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Sample records for beta-adrenergic antagonists

  1. Effects of beta-adrenergic antagonist, propranolol on spatial memory and exploratory behavior in mice.

    PubMed

    Sun, Huaying; Mao, Yu; Wang, Jianhong; Ma, Yuanye

    2011-07-08

    The beta-adrenergic system has been suggested to be involved in novelty detection and memory modulation. The present study aimed to investigate the role of beta-adrenergic receptors on novelty-based spatial recognition memory and exploratory behavior in mice using Y-maze test and open-field respectively. Mice were injected with three doses of beta-adrenergic receptor antagonist, propranolol (2, 10 and 20 mg/kg) or saline at three different time points (15 min prior to training, immediately after training and 15 min before test). The results showed that higher doses of propranolol (10 and 20 mg/kg) given before the training trial impaired spatial recognition memory while those injected at other two time points did not. A detailed analysis of exploratory behavior in open-field showed that lower dose (2 mg/kg) of propranolol reduced exploratory behavior of mice. Our findings indicate that higher dose of propranolol can impair acquisition of spatial information in the Y-maze without altering locomotion, suggesting that the beta-adrenergic system may be involved in modulating memory processes at the time of learning.

  2. Hypoxia-induced retinal ganglion cell death and the neuroprotective effects of beta-adrenergic antagonists.

    PubMed

    Chen, Yi-Ning; Yamada, Hideyuki; Mao, Wei; Matsuyama, Shigemi; Aihara, Makoto; Araie, Makoto

    2007-05-07

    Hypoxia-induced retinal ganglion cell (RGC) death has been implicated in glaucomatous optic neuropathy. However, the precise mechanism of death signaling and how neuroprotective agents affect it are still unclear. The aim of this study is to characterize the mechanisms of hypoxia-induced apoptosis of cultured purified RGCs and to study the neuroprotective effects of beta-adrenergic antagonists. Rat RGCs were purified utilizing a modified two-step immuno-panning procedure. First, the extent of apoptosis in RGCs under hypoxia was quantified. Next, the effects of glutamate-channel antagonists (MK801 or DNQX), Bax inhibiting peptide (BIP), and beta-adrenergic antagonists (betaxolol, nipradilol, timolol or carteolol) on hypoxia-induced RGC death were investigated by the cell viability assay. Third, the effects of beta-adrenergic antagonists on hypoxia-induced increase of intracellular calcium concentrations ([Ca(2+)](i)) and the additional effect of NO scavenger to nipradilol were evaluated. Apoptotic RGC percentages under hypoxia were significantly increased compared to the control. The viability of RGCs under hypoxia was not affected by MK801 or DNQX, whereas it was increased in a dose-dependent manner with exposure to BIP, and to betaxolol, nipradilol, timolol, but not to carteolol. These effective beta-adrenergic antagonists showed no significant change in hypoxia-induced [Ca(2+)](i) levels. The NO scavenger alleviated neuroprotective effect by nipradilol. In conclusion, purified RGC damage induced by hypoxia involves Bax-dependent apoptotic pathway, but mostly independent of glutamate receptor-mediated excitotoxicity. Betaxolol, timolol and nipradilol showed a protective effect against hypoxia-induced RGC death, which was thought to be irrelevant either to calcium channel or beta-adrenoceptor blocking effects.

  3. Management of beta-adrenergic blocker and calcium channel antagonist toxicity.

    PubMed

    Kerns, William

    2007-05-01

    State-of-the-art therapy for beta-adrenergic receptor blocker and calcium channel antagonist toxicity is reviewed in the light of new insights into drug-induced shock. A brief discussion of pathophysiology, including cardiac, hemodynamic, and metabolic effects of cardiac drug toxicity, provides a foundation for understanding the basis of therapy. The major focus of this review is a critical evaluation of antidotal use of calcium, glucagon, catecholamines, insulin-euglycemia, and other novel therapies based on investigational studies and cumulative clinical experience.

  4. Effect of beta adrenergic antagonist on the production of testosterone by rat's Leydig cells.

    PubMed

    Khan, Umar Ali; Aslam, Muhammad; Saeed, S Abdul

    2004-01-01

    The Leydig cell is the source of the male sex steroids, or androgens, which are essential for the maintenance of the male phenotype, the male gonads. and spermatogenesis. It has been reported that patients taking beta-blockers experience sexual dysfunction. The purpose of this study was to explore the direct mechanism by which beta adrenergic antagonist exert its' effect on testosterone production by rat Leydig cells. Enzymatic dispersion of rat Leydig cell was done. About 85000 cells per tube were taken. After removal of endogenous testosterone by preincubation, The rat Leydig cells were incubated with varying concentrations of Atenolol: [Selective Beta-Adrenergic Antagonist] (10(-6), 10(-7) and 10(-9) M) with or with out LH 250 IU for three hours to measure the testosterone release by RIA. Atenolol, in varying concentrations caused a significant (P<0.05) reduction in testosterone release by the rat Leydig cells as compared to the basal release of testosterone in a dose-dependent fashion. Atenolol decreased the testosterone release by LH stimulated Leydig cells more significantly (P<0.001) as compared to the effects of Atenolol produced on non-stimulated Leydig cells. The current data indirectly suggest that Atenolol inhibits testosterone releasee via mechanism involving decrease production of cAMP but not affecting the enzyme activities of steroidogenesis.

  5. Beta-adrenergic antagonist effects on a novel cognitive flexibility task in rodents.

    PubMed

    Hecht, Patrick M; Will, Matthew J; Schachtman, Todd R; Welby, Lauren M; Beversdorf, David Q

    2014-03-01

    Previous work examining animal models of cognitive flexibility have focused on tasks where animals are required to shift between cues in order to reach a food reward from among a limited set of choices. Performance by nonhuman animals on these tasks, including reversal learning, intradimensional set-shifting, and extradimensional set-shifting, are affected by pharmacological action on serotonergic, dopaminergic, and alpha-adrenergic, but not beta-adrenergic receptors. However, beta-adrenergic antagonists, such as propranolol, are widely utilized for conditions such as test anxiety. Propranolol improves performance in humans during cognitive flexibility tasks where there is a broad set of potential solutions. The current investigation utilized a digging task where the rodent must develop a novel solution in order to obtain a reward. Similar to the effects observed in humans, propranolol improved performance on this task, while not affecting performance on set-shifting tasks, as with previous animal studies. This may allow future investigation of the neurobiological mechanism by which propranolol affects context-specific anxiety, and could provide insight into the neurobiology of creativity. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Effect of beta-adrenergic antagonists on bioluminescence control in three species of brittlestars (Echinodermata: Ophiuroidea).

    PubMed

    Dupont, S; Mallefet, J; Vanderlinden, C

    2004-05-01

    The role of adrenaline in the nervous control of bioluminescence in three brittlestar species, Amphiura filiformis, Amphipholis squamata, and Ophiopsila aranea, was assessed by testing two different beta-adrenergic antagonists (propranolol and labetalol) over a wide concentration range (10(-10)-10(-3)M). We compared the effects of analogues (active vs. inactive) of the same substance (L- and D-enantiomers of propranolol). Propranolol presented both specific and nonspecific effects: (i) nonspecific effects were observed at the higher concentrations tested (10(-4) and 10(-3)M) in all three species; (ii) specific effects were detected only at the lower concentrations tested (10(-6)-10(-5)M). In A. squamata, the involvement of adrenaline in the nervous control of luminescence is supported by propranolol and labetolol specific inhibition. The neuropharmacological implications of nonspecific effects, the involvement of adrenaline and the interspecific differences in the brittlestar nervous control of bioluminescence are discussed.

  7. Systemic and ocular vascular roles of the antiglaucoma agents beta-adrenergic antagonists and Ca2+ entry blockers.

    PubMed

    Yu, D Y; Su, E N; Cringle, S J; Alder, V A; Yu, P K; DeSantis, L

    1999-06-01

    This review addresses whether the antiglaucoma agents beta-adrenergic antagonists and Ca2+ entry blockers cause vasoactive effects in the retinal and other ocular vasculatures, as they do in other tissues. The potent vasodilating effects of Ca2+ entry blockers on ocular vessels have recently been demonstrated in in vivo and in vitro studies, implying that the maintenance of ocular vascular tone relies almost exclusively on extracellular Ca2+. Ca2+ entry blockers may potentially play a role in relaxing the retinal, long posterior ciliary, and ophthalmociliary arteries to improve the ocular circulation in vascular diseases in which there is considerable vascular tone present. The beta-adrenergic antagonists are discussed with reference to their antihypertensive role, their effect on other vascular beds, and finally what is known of their effect in the ocular vasculature. The emerging evidence that particular selective beta-adrenergic antagonists, such as betaxolol, are also potent Ca2+ channel entry blockers in other vascular beds is presented. Betaxolol has been shown to induce vasodilatation in the retinal and other ocular vascular beds, although studies have shown that beta1-adrenergic receptors are sparse in these vascular beds. This implies that an alternative mechanism must be responsible for betaxolol-induced vasodilatation. Evidence is presented that betaxolol vasodilates via its potent Ca2+ channel entry blocking properties, and its potency and ability to vasodilate are compared with those of nimodipine and timolol, as well as with those of other Ca2+ channel entry blockers. Important areas for future research in this area are discussed.

  8. [Sleep disturbances in Smith-Magenis syndrome: treatment with melatonin and beta-adrenergic antagonists].

    PubMed

    Van Thillo, A; Devriendt, K; Willekens, D

    2010-01-01

    Smith-Magenis syndrome is a generic disorder, characterised by physical, neurological and behavioural features and caused by a 17p11.2 deletion. Patients with this syndrome typically display an inversion of the sleep-wake cycle. In this article we describe clinical developments in a two-year-old girl with Smith-Magenis syndrome whose sleep problems were successfully treated with melatonin and beta-adrenergic blockers. We also mention relevant data obtained in our literature search.

  9. Interaction of beta-adrenergic agonists and antagonists with the stimulation of growth hormone release induced by clonidine or by morphine in the rat.

    PubMed

    Bluet-Pajot, M T; Durand, D; Mounier, F; Schaub, C; Kordon, C

    1982-09-01

    The beta-adrenergic agonist, isoprenaline, and antagonist, propranolol, had no effect on the delayed basal secretion of GH consistently observed in rats treated with the narco-analgesic gamma-hydroxybutyrate. Under the same experimental conditions, GH release was distinctly stimulated by infusion of the alpha-adrenergic agonist, clonidine, and by morphine; both responses were dose-dependent. The effects of beta-adrenergic agonists and antagonists on these GH responses were as follows: in rats pretreated with isoprenaline -the GH release induced by clonidine and morphine was abolished whereas it was enhanced in rats pretreated with propranolol. These data confirmed and extended previous reports from this laboratory on the inhibitory role of beta-adrenergic receptors on GH regulation.

