efficacy of muscle regeneration to enhance functional recovery after injury. PMID:25000590

  16. Receptor-mediated activation of nitric oxide synthesis by arginine in endothelial cells

    PubMed Central

    Joshi, Mahesh S.; Ferguson, T. Bruce; Johnson, Fruzsina K.; Johnson, Robert A.; Parthasarathy, Sampath; Lancaster, Jack R.

    2007-01-01

    Arginine contains the guanidinium group and thus has structural similarity to ligands of imidazoline and α-2 adrenoceptors (α-2 AR). Therefore, we investigated the possibility that exogenous arginine may act as a ligand for these receptors in human umbilical vein endothelial cells and activate intracellular nitric oxide (NO) synthesis. Idazoxan, a mixed antagonist of imidazoline and α-2 adrenoceptors, partly inhibited l-arginine-initiated NO formation as measured by a Griess reaction. Rauwolscine, a highly specific antagonist of α-2 AR, at very low concentrations completely inhibited NO formation. Like l-arginine, agmatine (decarboxylated arginine) also activated NO synthesis, however, at much lower concentrations. We found that dexmedetomidine, a specific agonist of α-2 AR was very potent in activating cellular NO, thus indicating a possible role for α-2 AR in l-arginine-mediated NO synthesis. d-arginine also activated NO production and could be inhibited by imidazoline and α-2 AR antagonists, thus indicating nonsubstrate actions of arginine. Pertussis toxin, an inhibitor of G proteins, attenuated l-arginine-mediated NO synthesis, thus indicating mediation via G proteins. l-type Ca2+ channel blocker nifedipine and phospholipase C inhibitor U73122 inhibited NO formation and thus implicated participation of a second messenger pathway. Finally, in isolated rat gracilis vessels, rauwolscine completely inhibited the l-arginine-initiated vessel relaxation. Taken together, these data provide evidence for binding of arginine to membrane receptor(s), leading to the activation of endothelial NO synthase (eNOS) NO production through a second messenger pathway. These findings provide a previously unrecognized mechanistic explanation for the beneficial effects of l-arginine in the cardiovascular system and thus provide new potential avenues for therapeutic development. PMID:17535904

  17. Effect of beta-antagonists on isoprenaline-induced secretion of fluid, amylase and protein by the parotid gland of the red kangaroo, Macropus rufus.

    PubMed

    Beal, A M

    2000-02-01

    Selective and non-selective beta-adrenoceptor antagonists were used to block the increases in fluid, protein and amylase secretion caused by sympathomimetic stimulation of the parotid gland of red kangaroos during intracarotid infusion of isoprenaline. ICI118551 at antagonist/agonist ratios up to 300:1 caused increasing but incomplete blockade of fluid secretion, and protein/amylase release. Atenolol at antagonist/agonist ratios up to 300:1 was only marginally more potent than ICI118551 at blocking the fluid, protein and amylase responses. Propranolol at antagonist/agonist ratios of 30:1 was as effective at blocking fluid and protein secretion as the highest ratios of either atenolol or ICI118551. Simultaneous administration of atenolol (30:1) with ICI118551 (30:1) was not as potent as propranolol (30:1). Thus, the beta-adrenoceptor/s in the acini of the kangaroo parotid gland appear to have antagonist-binding affinities atypical of those found for eutherian tissues. The data are consistent with the gland possessing either a single anomalous beta-adrenoceptor or functional beta(2)-receptors in addition to the beta(1)-receptors which are characteristic of eutherian salivary glands.

  18. Comparison of the combination of dexmedetomidine and ketamine to propofol or propofol/sevoflurane for drug-induced sleep endoscopy in children.

    PubMed

    Kandil, Ali; Subramanyam, Rajeev; Hossain, Mohamed Monir; Ishman, Stacey; Shott, Sally; Tewari, Anurag; Mahmoud, Mohamed

    2016-07-01

    Examination of dynamic airway collapse in patients with obstructive sleep apnea (OSA) during drug-induced sleep endoscopy (DISE) can help identify the anatomic causes of airway obstruction. We hypothesized that a combination of dexmedetomidine and ketamine (Group DK) would result in fewer oxygen desaturations and a higher successful completion rate during DISE in children with OSA when compared to propofol (Group P) or sevoflurane/propofol (Group SP). In this retrospective study, we reviewed the records of 59 children who presented for DISE between October 2013 and March 2015. Data analyzed included demographics, OSA severity, and hemodynamics (heart rate and blood pressure). The primary outcomes were airway desaturation during DISE to <85% and successful completion of DISE; these were compared between the three groups: DK, P, and SP. Preoperative polysomnography was available for 49 patients. There were significantly more patients with severe OSA in Group P as compared to the other two groups. The mean (±sd) bolus dose for ketamine, dexmedetomidine, and propofol were 2.0 ± 0.6 mg·kg(-1) , 1.9 ± 0.9 mcg·kg(-1) , and 1.8 ± 1.1 mg·kg(-1) , respectively. The mean (±sd) infusion rate for dexmedetomidine was 1.6 ± 0.7 mcg·kg(-1) ·h(-1) and for propofol was 248 ± 68 mcg·kg(-1) ·min(-1) in Group P and 192 ± 48 mcg·kg(-1) ·min(-1) in Group SP. Patients in Group DK had significantly fewer desaturations to <85% during DISE compared to Group P. Patients in Group DK had significantly more successful completion of DISE (100% Group DK, 92% Group P, and 79% Group SP) as compared to Group SP. These results suggest that the described dose regimen of propofol used alone or in combination with sevoflurane appears to be associated with more oxygen desaturations and a lower rate of successful completion than a combination of dexmedetomidine and ketamine during DISE in children with OSA. © 2016 John Wiley & Sons Ltd.

  19. Dexmedetomidine decreases the required amount of bupivacaine for ultrasound-guided transversus abdominis plane block in pediatrics patients: a randomized study.

    PubMed

    Raof, Rehab Abdel; El Metainy, Shahira Ahmed; Alia, Doaa Abou; Wahab, Moataza Abdel

    2017-02-01

    The effect of dexmedetomidine on the potency of bupivacaine for transversus abdominis plane (TAP) block in pediatric patients has not been investigated. The primary objective of this study was to assess the effectiveness of dexmedetomidine to decrease the concentration of bupivacaine needed for analgesia for ultrasound-guided TAP block in a pediatric patient undergoing hernia repair or hydrocelectomy. This is a randomized, double-blind, up-down, dose-finding study. Operating room. Sixty American Society of Anesthesiologists I and II patients aged 1-4 years scheduled for elective unilateral herniorrhaphy or hydrocelectomy. Patients were randomly assigned to 1 of the 2 groups: group B (0.125% bupivacaine, 1mL/kg) TAP block or group BD (0.125% bupivacaine plus 2μg/kg dexmedetomidine, 1mL/kg) TAP block. The response of each child was observed for 60 seconds after skin incision and evaluated as 'unsuccessful' when skin incision caused a change in hemodynamic parameters (heart rate and mean blood pressure) 20% more than the preincision values. If the response was determined to be unsuccessful, the concentration of bupivacaine administrated to the next patient was increased by 0.02%. If it was successful, the concentration of bupivacaine administrated to the next patient was decreased by 0.02%. The minimum local anesthetic concentration of bupivacaine was 0.0839% (0.0137) in the B group and 0.0550% (0.0169) in the BD group. The difference was statistically significant (t=7.165, P=.0001). The total postoperative analgesic dosage of morphine was significantly higher in the B group (0.17±0.04 mg/kg) than the BD group (0.11±0.02 mg/kg, P=.001). The addition of 2μg/kg of dexmedetomidine reduced the minimum local anesthetic concentration of bupivacaine used for a TAP block and improved postoperative analgesia in children undergoing surgery for inguinal hernia repair or hydrocelectomy. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Sedative and antinociceptive effects of dexmedetomidine and buprenorphine after oral transmucosal or intramuscular administration in cats.

    PubMed

    Porters, Nathalie; Bosmans, Tim; Debille, Mariëlla; de Rooster, Hilde; Duchateau, Luc; Polis, Ingeborgh

    2014-01-01

    To compare sedation and antinociception after oral transmucosal (OTM) and intramuscular (IM) administration of a dexmedetomidine-buprenorphine combination in healthy adult cats. Randomized, 'blinded' crossover study, with 1 month washout between treatments. Six healthy neutered female cats, weighing 5.3-7.5 kg. A combination of dexmedetomidine (40 μg kg(-1) ) and buprenorphine (20 μg kg(-1) ) was administered by either the OTM (buccal cavity) or IM (quadriceps muscle) route. Sedation was measured using a numerical rating scale, at baseline and at various time points until 6 hours after treatment. At the same time points, analgesia was scored using a dynamic and interactive visual analogue scale, based on the response to an ear pinch, and by the cat's response to a mechanical stimulus exerted by a pressure rate onset device. Physiological and adverse effects were recorded, and oral pH measured. Signed rank tests were performed, with significance set at p < 0.05. Data are presented as median and range. There were no differences in sedation or antinociception scores between OTM and IM dosing at any of the time points. Nociceptive thresholds increased after both treatments but without significant difference between groups. Buccal pH remained between 8 and 8.5. Salivation was noted after OTM administration (n = 2) and vomiting after both OTM (n = 4), and IM (n = 3) dosing. In healthy adult cats, OTM administration of dexmedetomidine and buprenorphine resulted in comparable levels of sedation and antinociception to IM dosing. The OTM administration may offer an alternative route to administer this sedative-analgesic combination in cats. © 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  1. β2-adrenoceptor blockage induces G1/S phase arrest and apoptosis in pancreatic cancer cells via Ras/Akt/NFκB pathway.

    PubMed

    Zhang, Dong; Ma, Qingyong; Wang, Zheng; Zhang, Min; Guo, Kun; Wang, Fengfei; Wu, Erxi

    2011-11-26

    Smoking and stress, pancreatic cancer (PanCa) risk factors, stimulate nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and catecholamines production respectively. NNK and catecholamine bind the β-adrenoceptors and induce PanCa cell proliferation; and we have previously suggested that β-adrenergic antagonists may suppress proliferation and invasion and stimulate apoptosis in PanCa. To clarify the mechanism of apoptosis induced by β2-adrenergic antagonist, we hypothesize that blockage of the β2-adrenoceptor could induce G1/S phase arrest and apoptosis and Ras may be a key player in PanCa cells. The β1 and β2-adrenoceptor proteins were detected on the cell surface of PanCa cells from pancreatic carcinoma specimen samples by immunohistochemistry. The β2-adrenergic antagonist ICI118,551 significantly induced G1/S phase arrest and apoptosis compared with the β1-adrenergic antagonist metoprolol, which was determined by the flow cytometry assay. β2-adrenergic antagonist therapy significantly suppressed the expression of extracellular signal-regulated kinase, Akt, Bcl-2, cyclin D1, and cyclin E and induced the activation of caspase-3, caspase-9 and Bax by Western blotting. Additionally, the β2-adrenergic antagonist reduced the activation of NFκB in vitro cultured PanCa cells. The blockage of β2-adrenoceptor markedly induced PanCa cells to arrest at G1/S phase and consequently resulted in cell death, which is possibly due to that the blockage of β2-adrenoceptor inhibited NFκB, extracellular signal-regulated kinase, and Akt pathways. Therefore, their upstream molecule Ras may be a key factor in the β2-adrenoceptor antagonist induced G1/S phase arrest and apoptosis in PanCa cells. The new pathway discovered in this study may provide an effective therapeutic strategy for PanCa.

  2. ß-Adrenoceptor Activation Enhances L-Type Calcium Channel Currents in Anterior Piriform Cortex Pyramidal Cells of Neonatal Mice: Implication for Odor Learning

    ERIC Educational Resources Information Center

    Ghosh, Abhinaba; Mukherjee, Bandhan; Chen, Xihua; Yuan, Qi

    2017-01-01

    Early odor preference learning occurs in one-week-old rodents when a novel odor is paired with a tactile stimulation mimicking maternal care. ß-Adrenoceptors and L-type calcium channels (LTCCs) in the anterior piriform cortex (aPC) are critically involved in this learning. However, whether ß-adrenoceptors interact directly with LTCCs in aPC…

  3. Comparative Effects of Dexmedetomidine and Propofol on US-Guided Radiofrequency Ablation of Hepatic Neoplasm Under Monitored Anesthesia Care

    PubMed Central

    Joung, Kyoung-Woon; Choi, Seong-Soo; Jang, Dong-Min; Kong, Yu-Gyeong; Lee, Hwa-Mi; Shim, Ji-Hoon; Won, Hyung-Jin; Shin, Yong-Moon; Kim, Pyo-Nyun; Song, Myung-Hee

    2015-01-01

    Abstract Percutaneous radiofrequency ablation (RFA) is a useful and safe procedure for treating hepatic neoplasm. However, liver RFA causes severe pain, which thereby increases the demand for monitored anesthesia care (MAC). Here, we compared the efficacy and safety of propofol and dexmedetomidine, which are commonly administered during MAC when performing RFA to assess hepatic neoplasm. In this randomized controlled trial, 40 patients were randomly allocated to 2 groups for elective RFA. Patients received either dexmedetomidine (group D) or propofol (group P). Both groups received the continuous infusion of remifentanil for pain control. The primary outcomes were opioid consumption and differences in partial pressure of arterial carbon dioxide (PaCO2) between pre- and postprocedure RFA. In addition, hemodynamic parameters, patient satisfaction, and interventional radiologist satisfaction were determined. There were significant differences in opioid consumption (50.1 ± 16.8 ng/kg/min [group D] vs 71.2 ± 18.7 ng/kg/min [group P]; P = 0.001) and delta PaCO2 (10.4 ± 6.4 mm Hg vs 17.2 ± 9.2 mm Hg, respectively; P = 0.016). Moreover, respiratory rates were significantly different between groups during RFA (P < 0.001). However, blood pressure and heart rate did not significantly change during RFA. Neither patient nor interventional radiologist satisfaction was significantly different between groups. Dexmedetomidine provides better respiratory stability and reduces opioid consumption in comparison with propofol when administered under MAC when performing RFA for hepatic neoplasm. PMID:26266387

  4. Dexmedetomidine to control signs associated with lisdexamfetamine dimesylate toxidrome in a cat.

    PubMed

    Norkus, Christopher L; Keir, Iain; Means, Charlotte

    2017-03-01

    A 5-month-old intact female domestic shorthaired cat had mydriasis, agitation, and increased locomotion after ingestion of lisdexamfetamine, 10.3 mg/kg body weight (BW). Despite treatment with IV fluids, IV acepromazine, oral cyproheptadine and intravenous lipid emulsion the patient's clinical signs worsened. Dexmedetomidine administered at 2 μg/kg BW and continued at 0.5 μg/kg BW per hour rapidly controlled the patient's signs. An episode of vomiting and hematuria developed. Follow-up 5 days after discharge revealed that the cat appeared normal.

  5. Preferential reduction of binding of sup 125 I-iodopindolol to beta-1 adrenoceptors in the amygdala of rat after antidepressant treatments

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Ordway, G.A.; Gambarana, C.; Tejani-Butt, S.M.

    1991-05-01

    This study utilized quantitative receptor autoradiography to examine the effects of repeated administration of antidepressants to rats on the binding of the beta adrenoceptor antagonist, {sup 125}I-iodopindolol ({sup 125}I-IPIN) to either beta-1 or beta-2 adrenoceptors in various regions of brain. Antidepressants were selected to represent various chemical and pharmacological classes including tricyclic compounds (desipramine and protriptyline), monoamine oxidase inhibitors (clorgyline, phenelzine and tranylcypromine), atypical antidepressants (mianserin and trazodone) and selective inhibitors of the uptake of serotonin (citalopram and sertraline). Additionally, rats were treated with various psychotropic drugs that lack antidepressant efficacy (cocaine, deprenyl, diazepam and haloperidol). Repeated treatment of ratsmore » with desipramine, protriptyline, clorgyline, phenelzine, tranylcypromine or mianserin reduced the binding of {sup 125}I-IPIN to beta-1 adrenoceptors in many brain areas. Only in the basolateral and lateral nuclei of the amygdala did all six of these antidepressants significantly reduce {sup 125}I-IPIN binding to beta-1 adrenoceptors. In these amygdaloid nuclei, the magnitude of the reduction in the binding of {sup 125}I-IPIN caused by each of these drugs was comparable to or greater than the reduction in binding produced in any other region of brain. Reductions of binding of {sup 125}I-IPIN after antidepressant treatments were not consistently observed in the cortex, the area of brain examined most often in homogenate binding studies. Only the monoamine oxidase inhibitors caused reductions in the binding of {sup 125}I-IPIN to beta-2 adrenoceptors, and this effect was generally localized to the amygdala and hypothalamus.« less

  6. Presynaptic imidazoline receptors and non-adrenoceptor[3H]-idazoxan binding sites in human cardiovascular tissues

    PubMed Central

    Molderings, G J; Likungu, J; Jakschik, J; Göthert, M

    1997-01-01

    In segments of human right atrial appendages and pulmonary arteries preincubated with [3H]-noradrenaline and superfused with physiological salt solution containing desipramine and corticosterone, the involvement of imidazoline receptors in the modulation of [3H]-noradrenaline release was investigated. In human atrial appendages, the guanidines aganodine and DTG (1,3-di(2-tolyl)guanidine) which activate presynaptic imidazoline receptors, inhibited electrically-evoked [3H]-noradrenaline release. The inhibition was not affected by blockade of α2-adrenoceptors with 1 μM rauwolscine, but antagonized by extremely high concentrations of this drug (10 and/or 30 μM; apparent pA2 against aganodine and DTG: 5.55 and 5.21, respectively). In the presence of 1 μM rauwolscine, [3H]-noradrenaline release in human atrial appendages was also inhibited by the imidazolines idazoxan and cirazoline, but not by agmatine and noradrenaline. The inhibitory effects of 100 μM idazoxan and 30 μM cirazoline were abolished by 30 μM rauwolscine. In the atrial appendages, the rank order of potency of all guanidines and imidazolines for their inhibitory effect on electrically-evoked [3H]-noradrenaline release in the presence of 1 μM rauwolscine was: aganodine⩾BDF 6143 [4-chloro-2-(2-imidazolin-2-yl-amino)-isoindoline]>DTG⩾clonidine>cirazoline>idazoxan (BDF 6143 and clonidine were previously studied under identical conditions). This potency order corresponded to that previously determined at the presynaptic imidazoline receptors in the rabbit aorta. When, in the experiments in the human pulmonary artery, rauwolscine was absent from the superfusion fluid, the concentration-response curve for BDF 6143 (a mixed α2-adrenoceptor antagonist/imidazoline receptor agonist) for its facilitatory effect on electrically-evoked [3H]-noradrenaline release was bell-shaped. In the presence of 1 μM rauwolscine, BDF 6143 and cirazoline concentration-dependently inhibited the

  7. Relative myotoxic and haemodynamic effects of the β-agonists fenoterol and clenbuterol measured in conscious unrestrained rats

    PubMed Central

    Burniston, Jatin G; Tan, Lip-Bun; Goldspink, David F

    2007-01-01

    The β2-adrenoceptor (β2-AR) agonists clenbuterol and fenoterol have similar beneficial effects in animal models of heart failure. However, large doses of clenbuterol can induce cardiomyocyte death and it is not known which of these agents has the most favourable therapeutic profile. We have investigated the cardiotoxicity of clenbuterol and fenoterol alongside that of isoproterenol, and compared their haemodynamic effects. Wistar rats (n=6, per group) were subcutaneously injected with each β-agonist (0.003 mmol kg−1 to 3 mmol kg−1) or saline and cardiomyocyte apoptosis was detected by caspase 3 immunohistochemistry. In a separate experiment rats (n=4) were given equivalent doses to those used in the myotoxicity studies, in a randomised crossover design, and their blood pressure recorded via radio telemetry. Injection of 0.3 mmol kg−1 fenoterol or isoproterenol, but not clenbuterol, induced significant cardiomyocyte apoptosis (0.4±0.05%; P<0.05). At 3 mmol kg−1, all agonists induced apoptosis (fenoterol 1.1±0.1%; isoproterenol 0.9±0.8%; clenbuterol 0.4±0.07%; P<0.05). β1-AR antagonism (10 mg kg−1 bisoprolol) prevented (92%; P<0.05) apoptosis induced by all 3 agonists, but clenbuterol-induced apoptosis could also be prevented (96%; P<0.05) by β2-AR antagonism (10 mg kg−1 ICI118551). Clenbuterol decreased diastolic (1.3-1.6 fold; P<0.05) and systolic (1.3 fold; P<0.05) blood pressure and doses >0.3 mmol kg−1 increased heart rate (1.4 fold; P<0.05). Fenoterol increased heart rate (1.2-1.4 fold; P<0.05) and doses >0.3 mmol kg−1 decreased diastolic blood pressure (1.3 fold; P<0.05). In conclusion, the cardiotoxicity of fenoterol was similar to isoproterenol and greater than clenbuterol, and fenoterol had less desirable haemodynamic effects. PMID:16973691

  8. The new generation dihydropyridine type calcium blockers, bearing 4-phenyl oxypropanolamine, display alpha-/beta-adrenoceptor antagonist and long-acting antihypertensive activities.

    PubMed

    Liang, Jhy-Chong; Yeh, Jwu-Lai; Wang, Chia-Sui; Liou, Shwu-Fen; Tsai, Chieh-Ho; Chen, Ing-Jun

    2002-03-01

    A new series of dihydropyridine derivatives, bearing oxypropanolamine moiety on phenyl ring at the 4-position of the dihydropyridine base, were prepared. Oxypropanolamine was synthesized by replacing the phenolic OH of vanillin or other compounds, having a phenyl aldehyde group, with epichlorohydrin, followed by cleavaging the obtained epoxide compounds with tert-butylamine, n-butylamine or 2-methoxy-1-oxyethylamino benzene (guaiacoxyethylamine), respectively. Obtained various oxypropanolamine compounds, still remaining a phenyl aldehyde moiety, were then performed by Hantzsch condensation reaction with methylacetoacetate or ethylacetoacetate, respectively, to give our new series of dihydropyridine linked with the 4-phenyl ring. These compounds were evaluated for inotropic, chronotropic, and aorta contractility that associated with calcium channel and adrenoceptor antagonist activities. Dihydropyridine derivatives that with oxypropanolamine side chain on their 4-phenyl ring associated alpha-/beta-adrenoceptor blocking activities created a new family of calcium entry and the third generation beta-adrenoceptor blockers. Optimizing this research to obtain more potent alpha-/beta-adrenoceptor blocking and long-acting antihypertensive oxypropanolamine on the 4-phenyl ring of dihydropyridine series compounds was thus accomplished and classified as third generation dihydropyridine type calcium channel blockers, in comparison with previous short-acting type nifedipine and long-acting type amlodipine. We concluded that compounds 1a, 1b and 1g showed not only markedly high calcium-antagonistic activity but also the highest antihypertensive effect; compounds 1b, 1c, 1f, 1g, 1i and 1j induced sustained antihypertensive effects are major and attributed to their calcium entry and alpha-adrenoceptor blocking activities in the blood vessel due to their introduction of 2-methoxy, 1-oxyethylamino benzene moiety in the side chain on the 4-phenyl ring of dihydropyridine. Bradycardiac

  9. Dexmedetomidine prolongs the effect of bupivacaine in supraclavicular brachial plexus block

    PubMed Central

    Agarwal, Sandhya; Aggarwal, Ritu; Gupta, Praveen

    2014-01-01

    Background: We compared the effects of adding dexmedetomidine to a 30 ml solution of 0.325% bupivacaine in supraclavicular brachial plexus block. Onset and duration of sensory and motor block along with the duration of analgesia were the primary endpoints. Materials and Methods: Fifty patients posted for upper limb surgeries were enrolled for a prospective, randomized, double-blind, placebo-controlled trial. Patients were divided into two groups, the control group S and the study group SD. In group S (n = 25), 30 ml of 0.325% bupivacaine + 1 ml normal saline; and in group SD (n = 25), 30 ml of 0.325% bupivacaine + 1 ml (100 μg) dexmedetomidine were given for supraclavicular brachial plexus block using the peripheral nerve stimulator. Onset and duration of sensory and motor blocks were assessed along with the duration of analgesia, sedation, and adverse effects, if any. Hemodynamic parameters, like heart rate (HR), systolic arterial blood pressure (SBP), and diastolic arterial blood pressure (DBP) were also monitored. Results: Demographic data and surgical characteristics were comparable in both the groups. The onset times for sensory and motor blocks were significantly shorter in SD than S group (P < 0.001), while the duration of blocks was significantly longer (P < 0.001) in SD group. Except for the initial recordings (at 0, 5, 10, and 15 min), heart rate levels in group SD were significantly lower (P < 0.001). SBP and DBP levels in SD group at 15, 30, 45, 60, 90 and 120 min were significantly lower than in S group (P < 0.001). In fact, when the percentage changes in HR/SBP/DBP were compared from 0-5/0-10/0-15/0-30/0-45/0-60/0-90/0-120 min in SD with S group, they came out to be highly significant (P < 0.001) in group SD. The duration of analgesia (DOA) was significantly longer in SD group than S group (P < 0.001). Except that, bradycardia was observed in one patient in the group SD, no other adverse effects were observed in either of the groups. Conclusion

  10. Beta-Adrenoceptor Activation Reduces Both Dermal Microvascular Endothelial Cell Migration via a cAMP-Dependent Mechanism and Wound Angiogenesis.

    PubMed

    O'Leary, Andrew P; Fox, James M; Pullar, Christine E

    2015-02-01

    Angiogenesis is an essential process during tissue regeneration; however, the amount of angiogenesis directly correlates with the level of wound scarring. Angiogenesis is lower in scar-free foetal wounds while angiogenesis is raised and abnormal in pathophysiological scarring such as hypertrophic scars and keloids. Delineating the mechanisms that modulate angiogenesis and could reduce scarring would be clinically useful. Beta-adrenoceptors (β-AR) are G protein-coupled receptors (GPCRs) expressed on all skin cell-types. They play a role in wound repair but their specific role in angiogenesis is unknown. In this study, a range of in vitro assays (single cell migration, scratch wound healing, ELISAs for angiogenic growth factors and tubule formation) were performed with human dermal microvascular endothelial cells (HDMEC) to investigate and dissect mechanisms underpinning β-AR-mediated modulation of angiogenesis in chick chorioallantoic membranes (CAM) and murine excisional skin wounds. β-AR activation reduced HDMEC migration via cyclic adenosine monophosphate (cAMP)-dependent and protein kinase A (PKA)-independent mechanisms as demonstrated through use of an EPAC agonist that auto-inhibited the cAMP-mediated β-AR transduced reduction in HDMEC motility; a PKA inhibitor was, conversely, ineffective. ELISA studies demonstrated that β-AR activation reduced pro-angiogenic growth factor secretion from HDMECs (fibroblast growth factor 2) and keratinocytes (vascular endothelial growth factor A) revealing possible β-AR-mediated autocrine and paracrine anti-angiogenic mechanisms. In more complex environments, β-AR activation delayed HDMEC tubule formation and decreased angiogenesis both in the CAM assay and in murine excisional skin wounds in vivo. β-AR activation reduced HDMEC function in vitro and angiogenesis in vivo; therefore, β-AR agonists could be promising anti-angiogenic modulators in skin. © 2014 The Authors. Journal of Cellular Physiology Published by

  11. Difference between beta1-adrenoceptor autoantibodies of human and animal origin-Limitations detecting beta1-adrenoceptor autoantibodies using peptide based ELISA technology.

    PubMed

    Wenzel, Katrin; Schulze-Rothe, Sarah; Müller, Johannes; Wallukat, Gerd; Haberland, Annekathrin

    2018-01-01

    Cell-based analytics for the detection of the beta1-adrenoceptor autoantibody (beta1-AAB) are functional, yet difficult to handle, and should be replaced by easily applicable, routine lab methods. Endeavors to develop solid-phase-based assays such as ELISA to exploit epitope moieties for trapping autoantibodies are ongoing. These solid-phase-based assays, however, are often unreliable when used with human patient material, in contrast to animal derived autoantibodies. We therefore tested an immunogen peptide-based ELISA for the detection of beta1-AAB, and compared commercially available goat antibodies against the 2nd extracellular loop of human beta1-adrenoceptor (ADRB1-AB) to autoantibodies enriched from patient material. The functionality of these autoantibodies was tested in a cell based assay for comparison and their structural appearance was investigated using 2D gel electrophoresis. The ELISA showed a limit of detection for ADRB1-AB of about 1.5 nmol antibody/L when spiked in human control serum and only about 25 nmol/L when spiked in species identical (goat) matrix material. When applied to samples of human origin, the ELISA failed to identify the specific beta1-AABs. A low concentration of beta1-AAB, together with structural inconsistency of the patient originated samples as seen from the 2D Gel appearance, might contribute to the failure of the peptide based ELISA technology to detect human beta1-AABs.

  12. A randomized, blinded, controlled trial of the antiemetic effect of ondansetron on dexmedetomidine-induced emesis in cats.