  10. Direct intra-accumbal infusion of a beta-adrenergic receptor antagonist abolishes WIN 55,212-2-induced aversion

    PubMed Central

    Carvalho, Ana Franky; Van Bockstaele, Elisabeth J.

    2011-01-01

    The cannabinoid system is known to interact with a variety of neuromodulators in the central nervous system and impacts diverse behaviors. Previous studies have demonstrated that limbic norepinephrine is a critical determinant in the behavioral expression of cannabinoid-induced aversion. The present study was carried out to define the adrenergic receptor subtype involved in mediating cannabinoid-induced behavioral responses. An acute microinjection of the β1-adrenergic receptor blocker, betaxolol, directly into the nucleus accumbens (Acb), was able to prevent WIN 55,212-2-induced aversion, but not lithium-induced aversion, as measured in a place conditioning paradigm. These results suggest that noradrenergic transmission in the Acb is important for cannabinoid-induced aversion and that beta-adrenergic antagonists may be effective in counteracting negative side effects of cannabinoid-based agents. PMID:21693171

  11. Direct intra-accumbal infusion of a beta-adrenergic receptor antagonist abolishes WIN 55,212-2-induced aversion.

    PubMed

    Carvalho, Ana Franky; Van Bockstaele, Elisabeth J

    2011-08-01

    The cannabinoid system is known to interact with a variety of neuromodulators in the central nervous system and impacts diverse behaviors. Previous studies have demonstrated that limbic norepinephrine is a critical determinant in the behavioral expression of cannabinoid-induced aversion. The present study was carried out to define the adrenergic receptor subtype involved in mediating cannabinoid-induced behavioral responses. An acute microinjection of the β1-adrenergic receptor blocker, betaxolol, directly into the nucleus accumbens (Acb), was able to prevent WIN 55,212-2-induced aversion, but not lithium-induced aversion, as measured in a place conditioning paradigm. These results suggest that noradrenergic transmission in the Acb is important for cannabinoid-induced aversion and that beta-adrenergic antagonists may be effective in counteracting negative side effects of cannabinoid-based agents. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  12. Beta-adrenergic receptor agonists delay while antagonists accelerate epithelial wound healing: evidence of an endogenous adrenergic network within the corneal epithelium.

    PubMed

    Pullar, Christine E; Zhao, Min; Song, Bing; Pu, Jin; Reid, Brian; Ghoghawala, Shahed; McCaig, Colin; Isseroff, R Rivkah

    2007-04-01

    Wound healing is a complex and well-orchestrated biological process. Corneal epithelial cells (CECs) must respond quickly to trauma to rapidly restore barrier function and protect the eye from noxious agents. They express a high level of beta2-adrenergic receptors but their function is unknown. Here, we report the novel finding that they form part of a regulatory network in the corneal epithelium, capable of modulating corneal epithelial wound repair. Beta-adrenergic receptor agonists delay CEC migration via a protein phosphatase 2A-mediated mechanism and decrease both electric field-directed migration and corneal wound healing. Conversely, beta-adrenergic receptor antagonists accelerate CEC migration, enhance electric field-mediated directional migration, and promote corneal wound repair. We demonstrate that CECs express key enzymes required for epinephrine (beta-adrenergic receptor agonist) synthesis in the cytoplasm and can detect epinephrine in cell extracts. We propose that the mechanism for the pro-motogenic effect of the beta-adrenergic antagonist is blockade of the beta2-adrenergic receptor preventing autocrine catecholamine binding. Further investigation of this network will improve our understanding of one of the most frequently prescribed class of drugs. (c) 2007 Wiley-Liss, Inc.

  13. Beta-adrenergic receptor antagonists and chronic heart failure in children

    PubMed Central

    Filippo, Sylvie Di

    2007-01-01

    Chronic congestive heart failure (HF) occurs in infants and children as a result of systemic ventricle incompetence. Neurohormonal activation is thought to be the main consequence of cardiac pump failure and cause of further worsening. Several large multicenter randomized trials have demonstrated that beta-adrenergic blocking agents can improve ventricular ejection fraction, symptoms, and survival in adults with chronic congestive HF. Current literature about pediatric HF is very scarce. The only large, multicenter, randomized, placebo-controlled pediatric trial failed to demonstrate any beneficial effect of beta-blockers in infants and children with chronic HF. Other small-size reports showed significant improvement in ejection fraction and/or clinical outcomes. The HF pediatric population is characterized by wide heterogeneicity regarding causes, underlying cardiac disease, drug pharmacokinetics, and interactions, which may account for divergences. Further large-scale studies are needed to elucidate the optimal use (indications and dosages) of beta-blockers in the management of HF in children, with particular attention to the underlying cardiac disease. PMID:18473008

  14. Potentiation of thermoregulatory responses to isoproterenol by beta-adrenergic antagonists.

    PubMed

    Carlisle, H J; Stock, M J

    1992-10-01

    The thermoregulatory effects of isothermogenic doses of isoproterenol (Iso) and a novel beta-agonist (BRL 35135) were tested in rats at 22 degrees C and in rats trained to bar press for radiant heat at -8 degrees C. BRL 35135 produced hyperthermia at 22 degrees C and reduced operant responding for heat at -8 degrees C, whereas Iso reduced body temperature and increased operant responding. In both situations, the negative effects of Iso on thermal balance were abolished by propranolol at doses that did not inhibit heat production. In anesthetized rats, propranolol potentiated the Iso-induced rise in brown adipose tissue and colonic temperature. The potentiation was more marked with the beta 2-selective antagonist ICI 118,551, whereas treatment with the beta 1-selective antagonist atenolol resulted in a profound Iso-induced reduction in temperature. The two selective antagonists also produced divergent responses in operant behavior in Iso-treated rats at -8 degrees C. These experiments demonstrate the extent to which responses to a nonselective agonist can be manipulated using appropriately low doses of selective antagonists and indicate that the effects of Iso on thermal balance are due to its beta 2 activity.

  15. (-)(125I)-iodopindolol, a new highly selective radioiodinated beta-adrenergic receptor antagonist: measurement of beta-receptors on intact rat astrocytoma cells

    SciTech Connect

    Barovsky, K.; Brooker, G.

    1980-01-01

    (-)-Pindolol, one of the most potent beta-adrenergic receptor antagonists, was radioiodinated using chloramine-T oxidation of carrier-free Na 125I and separated from unreacted pindolol to yield 2200 Ci/mmole (-)-(125I)-iodopindolol ((-)-(125I)-IPin). Mass and ultraviolet spectra confirmed that the iodination occurred on the indole ring, presumably at the 3 position. The binding of radiolabeled (-)-(125I)-IPin to beta-adrenergic receptors has been studied using intact C6 rat astrocytoma cells (2B subclone) grown in monolayer cultures. Binding of (-)(125IPin was saturable with time and concentration. Using 13 pM (-)-(125I)IPin, binding equilibrium was reached in 90 min at 21-22 degrees C. The reverse rate constant was 0.026 min-1 at 21/sup 0/C. Specific binding (expressed as 1 microM(-)-propranolol displaceable counts) of (-)-(125I)-IPin was 95% of total binding. Scatchard analysis of (-)-(125I)-I)Pin binding revealed approximately 4300 receptors/cell and a dissociation constant of 30 pM. This was in excellent agreement with the kinetically determined dissociation constant of 35 pM. Displacement by propranolol and isoproterenol showed that (-)-(125I)-IPin binding sites were pharmacologically and stereospecifically selective. These results indicate that (-)-(125I)-IPin, a pure (-)-stereoisomer, high specific activity radioligand, selectively binds to beta-adrenergic receptors in whole cells with a high percentage of specific binding and should therefore be useful in the study and measurement of cellular beta-adrenergic receptors.

  16. Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma

    PubMed Central

    Wolter, Jennifer K; Wolter, Nikolaus E; Blanch, Alvaro; Partridge, Teresa; Cheng, Lynn; Morgenstern, Daniel A.; Podkowa, Monika; Kaplan, David R.; Irwin, Meredith S.

    2014-01-01

    Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system, which is often associated with elevated catecholamines. More than half of patients with metastatic NB relapse and survival is extremely poor with current therapies. In a high-throughput screen of FDA-approved drugs we identified anti-NB activity for the nonselective β-adrenergic receptor antagonist propranolol hydrochloride. Propranolol inhibited growth of a panel of fifteen NB cell lines irrespective of MYCN status, and treatment induced apoptosis and decreased proliferation. Activity was dependent on inhibition of the β2, and not β1, adrenergic receptor, and treatment resulted in activation of p53 and p73 signaling in vitro. The majority of NB cell lines and primary tumors express β2 adrenergic receptor and higher mRNA levels correlate with improved patient survival, but expression levels did not correlate with in vitro sensitivity to propranolol. Furthermore, propranolol is synergistic with the topoisomerase I inhibitor SN-38 and propranolol inhibits growth of NB xenografts in vivo at doses similar to those used to treat infants with hemangiomas and hypertension. Taken together, our results suggest that propranolol has activity against NB and thus should be considered in combination treatments for patients with relapsed and refractory NB. PMID:24389287

  17. Anti-tumor activity of the beta-adrenergic receptor antagonist propranolol in neuroblastoma.

    PubMed

    Wolter, Jennifer K; Wolter, Nikolaus E; Blanch, Alvaro; Partridge, Teresa; Cheng, Lynn; Morgenstern, Daniel A; Podkowa, Monika; Kaplan, David R; Irwin, Meredith S

    2014-01-15

    Neuroblastoma (NB) is a pediatric tumor of the sympathetic nervous system, which is often associated with elevated catecholamines. More than half of patients with metastatic NB relapse and survival is extremely poor with current therapies. In a high-throughput screen of FDA-approved drugs we identified anti-NB activity for the nonselective β-adrenergic receptor antagonist propranolol hydrochloride. Propranolol inhibited growth of a panel of fifteen NB cell lines irrespective of MYCN status, and treatment induced apoptosis and decreased proliferation. Activity was dependent on inhibition of the β2, and not β1, adrenergic receptor, and treatment resulted in activation of p53 and p73 signaling in vitro. The majority of NB cell lines and primary tumors express β2 adrenergic receptor and higher mRNA levels correlate with improved patient survival, but expression levels did not correlate with in vitro sensitivity to propranolol. Furthermore, propranolol is synergistic with the topoisomerase I inhibitor SN-38 and propranolol inhibits growth of NB xenografts in vivo at doses similar to those used to treat infants with hemangiomas and hypertension. Taken together, our results suggest that propranolol has activity against NB and thus should be considered in combination treatments for patients with relapsed and refractory NB.