    PubMed

    Santos, Luiz Cesar P; Ludders, John W; Erb, Hollis N; Martin-Flores, Manuel; Basher, Karen L; Kirch, Pati

    2011-07-01

    To determine the effect of ondansetron on the incidence of vomiting in cats pre-medicated with dexmedetomidine and buprenorphine. Randomized, blinded, controlled trial. Eighty-nine female domestic shorthair cats, aged 3-60 months (median, 12 months) and weighing 1.2-5.1 kg. Each cat received dexmedetomidine (40 μg kg(-1)) plus buprenorphine (20 μg kg(-1)), intramuscularly as pre-anesthetic medication. Cats were assigned to three treatment groups: ondansetron (0.22 mg kg(-1), intramuscular [IM]), either 30 minutes before the pre-anesthetic medication (ONDA group, n = 31) or with the pre-anesthetic medication (OPM group, n = 30) mixed with the pre-anesthetic medications in the same syringe, or not to receive the antiemetic (control group, n = 28). Emesis was recorded as an all-or-none response. The number of episodes of emesis and the time until onset of the first emetic episode were recorded for each cat. Clinical signs of nausea were recorded whenever they occurred, and a numerical rating scale was used to quantify these signs. Data were analyzed using Kruskal-Wallis and Chi-square test; a Bonferroni correction was made for six comparisons; thus, the two-sided p for significance was 0.05/6 = 0.008. There was a significant reduction in the number of cats vomiting, in the episodes of vomiting/cat, the time elapsed between the premedication and the first vomiting and the severity of nausea in the OPM group compared to the ONDA and control groups. In cats, the administration of ondansetron (0.22 mg kg(-1)) ameliorates and reduced the severity of dexmedetomidine-induced nausea and vomiting only when it was administered in association with this drug. © 2011 The Authors. Veterinary Anaesthesia and Analgesia. © 2011 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.

  13. Sedative and cardiorespiratory effects of dexmedetomidine and buprenorphine administered to cats via oral transmucosal or intramuscular routes.

    PubMed

    Santos, Luiz Cesar P; Ludders, John W; Erb, Hollis N; Basher, Karen L; Kirch, Pati; Gleed, Robin D

    2010-09-01

    To determine if buprenorphine plus dexmedetomidine administered via the oral transmucosal route produces sufficient sedation in cats so that students can insert intravenous catheters. Prospective, randomized, blinded, clinical trial. Eighty-seven shelter-owned female cats aged 4-48 months, weighing 1.1-4.9 kg. Cats were randomly allocated to two treatment groups based on route of drug administration: oral transmucosal (OTM), or intramuscular (IM). Buprenorphine (20 microg kg(-1)) plus dexmedetomidine (20 microg kg(-1)) were administered as pre-medicants via one of these two routes. Prior to and 20 minutes after drug administration, heart and respiratory rates, systolic arterial pressure, and posture were measured and recorded. Twenty minutes after drug administration the same variables plus each cat's response to clipper sound, clipping, and restraint were recorded; higher scores indicated more sedation. There were no significant differences between the two groups prior to pre-medication. Within each treatment group heart rate was significantly lower 20 minutes after treatment, but it did not differ significantly between the two groups. Twenty minutes after treatment, respiratory rate was significantly less in the OTM group, but did not differ significantly between the two groups. Systolic arterial pressure did not differ within or between the two groups at either time. Scores for posture increased significantly within both groups, and cats in the IM group had higher scores after treatment. Twenty minutes after treatment, cats in the IM group had higher scores for clipping and restraint than OTM cats. Ketamine (IM) was necessary to facilitate catheterization in 25% and 16% of cats in the OTM and IM groups, respectively, but this was not significantly different. Administration of dexmedetomidine plus buprenorphine by the OTM route is easy to perform, but produces less sedation than the IM route for IV catheterization in cats.

  14. Langerhans cells beta 2-adrenoceptors: role in migration, cytokine production, Th priming and contact hypersensitivity.

    PubMed

    Maestroni, Georges J M; Mazzola, Paola

    2003-11-01

    We showed that norepinephrine (NE) hampers IL-12 and stimulates IL-10 production via adrenoceptors (ARs) in bone marrow-derived dendritic cells (BMDC) influencing their Th priming ability. Others have shown that Langerhans cells (LC) express mRNA for beta1-, beta2- and alpha1(A)-(ARs) and that catecholamines may inhibit the antigen-presenting capability via beta2-ARs. Here, we show that also BMDC express mRNA for beta1-, beta2-, alpha2(A)- and alpha2(C)-ARs. Inhibition of IL-12 is mediated by both beta2- and alpha2(A)-ARs, while stimulation of IL-10 by beta2-ARs only. In addition, LC migration, the contact hypersensitivity response (CHS) and production of IFN-gamma and IL-2 in draining lymph node cells is increased in mice treated topically with the beta2-AR antagonist ICI 118,551 during FITC sensitization. Activation of beta2-ARs in BMDC before adoptive transfer could reduce both migration and CHS response to FITC. Finally, preincubation of BMDC with LPS in presence of the specific beta2-AR agonist salbutamol impaired their chemotactic response to CCL19 and CCL21 and this effect was neutralized by anti-IL-10 mAb. We suggest that the physiological activation of beta2-ARs in DC (LC) results in stimulation of IL-10 which in turn restrains DC (LC) migration influencing antigen presentation and the consequent CHS response.

  15. beta(2)-adrenoceptor antagonist ICI 118,551 decreases pulmonary vascular tone in mice via a G(i/o) protein/nitric oxide-coupled pathway.

    PubMed

    Wenzel, Daniela; Knies, Ralf; Matthey, Michaela; Klein, Alexandra M; Welschoff, Julia; Stolle, Vanessa; Sasse, Philipp; Röll, Wilhelm; Breuer, Johannes; Fleischmann, Bernd K

    2009-07-01

    beta(2)-adrenoceptors are important modulators of vascular tone, particularly in the pulmonary circulation. Because neurohormonal activation occurs in pulmonary arterial hypertension, we have investigated the effect of different adrenergic vasoactive substances on tone regulation in large and small pulmonary arteries, as well as in systemic vessels of mice. We found that the beta(2)-adrenoceptor antagonist ICI 118,551 (ICI) evoked a decrease of vascular tone in large pulmonary arteries and reduced the sensitivity of pulmonary arteries toward different contracting agents, eg, norepinephrine, serotonin, or endothelin. ICI proved to act specifically on pulmonary vessels, because it shifted the dose-response curve of norepinephrine to the right in pulmonary arteries, whereas there was no effect in the aorta. Pharmacological experiments proved that the right shift of the norepinephrine dose-response curve by ICI was mediated via a beta(2)-adrenoceptor/G(i/o) protein-dependent pathway enhancing NO production in the endothelium; these results were corroborated in beta-adrenoceptor and endothelial NO synthase knockout mice where ICI had no effect. ICI increased vascular lumen diameter in lung sections and reduced pulmonary arterial pressure under normoxia and under hypoxia in the isolated perfused lung model. These effects were found to be physiologically relevant, because ICI specifically decreased pulmonary but not systemic blood pressure in vivo. Thus, the beta(2)-adrenoceptor antagonist ICI is a pulmonary arterial-specific vasorelaxant and, therefore, a potentially interesting novel therapeutic agent for the treatment of pulmonary arterial hypertension.

  16. CREB-binding protein (CBP) regulates β-adrenoceptor (β-AR)−mediated apoptosis

    PubMed Central

    Lee, Y Y; Moujalled, D; Doerflinger, M; Gangoda, L; Weston, R; Rahimi, A; de Alboran, I; Herold, M; Bouillet, P; Xu, Q; Gao, X; Du, X-J; Puthalakath, H

    2013-01-01

    Catecholamines regulate the β-adrenoceptor/cyclic AMP-regulated protein kinase A (cAMP/PKA) pathway. Deregulation of this pathway can cause apoptotic cell death and is implicated in a range of human diseases, such as neuronal loss during aging, cardiomyopathy and septic shock. The molecular mechanism of this process is, however, only poorly understood. Here we demonstrate that the β-adrenoceptor/cAMP/PKA pathway triggers apoptosis through the transcriptional induction of the pro-apoptotic BH3-only Bcl-2 family member Bim in tissues such as the thymus and the heart. In these cell types, the catecholamine-mediated apoptosis is abrogated by loss of Bim. Induction of Bim is driven by the transcriptional co-activator CBP (CREB-binding protein) together with the proto-oncogene c-Myc. Association of CBP with c-Myc leads to altered histone acetylation and methylation pattern at the Bim promoter site. Our findings have implications for understanding pathophysiology associated with a deregulated neuroendocrine system and for developing novel therapeutic strategies for these diseases. PMID:23579242

  17. Comparison of propofol and dexmedetomidine infused overnight to treat hyperactive and mixed ICU delirium: a protocol for the Basel ProDex clinical trial

    PubMed Central

    Ledergerber, Katrin; von Felten, Stefanie; Sutter, Raoul; Rüegg, Stephan; Gantner, Lukas; Zimmermann, Sibylle; Blum, Andrea; Steiner, Luzius A; Marsch, Stephan; Siegemund, Martin

    2017-01-01

    Background/objectives Delirium is a neurobehavioural disturbance that frequently develops particularly in the intensive care unit (ICU) population. It was first described more than half a century ago, where it was already discovered as a state that might come along with serious complications such as prolonged ICU and hospital stay, reduced quality of life and increased mortality. However, in most cases, there is still lack of proof for causal relationship. Its presence frequently remains unrecognised due to suggested predominance of the hypoactive form. Furthermore, in the general ICU population, it has been shown that the duration of delirium is associated with worse long-term cognitive function. Due to the multifactorial origin of delirium, we have several but no incontestable treatment options. Nonetheless, delirium bears a high burden for patient, family members and the medical care team. The Basel ProDex Study targets improvement of hyperactive and mixed delirium therapy in critically ill patients. We will focus on reducing the duration and severity of delirium by implementing dexmedetomidine into the treatment plan. Dexmedetomidine compared with other sedatives shows fewer side effects representing a better risk profile for delirium treatment in general. This could further contribute to higher patient safety. The aim of the BaProDex Trial is to assess the superiority of dexmedetomidine to propofol for treatment of hyperactive and mixed delirium in the ICU. We hypothesise that dexmedetomidine, compared with propofol administered at night, shortens both the duration and severity of delirium. Methods/design The Basel ProDex Study is an investigator-initiated, one-institutional, two-centre randomised controlled clinical trial for the treatment of delirium with dexmedetomidine versus propofol in 316 critically ill patients suffering from hyperactive and mixed delirium. The primary outcome measure is delirium duration in hours. Secondary outcomes include delirium

  18. Effect of Continuous Paravertebral Dexmedetomidine Administration on Intraoperative Anesthetic Drug Requirement and Post-Thoracotomy Pain Syndrome After Thoracotomy: A Randomized Controlled Trial.

    PubMed

    Dutta, Vikas; Kumar, Bhupesh; Jayant, Aveek; Mishra, Anand K

    2017-02-01

    To assess the effect of paravertebral administration of dexmedetomidine as an adjuvant to local anesthetic on the intraoperative anesthetic drug requirement and incidence of post-thoracotomy pain syndrome. Prospective, randomized, controlled, double-blind trial. Single university hospital. The study comprised 30 patients who underwent elective thoracotomy and were assigned randomly to either the Ropin or Dexem group (n = 15 each). All patients received the study medications through paravertebral catheter. Patients in the Ropin group received a bolus of 15 mL of 0.75% ropivacaine over 3-to-5 minutes followed by an infusion of 0.2% ropivacaine at 0.1 mL/kg/hour. Patients in the Dexem group received 15 mL of 0.75% ropivacaine plus dexmedetomidine, 1 µg/kg bolus over 3-to-5 minutes followed by an infusion of 0.2% ropivacaine plus 0.2 µg/kg/hour of dexmedetomidine at 0.1 mL/kg/hour. The primary outcome of the study was intraoperative anesthetic drug requirement. The secondary outcome was the incidence of post-thoracotomy pain syndrome 2 months after surgery. The amount of propofol required for induction of anesthesia was significantly less in the Dexem group (Dexem 49.33±20.51 v 74.33±18.40 in the Ropin group, p = 0.002). End-tidal isoflurane needed to maintain target entropy was significantly less in the Dexem group at all time points. Intraoperative fentanyl requirement was lower in the Dexem group (Dexem 115.33±33.77 v 178.67±32.48 in the Ropin group, p = 0.002). Postoperative pain scores and morphine consumption were significantly less in the Dexem group (p<0.001). The incidence of post-thoracotomy pain syndrome was comparable between the 2 groups (69.23% v 50%, p = 0.496). Paravertebral dexmedetomidine administration resulted in decreased intraoperative anesthetic drug requirement, less pain, and lower requirements of supplemental opioid in the postoperative period. However, it had no effect on the incidence of post-thoracotomy pain syndrome. Copyright

  19. Regulation of β1- and β3-adrenergic agonist-stimulated lipolytic response in hyperthyroid and hypothyroid rat white adipocytes

    PubMed Central

    Germack, Renée; Starzec, Anna; Perret, Gérard Y

    2000-01-01

    This study examined the effects of thyroid status on the lipolytic responses of rat white adipocytes to β-adrenoceptor (β-AR) stimulation. The β1- and β3-AR mRNAs and proteins were measured by Northern and saturation analyses, respectively. Glycerol production and adenyl cyclase (AC) activity induced by various non-selective and selective β1/β3-AR agonists and drugs which act distal to the receptor in the signalling cascade were measured in cells from untreated, tri-iodothyronine (T3)-treated and thyroidectomized rats. The β3-AR density was enhanced (72%) by T3-treatment and reduced (50%) by introduction of a hypothyroid state while β1-AR number remained unaffected. The β1- and β3-AR density was correlated with the specific mRNA level in all thyroid status. The lipolytic responses to isoprenaline, noradrenaline (β1/β3/β3-AR agonists) and BRL 37344 (β3-AR agonist) were potentiated by 48, 58 and 48%, respectively in hyperthyroidism and reduced by about 80% in hypothyroidism. T3-treatment increased the maximal lipolytic response to the partial β3-AR (CGP 12177) and β1-AR (xamoterol) agonists by 234 and 260%, respectively, increasing their efficacy (intrinsic activity: 0.95 versus 0.43 and 1.02 versus 0.42). The maximal AC response to these agonists was increased by 84 and 58%, respectively, without changing their efficacy. In the hypothyroid state, the maximal lipolytic and AC responses were decreased with CGP (0.17±0.03 versus 0.41±0.08 μmol glycerol/106 adipocytes; 0.048±0.005 versus 0.114±0.006 pmol cyclic AMP min−1 mg−1) but not changed with xamoterol. The changes in lipolytic responses to postreceptor-acting agents (forskolin, enprofylline and dibutenyl cyclic AMP, (Bu)2cAMP) suggest the modifications on receptor coupling and phosphodiesterase levels in both thyroid states. Thyroid status affects lipolysis by modifying β3-AR density and postreceptor events without changes in the β1-AR functionality. PMID:10711342

  20. Efficacy and pharmacokinetics of bupivacaine with epinephrine or dexmedetomidine after intraperitoneal administration in cats undergoing ovariohysterectomy.