  18. [Beta-adrenergic receptor blocker poisoning].

    PubMed

    Reingardiene, Dagmara

    2007-01-01

    Beta-adrenergic receptor blocking drugs are used in the treatment of hypertension, angina, myocardial infarction, cardiac dysrhythmia, cardiomyopathy, migraine headache, thyrotoxicosis, and glaucoma. beta-adrenergic receptor blocking agents are competitive antagonist at beta(1), beta(2), or both types of adrenergic receptors. Overdoses of beta-adrenergic receptor blockers are uncommon, but are associated with significant morbidity and mortality. This review article discusses the properties of beta-adrenergic receptor blockers, presents the doses of these drugs causing toxicity and doses, after ingestion of which, referral to an emergency department is recommended. Clinical presentation of overdose (the cardiovascular, neurologic manifestations, pulmonary and other complications), diagnosis, and treatment (gastrointestinal decontamination; the usage of atropine, phosphodiesterase inhibitors, glucagon, insulin; indications for cardiac pacing, extracorporeal procedures of drug removal, etc.) are analyzed. In addition, this article focuses on clinical course and prognosis of beta-blocker overdose.

  19. Effect of a beta-adrenergic antagonist on blood pressure, heart rate and beta-adrenoceptors in turkey poults.

    PubMed

    Kuenzel, W J; Kusiak, J W; Augustine, P C; Pitha, J

    1983-01-01

    An irreversible beta-adrenergic blocker, bromoacetylalprenololmenthane (BAAM), was administered both peripherally and centrally to turkey poults, Meleagris gallopavo. Peripheral administration of BAAM (60 mg/kg body weight) effected a significant reduction in blood pressure and heart rate. Twenty minutes postinjection, mean blood pressure and heart rate were reduced 34.5 and 24.2%, respectively. Two days later, mean blood pressure values remained significantly depressed at 17.3% below preinjection determinations. Biochemical analysis of heart tissue following peripheral (intraperitoneal) injections of BAAM (60 mg/kg body weight) showed a significant decrease in beta-adrenergic receptors (BAR). Little or no change in the number of BAR in brain tissue was observed. Central (intraventricular) administration of BAAM (0.72 mg/g brain weight) resulted in no change in mean blood pressure or heart rate during a 20 min postinjection period. Biochemical analysis of heart tissue following central injections of BAAM showed little or no change in the number of BAR. There was, however, a significant decrease in the number of BAR in brain tissue.

  20. Influence of beta-adrenergic antagonists, H1-receptor blockers, analgesics, diuretics, and quinolone antibiotics on the cellular accumulation of the anticancer drug, daunorubicin: P-glycoprotein modulation.

    PubMed

    Ibrahim, S; Peggins, J; Knapton, A; Licht, T; Aszalos, A

    2001-01-01

    Treatment of patients with several drugs simultaneously may result in modulation of the naturally expressed P-glycoprotein (Pgp) at different tissues. With this possibility in mind, we have assessed the ability of different classes of drugs to modulate Pgp function in vitro. Modulation of the Pgp function was studied at in vitro drug concentrations comparable to therapeutic blood levels of the drugs. Human blood brain barrier endothelial cells and human colon adenocarcinoma cells were transduced or transfected with the multidrug resistance gene (MDR1) to express Pgp. The uptake of fluorescent substrates of Pgp, Rhodamine 123 and daunorubicin, into these cells and NIH3T3/MDR1 and MDCK/MDR1 cells was measured by flow cytometry and in monolayers in the presence and absence of the different drugs. From the tested six H1-receptor blockers, seven beta-adrenergic antagonists, four analgesics, ten diuretics and five quinolons, five drugs inhibited Pgp at therapeutic blood levels and two at somewhat higher concentrations. Significant synergism for blocking Pgp could be demonstrated for several drugs. We conclude that administration of several drugs which modulate the function of Pgp to patients may adversely affect the natural function of this efflux pump and may cause drug-drug interactions induced side effects.

  1. Discriminative stimulus properties of clenbuterol: evidence for beta adrenergic involvement.

    PubMed

    McElroy, J F; O'Donnell, J M

    1988-04-01

    Thirty rats were trained to discriminate the centrally acting beta adrenergic agonist clenbuterol (0.1 mg/kg) from saline using a water-reinforced (fixed-ratio 10 schedule) two-lever operant task. Discrimination acquisition required a mean +/- S.E.M. of 42 +/- 7 training sessions (median of 26 training sessions). The clenbuterol stimulus was dose-dependent (ED50 = 0.03 mg/kg) and stereoselective, and had a rapid onset (5 min) and a duration of approximately 1 hr. The beta adrenergic antagonist propranolol fully antagonized the clenbuterol discriminative stimulus (IC50 = 0.18 mg/kg). Other beta adrenergic agonists such as SOM 1122 (ED50 = 0.01 mg/kg), zinterol (ED50 = 0.03 mg/kg), salbutamol (ED50 = 0.23 mg/kg) and prenalterol (ED50 = 1.91 mg/kg) substituted for clenbuterol. The monoamine uptake inhibitor despiramine (ED50 = 2.25 mg/kg), the psychomotor stimulants amphetamine (ED50 = 0.33 mg/kg) and pentylenetetrazol (ED50 = 0.31 mg/kg), and the dopamine receptor antagonists haloperidol (ED50 = 0.08 mg/kg) and chlorpromazine (ED50 = 2.32 mg/kg) similarly substituted for clenbuterol. However, chlordiazepoxide, pentobarbital, fentanyl, cocaine and fenfluramine produced little or no clenbuterol lever selection up to doses that decreased response rate markedly. The ability of SOM 1122, zinterol, salbutamol, despiramine, amphetamine, pentylenetetrazol and haloperiol to substitute for the clenbuterol stimulus was antagonized by prior treatment with propranolol. Taken together, these results suggest that the discriminative stimulus properties of clenbuterol are mediated, at least in part, through an interaction with beta adrenergic receptors. The same drugs also were assayed for in vitro inhibition of [125I]iodopindolol binding to beta adrenergic receptor preparations of rat cerebral cortex and cerebellum.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. [Beta]-Adrenergic Receptors in the Insular Cortex are Differentially Involved in Aversive vs. Incidental Context Memory Formation

    ERIC Educational Resources Information Center

    Miranda, Maria Isabel; Sabath, Elizabeth; Nunez-Jaramillo, Luis; Puron-Sierra, Liliana

    2011-01-01

    The goal of this research was to determine the effects of [beta]-adrenergic antagonism in the IC before or after inhibitory avoidance (IA) training or context pre-exposure in a latent inhibition protocol. Pretraining intra-IC infusion of the [beta]-adrenergic antagonist propranolol disrupted subsequent IA retention and impaired latent inhibition…

  3. [Beta]-Adrenergic Receptors in the Insular Cortex are Differentially Involved in Aversive vs. Incidental Context Memory Formation

    ERIC Educational Resources Information Center

    Miranda, Maria Isabel; Sabath, Elizabeth; Nunez-Jaramillo, Luis; Puron-Sierra, Liliana

    2011-01-01

    The goal of this research was to determine the effects of [beta]-adrenergic antagonism in the IC before or after inhibitory avoidance (IA) training or context pre-exposure in a latent inhibition protocol. Pretraining intra-IC infusion of the [beta]-adrenergic antagonist propranolol disrupted subsequent IA retention and impaired latent inhibition…

  4. Developmental changes of beta-adrenergic receptor-linked adenylate cyclase of rat liver

    SciTech Connect

    Katz, M.S.; Boland, S.R.; Schmidt, S.J.

    1985-06-01

    beta-Adrenergic agonist-sensitive adenylate cyclase activity and binding of the beta-adrenergic antagonist(-)-(/sup 125/I)iodopindolol were studied in rat liver during development of male Fischer 344 rats ages 6-60 days. In liver homogenates maximum adenylate cyclase response to beta-adrenergic agonist (10(-5) M isoproterenol or epinephrine) decreased by 73% (P less than 0.01) between 6 and 60 days, with most of the decrease (56%; P less than 0.01) occurring by 20 days. beta-adrenergic receptor density (Bmax) showed a corresponding decrease of 66% (P less than 0.01) by 20 days without subsequent change. Binding characteristics of stereospecificity, pharmacological specificity, saturability with time, and reversibility were unchanged with age. GTP-, fluoride-, forskolin-, and Mn2+-stimulated adenylate cyclase activities also decreased during development, suggesting a decrease of activity of the catalytic component and/or guanine nucleotide regulatory component of adenylate cyclase. These results indicate that the developmental decrease of beta-adrenergic agonist-sensitive adenylate cyclase activity may result from decreased numbers of beta-adrenergic receptors. Developmental alterations of nonreceptor components of the enzyme may also contribute to changes of catecholamine-sensitive adenylate cyclase.

  5. Photoaffinity labeling the. beta. -adrenergic receptor with an iodoazido derivative of norepinephrine

    SciTech Connect

    Resek, J.F.

    1989-01-01

    The {beta}-adrenergic receptor is an integral membrane protein coupled to adenylate cyclase by the guanine nucleotide binding protein, Gs. Agonist binding to the receptor results in coupling the receptor to Gs, increased adenylate cyclase activity, and receptor desensitization. In contrast, antagonists bind but do not activate the receptor or result in desensitization. To study the structure and regulation of the {beta}-adrenergic receptor in the membrane, it is useful to develop ligands which covalently label the binding site. In this thesis the synthesis and characterization of the first agonist photolabel for the {beta}-adrenergic receptor is presented. The agonist photoaffinity label, N-(p-azido-m-iodophenethylamidoisobutyl)-norepinephrine (NAIN), was synthesized in non-radioactive and radioactive carrier-free forms with {sup 125}I (2,200 Ci/mmole). NAIN was chemically characterized by TLC mobility, melting point, NMR, IR, and Mass Spectroscopy. NAIN was shown to be competitive with the {beta}-adrenergic ligand ({sup 125}I)-ICYP in several membranes containing {beta}-adrenergic receptors. Binding data indicated that NAIN coupled the receptor to Gs and had an affinity for the receptor which was similar to isoproterenol. NAIN stimulated adenylate cyclase activity in guinea pig lung and S49 WT mouse lymphoma cell membranes with a K{sub act} and V max similar to isoproterenol while in frog erythrocyte ghosts, NAIN produced 77% of the maximally stimulated adenylate cyclase activity of isoproterenol. These data show that NAIN is an agonist for the {beta}-adrenergic receptor.