    PubMed

    Benito, Javier; Monteiro, Beatriz; Beaudry, Francis; Steagall, Paulo

    2018-04-01

    The aim of this study was to determine the efficacy and pharmacokinetics of bupivacaine in combination with epinephrine or dexmedetomidine after intraperitoneal administration in cats undergoing ovariohysterectomy. Sixteen healthy adult cats (3.3 ± 0.6 kg) were included in a prospective, randomized, masked clinical trial after obtaining owners' consent. Anesthetic protocol included buprenorphine-propofol-isoflurane. Meloxicam [0.2 mg/kg body weight (BW)] was administered subcutaneously before surgery. Cats were randomly divided into 2 groups to receive 1 of 2 treatments. Intraperitoneal bupivacaine 0.25% (2 mg/kg BW) was administered with epinephrine (BE group; 2 μg/kg BW) or dexmedetomidine (BD group; 1 μg/kg BW) before ovariohysterectomy ( n = 8/group). A catheter was placed in the jugular vein for blood sampling. Blood samples were collected for up to 8 h after bupivacaine was administered. Plasma concentrations and pharmacokinetics of bupivacaine were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS) and non-compartmental model, respectively. Pain was evaluated using the UNESP-Botucatu multidimensional composite pain scale (MCPS), the Glasgow composite feline pain scale (GPS), and a dynamic visual analog scale up to 8 h after extubation. Rescue analgesia was provided with buprenorphine if MCPS was ≥ 6. Repeated measures linear models were used for analysis of pain and sedation scores ( P < 0.05). Maximum bupivacaine plasma concentrations (Cmax) for BE and BD were 1155 ± 168 ng/mL and 1678 ± 364 ng/mL ( P = 0.29) at 67 ± 13 min (Tmax) and 123 ± 59 min ( P = 0.17), respectively. Pharmacokinetic parameters and pain scores were not different between treatments ( P > 0.05). One cat in the BE group received rescue analgesia ( P = 0.30). Intraperitoneal bupivacaine with epinephrine or dexmedetomidine produced concentrations below toxic levels and similar analgesic effects. It is therefore safe to administer these drug combinations in

  1. beta-Adrenoceptor blockers protect against staurosporine-induced apoptosis in SH-SY5Y neuroblastoma cells.

    PubMed

    Mikami, Maya; Goubaeva, Farida; Song, Joseph H; Lee, H T; Yang, Jay

    2008-07-28

    The beta-adrenoceptor blockers exhibit a well-characterized anti-apoptotic property in the heart and kidney while less is known about the effect of this class of drugs on neuronal apoptosis. We studied the effects of three beta-adrenoceptor blockers propranolol (1-(isoproplyamino)-3-(naphthalene-1-yloxy)propan-2-ol), atenolol (2-[4-[2-hydroxy-3-(1-methylethylamino)propoxyl]phenyl]ehanamide), and ICI 118551 (1-[2,3-(dihydro-7-methyl-1H-iden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol), against staurosporine-induced apoptosis in SH-SY5Y human neuroblastoma cells. Staurosporine increased caspase 3-like activity, DNA fragmentation, PARP cleavage, and the number of TUNEL positive cells consistent with the induction of apoptosis. Propranolol and ICI 118551, but not atenolol, demonstrated a concentration-dependent inhibition of caspase 3-like activity. Propranolol and ICI 118551 directly inhibited the enzymatic activity of recombinant caspase 9 while atenolol did not; however, none of the beta-adrenoceptor blockers that were examined directly blocked caspases 2 or 3 activity. In isolated mitochondria, propranolol and ICI 118551 inhibited staurosporine-induced cytochrome c release while atenolol did not. We conclude that propranolol and ICI 118551 protect SH-SY5Y cells against staurosporine-induced apoptosis through a dual action on the mitochondria and on caspase 9 in a cell type and an apoptotic paradigm where the conventional inhibitors of mitochondrial permeability transition such as cyclosporin A and bongkrekic acid demonstrate no protection.

  2. Comparison of dexmedetomidine and propofol used for drug-induced sleep endoscopy in patients with obstructive sleep apnea syndrome.

    PubMed

    Kuyrukluyıldız, Ufuk; Binici, Orhan; Onk, Didem; Ayhan Celik, Serap; Torun, Mumtaz Taner; Unver, Edhem; Ozcicek, Adalet; Alagol, Aysin

    2015-01-01

    Backround: Surgical operations are alternative treatments in persons with Obstructive Sleep Apnea Syndrome who cannot tolerate continuous positive airway pressure therapy. Drug-Induced Sleep Endoscopy is a method with which somnolence is pharmacologically induced and collapse is evaluated through nasal endoscopy in patients with Obstructive Sleep Apnea Syndrome. We aimed to evaluate efficiency of dexmedetomidine or propofol used for sedation in patients undergoing drug-induced sleep endoscopy. A total of 40 patients aged between 18 and 65 years old in the ASA STATUS I-II group were included in the study. After premedicatıon wıth midazolam 0.05 mg/kg intravenously, patients were randomly divided into two groups and administered intravenous (iv) propofol with the loading dose of 0.7 mg/kg for 10 minutes, followed 0.5 mg/kg/h infusion (Group P); or dexmedetomidine with the loading dose of 1 mcg/kg for 10 minutes, followed by 0.3 mcg/kg/h infusion (Group D). Haemodynamic and respiratuary parameters, Bispectral index score, Ramsey sedation score, time to achieve sufficient sedation, surgeon's and patients' satisfaction, postoperative Aldrete score and side effects were recorded. Time to achieve sufficient sedation, Bispectral index scores at 5, 10 and 15th. minutes intraoperatively, first Aldrete score in the recovery room, SpO2 values and respiratory rates all over the surgical procedure and in the recovery room were found lower in Group P (P<0.05). Bispectral index scores, mean arterial pressure and heart rate in the recovery room were significantly lower in Group D (P<0.05). Dexmedetomidine may be preferred as a safer agent with respecting to respiratory function compared with propofol in obstructive sleep apnea patients who known to be susceptible to hypoxia and hypercarbia.

  3. Comparison of dexmedetomidine and propofol used for drug-induced sleep endoscopy in patients with obstructive sleep apnea syndrome

    PubMed Central

    Kuyrukluyıldız, Ufuk; Binici, Orhan; Onk, Didem; Ayhan Celik, Serap; Torun, Mumtaz Taner; Unver, Edhem; Ozcicek, Adalet; Alagol, Aysin

    2015-01-01

    Backround: Surgical operations are alternative treatments in persons with Obstructive Sleep Apnea Syndrome who cannot tolerate continuous positive airway pressure therapy. Drug-Induced Sleep Endoscopy is a method with which somnolence is pharmacologically induced and collapse is evaluated through nasal endoscopy in patients with Obstructive Sleep Apnea Syndrome. Aims: We aimed to evaluate efficiency of dexmedetomidine or propofol used for sedation in patients undergoing drug-induced sleep endoscopy. Methods: A total of 40 patients aged between 18 and 65 years old in the ASA STATUS I-II group were included in the study. After premedicatıon wıth midazolam 0.05 mg/kg intravenously, patients were randomly divided into two groups and administered intravenous (iv) propofol with the loading dose of 0.7 mg/kg for 10 minutes, followed 0.5 mg/kg/h infusion (Group P); or dexmedetomidine with the loading dose of 1 mcg/kg for 10 minutes, followed by 0.3 mcg/kg/h infusion (Group D). Haemodynamic and respiratuary parameters, Bispectral index score, Ramsey sedation score, time to achieve sufficient sedation, surgeon’s and patients’ satisfaction, postoperative Aldrete score and side effects were recorded. Results: Time to achieve sufficient sedation, Bispectral index scores at 5, 10 and 15th. minutes intraoperatively, first Aldrete score in the recovery room, SpO2 values and respiratory rates all over the surgical procedure and in the recovery room were found lower in Group P (P<0.05). Bispectral index scores, mean arterial pressure and heart rate in the recovery room were significantly lower in Group D (P<0.05). Conclusion: Dexmedetomidine may be preferred as a safer agent with respecting to respiratory function compared with propofol in obstructive sleep apnea patients who known to be susceptible to hypoxia and hypercarbia. PMID:26131153

  4. CCK receptors-related signaling involved in nitric oxide production caused by gastrin 17 in porcine coronary endothelial cells.

    PubMed

    Grossini, Elena; Caimmi, Philippe; Molinari, Claudio; Uberti, Francesca; Mary, David; Vacca, Giovanni

    2012-03-05

    In anesthetized pigs gastrin-17 increased coronary blood flow through CCK1/CCK2 receptors and β(2)-adrenoceptors-related nitric oxide (NO) release. Since the intracellular pathway has not been investigated the purpose of this study was to examine in coronary endothelial cells the CCK1/CCK2 receptors-related signaling involved in the effects of gastrin-17 on NO release. Gastrin-17 caused a concentration-dependent increase of NO production (17.3-62.6%; p<0.05), which was augmented by CCK1/CCK2 receptors agonists (p<0.05). The effect of gastrin-17 was amplified by the adenylyl-cyclase activator and β(2)-adrenoceptors agonist (p<0.05), abolished by cAMP/PKA and β(2)-adrenoceptors and CCK1/CCK2 receptors blockers, and reduced by PLC/PKC inhibitor. Finally, Western-blot revealed the preferential involvement of PKA vs. PKC as downstream effectors of CCK1/CCK2 receptors activation leading to Akt, ERK, p38 and endothelial NOS (eNOS) phosphorylation. In conclusion, in coronary endothelial cells, gastrin-17 induced eNOS-dependent NO production through CCK1/CCK2 receptors- and β(2)-adrenoceptors-related pathway. The intracellular signaling involved a preferential PKA pathway over PKC. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  5. Dexmedetomidine Added to Local Anesthetic Mixture of Lidocaine and Ropivacaine Enhances Onset and Prolongs Duration of a Popliteal Approach to Sciatic Nerve Blockade.

    PubMed

    Hu, Xiawei; Li, Jinlei; Zhou, Riyong; Wang, Quanguang; Xia, Fangfang; Halaszynski, Thomas; Xu, Xuzhong

    2017-01-01

    A literature review of multiple clinical studies on mixing additives to improve pharmacologic limitation of local anesthetics during peripheral nerve blockade revealed inconsistency in success rates and various adverse effects. Animal research on dexmedetomidine as an adjuvant on the other hand has promising results, with evidence of minimum unwanted results. This randomized, double-blinded, contrastable observational study examined the efficacy of adding dexmedetomidine to a mixture of lidocaine plus ropivacaine during popliteal sciatic nerve blockade (PSNB). Sixty patients undergoing varicose saphenous vein resection using ultrasonography-guided PSNB along with femoral and obturator nerve blocks as surgical anesthesia were enrolled. All received standardized femoral and obturator nerve blocks, and the PSNB group was randomized to receive either 0.5 mL (50 µg) of dexmedetomidine (DL group) or 0.5 mL of saline (SL group) together with 2% lidocaine (9.5 mL) plus 0.75% ropovacaine (10 mL). Sensory onset and duration of lateral sural cutaneous nerve, sural nerve, superficial peroneal nerve, deep peroneal nerve, lateral plantar nerve, and medial plantar nerve were recorded. Motor onset and duration of tibial nerve and common peroneal nerve were also examined. Sensory onset of sural nerve, superficial peroneal nerve, lateral plantar nerve, and medial plantar nerve was significantly quicker in the DL group than in the SL group (P < 0.05). Sensory onset of lateral sural cutaneous nerve and deep peroneal nerve was not statistically different between the groups (P > 0.05). Motor onset of tibial nerve and common peroneal nerve was faster in the DL group than in in the SL group (P < 0.05). Duration of both sensory and motor blockade was significantly longer in the DL group than in the SL group (P < 0.05). Perineural dexmedetomidine added to lidocaine and ropivacaine enhanced efficacy of popliteal approach to sciatic nerve blockade with faster onset and longer duration

  6. Identification and characterization of (/sup 3/H)-rauwolscine binding to alpha2-adrenoceptors in the canine saphenous vein

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Gout, B.

    1988-01-01

    The biochemical exploration of the alpha2-adrenergic receptors was investigated in the canine saphenous vein using the highly selective alpha2-adrenergic antagonist rauwolscine as a tritiated ligand. Following an enzymatic digestive pretreatment, the authors isolated a purified smooth muscle cell membranes fraction from saphenous veins in quantity sufficient to permit them to study the venous alpha2-adrenoreceptor content. The binding of tritiated rauwolscine was rapid, specific, saturable and reversible. The presence of high affinity sites with a density of binding Bmax of 125.2 /+ -/ 43.1 fmol/mg protein was demonstrated on a unique class of non interacting sites. The kinetically derived Kd wasmore » 1.28 nM, in good agreement with the value obtained from saturation isotherms. The pharmacological profile of these sites was assessed by the comparison of the potency of alpha-adrenergic agonists and antagonists to inhibit 1 nM (/sup 3/H)-rauwolscine. Their efficacy was respectively: rauwolscine > phentolamine > RX 781094 > clonidine >> prazosin > (-)-phenylephrine > (-)-noradrenaline. The results showed that (/sup 3/H)-rauwolscine bound specifically to sites in their membranal preparation, which had the pharmacological characteristics of the alpha2-adrenoceptors. The correlation between biochemical and pharmacological data revealed the usefulness of binding methods in the further study of adrenergic mechanisms in the canine saphenous vein.« less

  7. A comparison of medetomidine and its active enantiomer dexmedetomidine when administered with ketamine in mice

    PubMed Central

    2013-01-01

    Background Medetomidine-ketamine (MK) and dexmedetomidine-ketamine (DK) are widely used to provide general anaesthesia in laboratory animals, but have not been compared directly in many of these species, including rodents. This study aimed to compare the onset and depth of anaesthesia, and changes in vital signs, after intraperitoneal (IP) or subcutaneous (SC) administration of ketamine (75 mg kg-1) combined with medetomidine (1 mg kg-1) or dexmedetomidine (0.5 mg kg-1) using a randomised semi-crossover design with ≥ 48 hours between treatments in 10 male and 10 female mice. Each mouse was anaesthetised twice using the same administration route (IP or SC): once with each drug-ketamine combination. Anaesthetised mice were monitored on a heating pad without supplemental oxygen for 89 minutes; atipamezole was administered for reversal. The times that the righting reflex was lost post-injection and returned post-reversal were analysed using general linear models. Tail-pinch and pedal reflexes were examined using binomial generalized linear models. Pulse rate (PR), respiratory rate (fr), and arterial haemoglobin saturation (SpO2) were compared using generalized additive mixed models. Results There were no significant differences among treatments for the times taken for loss and return of the righting reflex, or response of the tail-pinch reflex. The pedal withdrawal reflex was abolished more frequently with MK than DK over time (P = 0.021). The response of PR and SpO2 were similar among treatments, but fr was significantly higher with MK than DK (P ≤ 0.0005). Markedly low SpO2 concentrations occurred within 5 minutes post-injection (83.8 ± 6.7%) in all treatment groups and were most severe after 89 minutes lapsed (66.7 ± 7.5%). No statistical differences were detected in regards to administration route (P ≤ 0.94). Conclusions This study failed to demonstrate clinical advantages of the enantiomer dexmedetomidine over medetomidine when combined with ketamine to

  8. Comparison of intramuscular alfaxalone and ketamine combined with dexmedetomidine and butorphanol for castration in cats.

    PubMed

    Khenissi, Latifa; Nikolayenkova-Topie, Olga; Broussaud, Ségolène; Touzot-Jourde, Gwenola

    2017-08-01

    Objectives Cardiorespiratory parameters and anaesthesia quality in cats anaesthetised with either intramuscular (IM) alfaxalone or ketamine both combined with dexmedetomidine and butorphanol for castration were evaluated. Methods Thirty-two client-owned cats were randomly assigned to receive either alfaxalone (A; 3 mg/kg IM) or ketamine (K; 5 mg/kg IM), combined with dexmedetomidine (10 μg/kg) and butorphanol (0.2 mg/kg). Heart rate (HR), respiratory rate (RR) and rectal temperature (T°) were recorded prior to drug administration. Pulse rate (PR) and RR were recorded 10 (T 10 ) and 15 (T 15 ) mins after injection (T 0 ). Cardiorespiratory values (PR, RR, SPO 2 , blood pressure, P E 'CO 2 ) were recorded every 5 mins for the duration of the procedure. Pain at injection, intubation and recovery were evaluated with simple descriptive scores. Feasibility of anaesthesia was evaluated by the number of top-ups of anaesthetic needed. Cat attitude, ability to walk and presence of ataxia were assessed several times after extubation (T exmin ) and the time between injection and extubation recorded. Pain was assessed at T ex120 and T ex240 with the 4Avet-pain score. Results The RR was significantly lower in group K at T 10 (RR K = 28 ±13.35 breaths per minute [brpm], RR A = 43.24 ±7.04 brpm) and T 15 (RR K = 28 ±11.53 brpm vs RR A = 43 ±12.18 brpm). Time to extubation was significantly longer in group A (T A = 62 ±14.6 mins, T K = 45.13 ± 7.38 mins). Cats in group K needed more top-ups, were more ataxic at T ex120 , had a worse recovery score at T ex60 and were less willing to walk at T ex30 . Conclusions and relevance Cats receiving alfaxalone had a longer but better quality recovery. Cardiorespiratory parameters were stable and within clinically acceptable values following IM injection of either alfaxalone or ketamine in healthy cats. Intramuscular alfaxalone is a suitable alternative to ketamine for short procedures requiring anaesthesia when used in combination

  9. Adrenoceptors in Brain: Cellular Gene Expression and Effects on Astrocytic Metabolism and [Ca2+]i

    PubMed Central

    Hertz, Leif; Lovatt, Ditte; Goldman, Steven A.; Nedergaard, Maiken

    2010-01-01

    Recent in vivo studies have established astrocytes as a major target for locus coeruleus activation (Bekar et al., Cereb. Cortex 18, 2789–2795), renewing interest in cell culture studies on noradrenergic effects on astrocytes in primary cultures and calling for additional information about the expression of adrenoceptor subtypes on different types of brain cells. In the present communication, mRNA expression of α1-, α2- and β-adrenergic receptors and their subtypes was determined in freshly-isolated, cell marker-defined populations of astrocytes, NG2-positive cells, microglia, endothelial cells, and Thy1-positive neurons (mainly glutamatergic projection neurons) in murine cerebral cortex. Immediately after dissection of frontal, parietal and occipital cortex of 10–12-week-old transgenic mice, which combined each cell-type marker with a specific fluorescent signal, the tissue was digested, triturated and centrifuged, yielding a solution of dissociated cells of all types, which were separated by fluorescence-activated cell sorting (FACS). mRNA expression in each cell fraction was determined by microarray analysis. α1A-Receptors were unequivocally expressed in astrocytes and NG2-positive cells, but absent in other cell types, and α1B-receptors were not expressed in any cell population. Among α2-receptors only α2A-receptors were expressed, unequivocally in astrocytes and NG-positive cells, tentatively in microglia and questionably in Thy1-positive neurons and endothelial cells. β1-Receptors were unequivocally expressed in astrocytes, tentatively in microglia, and questionably in neurons and endothelial cells, whereas β2-adrenergic receptors showed tentative expression in neurons and astrocytes and unequivocal expression in other cell types. This distribution was supported by immunochemical data and its relevance established by previous studies in well-differentiated primary cultures of mouse astrocytes, showing that stimulation of α2-adrenoceptors

  10. Population Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children Undergoing Ambulatory Surgery.

    PubMed

    Pérez-Guillé, María-Gabriela; Toledo-López, Alejandra; Rivera-Espinosa, Liliana; Alemon-Medina, Radames; Murata, Chiharu; Lares-Asseff, Ismael; Chávez-Pacheco, Juan Luis; Gómez-Garduño, Josefina; Zamora Gutiérrez, Ana-Lilia; Orozco-Galicia, Claudia; Ramírez-Morales, Karina; Lugo-Goytia, Gustavo

    2018-05-17

    Dexmedetomidine (DEX) is an α-2 adrenergic agonist with sedative and analgesic properties. Although not approved for pediatric use by the Food and Drug Administration, DEX is increasingly used in pediatric anesthesia and critical care. However, very limited information is available regarding the pharmacokinetics of DEX in children. The aim of this study was to investigate DEX pharmacokinetics and pharmacodynamics (PK-PD) in Mexican children 2-18 years of age who were undergoing outpatient surgical procedures. Thirty children 2-18 years of age with American Society of Anesthesiologists physical status score of I/II were enrolled in this study. DEX (0.7 µg/kg) was administered as a single-dose intravenous infusion. Venous blood samples were collected, and plasma DEX concentrations were analyzed with a combination of high-performance liquid chromatography and electrospray ionization-tandem mass spectrometry. Population PK-PD models were constructed using the Monolix program. A 2-compartment model adequately described the concentration-time relationship. The parameters were standardized for a body weight of 70 kg by using an allometric model. Population parameters estimates were as follows: mean (between-subject variability): clearance (Cl) (L/h × 70 kg) = 20.8 (27%); central volume of distribution (V1) (L × 70 kg) = 21.9 (20%); peripheral volume of distribution (V2) (L × 70 kg) = 81.2 (21%); and intercompartmental clearance (Q) (L/h × 70 kg) = 75.8 (25%). The PK-PD model predicted a maximum mean arterial blood pressure reduction of 45% with an IC50 of 0.501 ng/ml, and a maximum heart rate reduction of 28.9% with an IC50 of 0.552 ng/ml. Our results suggest that in Mexican children 2-18 years of age with American Society of Anesthesiologists score of I/II, the DEX dose should be adjusted in accordance with lower DEX clearance.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4

  11. Are patients with hormonally functional phaeochromocytoma and paraganglioma initially receiving a proper adrenoceptor blockade? A retrospective cohort study.

    PubMed

    Luiz, Henrique Vara; Tanchee, Mary Jane; Pavlatou, Maria G; Yu, Run; Nambuba, Joan; Wolf, Katherine; Prodanov, Tamara; Wesley, Robert; Adams, Karen; Fojo, Tito; Pacak, Karel

    2016-07-01

    Pharmacological treatment is mandatory in patients with hormonally functional phaeochromocytoma and paraganglioma (PHAEO/PGL). We evaluated if patients initially diagnosed with hormonally functional PHAEO/PGL by various medical subspecialties received proper adrenoceptor blockade, and analysed factors predicting the prescription of adequate treatment. In a retrospective cohort study, we reviewed data from patients initially diagnosed with hormonally functional PHAEO/PGL outside the National Institutes of Health and Cedars-Sinai Medical Center, who were referred to these institutions between January 2001 and April 2015. Logistic regression was used to assess factors associated with proper adrenoceptor blockade. A total of 381 patients were included. Adequate pharmacological treatment was prescribed to 69·3%, of which 93·1% received α-adrenoceptor blockers. Regarding patients who were inappropriately treated, 53% did not receive any medication. Independent predictors of the prescription of a proper blockade were the diagnosis by endocrinologists [odds ratio (OR) 4·14; 95% confidence interval (CI), 2·51-6·85; P < 0·001], the presence of high blood pressure (OR 5·94; 95% CI, 3·11-11·33; P < 0·001) and the evidence of metastasis (OR 5·96; 95% CI, 1·93-18·46; P = 0·002). Although most patients received adequate pharmacological treatment, almost one-third were either not treated or received inappropriate medications. The diagnosis by endocrinologists, the presence of high blood pressure and the evidence of metastatic disease were identified as independent predictors of a proper blockade. These results highlight the need to educate physicians about the importance of starting adequate adrenoceptor blockade in all patients with hormonally functional PHAEO/PGL. © 2016 John Wiley & Sons Ltd.

  12. Anti-inflammatory actions of clonidine, guanfacine and B-HT 920 against various inflammagen-induced acute paw oedema in rats.

    PubMed

    Kulkarni, S K; Mehta, A K; Kunchandy, J

    1986-02-01

    Clonidine (0.1-1.0 mg/kg, i.p.) exhibited anti-inflammatory activity in carrageenan-, formalin-, 5-HT- and histamine-induced paw oedema in rats. Similarly, other two alpha 2-adrenoceptor agonists, guanfacine and B-HT 920, also displayed an anti-inflammatory action in these models. The anti-inflammatory effect of all the three alpha 2-adrenoceptor agonists was reversed by yohimbine. However, prazosin failed to block the anti-inflammatory effect of clonidine. Intracerebroventricularly administered clonidine had a delayed onset of anti-inflammatory action, starting only from 60 min post carrageenan administration. This was in contrast to the systemically administered clonidine which was effective against both phases of carrageenan-induced oedema. On the other hand, irrespective of the route of administration, i.e. peripheral or central, guanfacine and B-HT 920 were effective against the early as well as against the delayed phases of the inflammatory reaction. The studies suggest that it is not the imidazoline moiety but the activation of alpha 2-adrenoceptors which is essential for the anti-inflammatory action of these agents.

  13. Clenbuterol Induces Cell Cycle Arrest in C2C12 Myoblasts by Delaying p27 Degradation through β-arrestin 2 Signaling

    PubMed Central

    Chen, Min; Liu, Chuncheng; Wang, Meng; Wang, Hong; Zhang, Kuo; Zheng, Yu; Yu, Zhengquan; Li, Xiangdong; Guo, Wei; Li, Ning; Meng, Qingyong

    2017-01-01

    β2-Adrenoceptor (β2-AR) agonists promote muscle growth. The aim of this study was to elucidate some effects of the selective β2-adrenoceptor agonist clenbuterol (CLB) on myoblast proliferation. We found that CLB induces cell cycle arrest in C2C12 myoblasts. This effect is partly due to the enhanced stability of p27, rather than the increased gene transcription via cAMP response element-binding protein (CREB). Specifically, CLB treatment enhanced the accumulation of p27 in the nucleus while depleting it from the cytosol via a mechanism that requires β2-AR. Surprisingly, p27 accumulation was not reversed by the protein kinase A (PKA) inhibitor H-89, but interestingly, was alleviated by the knockdown of β-arrestin 2. Thus, our work provides a basis for β2-AR agonists inhibit myoblasts proliferation through signaling via β2-AR, β-arrestin 2, and p27. PMID:29104500

  14. Modulation of sibutramine-induced increases in extracellular noradrenaline concentration in rat frontal cortex and hypothalamus by α2-adrenoceptors

    PubMed Central

    Wortley, K E; Heal, D J; Stanford, S C

    1999-01-01

    The effects of sibutramine (0.25–10 mg kg−1 i.p.) on extracellular noradrenaline concentration in the frontal cortex and hypothalamus of freely-moving rats were investigated using microdialysis. The role of presynaptic α2-adrenoceptors in modulating the effects of sibutramine in these brain areas was also determined.Sibutramine induced an increase in extracellular noradrenaline concentration, the magnitude of which paralleled dose, in both brain areas. In the cortex, this increase was gradual and sustained, whereas in the hypothalamus it was more rapid and of shorter duration.In both the cortex and hypothalamus, pretreatment of rats with the α2-adrenoceptor antagonist RX821002 (3 mg kg−1 i.p.) potentiated increases in the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg−1 i.p.), by 7 and 10 fold respectively. RX821002 also reduced the latency of sibutramine to reach its maximum effect in the cortex, but not in the hypothalamus.Infusion of RX821002 (1 μM) via the probe increased the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg−1 i.p.) in both brain areas. In the hypothalamus, the effects of RX821002 on the accumulation of noradrenaline induced by sibutramine were 2 fold greater than those in the cortex.These findings support evidence that sibutramine inhibits the reuptake of noradrenaline in vivo, but that the accumulation of extracellular noradrenaline is limited by noradrenergic activation of presynaptic α2-adrenoceptors. Furthermore, the data suggest that terminal α2-adrenoceptors in the hypothalamus exert a greater inhibitory effect over the control of extracellular noradrenaline accumulation than do those in the cortex. PMID:10516646

  15. Expression of beta 3-adrenoceptor mRNA in rat tissues.

    PubMed

    Evans, B A; Papaioannou, M; Bonazzi, V R; Summers, R J

    1996-01-01

    1. This study examines the expression of beta 3-adrenoceptor messenger RNA (beta 3-AR mRNA) in rat tissues to allow comparison with atypical beta-adrenoceptors determined by functional and radioligand binding techniques. 2. A reverse transcription/polymerase chain reaction protocol has been developed for determining the relative amounts of beta 3-AR mRNA in rat tissues. 3. Measurement of adipsin and uncoupling protein (UCP) mRNA was used to examine all tissues for the presence of white and brown adipose tissue which may contribute beta 3-AR mRNA. 4. The beta 3-AR mRNA is expressed at high levels in brown and white adipose tissue, stomach fundus, the longitudinal/circular smooth muscle of both colon and ileum, and colon submucosa. There was substantial expression of adipsin in colon submucosa and moderate expression in fundus, suggesting that in these regions at least some of the beta 3-AR signal may be contributed by fat. Pylorus and colon mucosa showed moderate levels of beta 3-AR mRNA with lower levels of adipsin. Ileum mucosa and submucosa showed low but readily detectable levels of beta 3-AR. 5. Expression of adipsin in rat skeletal muscles coupled to very low levels of beta 3-AR mRNA indicates that the observed beta 3-AR may be due to the presence of intrinsic fat. beta 3-AR mRNA was virtually undetectable in heart, lung and liver. These results raise the possibility that the atypical beta-AR demonstrated by functional and/or binding studies in muscle and in heart is not the beta 3-AR. 6. By use of two different sets of primers for amplification of beta 3-AR cDNA, no evidence was found for differential splicing of the mRNA in any of the tissues examined. 7. The detection of beta 3-AR mRNA in the gut mucosa and submucosa suggests that in addition to its established roles in lipolysis, thermogenesis and regulation of gut motility beta 3-AR may subserve other functions in the gastrointestinal tract. The absence of beta 3-AR mRNA in rat heart or its presence with

  16. Addition of dexmedetomidine to bupivacaine in supraclavicular brachial plexus block.

    PubMed

    Aksu, Recep; Bicer, Cihangir

    2017-06-26

    Research is ongoing to determine the lowest dose of local anesthetics in brachial plexus block that provides adequate anesthesia and postoperative analgesia and reduces complications related to local anesthetics. Patients 18-65 years of age who underwent upper limb surgery and who received ultrasound-guided supraclavicular brachial plexus block at the Erciyes University Faculty of Medicine Hospital between February 2014 and January 2015 were included in the study (n=50). Supraclavicular brachial plexus blocks were performed on Group B cases by adding 30 ml 0.33% bupivacaine and on Group BD cases by adding 15 ml 0.33% bupivacaine and 1 µg / kg dexmedetomidine. Block success was evaluated by the onset and block duration of motor and sensory block and the duration of analgesia. The block success of Group B and Group BD was 92.6% and 89.3%, respectively (P = 1.000). Onset time of sensory block, degree of sensory block, duration of sensory block, onset time of motor block, degree of motor block and duration of motor block were similar in both groups in the intergroup comparison (P > 0.05). Duration of analgesia and the operative conditions of groups were similar (P > 0.05). In the implementation of ultrasound-guided supraclavicular brachial plexus block, block success, sensory and motor block and analgesia duration were similar for patients anaesthetized with 30 ml of bupivacaine in comparison with dexmedetomidine+bupivacaine (when the bupivacaine dose was reduced by 50% by the addition of the adjuvant).