  6. Levobetaxolol (Betaxon) and other beta-adrenergic antagonists: preclinical pharmacology, IOP-lowering activity and sites of action in human eyes.

    PubMed

    Sharif, N A; Xu, S X; Crider, J Y; McLaughlin, M; Davis, T L

    2001-08-01

    The pharmacological characteristics of levobetaxolol, a single active isomer of betaxolol, were determined and compared with activities of other beta-adrenoceptor antagonists. Levobetaxolol (43-fold beta1-selective) exhibited a higher affinity at cloned human beta1 (Ki = 0.76 nM) than at beta2 (Ki = 32.6 nM) receptors, while dextrobetaxolol was much weaker at both receptors. Levobetaxolol potently antagonized functional activities at cloned human beta1 and beta2 receptors, and also at guinea pig atrial beta1, tracheal beta2 and rat colonic beta3 receptors (IC50s = 33.2 nM, 2970 nM and 709 nM, respectively). Thus, levobetaxolol was 89-times beta1-selective (vs beta2). Levobetaxolol (Ki = 16.4 nM) was more potent than dextrobetaxolol (Ki = 2.97 microM) at inhibiting isoproterenol-induced cAMP production in human non-pigmented ciliary epithelial cells. Levobunolol and (l)-timolol had high affinities at beta1 and beta2 receptors but were considerably less beta1-selective than levobetaxolol. Levo-, dextro- and racemic-betaxolol exhibited little or no affinity, except at sigma sites and Ca2+-channels (IC50s > 1 microM), at 89 other receptor/ligand binding sites. Levobetaxolol exhibited a micromolar affinity for L-type Ca2+-channels. In conscious ocular hypertensive cynomolgus monkeys, levobetaxolol was more potent than dextrobetaxolol, reducing intraocular pressure by 25.9+/-3.2% at a dose of 150 microg/eye (n = 15-30). Quantitative [3H]-levobetaxolol autoradiography revealed high levels of binding to human ciliary processes, iris, choroid/retina, and ciliary muscles. In conclusion, levobetaxolol is a potent, high affinity and beta1-selective IOP-lowering beta-adrenoceptor antagonist.

  7. Effects of the beta-adrenergic receptor antagonist Propranolol on dyskinesia and L-DOPA-induced striatal DA efflux in the hemi-parkinsonian rat

    PubMed Central

    Bhide, Nirmal; Lindenbach, David; Barnum, Christopher J.; George, Jessica A.; Surrena, Margaret A.; Bishop, Christopher

    2015-01-01

    Dopamine (DA) replacement therapy with L-DOPA continues to be the primary treatment of Parkinson's disease; however, long-term therapy is accompanied by L-DOPA-induced dyskinesias (LID). Several experimental and clinical studies have established that Propranolol, a β-adrenergic receptor antagonist, reduces LID without affecting L-DOPA's efficacy. However, the exact mechanisms underlying these effects remain to be elucidated. The aim of the current study was to evaluate the anti-dyskinetic profile of Propranolol against a panel of DA replacement strategies, as well as elucidate the underlying neurochemical mechanisms. Results indicated that Propranolol, in a dose-dependent manner, reduced LID, without affecting motor performance. Propranolol failed to alter dyskinesia produced by the D1 receptor agonist, SKF81297 (0.08 mg/kg, sc), or the D2 receptor agonist, Quinpirole (0.05 mg/kg, sc). These findings suggested a presynaptic mechanism for Propranolol's anti-dyskinetic effects, possibly through modulating L-DOPA-mediated DA efflux. To evaluate this possibility, microdialysis studies were carried out in the DA-lesioned striatum of dyskinetic rats and results indicated that co-administration of Propranolol (20 mg/kg, ip) was able to attenuate L-DOPA- (6 mg/kg, sc) induced DA efflux. Therefore, Propranolol's anti-dyskinetic properties appear to be mediated via attenuation of L-DOPA-induced extraphysiological efflux of DA. PMID:25866285

  8. Effects of the beta-adrenergic receptor antagonist Propranolol on dyskinesia and L-DOPA-induced striatal DA efflux in the hemi-parkinsonian rat.

    PubMed

    Bhide, Nirmal; Lindenbach, David; Barnum, Christopher J; George, Jessica A; Surrena, Margaret A; Bishop, Christopher

    2015-07-01

    Dopamine (DA) replacement therapy with L-DOPA continues to be the primary treatment of Parkinson's disease; however, long-term therapy is accompanied by L-DOPA-induced dyskinesias (LID). Several experimental and clinical studies have established that Propranolol, a β-adrenergic receptor antagonist, reduces LID without affecting L-DOPA's efficacy. However, the exact mechanisms underlying these effects remain to be elucidated. The aim of this study was to evaluate the anti-dyskinetic profile of Propranolol against a panel of DA replacement strategies, as well as elucidate the underlying neurochemical mechanisms. Results indicated that Propranolol, in a dose-dependent manner, reduced LID, without affecting motor performance. Propranolol failed to alter dyskinesia produced by the D1 receptor agonist, SKF81297 (0.08 mg/kg, sc), or the D2 receptor agonist, Quinpirole (0.05 mg/kg, sc). These findings suggested a pre-synaptic mechanism for Propranolol's anti-dyskinetic effects, possibly through modulating L-DOPA-mediated DA efflux. To evaluate this possibility, microdialysis studies were carried out in the DA-lesioned striatum of dyskinetic rats and results indicated that co-administration of Propranolol (20 mg/kg, ip) was able to attenuate L-DOPA- (6 mg/kg, sc) induced DA efflux. Therefore, Propranolol's anti-dyskinetic properties appear to be mediated via attenuation of L-DOPA-induced extraphysiological efflux of DA.

  9. Depression and topical ophthalmic beta adrenergic blockade.

    PubMed

    Bourgeois, J A

    1991-05-01

    Beta adrenergic blocking agents are in widespread use as both systemic and topical medications. While they are safely used in the great majority of cases, several side effects are well known. Central nervous system side effects, specifically depression, can be among the most clinically important of these and must be investigated by the clinician.

  10. Beta adrenergic receptors in human cavernous tissue

    SciTech Connect

    Dhabuwala, C.B.; Ramakrishna, C.V.; Anderson, G.F.

    1985-04-01

    Beta adrenergic receptor binding was performed with /sup 125/I iodocyanopindolol on human cavernous tissue membrane fractions from normal tissue and transsexual procedures obtained postoperatively, as well as from postmortem sources. Isotherm binding studies on normal fresh tissues indicated that the receptor density was 9.1 fmoles/mg. with a KD of 23 pM. Tissue stored at room temperature for 4 to 6 hours, then at 4C in saline solution for 19 to 20 hours before freezing showed no significant changes in receptor density or affinity, and provided evidence for the stability of postmortem tissue obtained within the same time period. Beta receptor density of 2 cavernous preparations from transsexual procedures was not significantly different from normal control tissues, and showed that high concentrations of estrogen received by these patients had no effect on beta adrenergic receptor density. Displacement of /sup 125/iodocyanopindolol by 5 beta adrenergic agents demonstrated that 1-propranolol had the greatest affinity followed by ICI 118,551, zinterol, metoprolol and practolol. When the results of these displacement studies were subjected to Scatfit, non- linear regression line analysis, a single binding site was described. Based on the relative potency of the selective beta adrenergic agents it appears that these receptors were of the beta 2 subtype.

  11. Agonist photoaffinity label for the. beta. -adrenergic receptor

    SciTech Connect

    Resek, J.F.; Ruoho, A.E.

    1987-05-01

    An iodinated photosensitive derivative of norepinephrine, N-(p-azido-m-iodophenethylamidoisobutyryl)norepinephrine (NAIN), has been synthesized and characterized. Carrier-free radioiodinated NAIN ((/sup 125/I)-NAIN) was used at 1-2 x 10/sup -9/ M to photoaffinity label the ..beta..-adrenergic receptor in guinea pig lung membranes. SDS-PAGE analysis of (-)-alprenolol (10/sup -5/M) protectable (/sup 125/I)-NAIN labeling showed the same molecular weight polypeptide (65 kDa) that was specifically derivatized with the antagonist photolabel, (/sup 125/I)-IABP. Specific labeling of the ..beta..-adrenergic receptor with (/sup 125/I)-NAIN was dependent on the presence of MgCl/sub 2/ and the absence of guanyl nucleotide. GTP..gamma..S (10/sup -4/ M) abolished specific receptor labeling by (/sup 125/I)-NAIN. N-ethylmaleimide (2 mm) in the presence of (/sup 125/I)-NAIN protected against the guanyl nucleotide effect. These data are consistent with photolabeling by (/sup 125/I)-NAIN while the agonist, receptor, and GTP binding protein are in a high affinity complex.

  12. Distribution of beta-adrenergic receptors on human lymphocyte subpopulations.

    PubMed Central

    Pochet, R; Delespesse, G; Gausset, P W; Collet, H

    1979-01-01

    A technique is described allowing the quantification and the characterization of specific beta-adrenergic receptors in intact living human lymphocytes. 125I-Iodohydroxybenzylpindolol, a potent beta-adrenergic antagonist was used to label specific binding sites on unfractionated lymphoid cells and on purified subpopulations of T (F1 and F2) and B cells. F1 and F2 were obtained by filtration through nylon wool column as previously described (Delespesse et al., 1976), they differ in their response to mitogens, and in their interactions with adherent cells and B cells. 125I-HYP binding to unfractionated lymphocytes was a saturable, stereospecific and rapid process with a dissociation constant of 2.5 10(-10) M and a binding capacity of 400--600 sites/cell. Bindings on unfractionated lymphocytes, purified B cells and T cells of the F2 fraction were similar. No detectable binding was noted on T cells from the F1 fraction. Enriched T cells obtained by a rosetting technique displayed 200 receptors/cell. PMID:43789

  13. Human myometrial adrenergic receptors: identification of the beta-adrenergic receptor by (/sup 3/H)dihydroalprenolol binding

    SciTech Connect

    Hayashida, D.N.; Leung, R.; Goldfien, A.; Roberts, J.M.

    1982-02-15

    The radioactive beta-adrenergic antagonist (/sup 3/H) dihydroalprenolol (DHA) binds to particulate preparations of human myometrium in a manner compatible with binding to the beta-adrenergic receptor. The binding of DHA is rapid (attaining equilibrium in 12 minutes), readily reversible (half time = 16 minutes), high affinity (K/sub D/ = 0.50 nM), low capacity (Bmax = 70 fmoles/mg of protein), and stereoselective ((-)-propranolol is 100 times as potent as (+) -propranolol in inhibiting DHA binding). Adrenergic agonists competed for DHA binding sites in a manner compatible with beta-adrenergic interactions and mirrored ..beta../sub 2/ pharmacologic potencies: isoproterenol > epinephrine >> norepinephrine. Studies in which zinterol, a ..beta../sub 2/-adrenergic agonist, competed for DHA binding sites in human myometrial particulate indicated that at least 87% of the beta-adrenergic receptors present are ..beta../sub 2/-adrenergic receptors. Binding of DHA to human myometrial beta-adrenergic receptors provides a tool which may be used in the examination of gonadal hormonal modification of adrenergic response in human uterus as well as in the analysis of beta-adrenergic agents as potentially useful tocolytic agents.

  14. Respiratory effects of beta-adrenergic receptor blockers.

    PubMed

    Antonelli-Incalzi, Raffaele; Pedone, Claudio

    2007-01-01

    Antagonists of the beta-adrenergic receptor (beta-AR antagonists) are a heterogeneous class of drugs. Selected members of this class are highly recommended in congestive heart failure (HF) and after acute myocardial infarction. Hydrosolubility, half life and prevalent route of excretion define the pharmacokinetic profile of individual drugs, whereas the respective degree of affinity for beta1-AR and beta2-AR, the level of coexistent agonist properties and several beta-AR independent properties (e. g. antioxidant, direct vasodilating effect) contribute to shape the pharmacodynamic profile. Genetically determined differences in the response to beta-AR antagonists and, probably, age-related changes in the neuroautonomic system are further source of variability in the effect of beta-AR antagonists on bronchial tone. Patients with chronic obstructive pulmonary disease (COPD) are theoretically at risk of worsening respiratory flows and symptoms caused by beta-AR antagonists prescribed for concurrent HF or myocardial infarction. Most of these patients, however, do not experience side effects, maybe because the improved haemodynamic due to beta-AR antagonists therapy may in turn improve the respiratory function. Occasional patients can develop untoward respiratory effects of beta-AR antagonists, and this risk is higher for those with severe COPD or active asthma. We provide some simple common sense rules for selecting patients with COPD or asthma that are suitable for beta-AR antagonists therapy while minimizing the risk of adverse respiratory effects.

  15. During a corticotropin-releasing hormone test in healthy subjects, administration of a beta-adrenergic antagonist induced secretion of cortisol and dehydroepiandrosterone sulfate and inhibited secretion of ACTH.

    PubMed

    Kizildere, Selda; Glück, Thomas; Zietz, Bettina; Schölmerich, Jürgen; Straub, Rainer H

    2003-01-01

    In chronic inflammatory diseases, serum levels of dehydroepiandrosterone (DHEA) sulfate (DHEAS) are low. Interestingly, several non-inflammatory diseases display similarly low levels of DHEAS which points to other inhibitory factors such as an activated sympathetic nervous system (SNS) (e.g. in patients with heart failure, fibromyalgia, or cancer cachexia). We aimed to identify the influence of the SNS tone on stimulated adrenal steroid secretion in 16 male and 12 female healthy subjects. One group were given oral propranolol 2 h before a corticotropin-releasing hormone (CRH) test, and levels of adrenocorticotropin (ACTH), cortisol, 17-hydroxyprogesterone (17OHP), androstenedione, DHEA, and DHEAS were measured. Propranolol treatment decreased heart rate (by 20%), diastolic blood pressure (by 20%), and plasma ACTH, and increased serum cortisol, serum DHEAS, and the molar ratio of cortisol/17OHP, cortisol/DHEA, and DHEAS/DHEA similarly in female and male subjects. A beta-adrenergic influence seems to decrease CRH-stimulated cortisol in relation to ACTH and 17OHP, and decreases DHEAS in relation to DHEA. Although other workers have found beta-adrenergic stimulation of steroid secretion in cultured adrenocortical cells, the overall systemic influence of the SNS via beta-adrenoceptors seems to inhibit adrenal steroids under unstimulated and stimulated conditions. Sympathetic hyperactivity may be a common denominator for low levels of DHEAS in inflammatory and non-inflammatory diseases.

  16. Homologous beta-adrenergic desensitization in isolated rat hepatocytes.

    PubMed Central

    García-Sáinz, J A; Michel, B

    1987-01-01

    Hepatocytes from hypothyroid rats have a marked beta-adrenergic responsiveness. Preincubation of these hepatocytes with isoprenaline induced a time-dependent and concentration-dependent desensitization of the beta-adrenergic responsiveness without altering that to glucagon (homologous desensitization). The desensitization was evidenced both in the cyclic AMP accumulation and in the stimulation of ureagenesis induced by the beta-adrenergic agonists. Under the same conditions, preincubation with glucagon induced no desensitization. Propranolol was also unable to induce desensitization, but blocked that induced by isoprenaline. Pertussis-toxin treatment did not alter the homologous beta-adrenergic desensitization induced by isoprenaline. PMID:2825633

  17. Species differences in the localization and number of CNS beta adrenergic receptors: Rat versus guinea pig

    SciTech Connect

    Booze, R.M.; Crisostomo, E.A.; Davis, J.N.

    1989-06-01

    The localization and number of beta adrenergic receptors were directly compared in the brains of rats and guinea pigs. The time course of association and saturability of (125I)cyanopindolol (CYP) binding to slide-mounted tissue sections was similar in rats (Kd = 17 pM) and guinea pigs (Kd = 20 pM). The beta-1 and beta-2 receptor subtypes were examined through the use of highly selective unlabeled receptor antagonists, ICI 118,551 (50 nM) and ICI 89,406 (70 nM). Dramatic species differences between rats and guinea pigs were observed in the neuroanatomical regional localization of the beta adrenergic receptor subtypes. For example, in the thalamus prominent beta-1 and beta-2 receptor populations were identified in the rat; however, the entire thalamus of the guinea pig had few, if any, beta adrenergic receptors of either subtype. Hippocampal area CA1 had high levels of beta-2 adrenergic receptors in both rats and guinea pigs but was accompanied by a widespread distribution of beta-2 adrenergic receptors only in rats. Quantitative autoradiographic analyses of 25 selected neuroanatomical regions (1) confirmed the qualitative differences in CNS beta adrenergic receptor localization, (2) determined that guinea pigs had significantly lower levels of beta adrenergic receptors than rats and (3) indicated a differential pattern of receptor subtypes between the two species. Knowledge of species differences in receptor patterns may be useful in designing effective experiments as well as in exploring the relationships between receptor and innervation patterns. Collectively, these data suggest caution be used in extrapolation of the relationships of neurotransmitters and receptors from studies of a single species.

  18. DNA synthesis in mouse brown adipose tissue is under. beta. -adrenergic control

    SciTech Connect

    Rehnmark, S.; Nedergaard, J. )

    1989-02-01

    The rate of DNA synthesis in mouse brown adipose tissue was followed with injections of ({sup 3}H)thymidine. Cold exposure led to a large increase in the rate of ({sup 3}H)thymidine incorporation, reaching a maximum after 8 days, after which the activity abruptly ceased. A series of norepinephrine injections was in itself able to increase ({sup 3}H)thymidine incorporation. When norepinephrine was injected in combination with the {alpha}-adrenergic antagonist phentolamine or with the {beta}-adrenergic antagonist propranolol, the stimulation was fully blocked by propranolol. It is suggested that stimulation of DNA synthesis in brown adipose tissue is a {beta}-adrenergically mediated process and that the tissue is an interesting model for studies of physiological control of DNA synthesis.

  19. Catecholamine-induced desensitization of turkey erythrocyte adenylate cyclase. Structural alterations in the beta-adrenergic receptor revealed by photoaffinity labeling.

    PubMed

    Stadel, J M; Nambi, P; Lavin, T N; Heald, S L; Caron, M G; Lefkowitz, R J

    1982-08-25

    Preincubation of turkey erythrocytes with isoproterenol results in an impaired ability of beta-adrenergic agonists to stimulate adenylate cyclase in membranes prepared from these cells. The biochemical basis for this agonist-induced desensitization was investigated using the new beta-adrenergic antagonist photoaffinity label [125I]p-azidobenzylcarazolol ([125I]PABC). Exposure of [125I]PABC-labeled turkey erythrocyte membranes to high intensity light leads to specific covalent incorporation of the labeled compound into two polypeptides, Mr approximately equal to 38,000 and 50,000, as determined by sodium dodecyl sulfate-polyacrylamide electrophoresis. Incorporation of [125I]PABC into these two polypeptides is completely blocked by a beta-adrenergic agonist and antagonist consistent with covalent labeling of the beta-adrenergic receptor. After desensitization of the turkey erythrocyte by preincubation with 10(-5) M isoproterenol, the beta-adrenergic receptor polypeptides specifically labeled by [125I]PABC in membranes prepared from desensitized erythrocytes were of larger apparent molecular weight (Mr approximately equal to 42,000 versus 38,000, and 53,000 versus 50,000) compared to controls. When included during the preincubation of the erythrocytes with isoproterenol, the antagonist propranolol (10(-5) M) inhibited both agonist-promoted desensitization of the adenylate cyclase and the altered mobility of the [125I]PABC-labeled receptor polypeptides. These data indicate that structural alterations in the beta-adrenergic receptor accompany the desensitization process in turkey erythrocytes.

  20. Exercise Testing, Training, and Beta-Adrenergic Blockade.

    ERIC Educational Resources Information Center

    Wilmore, Jack H.

    1988-01-01

    This article summarizes the current knowledge on the effects of beta-adrenergic blocking drugs, used widely for treatment of cardiovascular diseases, on exercise performance, training benefits, and exercise prescription. (IAH)

  1. Exercise Testing, Training, and Beta-Adrenergic Blockade.

    ERIC Educational Resources Information Center

    Wilmore, Jack H.