  17. The cardiovascular status of isoflurane-anaesthetized horses with and without dexmedetomidine constant rate infusion evaluated at equivalent depths of anaesthesia.

    PubMed

    Risberg, Åse I; Ranheim, Birgit; Krontveit, Randi I; Lervik, Andreas; Haga, Henning A

    2016-07-01

    To compare cardiac index and oxygen extraction at equivalent depths of anaesthesia between isoflurane-anaesthetized horses and horses anesthetized with isoflurane and dexmedetomidine CRI. Sequential, blinded, randomized, balanced, crossover study. Eight horses weighing a mean ± standard deviation of 478 ± 58 kg. Horses were premedicated with 0.03 mg kg(-1) acepromazine intramuscularly (IM) and 8 μg kg(-1) dexmedetomidine intravenously (IV). Anaesthesia was induced with 2.5 mg kg(-1) ketamine and 0.1 mg kg(-1) midazolam IV and maintained with isoflurane in oxygen and air. Horses were mechanically ventilated. Fractional concentration of end-tidal isoflurane (Fe'Iso) was stabilized at 1.7% with a CRI of 0.9% NaCl (IsoNaCl), or at 1.1% with 1.75 μg kg(-1)  hour(-1) dexmedetomidine (IsoDex). Mean arterial blood pressure was maintained above 60 mmHg by dobutamine infusion. Following nociceptive electrical stimulation, Fe'Iso was stabilized at a 0.1% lower concentration and nociceptive stimulation was repeated. This procedure was continued until the horse moved. Fe'Iso values prior to the concentration at which movement occurred were considered to indicate equivalent depths of anaesthesia between treatments. Cardiac index and oxygen extraction were compared at equivalent depths of anaesthesia using a paired Student's t-test. Cardiac index differed between IsoNaCl at 61 ± 12 mL kg(-1)  minute(-1) and IsoDex at 48 ± 10 mL kg(-1)  minute(-1) (p = 0.047). In addition, oxygen extraction differed between IsoNaCl at 3.4 ± 0.8 mL kg(-1)  minute(-1) and IsoDex at 4.5 ± 0.5 mL kg(-1)  minute(-1) (p = 0.0042). Two horses receiving IsoNaCl were administered dobutamine at equivalent depths of anaesthesia (7.0 and 28.8 μg kg(-1)  hour(-1) , respectively). Cardiovascular function in horses receiving isoflurane and 1.75 μg kg(-1)  minute(-1) dexmedetomidine is more compromised than in horses receiving a higher concentration of

  18. Translational science approach for assessment of cardiovascular effects and proarrhythmogenic potential of the beta-3 adrenergic agonist mirabegron.

    PubMed

    Korstanje, Cees; Suzuki, Masanori; Yuno, Koichiro; Sato, Shuichi; Ukai, Masashi; Schneidkraut, Marlowe J; Yan, Gan X

    2017-09-01

    Translational assessment of cardiac safety parameters is a challenge in clinical development of beta-3 adrenoceptor agonists. The preclinical tools are presented that were used for assessing human safety for mirabegron. Studies were performed on electrical conductance at ion channels responsible for cardiac repolarization (I Kr , I Ks , I to , I Na , and I Ca,L ), on QT-interval, subendocardial APD 90 , T peak-end interval, and arrhythmia's in ventricular dog wedge tissue in vitro and on cardiovascular function (BP, HR, and QT c ) in conscious dogs. In conscious dogs, mirabegron (0.01-10mg/kg, p.o.) dose-dependently increased HR, reduced SBP but DBP was unchanged. Propranolol blocked the decrease in SBP and attenuated HR increase at 100mg/kg mirabegron. Mirabegron, at 30, 60, or 100mg/kg, p.o., had no significant effect on the QT c interval. In paced dog ventricular wedge, neither mirabegron nor metabolites M5, M11, M12, M14, and M16 prolonged QT, altered transmural dispersion of repolarization, induced premature ventricular contractions, or induced ventricular tachycardia. Mirabegron nor its metabolites inhibited I Kr , I Ks , I to I Na , or I Ca,L at clinically relevant concentrations. Up to exposure levels well exceeding human clinical exposure no discernible effects on ion channel conductance or on arrhythmogenic parameters in ventricular wedge resulted for mirabegron, or its main metabolites, confirming human cardiac safety findings. In vivo, dose-related increases in HR with effects markedly higher than seen clinically, was mediated in part by cross-activation of beta-1 adrenoceptors. This non-clinical cardiac safety test program therefore proved predictive for human cardiac safety for mirabegron. Copyright © 2017. Published by Elsevier Inc.

  19. Determinants of Ligand Subtype-Selectivity at α1A-Adrenoceptor Revealed Using Saturation Transfer Difference (STD) NMR.

    PubMed

    Yong, Kelvin J; Vaid, Tasneem M; Shilling, Patrick J; Wu, Feng-Jie; Williams, Lisa M; Deluigi, Mattia; Plückthun, Andreas; Bathgate, Ross A D; Gooley, Paul R; Scott, Daniel J

    2018-04-20

    α 1A - and α 1B -adrenoceptors (α 1A -AR and α 1B -AR) are closely related G protein-coupled receptors (GPCRs) that modulate the cardiovascular and nervous systems in response to binding epinephrine and norepinephrine. The GPCR gene superfamily is made up of numerous subfamilies that, like α 1A -AR and α 1B -AR, are activated by the same endogenous agonists but may modulate different physiological processes. A major challenge in GPCR research and drug discovery is determining how compounds interact with receptors at the molecular level, especially to assist in the optimization of drug leads. Nuclear magnetic resonance spectroscopy (NMR) can provide great insight into ligand-binding epitopes, modes, and kinetics. Ideally, ligand-based NMR methods require purified, well-behaved protein samples. The instability of GPCRs upon purification in detergents, however, makes the application of NMR to study ligand binding challenging. Here, stabilized α 1A -AR and α 1B -AR variants were engineered using Cellular High-throughput Encapsulation, Solubilization, and Screening (CHESS), allowing the analysis of ligand binding with Saturation Transfer Difference NMR (STD NMR). STD NMR was used to map the binding epitopes of epinephrine and A-61603 to both receptors, revealing the molecular determinants for the selectivity of A-61603 for α 1A -AR over α 1B -AR. The use of stabilized GPCRs for ligand-observed NMR experiments will lead to a deeper understanding of binding processes and assist structure-based drug design.

  20. Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists.

    PubMed

    Franchini, Silvia; Manasieva, Leda Ivanova; Sorbi, Claudia; Battisti, Umberto M; Fossa, Paola; Cichero, Elena; Denora, Nunzio; Iacobazzi, Rosa Maria; Cilia, Antonio; Pirona, Lorenza; Ronsisvalle, Simone; Aricò, Giuseppina; Brasili, Livio

    2017-01-05

    Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT 1A R agonist with a moderate 5-HT 1A R selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HT 1A R and α 1 adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT 1A R partial agonists, the first being outstanding for selectivity (5-HT 1A /α 1d  = 80), the latter for potency (pD 2  = 9.58) and efficacy (E max  = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  1. PDE3, but not PDE4, reduces β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients

    PubMed Central

    Molenaar, Peter; Christ, Torsten; Hussain, Rizwan I; Engel, Andreas; Berk, Emanuel; Gillette, Katherine T; Chen, Lu; Galindo-Tovar, Alejandro; Krobert, Kurt A; Ravens, Ursula; Levy, Finn Olav; Kaumann, Alberto J

    2013-01-01

    Background and Purpose PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3–1 μM) or PDE4 inhibitor rolipram (1–10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. Experimental Approach Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β1 adrenoceptors (β2 adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2 adrenoceptors (β1 adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from –logEC50s. Key Results Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. Conclusions and Implications Metoprolol induces a control by PDE3 of ventricular effects mediated through both β1 and β2 adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β2 adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of

  2. Acute orexigenic effect of agmatine involves interaction between central α2-adrenergic and GABAergic receptors.

    PubMed

    Taksande, Brijesh Gulabrao; Sharma, Omi; Aglawe, Manish Manohar; Kale, Mayur Bhimrao; Gawande, Dinesh Yugraj; Umekar, Milind Janraoji; Kotagale, Nandkishor Ramdas

    2017-09-01

    Agmatine and GABA have been abundantly expressed in brain nuclei involved in regulation of energy homeostasis and promoting stimulation of food intake in rodents. However, their mutual interaction, if any, in the elicitation of feeding behavior is largely remains unclear. The current study provides experimental evidence for the possible interaction of agmatine, adrenergic and GABAergic systems in stimulation of feeding in satiated rats. Satiated rats fitted with intracerebroventricular (i.c.v.) cannulae and were administered agmatine, alone or jointly with (a) GABA A receptor agonist, muscimol, diazepam or antagonist bicuculline and flumazenil, GABA A positive modulator, allopregnanolone or negative modulator of GABA A receptor, dehydroepiandrosterone (b) In view of the high affinity of agmatine for α 2 -adrenoceptors and the close association between α 2 -adrenoceptors and GABAergic system, the effect of their modulators on feeding elicited by agmatine/GABAergic agonists were also examined. I.c.v. administration of agmatine (40-80μg/rat) induces the significant orexigenic effect in satiated rats. The orexigenic effect of agmatine was potentiated by muscimol (25ng/rat, i.c.v.); diazepam (0.5mg/kg, i.p.); allopregnanolone (0.5mg/kg, s.c.) and blocked by bicuculline (1mg/kg, i.p.) and dehydroepiandrosterone (4mg/kg,s.c.). However, it remained unaffected in presence of flumazenil (25ng/rat, i.c.v.). The orexigenic effect of agmatine and GABAergic agonists was potentiated by a α 2 -adrenoceptors agonist, clonidine (10ng/rat, i.c.v.) and blocked by its antagonist, yohimbine (5μg/rat, i.c.v.). Yohimbine also blocked the hyperphagic effect elicited by ineffective dose combination of agmatine (5μg/rat, i.c.v.) with muscimol (25ng/rat, i.c.v.) or diazepam (0.5mg/kg, i.p.) or allopregnanolone (0.5mg/kg,s.c.). The results of the present study suggest that agmatine induced α 2 -adrenoceptors activation might facilitate GABAergic activity to stimulate food intake in

  3. Effect of parecoxib sodium pretreatment combined with dexmedetomidine on early postoperative cognitive dysfunction in elderly patients after shoulder arthroscopy: A randomized double blinded controlled trial.

    PubMed

    Lu, Jian; Chen, Gang; Zhou, Hongmei; Zhou, Qinghe; Zhu, Zhipeng; Wu, Cheng

    2017-09-01

    To evaluate effect of parecoxib sodium pretreatment combined with dexmedetomidine on early postoperative cognitive dysfunction in elderly patients after shoulder arthroscopy. Randomized, double-blind study. University-affiliated teaching hospital. One hundred and fifty-two elderly patients scheduled for shoulder arthroscopy. At 15min before the induction of anesthesia, 152 patients received intravenously parecoxib sodium 40mg and dexmedetomidine at a dose of 0.5μg/kg over 15min, followed by a continuous infusion at a rate of 0.5μg/kg/h until the end of surgery. Then all patients who received postoperative patient-controlled intravenous analgesia were divided 2 groups: sufentanil(0.04μg/kg/h, S group), sufentanil (0.04μg/kg/h) plus dexmedetomidine(0.06μg/kg/h) (SD group). The mini-mental status examination score in SD group was significantly higher than S group at 1, 2 and 7days after surgery. The incidence of postoperative cognitive dysfunction during 7days after surgery in S and SD groups was respectively 17.1% and 6.7%. Compared with the S group, the visual analogue scale scores at rest and upon movement were significantly lower at 6, 14, 24, 36 and 48h after surgery in SD group; analgesia pump liquid amount during 24h after surgery and number of rescue analgesia during 48h after surgery were significantly lower in SD group. Jugular venous oxygen partial pressure and jugular venous oxygen saturation values in SD group were significantly higher than S group at postoperative 24h. The occurrence of nausea and vomiting within 48h after surgery in SD group were significantly lower than S group. We found no complications including respiratory depression and sinus bradycardia within 48h after surgery in all patients. Parecoxib sodium pretreatment combined with dexmedetomidine could reduce the incidence of early postoperative cognitive dysfunction in elderly patients. This might be related to the improvement of postoperative analgesia effect and cerebral oxygen

  4. Dexmedetomidine Dose Dependently Enhances the Local Anesthetic Action of Lidocaine in Inferior Alveolar Nerve Block: A Randomized Double-Blind Study.

    PubMed

    Ouchi, Kentaro; Sugiyama, Kazuna

    2016-01-01

    Dexmedetomidine (DEX) dose dependently enhances the local anesthetic action of lidocaine in rats. We hypothesized that the effect might also be dose dependent in humans. We evaluated the effect of various concentrations of DEX with a local anesthetic in humans. Eighteen healthy volunteers were randomly assigned by a computer to receive 1.8 mL of 1 of 4 drug combinations: (1) 1% lidocaine with 2.5 ppm (parts per million) (4.5 μg) DEX, (2) lidocaine with 5.0 ppm (9.0 μg) DEX, (3) lidocaine with 7.5 ppm (13.5μg) DEX, or (4) lidocaine with 1:80,000 (22.5 μg) adrenaline (AD), to produce inferior alveolar nerve block. Pulp latency and lower lip numbness (for assessing onset and duration of anesthesia) were tested, and sedation level, blood pressure, and heart rate were recorded every 5 minutes for 20 minutes, and every 10 minutes from 20 to 60 minutes. Pulp latency of each tooth increased compared with baseline, from 5 to 15 minutes until 60 minutes. There were no significant intergroup differences at any time point. Anesthesia onset was not different between groups. Anesthesia duration was different between groups (that with DEX 7.5 ppm was significantly longer than that with DEX 2.5 ppm and AD; there was no difference between DEX 2.5 ppm and AD). Blood pressure decreased from baseline in the 5.0 and 7.5 ppm DEX groups at 30 to 60 minutes, although there was no hypotension; moreover, heart rate did not change in any group. Sedation score did not indicate deep sedation in any of the groups. Dexmedetomidine dose dependently enhances the local anesthetic action of lidocaine in humans. Dexmedetomidine at 2.5 ppm produces similar enhancement of local anesthesia effect as addition of 1:80,000 AD.

  5. Effect of local wound infiltration with ketamine versus dexmedetomidine on postoperative pain and stress after abdominal hysterectomy, a randomized trial.

    PubMed

    Mohamed, S A; Sayed, D M; El Sherif, F A; Abd El-Rahman, A M

    2018-05-01

    Postoperative pain and stress elicit hormonal changes. We aimed at comparing the effects of wound infiltration with ketamine versus dexmedetomidine on postoperative pain and stress response. This double-blinded study included ninety patients scheduled for total abdominal hysterectomy and were randomly assigned into three groups to receive local wound infiltration with 40 mL of 0.25% bupivacaine (group C), plus 2 mg/kg ketamine (group K) or 2 μg/kg dexmedetomidine (group D). Primary outcome was postoperative morphine consumption; secondary outcomes included first request of analgesia, VAS scores at rest and movement (VAS-R/M) and side effects. Serum cortisol, prolactin and glucose levels at baseline, pre-infiltration, 6 and 24 h postoperatively were measured. Rescue analgesia was less in K (6.80 ± 3.19 mg) and D (8.39 ± 3.86 mg) compared to C (13.33 ± 4.01 mg) (p < 0.05). First request of analgesia was delayed in K (7.60 ± 4.16 h) and D (6.00 ± 3.73 h) compared to C (4.20 ± 1.13 h) (p < 0.05). Both VAS and R/M were significantly lower in K (all over 24 h) and D (for 8 and 4 h, respectively) compared to C. Stress markers were significantly lower in K and D compared to C at 6 and 24 h, and in K compared to D at 24 h (p < 0.05). Local wound infiltration with ketamine or dexmedetomidine added to bupivacaine had an opioid-sparing effect, delayed first request of rescue analgesia, and attenuated postoperative stress response, especially with ketamine in patients underwent total abdominal hysterectomy. © 2018 European Pain Federation - EFIC®.

  6. Discrimination between olfactory receptor agonists and non-agonists.

    PubMed

    Topin, Jérémie; de March, Claire A; Charlier, Landry; Ronin, Catherine; Antonczak, Serge; Golebiowski, Jérôme

    2014-08-11

    A joint approach combining free-energy calculations and calcium-imaging assays on the broadly tuned human 1G1 olfactory receptor is reported. The free energy of binding of ten odorants was computed by means of molecular-dynamics simulations. This state function allows separating the experimentally determined eight agonists from the two non-agonists. This study constitutes a proof-of-principle for the computational deorphanization of olfactory receptors. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Dexmedetomidine inhibits inflammatory reaction in the hippocampus of septic rats by suppressing NF-κB pathway.

    PubMed

    Zhang, Xiaobao; Yan, Fang; Feng, Jiying; Qian, Haitao; Cheng, Zhi; Yang, Qianqian; Wu, Yong; Zhao, Zhibin; Li, Aimin; Xiao, Hang

    2018-01-01

    Dexmedetomidine (DEX) is known to provide neuroprotective effect in the central nervous system. However, the detailed mechanism remains far more elusive. This study was designed to investigate the relevant mechanisms of DEX's neuroprotective effect. Sprague-Dawley (SD) rats were injected with dexmedetomidine and/or Lipopolysaccharide (LPS) intraperitoneally, and inflammatory cytokines in serum and in the hippocampus were measured by enzyme linked immunosorbent assay (ELISA). NF-κB in the brain tissue extracts was analyzed with western-blot. Then, we investigated whether NF-κB inhibitor prevents the elevation of inflammatory cytokines in rats injected with LPS. Our results indicated that compared with the control group, the rats exposed to LPS showed significant cognitive dysfunction. When compared to controls, the levels of TNF-α and IL-6 in the serum and hippocampus homogenate were increased in rats treated with LPS. DEX pretreatment inhibited the rats' TNF-α, IL-6 and NF-κB levels induced by LPS. In response to LPS, PDTC pretreatment restrains the production of proinflammatory cytokines (TNF-α and IL-6). Rats treated with PDTC and DEX alongside LPS exhibited less TNF-α and IL-6 than the LPS treated group. In combination, PDTC and DEX showed addictive effects. Our data suggest that DEX exerts a neuroprotective effect through NF-κB in part after LPS-induced cognitive dysfunction.

  8. Clonidine-induced nitric oxide-dependent vasorelaxation mediated by endothelial α2-adrenoceptor activation

    PubMed Central

    Figueroa, Xavier F; Poblete, M Inés; Boric, Mauricio P; Mendizábal, Victoria E; Adler-Graschinsky, Edda; Huidobro-Toro, J Pablo

    2001-01-01

    To assess the involvement of endothelial α2-adrenoceptors in the clonidine-induced vasodilatation, the mesenteric artery of Sprague Dawley rats was cannulated and perfused with Tyrode solution (2 ml min−1). We measured perfusion pressure, nitric oxide (NO) in the perfusate using chemiluminescence, and tissue cyclic GMP by RIA.In phenylephrine-precontracted mesenteries, clonidine elicited concentration-dependent vasodilatations associated to a rise in luminal NO. One hundred nM rauwolscine or 100 μM Lω-nitro-L-arginine antagonized the clonidine-induced vasodilatation. Guanabenz, guanfacine, and oxymetazoline mimicked the clonidine-induced vasorelaxation.In non-contracted mesenteries, 100 nM clonidine elicited a maximal rise of NO (123±13 pmol); associated to a peak in tissue cyclic GMP. Endothelium removal, Lω-nitro-L-arginine, or rauwolscine ablated the rise in NO. One hundred nM aminoclonidine, guanfacine, guanabenz, UK14,304 and oxymetazoline mimicked the clonidine-induced surge of NO. Ten μM ODQ obliterated the clonidine-induced vasorelaxation and the associated tissue cyclic GMP accumulation; 10 – 100 nM sildenafil increased tissue cyclic GMP accumulation without altering the clonidine-induced NO release.α2-Adrenergic blockers antagonized the clonidine-induced rise in NO. Consistent with a preferential α2D-adrenoceptor activation, the KBs for yohimbine, rauwolscine, phentolamine, WB-4101, and prazosin were: 6.8, 24, 19, 165, and 1489 nM, respectively.Rat pretreatment with 100 mg kg−1 6-hydroxydopamine reduced 95% tissue noradrenaline and 60% neuropeptide Y. In these preparations, 100 nM clonidine elicited a rise of 91.9±15.5 pmol NO. Perfusion with 1 μM guanethidine or 1 μM guanethidine plus 1 μM atropine did not modify the NO surge evoked by 100 nM clonidine.Clonidine and congeners activate endothelial α2D-adrenoceptors coupled to the L-arginine pathway, suggesting that the antihypertensive action of

  9. Immobilization of wild giant panda (Ailuropoda melanoleuca) with dexmedetomidine-tiletamine-zolazepam.

    PubMed

    Jin, Yipeng; Qiao, Yanchao; Liu, Xiaobin; Pu, Tianchun; Xu, Hongqian; Lin, Degui

    2016-05-01

    To assess the effects and utility of dexmedetomidine combined with tiletamine and zolazepam (dexMTZ) to immobilize the wild giant panda. Prospective clinical study. Seven giant pandas (Ailuropoda melanoleuca), five males and two females, aged 7-20 years and weighing 69.2-132.9 kg. Once an animal was located, prior data on the individual was reviewed and the panda's previously estimated body weight was used to calculate the volumes of drugs to administer: dexmedetomidine (dexM; 8 μg kg(-1) ; 0.5 mg mL(-1) ) and tiletamine-zolazepam (TZ; 2 mg kg(-1) ; 50 mg mL(-1) ). The mixture was injected intramuscularly (IM) using the Dan-Inject pistol system. When the panda was immobilized, it was weighed, a physical examination was performed and a blood sample collected. Every 5 minutes, the heart rate (HR), respiratory rate (fR ), rectal temperature (T), noninvasive systolic arterial pressure (SAP), capillary refill time (CRT), mucous membrane color and pulse quality were recorded. After all procedures had been completed, atipamezole (40 μg kg(-1) ) was injected IM. A single injection of dexMTZ resulted in the immobilization of all seven giant pandas. The median (range) of anesthetic agents administered was dexM 8.4 μg kg(-1) (7.3-10.5 μg kg(-1) ) and TZ 2.0 mg kg(-1) (1.8-2.5 mg kg(-1) ). The palpebral reflex was lost 8 (7-12) minutes after the injection. Most of the physiological variables remained in the acceptable range. All procedures were completed in approximately 1 hour. Six out of the seven (85.7%) giant pandas recovered smoothly; one panda had a rough recovery. DexMTZ produced a satisfactory immobilization and a smooth recovery for wild giant pandas while allowing approximately 55 minutes for planned noninvasive procedures. © 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  10. Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy

    PubMed Central

    Jakubík, J; Janíčková, H; El-Fakahany, EE; Doležal, V

    2011-01-01

    BACKGROUND AND PURPOSE Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5′-γ−thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M2 muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. EXPERIMENTAL APPROACH Filtration and scintillation proximity assays measured equilibrium binding as well as binding kinetics of [35S]GTPγS and [3H]GDP to a mixture of G-proteins as well as individual classes of G-proteins upon binding of structurally different agonists to the M2 muscarinic acetylcholine receptor. KEY RESULTS Agonists displayed biphasic competition curves with the antagonist [3H]-N-methylscopolamine. GTPγS (1 µM) changed the competition curves to monophasic with low affinity and 50 µM GDP produced a similar effect. Depletion of membrane-bound GDP increased the proportion of agonist high-affinity sites. Carbachol accelerated the dissociation of [3H]GDP from membranes. The inverse agonist N-methylscopolamine slowed GDP dissociation and GTPγS binding without changing affinity for GDP. Carbachol affected both GDP association with and dissociation from Gi/o G-proteins but only its dissociation from Gs/olf G-proteins. CONCLUSIONS AND IMPLICATIONS These findings suggest the existence of a low-affinity agonist-receptor conformation complexed with GDP-liganded G-protein. Also the negative cooperativity between GDP and agonist binding at the receptor/G-protein complex determines agonist efficacy. GDP binding reveals differences in action of agonists versus inverse agonists as well as differences in activation of Gi/o versus Gs/olf G-proteins that are not identified by conventional GTPγS binding. PMID:20958290

  11. Negative cooperativity in binding of muscarinic receptor agonists and GDP as a measure of agonist efficacy.

    PubMed

    Jakubík, J; Janíčková, H; El-Fakahany, E E; Doležal, V

    2011-03-01

    Conventional determination of agonist efficacy at G-protein coupled receptors is measured by stimulation of guanosine-5'-γ-thiotriphosphate (GTPγS) binding. We analysed the role of guanosine diphosphate (GDP) in the process of activation of the M₂ muscarinic acetylcholine receptor and provide evidence that negative cooperativity between agonist and GDP binding is an alternative measure of agonist efficacy. Filtration and scintillation proximity assays measured equilibrium binding as well as binding kinetics of [³⁵S]GTPγS and [³H]GDP to a mixture of G-proteins as well as individual classes of G-proteins upon binding of structurally different agonists to the M₂ muscarinic acetylcholine receptor. Agonists displayed biphasic competition curves with the antagonist [³H]-N-methylscopolamine. GTPγS (1 µM) changed the competition curves to monophasic with low affinity and 50 µM GDP produced a similar effect. Depletion of membrane-bound GDP increased the proportion of agonist high-affinity sites. Carbachol accelerated the dissociation of [³H]GDP from membranes. The inverse agonist N-methylscopolamine slowed GDP dissociation and GTPγS binding without changing affinity for GDP. Carbachol affected both GDP association with and dissociation from G(i/o) G-proteins but only its dissociation from G(s/olf) G-proteins. These findings suggest the existence of a low-affinity agonist-receptor conformation complexed with GDP-liganded G-protein. Also the negative cooperativity between GDP and agonist binding at the receptor/G-protein complex determines agonist efficacy. GDP binding reveals differences in action of agonists versus inverse agonists as well as differences in activation of G(i/o) versus G(s/olf) G-proteins that are not identified by conventional GTPγS binding. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  12. A Combination of Dexmedetomidine and Lidocaine Is a Cardiovascularly Safe Dental Local Anesthetic for Hypertensive Rats Treated With a Nonselective β-Adrenergic Antagonist.

    PubMed

    Tsutsui, Yukako; Sunada, Katsuhisa

    2017-01-01

    Hypertensive patients receiving nonselective β-adrenergic antagonists are vulnerable to hypertension and bradycardia when injected with dental local anesthetic formulations containing epinephrine. Dexmedetomidine (DEX), an α 2 -adrenergic agonist, has been reported to prolong and enhance the local anesthetic effects of lidocaine. The cardiovascular effects of the DEX-lidocaine combination have not yet been investigated in the presence of nonselective β-adrenergic antagonists. Therefore, we assessed the cardiovascular effects of the DEX-lidocaine combination in spontaneously hypertensive rats (SHR) treated with a nonselective β-adrenergic antagonist (propranolol). We injected propranolol-treated rats with various concentrations of DEX alone, 100 μg/kg epinephrine alone, or 5 μg/kg DEX combined with 2% lidocaine and measured their blood pressure (BP) and heart rates (HR) to assess the cardiovascular effects. The BP of propranolol-treated SHR was significantly increased by treatment with 100 μg/kg epinephrine alone. The BP and HR of propranolol-treated SHR were not significantly changed by treatment with low concentrations of DEX, but they were significantly decreased by treatment with a high concentration of DEX (50 μg/kg). Moreover, there was no significant difference in the BP and HR of propranolol-treated SHR after the injection of a combination of 5 μg/kg DEX and 2% lidocaine. Thus, the DEX-lidocaine combination may be an acceptable addition to dental local anesthetic solutions from a cardiovascular standpoint for hypertensive patients receiving nonselective β-adrenergic antagonists.

  13. β3-Adrenoceptor activation upregulates apolipoprotein A-I expression in HepG2 cells, which might further promote cholesterol efflux from macrophage foam cells.