    1988-01-01

    This article summarizes the current knowledge on the effects of beta-adrenergic blocking drugs, used widely for treatment of cardiovascular diseases, on exercise performance, training benefits, and exercise prescription. (IAH)

  2. Beta-adrenergic receptors are different in subpopulations of human circulating lymphocytes.

    PubMed

    Landmann, R M; Bürgisser, E; Wesp, M; Bühler, F R

    1984-01-01

    Mononuclear leucocytes (MNL) were isolated from blood of 11 healthy blood donors. Lymphocyte subsets were sorted in a Cytofluorograf after direct (B cells) or indirect immunofluorescence labeling with monoclonal antibodies directed against the phenotypes of T-, T helper (Th)- and T suppressor (Ts) cells. The sorted cells were incubated with (+/-)125iodocyanopindolol ([125I]CYP) for the determination of beta-adrenergic receptors. Beta-adrenergic receptors on B cells were increased two-fold (3700 sites/cell, p less than 0.004) and had a lower affinity (dissociation constant KD 40pM, p less than 0.03) when compared with T cells (1400 sites/cell, KD 17pM). Receptors on Th- and Ts cells showed a similar binding capacity, but Ts cells had a slightly higher [125I]CYP binding affinity (KD 13 pM) than Th cells (KD 27 pM, p less than 0.02). The different densities and affinities of beta-adrenergic receptors in human lymphocyte subsets, as assessed by antagonist binding should be considered in the interpretation of receptor alterations of unfractionated MNL, which may occur simultaneously to changes of the blood leucocyte distribution.

  3. Effects of halothane on the human beta-adrenergic receptor of lymphocyte membranes

    SciTech Connect

    Marty, J.; Nivoche, Y.; Nimier, M.; Rocchiccioli, C.; Luscombe, F.; Henzel, D.; Loiseau, A.; Desmonts, J.M.

    1987-12-01

    The effects of halothane on beta-adrenergic receptor antagonist interaction were studied using the membranes of human lymphocytes as a model. Membrane preparations of lymphocytes were obtained from blood samples withdrawn from seven healthy young volunteers. Beta-receptor studies were performed using (-)/sup 125/I iodocyanopindolol (/sup 125/ICP) binding. Non-specific binding was determined in the presence of (-)isoproterenol. Beta-receptor density (Bmax) and the dissociation constant (KD) for /sup 125/ICP were determined from saturation curves. Beta-receptor affinity for agonists evaluated by the IC50 (the concentration of isoproterenol required to inhibit 50% of specific /sup 125/ICP binding) and the dissociation constant (KL) for isoproterenol was established from competition curves. The effect of halothane 1%, in an air oxygen mixture (oxygen fraction: 0.3) administered by tonometry during ligand membrane incubation, on beta-adrenergic receptor, was compared to that of control experiments not exposed to halothane. Halothane produced a moderate but significant decrease of Bmax (-10%) and a significant increase in non-specific binding (+30%), while KD, IC50, and KL were unchanged. The authors conclude that halothane, in vitro, decreases beta-adrenergic receptor density. This effect could be mediated by an alteration of the receptor in the membrane due to action of halothane on the lipid phase of the membrane.

  4. beta. -Adrenergic stimulation of brown adipocyte proliferation

    SciTech Connect

    Geloeen, A.; Collet, A.J.; Guay, G.; Bukowiecki, L.J. Laboratoire de Thermoregulation et Metabolisme Energetique, Lyon )

    1988-01-01

    The mechanisms of brown adipose tissue (BAT) growth were studied by quantitative photonic radioautography using tritiated thymidine to follow mitotic activity. To identify the nature of the adrenergic pathways mediating brown adipocyte proliferation and differentiation, the effects of cold exposure (4 days at 4{degree}C) on BAT growth were compared with those induced by treating rats at 25{degree}C with norepinephrine (a mixed agonist), isoproterenol (a {beta}-agonist), and phenylephrine (an {alpha}-agonist). Norepinephrine mimicked the effects of cold exposure, not only on the mitotic activity, but also on the distribution of the labeling among the various cellular types. Isoproterenol entirely reproduced the effects of norepinephrine both on the labeling index and on the cellular type labeling frequency. These results demonstrate that norepinephrine triggers a coordinated proliferation of brown adipocytes and endothelial cells in warm-exposed rats that is similar to that observed after cold exposure. They also suggest that cold exposure stimulates BAT growth by increasing the release of norepinephrine from sympathetic nerves and that the neurohormone activates mitoses in BAT precursor cells via {beta}-adrenergic pathways.

  5. In vivo autoradiographic demonstration of. beta. -adrenergic binding sites in adult rat type II alveolar epithelial cells

    SciTech Connect

    Smith, D.M.; Sidhu, M.K.

    1984-02-06

    Adult male rats were injected intravenously with the muscarinic binding probe /sup 3/H-Quinuclidinyl benzilate (QNB) or the ..beta..-adrenergic probe /sup 3/H-dihydroalprenolol (DHA). Other rats were pre-treated with an intraperitoneal injection of a 500-fold excess of L-isoproterenol prior to the DHA. Light microscopic autoradiography of 0.5 ..mu..m sections of lung from the QNB group demonstrated very little labelling even after 6 months of exposure. In constrast, trachealis smooth muscle from these animals contained substantial labelling. Autoradiographs of lung from rats injected with DHA demonstrated labelling which was well localized over alveolar septa and concentrated over the cytoplasm of type II cells. Quantitative analysis of labelling in the DHA groups indicated a significant reduction of labelling in animals treated with L-isoproterenol prior to DHA, in both the alveolar parenchyma in general and over type II cells. The results of this study provide morphologic evidence for the uptake and specific binding of ..beta..-adrenergic antagonists by the adult lung in vivo, while failing to demonstrate similar binding of a muscarinic probe. In addition, the results demonstrate specific ..beta..-adrenergic receptors on type II cells in vivo and substantiate the view of a direct effect of ..beta..-adrenergic agonists on alveolar type II cells.

  6. Synthesis of iodine-125 labeled (+/-)-15-(4-azidobenzyl)carazolol: a potent beta-adrenergic photoaffinity probe

    SciTech Connect

    Heald, S.L.; Jeffs, P.W.; Lavin, T.N.; Nambi, P.; Lefkowitz, R.J.; Caron, M.G.

    1983-06-01

    (+/-)-15-(4-Azidobenzyl)carazolol (2), a potent beta-adrenergic photoaffinity ligand has been radioiodinated to theoretical specific activity (2175 Ci/mmol) and shown to label covalently beta-adrenergic receptor peptides in avian and amphibian erythrocyte membrane preparations. The radioiodinated analogues of the desired compound (2) were optimally prepared by two synthetic steps from (+/-)-15-(4-aminobenzyl)carazolol (8). The latter was iodinated with carrier-free Na/sup 125/I and chloramine T to yield two major isotopomers (the monoiodinated derivatives 9 and 10), which were separated by thin-layer chromatography and converted via diazonium salt formation to their respective 4-azides, 12 and 6. These azides can be used interchangeably in ligand binding or photoaffinity labeling experiments. Compound 8 was obtained by catalytic reduction of the nitro derivative (7), which was arrived at by direct reaction of 1,1-dimethyl-2-(4-nitrophenyl)ethylamine (3) with 4-(2,3-epoxypropoxy)carbazole (5). Of the desired isomers, (+/-)-15-(4-azido-3-iodobenzyl)carazolol (6) could be synthesized from 1,1-dimethyl-2-(4-azido-3-iodophenyl)ethylamine (4) by direct reaction with 5. This and the preceding sequence of reactions were carried out by using nonradioactive materials, and separation and purification of products were accomplished by high-performance liquid chromatography. The compounds described have been shown to be potent beta-adrenergic antagonistsec The photoactive azide derivatives of these compounds (6 and 12) have been shown to covalently incorporate into the beta-adrenergic receptor binding subunit of frog and turkey erythrocyte membrane preparations. Incorporation of the ligands into these polypeptides can be blocked specifically by both beta-adrenergic agonists and antagonists.

  7. Characterization of beta-adrenergic receptors in dispersed rat testicular interstitial cells

    SciTech Connect

    Poyet, P.; Labrie, F.

    1987-01-01

    Recent studies have shown that beta-adrenergic agents stimulate steroidogenesis and cyclic AMP formation in mouse Leydig cells in culture. To obtain information about the possible presence and the characteristics of a beta-adrenergic receptor in rat testicular interstitial cells, the potent beta-adrenergic antagonist (/sup 125/I)cyanopindolol (CYP) was used as ligand. Interstitial cells prepared by collagenase dispersion from rat testis were incubated with the ligand for 2 h at room temperature. (/sup 125/I)cyanopindolol binds to a single class of high affinity sites at an apparent KD value of 15 pM. A number of sites of 6,600 sites/cell is measured when 0.1 microM (-) propranolol is used to determine non-specific binding. The order of potency of a series of agonists competing for (/sup 125/I)cyanopindolol binding is consistent with the interaction of a beta 2-subtype receptor: zinterol greater than (-) isoproterenol greater than (-) epinephrine = salbutamol much greater than (-) norepinephrine. In addition, it was observed that the potency of a large series of specific beta 1 and beta 2 synthetic compounds for displacing (/sup 125/I)cyanopindolol in rat interstitial cells is similar to the potency observed for these compounds in a typical beta 2-adrenergic tissue, the rat lung. For example, the potency of zinterol, a specific beta 2-adrenergic agonist, is 10 times higher in interstitial cells and lung than in rat heart, a typical beta 1-adrenergic tissue. Inversely, practolol, a typical beta 1-antagonist, is about 50 times more potent in rat heart than in interstitial cells and lung.

  8. Beta adrenergic blocking agents for open-angle glaucoma.

    PubMed

    Lee, M E

    1988-07-01

    Beta adrenergic blocking agents have gained wide acceptance among practitioners and patients alike as extremely useful drugs for the treatment of open-angle glaucoma. This new class of antiglaucoma agents usually is effective in reducing elevated intraocular pressure and is generally well tolerated. This paper is intended to provide an understanding of the ophthalmic beta adrenergic blocking agents to optometrists who are actively involved in the treatment of glaucoma and/or in the monitoring of glaucoma patients. The clinical pharmacology of the three FDA-approved beta blockers -- timolol, levobunolol, and betaxolol, is evaluated and the drugs are compared.

  9. Opioid peptide receptor stimulation reverses beta-adrenergic effects in rat heart cells.

    PubMed

    Xiao, R P; Pepe, S; Spurgeon, H A; Capogrossi, M C; Lakatta, E G

    1997-02-01

    Opioid peptide receptor (OPR) agonists are co-released with the beta-adrenergic receptor (beta-AR) agonist norepinephrine (NE) from nerve terminals in the heart during sympathetic stimulation. Whereas recent studies indicate that OPR and beta-AR coexist on the surface of cardiac myocytes, whether significant "cross talk" occurs between OPR and beta-AR signaling cascades within heart cells is unknown. In the present study we demonstrate a marked effect of delta-OPR stimulation to modulate beta-adrenergic responses in single isolated rat ventricular myocytes. Nanomolar concentrations (10(-8) M) of the OPR agonist leucine enkephalin (LE), a naturally occurring delta-opioid peptide, inhibited NE-induced increases in sarcolemmal L-type Ca2+ current, cytosolic Ca2+ transient, and contraction. The antiadrenergic effect of LE was pertussis toxin sensitive and abolished by naloxone, an opioid receptor antagonist. In contrast, LE was unable to inhibit the positive inotropic effects induced by equipotent concentrations of 8-(4 chlorophenylthio)-adenosine 3',5'-cyclic monophosphate, a cell-permeant adenosine 3',5'-cyclic monophosphate analog, or by the non-receptor-induced increase in contraction by elevated bathing Ca2+ concentration. These results indicate that an interaction of the OPR and beta-AR systems occurs proximal to activation of the adenosine 3',5'-cyclic monophosphate-dependent protein kinase of the beta-AR intracellular signaling pathway. This modulation of beta-adrenergic effects by OPR activation at the myocyte level may have important implications in the regulation of cardiac Ca2+ metabolism and contractility, particularly during the myocardial response to stress.

  10. The (--)(/sup 3/H)dihydroalprenolol binding to rat adipocyte membranes: an explanation of curvilinear Scatchard plots and implications for quantitation of beta-adrenergic sites

    SciTech Connect

    Dax, E.M.; Partilla, J.S.; Gregerman, R.I.

    1982-09-01

    In rat adipocyte membranes, both beta-adrenergic agonists and beta-adrenergic antagonists competed with (--)(/sup 3/H)dihydroalprenolol for high affinity (KD 2-4 nM) and low capacity binding sites. The antagonists but not the agonists competed with (--)(/sup 3/H)dihydroalprenolol for lower affinity and higher capacity sites. The present studies were performed in order to characterize the adipocyte beta-adrenergic receptor and distinguish it from low affinity, higher capacity sites which were heat-labile and not stereoselective. When isoproterenol was used to define the nonspecific binding, saturation studies showed a single binding site with a capacity of approximately 100 fmol/mg membrane protein (corresponding to approximately 50,000 sites/adipocyte). Binding was saturated by 10 nM (--)(/sup 3/H)dihydroalprenolol. Approximate KD's of 204 nM were observed. Kinetic analysis of (--)(/sup 3/H)dihydroalprenolol binding provided an independent measurement of KD between 0.75 and 1.1 nM. This binding site had the characteristics of a beta 1-adrenergic receptor with the potency of isoproterenol greater than norepinephrine greater than or equal to epinephrine as competitors of binding. Furthermore, the KD of inhibition of (--)(/sup 3/H)dihydroalprenolol binding correlated with the Ki of inhibition by antagonists or Ka of activation by agonists of glycerol release in isolated adipocytes (r . 0.968, P less than 0.001). These results suggest that beta-adrenergic agonists compete with (--)(/sup 3/H)dihydroalprenolol for the high affinity binding site which represents the physiological site. Furthermore, the use of antagonists (propranolol, alprenolol) to define specific beta-binding includes nonspecific site(s) as well as the beta-adrenergic site. Previous characterization and quantitation of beta receptors in rat fat cell membranes may have been in error by incorporating both types of binding in their measurement.

  11. Coregulation of calcium channels and beta-adrenergic receptors in cultured chick embryo ventricular cells

    SciTech Connect

    Marsh, J.D. )

    1989-09-01

    To examine mechanisms whereby the abundance of functional Ca channels may be regulated in excitable tissue, Ca channel number was estimated by binding of the dihydropyridine (DHP) antagonist {sup 3}H (+)PN200-110 to monolayers of intact myocytes from chick embryo ventricle. Beta adrenergic receptor properties were studied in cultured myocytes using ({sup 3}H)CGP12177, an antagonist ligand. Physiological correlates for alterations in DHP binding site number included {sup 45}Ca uptake and contractile response to (+)BAYk 8644, a specific L-type Ca channel activator. All binding and physiological determinations were performed in similar intact cell preparations under identical conditions. 4-h exposure to 1 microM isoproterenol reduced cell surface beta-adrenergic receptor number from 44 +/- 3 to 17 +/- 2 fmol/mg (P less than 0.05); DHP binding sites declined in number from 113 +/- 25 to 73 +/- 30 fmol/mg (P less than 0.03). When protein kinase A was activated by a non-receptor-dependent mechanism, DHP binding declined similarly to 68% of control. Exposure to diltiazem, a Ca channel antagonist, for 18-24 h had no effect on number of DHP binding sites. After 4-h isoproterenol exposure, {sup 45}Ca uptake stimulated by BAYk 8644 declined from 3.3 +/- 0.2 nmol/mg to 2.9 +/- 0.3 nmol/mg (P less than 0.01) and BAYk 8644-stimulated increase in amplitude of contraction declined from 168 +/- 7 to 134 +/- 11% (P = 0.02). Thus, elevation of (cAMP) in myocytes is associated with a time-dependent decline in Ca channel abundance as estimated by DHP binding and a decline in physiological responses that are in part dependent on abundance of Ca channels. Binding of a directly acting Ca channel antagonist for 18-24 h does not modulate the number of DHP binding sites.

  12. Genetic manipulation of beta-adrenergic signalling in heart failure.

    PubMed

    Davidson, M J; Koch, W J

    2001-09-01

    Heart failure (HF) represents one of the leading causes for hospitalization in developed nations. Despite advances in the management of coronary artery disease, no significant improvements in prognosis have been achieved for HF over the last several decades. Heart failure itself represents a final common endpoint for several disease entities, including hypertension, coronary artery disease, and cardiomyopathy. However, certain biochemical features remain common to the failing myocardium. Foremost amongst these are alterations in the beta-adrenergic receptor signalling cascade. Recent advances in transgenic and gene therapy techniques have presented novel therapeutic strategies for the management of HF via enhancement of beta-adrenergic signalling. In this review, we will discuss the biochemical changes that accompany HF as well as corresponding therapeutic strategies. We will then review the evidence from transgenic mouse work supporting the use of adrenergic receptor augmentation in the failing heart and more recent in vivo applications of gene therapy directed at reversing or preventing HF.

  13. The role of beta-adrenergic activity in the production of cardiac and aortic arch anomalies in chick embryos.

    PubMed

    Hodach, R J; Hodach, A E; Fallon, J F; Folts, J D; Bruyere, H J; Gilbert, E F

    1975-08-01

    The sympathomimetic amines isoproterenol, epinephrine, norepinephrine, and phenylephrine are structural derivatives of beta-phenylethylamine and have proportionately different effects on alpha- and beta-adrenergic receptors. Chick embryos in ovo were each administered a single dose of one of these compounds at concentrations ranging from 0.4 times 10(-9) to 20 times 10(-9) mol/5 mul saline during Hamburger and Hamilton stages 20-27. In other experiments embryos were pretreated with the beta-antagonist propranolol and subsequently administered isoproterenol. 743 cardiovascular anomalies were produced. The production of cardiovascular anomalies was proportional to the degree of beta-adrenergic activity of each drug. The frequency of anomalies was significantly reduced by pretreatment with propranolol. At all concentrations tested the anomaly rate was greater in chick embryos receiving an experimental compound than in controls. The general types of anomalies included aortic arch defects, ventricular septal defect, double outlet right ventricle, aortic hypoplasia, and truncus arteriosus. These results demonstrate that activation of the beta-adrenergic receptor mechanism is directly related to the cardiovascular anomalies produced in the chick embryos.

  14. beta. -adrenergic ((/sup 3/H) CGP-12177) receptors are elevated in slices of soleus muscle from CHF 147 dystrophic hamsters

    SciTech Connect

    Watson-Wright, W.M.; Wilkinson, M.

    1987-03-23

    The authors utilized a muscle slice technique to compare the ontogeny of cell surface ..beta..-adrenergic receptor binding in soleus and extensor digitorum longus (EDL) muscles of male Golden Syrian (GS) and Canadian Hybrid Farms 147 (CHF 147) dystrophic hamsters. Binding of the ..beta..-adrenergic antagonist, (/sup 3/H) CGP-12177 (CGP), to GS muscle slices was reversible, saturable, stereospecific and of high affinity. Bmax was higher in the soleus (2.57+/-.12 fmol/mg wet wt) than in the EDL (1.61+/-.17 fmol/mg wet wt) of adult animals while affinities were similar (0.35+/-.06 and 0.24+/-.04 nM respectively). No differences in binding characteristics were seen in EDL of GS compared to CHF 147 animals. In soleus slices from GS hamsters, Bmax was highest at 16 days of age (5.72+/-0.26 fmol/mg), decreased between 16 and 29 days and remained constant until 300 days (2.51+/-0.52 fmol/mg). In dystrophic soleus slices, Bmax was also higher at 16 days than at any other age but receptor number decreased gradually, remaining higher than in GS until 90 days of age (p<0.05). The failure of ..beta..-adrenergic receptor number to decrease at a normal rate may be implicated in the pathogenesis of hamster polymyopathy. 21 references, 5 figures, 1 table.

  15. Ultraviolet radiation augments epidermal beta-adrenergic adenylate cyclase response

    SciTech Connect

    Iizuka, H.; Kajita, S.; Ohkawara, A.

    1985-05-01

    Pig skin was irradiated in vivo with fluorescent sunlamp tubes (peak emission at 305 nm). A significant increase in epidermal beta-adrenergic adenylate cyclase response was observed as early as 12 h following 1-2 minimum erythema doses (MEDs) UVB exposure, which lasted at least 48 h. The augmentation of adenylate cyclase response was relatively specific to the beta-adrenergic system and there was no significant difference in either adenosine- or histamine-adenylate cyclase response of epidermis. The increased beta-adrenergic adenylate cyclase response was less marked at higher doses of UVB exposure (5 MEDs); in the latter condition, a significant reduction in adenosine- or histamine-adenylate cyclase response was observed. There was no significant difference in either low- or high-Km cyclic AMP phosphodiesterase activity between control and UVB-treated skin at 1-2 MEDs. These data indicate that the epidermal adenylate cyclase responses are affected in vivo by UVB irradiation, which might be a significant regulatory mechanism of epidermal cyclic AMP systems.