    PubMed

    Gao, Xia-Qing; Li, Yan-Fang; Jiang, Zhi-Li

    2017-01-01

    The aim of this study was to explore the effects of β 3 -adrenoceptor (β 3 -AR) activation on HepG2 cells and its influence on cholesterol efflux from macrophage foam cells. HepG2 cells were cultured and treated with the β 3 -AR agonist, BRL37344, and antagonist, SR52390A, and the expression of apolipoprotein (Apo) A-I, ApoA-II, ApoB, and β 3 -AR in the supernatants and cells was determined. The expression of peroxisome proliferator-activated receptor (PPAR) γ and PPARα in the HepG2 cells was also assessed. Next, using the RAW264.7 macrophage foam cell model, we also assessed the influence of the HepG2 cell supernatants on lipid efflux. The cholesterol content of the foam cells was also measured, and the cholesterol efflux from the macrophages was examined by determining 3 H-labeled cholesterol levels. Expression of ATP-binding cassette transporter (ABC) A1 and ABCG1 of the macrophage foam cells was also assessed. β 3 -AR activation increased ApoA-I expression in both the HepG2 cells and the supernatants; PPARγ expression was upregulated, but PPARα expression was not. Treatment with GW9662 abolished the increased expression of ApoA-I induced by the β 3 -AR agonist. The HepG2 cell supernatants decreased the lipid accumulation and increased the cholesterol efflux from the macrophage foam cells. ABCA1 expression, but not ABCG1 expression, increased in the macrophage foam cells treated with BRL37344-treated HepG2 cell supernatants. Activation of β 3 -AR in HepG2 cells upregulates ApoA-I expression, which might further promote cholesterol efflux from macrophage foam cells. PPARγ might be required for the induction of ApoA-I expression.

  14. Postoperative Analgesia After Wound Infiltration With Tramadol and Dexmedetomidine as an Adjuvant to Ropivacaine for Lumbar Discectomies: A Randomized-controlled Clinical Trial.

    PubMed

    Mitra, Saikat; Purohit, Shobha; Sharma, Mamta

    2017-10-01

    Crippling postoperative pain linked with lumbar discectomies not only shackles patient's normal daily activities but also lengthens their hospital stay. So, allaying postoperative pain in these patients has become a substantive component in neuroanesthesia to expedite neurological recovery. Wound infiltration with local anesthetics is widely used to optimize postoperative pain. Different adjuvants like dexmedetomidine and tramadol when added to local anesthetics prolongs postoperative analgesia. The aim of this trial was to evaluate the analgesic efficacy of tramadol and dexmedetomidine when added to ropivacaine for wound infiltration in lumbar discectomies. This study was prospective, randomized, double-blind, controlled in nature conducted among 45 adult patients belonging to American Society of Anesthesiologists' physical status 1 and 2, of either sex aged between 30 and 70 years undergoing elective lumbar discectomies. They were randomly allocated into 3 equal groups: group R received 100 mg of 0.5% ropivacaine (20 mL) and 2 mL normal saline, group RT received 100 mg of 0.5% ropivacaine (20 mL) and 2 mg/kg tramadol (2 mL), and group RD received 100 mg of 0.5% ropivacaine (20 mL) and 0.5 μg/kg dexmedetomidine (2 mL) (total volume, 22 mL). Visual analog scale at 0, 2, 4, 6, 12, 18, and 24 hours; time to first rescue analgesia, total supplemental analgesic consumption and side effects (if any) were assessed during first 24 hours postoperatively. The median time to first rescue analgesia (median; 95% confidence interval [CI]) in group RD was 930 (854.3 to 1005.7) minutes. This was significantly longer (P=0.000) than group RT (420 [366.3 to 473.7] min) or group R (270 [243.2 to 296.8] min). Postoperative diclofenac consumed (median [interquartile range]) was 150 (150 to 200) mg in group R, 150 (75 to 150) mg in group RT and 75 (75 to 150) mg in group RD (P=0.008). Significant differences in mean visual analog scale scores were observed among the 3 groups at hours 0

  15. Interaction of metabolic and respiratory acidosis with α and β-adrenoceptor stimulation in rat myocardium.

    PubMed

    Biais, Matthieu; Jouffroy, Romain; Carillion, Aude; Feldman, Sarah; Jobart-Malfait, Aude; Riou, Bruno; Amour, Julien

    2012-12-01

    The effects of acute respiratory versus metabolic acidosis on the myocardium and their consequences on adrenoceptor stimulation remain poorly described. We compared the effects of metabolic and respiratory acidosis on inotropy and lusitropy in rat myocardium and their effects on the responses to α- and β-adrenoceptor stimulations. The effects of acute respiratory and metabolic acidosis (pH 7.10) and their interactions with α and β-adrenoceptor stimulations were studied in isolated rat left ventricular papillary muscle (n=8 per group). Intracellular pH was measured using confocal microscopy and a pH-sensitive fluorophore in isolated rat cardiomyocytes. Data are mean percentages of baseline±SD. Respiratory acidosis induced more pronounced negative inotropic effects than metabolic acidosis did both in isotonic (45±3 versus 63±6%, P<0.001) and isometric (44±5 versus 64±3%, P<0.001) conditions concomitant with a greater decrease in intracellular pH (6.85±0.07 versus 7.12±0.07, P<0.001). The response to α-adrenergic stimulation was not modified by respiratory or metabolic acidosis. The inotropic response to β-adrenergic stimulation was impaired only in metabolic acidosis (137±12 versus 200±33%, P<0.001), but this effect was not observed with administration of forskolin or dibutiryl-cyclic adenosine monophosphate. This effect might be explained by a change in transmembrane pH gradient only observed with metabolic acidosis. The lusitropic response to β-adrenergic stimulation was not modified by respiratory or metabolic acidosis. Acute metabolic and respiratory acidosis induce different myocardial effects related to different decreases in intracellular pH. Only metabolic acidosis impairs the positive inotropic effect of β-adrenergic stimulation.

  16. Dexmedetomidine for an awake fiber-optic intubation of a parturient with Klippel-Feil syndrome, Type I Arnold Chiari malformation and status post released tethered spinal cord presenting for repeat cesarean section

    PubMed Central

    Shah, Tanmay H.; Badve, Manasi S.; Olajide, Kowe O.; Skorupan, Havyn M.; Waters, Jonathan H.; Vallejo, Manuel C.

    2011-01-01

    Patients with Klippel-Feil Syndrome (KFS) have congenital fusion of their cervical vertebrae due to a failure in the normal segmentation of the cervical vertebrae during the early weeks of gestation and also have myriad of other associated anomalies. Because of limited neck mobility, airway management in these patients can be a challenge for the anesthesiologist. We describe a unique case in which a dexmedetomidine infusion was used as sedation for an awake fiber-optic intubation in a parturient with Klippel-Feil Syndrome, who presented for elective cesarean delivery. A 36-year-old female, G2P1A0 with KFS (fusion of cervical vertebrae) who had prior cesarean section for breech presentation with difficult airway management was scheduled for repeat cesarean delivery. After obtaining an informed consent, patient was taken in the operating room and non-invasive monitors were applied. Dexmedetomidine infusion was started and after adequate sedation, an awake fiber-optic intubation was performed. General anesthetic was administered after intubation and dexmedetomidine infusion was continued on maintenance dose until extubation. Klippel-Feil Syndrome (KFS) is a rare congenital disorder for which the true incidence is unknown, which makes it even rare to see a parturient with this disease. Patients with KFS usually have other congenital abnormalities as well, sometimes including the whole thoraco-lumbar spine (Type III) precluding the use of neuraxial anesthesia for these patients. Obstetric patients with KFS can present unique challenges in administering anesthesia and analgesia, primarily as it relates to the airway and dexmedetomidine infusion has shown promising result to manage the airway through awake fiberoptic intubation without any adverse effects on mother and fetus. PMID:24765318

  17. The 5-HT1A Receptor PET Radioligand 11C-CUMI-101 Has Significant Binding to α1-Adrenoceptors in Human Cerebellum, Limiting Its Use as a Reference Region.

    PubMed

    Shrestha, Stal S; Liow, Jeih-San; Jenko, Kimberly; Ikawa, Masamichi; Zoghbi, Sami S; Innis, Robert B

    2016-12-01

    Prazosin, a potent and selective α 1 -adrenoceptor antagonist, displaces 25% of 11 C-CUMI-101 ([O-methyl- 11 C]2-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione) binding in monkey cerebellum. We sought to estimate the percentage contamination of 11 C-CUMI-101 binding to α 1 -adrenoceptors in human cerebellum under in vivo conditions. In vitro receptor-binding techniques were used to measure α 1 -adrenoceptor density and the affinity of CUMI-101 for these receptors in human, monkey, and rat cerebellum. Binding potential (maximum number of binding sites × affinity [(1/dissociation constant]) was determined using in vitro homogenate binding assays in human, monkey, and rat cerebellum. 3 H-prazosin was used to determine the maximum number of binding sites, as well as the dissociation constant of 3 H-prazosin and the inhibition constant of CUMI-101. α 1 -adrenoceptor density and the affinity of CUMI-101 for these receptors were similar across species. Cerebellar binding potentials were 3.7 for humans, 2.3 for monkeys, and 3.4 for rats. Reasoning by analogy, 25% of 11 C-CUMI-101 uptake in human cerebellum reflects binding to α 1 -adrenoceptors, suggesting that the cerebellum is of limited usefulness as a reference tissue for quantification in human studies. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  18. The safety and efficacy of dexmedetomidine-remifentanil in children undergoing flexible bronchoscopy

    PubMed Central

    Li, Xia; Wang, Xue; Jin, Shuguang; Zhang, Dongsheng; Li, Yanuo

    2017-01-01

    Abstract Flexible bronchoscopy is more and more used for diagnosis and management of various pulmonary diseases in pediatrics. As poor coordination of children, the procedure is usually performed under general anesthesia with spontaneous or controlled ventilation to increase children and bronchoscopists’ safety and comfort. Previous studies have reported that dexmedetomidine (DEX) could be safely and effectively used for flexible bronchoscopy in both adulate and children. However, there is no trial to evaluate the dose-finding of safety and efficacy of dexmedetomidine-remifentanil (DEX-RF) in children undergoing flexible bronchoscopy. The objective of this study is to evaluate the dose-finding of safety and efficacy of DEX-RF in children undergoing flexible bronchoscopy. One hundred thirty-five children undergoing flexible bronchoscopy with DEX-RF were divided into 3 groups: Group DR1 (n = 47, DEX infusion at 0.5 μg·kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 0.5 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1), Group DR2 (n = 43, DEX infusion at 1 μg kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 1 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1), Group DR3 (n = 45, DEX infusion at 1.5 μg kg–1 for 10 minutes, then adjusted to 0.5–0.7 μg kg–1 h–1; RF infusion at 1 μg kg–1 for 2 minutes, then adjusted to 0.05–0.2 μg kg–1 min–1). Ramsay sedation scale of the 3 groups was maintained 3. Anesthesia onset time, total number of intraoperative children movements, hemodynamics (heart rate, arterial pressure, pulse oxygen saturation (SpO2), respiratory rate), total cumulative dose of dexmedetomidine and remifentanil, the amount of midazolam and lidocaine, time to first dose of rescue midazolam and lidocaine, postoperative recovery time, adverse events, bronchoscopist satisfaction

  19. The effects of dexmedetomidine and magnesium sulphate in adult patients undergoing endoscopic transnasal transsphenoidal resection of pituitary adenoma: A double-blind randomised study

    PubMed Central

    Soliman, Rabie; Fouad, Eman

    2017-01-01

    Background and Aim: Transnasal transsphenoidal resection of pituitary tumours is associated with blood loss and wide fluctuations in haemodynamic parameters. The aim of the present study was to compare the effect of dexmedetomidine and magnesium sulphate during the transsphenoidal resection of pituitary tumours. Methods: The study was a double-blind, randomised study and included 152 patients classified randomly into two groups: Group D: Dexmedetomidine was given as a loading dose 1 μg/kg over 10 min before induction followed by an infusion at 0.5 μg/kg/h during the surgery. Group M: Magnesium sulphate was given as loading dose of 50 mg/kg over 10 min followed by an infusion at 15 mg/kg/h during the surgery. The systolic, diastolic and mean arterial blood pressures, in addition to the amount of blood loss were measured at specific timepoints. Data were described in terms of mean ± standard deviation, median, frequencies, 95% confidence of interval of mean and percentages. Results: Mean bleeding score was lower in Group D than Group M (1.36 ± 0.48 vs. 3.05 ± 0.65, respectively; P = 0.002). Mean blood loss was lower in Group D (157.43 ± 48.79 ml vs.299.47 ± 77.28 ml in Group M; P < 0.001)Heart rate, mean arterial pressure, fentanyl requirements, end-tidal sevoflurane concentration, and extubation and emergence times were lower, while incidence of bradycardia and hypotension were higher in Group D. Conclusions: During transsphenoidal pituitary resection, dexmedetomidine, compared to magnesium, is associated with lower blood loss and better operating conditions but with more hypotension and bradycardia PMID:28584351

  20. α2 Adrenergic receptor-mediated inhibition of thermogenesis.

    PubMed

    Madden, Christopher J; Tupone, Domenico; Cano, Georgina; Morrison, Shaun F

    2013-01-30

    α2 adrenergic receptor (α2-AR) agonists have been used as antihypertensive agents, in the management of drug withdrawal, and as sedative analgesics. Since α2-AR agonists also influence the regulation of body temperature, we explored their potential as antipyretic agents. This study delineates the central neural substrate for the inhibition of rat brown adipose tissue (BAT) and shivering thermogenesis by α2-AR agonists. Nanoinjection of the α2-AR agonist clonidine (1.2 nmol) into the rostral raphe pallidus area (rRPa) inhibited BAT sympathetic nerve activity (SNA) and BAT thermogenesis. Subsequent nanoinjection of the α2-AR antagonist idazoxan (6 nmol) into the rRPa reversed the clonidine-evoked inhibition of BAT SNA and BAT thermogenesis. Systemic administration of the α2-AR agonists dexmedetomidine (25 μg/kg, i.v.) and clonidine (100 μg/kg, i.v.) inhibited shivering EMGs, BAT SNA, and BAT thermogenesis, effects that were reversed by nanoinjection of idazoxan (6 nmol) into the rRPa. Dexmedetomidine (100 μg/kg, i.p.) prevented and reversed lipopolysaccharide-evoked (10 μg/kg, i.p.) thermogenesis in free-behaving rats. Cholera toxin subunit b retrograde tracing from rRPa and pseudorabies virus transynaptic retrograde tracing from BAT combined with immunohistochemistry for catecholaminergic biosynthetic enzymes revealed the ventrolateral medulla as the source of catecholaminergic input to the rRPa and demonstrated that these catecholaminergic neurons are synaptically connected to BAT. Photostimulation of ventrolateral medulla neurons expressing the PRSx8-ChR2-mCherry lentiviral vector inhibited BAT SNA via activation of α2-ARs in the rRPa. These results indicate a potent inhibition of BAT and shivering thermogenesis by α2-AR activation in the rRPa, and suggest a therapeutic potential of α2-AR agonists for reducing potentially lethal elevations in body temperature during excessive fever.