  16. The beta-adrenergic blocking agents and the treatment of glaucoma.

    PubMed

    Zimmerman, T J; Boger, W P

    1979-01-01

    The autonomic nervous system is divided into the parasympathetic and sympathetic systems, with three types of adrenergic receptors: alpha (smooth muscle contraction), beta1 (cardiac acceleration and fatty acid mobilization) and beta2 (smooth muscle relaxation). Substances affecting the function of the adrenergic system are the agonists or stimulators, which mimic the effects of endogenous norepinephrine or epinephrine, and antagonists or blockers, which block the receptors and prevent stimulation by the agonists. Autonomic stimulation in the eye mediates various changes which apparently affect outflow facility and rate of formation of aqueous humor. Alteration of either or both of these factors by autonomic agonists or antagonists may have a direct or an indirect effect on intraocular pressure. Beta-adrenergic blocking substances have been used to treat a variety of diseases. Some of the effects of these drugs are attributable to properties other than beta blockade, such as intrinsic sympathomimetic activity and local anaesthetic activity. Side effects of this class of drugs require caution in cases of congestive heart failure and in asthmatics. Autonomic agents used in the treatment of ocular hypertension and glaucoma include pilocarpine, a chilinergic agonist, epinephrine, an adrenergic agonist, and various beta adrenergic blockers or antagonists including propranolol, atenolol and timolol. The physico-chemical properties and pharmacokinetics of timolol are reviewed. Data showing a significant reduction in intraocular pressure as a result of ocular instillation of timolol are presented. Reduction of the rate of aqueous formation appears to be the mechanism of action. A low incidence of non-serious side effects is reported.

  17. Beta-Adrenergic Receptor 1 Selective Antagonism Inhibits Norepinephrine-Mediated TNF-Alpha Downregulation in Experimental Liver Cirrhosis

    PubMed Central

    Zapater, Pedro; Gómez-Hurtado, Isabel; Peiró, Gloria; González-Navajas, José Manuel; García, Irma; Giménez, Paula; Moratalla, Alba; Such, José; Francés, Rubén

    2012-01-01

    Background Bacterial translocation is a frequent event in cirrhosis leading to an increased inflammatory response. Splanchnic adrenergic system hyperactivation has been related with increased bacterial translocation. We aim at evaluating the interacting mechanism between hepatic norepinephrine and inflammation during liver damage in the presence of bacterial-DNA. Animals and Methods Forty-six mice were included in a 16-week protocol of CCl4-induced cirrhosis. Laparotomies were performed at weeks 6, 10, 13 and 16. A second set of forty mice injected with a single intraperitoneal dose of CCl4 was treated with saline, 6-hydroxidopamine, Nebivolol or Butoxamine. After 5 days, mice received E. coli-DNA intraperitoneally. Laparotomies were performed 24 hours later. Liver bacterial-DNA, norepinephrine, TNF-alpha, IL-6 and beta-adrenergic receptor levels were measured. Results Bacterial-DNA translocation was more frequent in CCl4-treated animals compared with controls, and increased as fibrosis progressed. Liver norepinephrine and pro-inflammatory cytokines were significantly higher in mice with vs without bacterial-DNA (319.7±120.6 vs 120.7±68.6 pg/g for norepinephrine, 38.4±6.1 vs 29.7±4.2 pg/g for TNF-alpha, 41.8±7.4 vs 28.7±4.3 pg/g for IL-6). Only beta-adrenergic receptor-1 was significantly increased in treated vs control animals (34.6±7.3 vs 12.5±5.3, p = 0.01) and correlated with TNF-alpha, IL-6 and norepinephrine hepatic levels in animals with bacterial-DNA. In the second set of mice, cytokine levels were increased in 6-hydroxidopamine and Nebivolol (beta-adrenergic receptor-1 antagonist) treated mice compared with saline. Butoxamine (beta-adrenergic receptor-2 antagonist) didn’t inhibit liver norepinephrine modulation of pro-inflammatory cytokines. Conclusions Beta-adrenergic receptor-1 mediates liver norepinephrine modulation of the pro-inflammatory response in CCl4-treated mice with bacterial-DNA. PMID:22916250

  18. Beta adrenergic blockade reduces utilitarian judgement.

    PubMed

    Terbeck, Sylvia; Sylvia, Terbeck; Kahane, Guy; Guy, Kahane; McTavish, Sarah; Sarah, McTavish; Savulescu, Julian; Julian, Savulescu; Levy, Neil; Neil, Levy; Hewstone, Miles; Miles, Hewstone; Cowen, Philip J

    2013-02-01

    Noradrenergic pathways are involved in mediating the central and peripheral effects of physiological arousal. The aim of the present study was to investigate the role of noradrenergic transmission in moral decision-making. We studied the effects in healthy volunteers of propranolol (a noradrenergic beta-adrenoceptor antagonist) on moral judgement in a set of moral dilemmas pitting utilitarian outcomes (e.g., saving five lives) against highly aversive harmful actions (e.g., killing an innocent person) in a double-blind, placebo-controlled, parallel group design. Propranolol (40 mg orally) significantly reduced heart rate, but had no effect on self-reported mood. Importantly, propranolol made participants more likely to judge harmful actions as morally unacceptable, but only in dilemmas where harms were 'up close and personal'. In addition, longer response times for such personal dilemmas were only found for the placebo group. Finally, judgments in personal dilemmas by the propranolol group were more decisive. These findings indicate that noradrenergic pathways play a role in responses to moral dilemmas, in line with recent work implicating emotion in moral decision-making. However, contrary to current theorising, these findings also suggest that aversion to harming is not driven by emotional arousal. Our findings are also of significant practical interest given that propranolol is a widely used drug in different settings, and is currently being considered as a potential treatment for post-traumatic stress disorder in military and rescue service personnel.

  19. Beta adrenergic blockade reduces utilitarian judgement

    PubMed Central

    Sylvia, Terbeck; Guy, Kahane; Sarah, McTavish; Julian, Savulescu; Neil, Levy; Miles, Hewstone; Cowen, Philip J.

    2013-01-01

    Noradrenergic pathways are involved in mediating the central and peripheral effects of physiological arousal. The aim of the present study was to investigate the role of noradrenergic transmission in moral decision-making. We studied the effects in healthy volunteers of propranolol (a noradrenergic beta-adrenoceptor antagonist) on moral judgement in a set of moral dilemmas pitting utilitarian outcomes (e.g., saving five lives) against highly aversive harmful actions (e.g., killing an innocent person) in a double-blind, placebo-controlled, parallel group design. Propranolol (40 mg orally) significantly reduced heart rate, but had no effect on self-reported mood. Importantly, propranolol made participants more likely to judge harmful actions as morally unacceptable, but only in dilemmas where harms were ‘up close and personal’. In addition, longer response times for such personal dilemmas were only found for the placebo group. Finally, judgments in personal dilemmas by the propranolol group were more decisive. These findings indicate that noradrenergic pathways play a role in responses to moral dilemmas, in line with recent work implicating emotion in moral decision-making. However, contrary to current theorising, these findings also suggest that aversion to harming is not driven by emotional arousal. Our findings are also of significant practical interest given that propranolol is a widely used drug in different settings, and is currently being considered as a potential treatment for post-traumatic stress disorder in military and rescue service personnel. PMID:23085134

  20. Beta-adrenergic regulation of secretion in Clara cell adenomas of the mouse lung

    SciTech Connect

    Palmer, K.C.; Grammas, P.

    1986-03-05

    Certain chemically-induced pulmonary adenomas of the mouse have been characterized as being Clara cell in origin. In examining these Clara cell tumors as a model of normal Clara cell biology, they studied the response of tumor cells in vivo to the secretory agonist, isoproterenol (10 mg/kg) and the antagonist propranolol (2.0 mg/kg) 1 hr. following intraperitoneal injection of 120 day old tumor-bearing mice. Ultrastructural morphometry was used to quantitate the secretory response of tumor cells by measuring the volume density of the secretory granules. In the intact animal, isoproterenol stimulated secretion in the Clara cell adenomas (40% decrease in vol. dens. with no change in surface to volume ratio of granules) while propranolol prevented this effect. Beta-adrenergic receptors on isolated tumor Clara cells were demonstrated by radioligand binding assay using /sup 125/I-iodocyanopindolol (ICYP). Scatchard analysis of data derived from whole cells indicates a maximum receptor binding capacity of 27 fmol/mg protein and a K/sub D/ of 0.029 nM. Isoproterenol displacement of ICYP binding yields an IC/sub 50/ of 8 x 10/sup -7/M and a calculated K/sub D/ of 3.36 x 10/sup -7/M. The beta/sub 2/ identity of these receptors was determined utilizing the relatively specific beta/sub 1/ and beta/sub 2/ antagonists practolol and ICI-118,551, respectively. Practolol failed to displace more than 30% of ICYP binding even at 100 ..mu..M, while ICI-118,551 displacement of ICYP yielded a linear (r = 0.93) Hofstee plot and a K/sub D/ of 5.04 x 10/sup -9/M. These findings suggest that the secretory activity of adenoma-derived Clara cells is under beta-adrenergic control similar to that of normal bronchiolar Clara cells.

  1. Cellular interactions uncouple beta-adrenergic receptors from adenylate cyclase.

    PubMed

    Ciment, G; de Vellis, J

    1978-11-17

    C6 glioma cells and B104 neuroblastoma cells both possess adenylate cyclase activity, but only C6 cells have beta-adrenergic receptors. However, when cocultured with B104 cells, C6 cells show a marked decrease in their ability to accumulate adenosine 3', 5'-monophosphate upon stimulation with beta receptor agonists. Since both beta receptors and cholera toxin-stimulated adenylate cyclase activities are present in C6/B104 cocultures, we conclude that the beta receptor/adenylate cyclase transduction mechanism in cocultured C6 cells is uncoupled.

  2. Interactions of. beta. -adrenergic receptors with guanine nucleotide-binding proteins

    SciTech Connect

    Abramson, S.N.

    1985-01-01

    The properties of ..beta..-adrenergic receptors were investigated with radioligand binding assays using the agonists (/sup 3/H)hydroxybenzyl-isoproterenol (/sup 3/H-HBI) and (/sup 3/H)epinephrine (/sup 3/H-EPI), and the antagonist (/sup 125/I)iodopindolol (/sup 125/I-IPIN). Membranes prepared from L6 myoblasts bound (/sup 3/H)HBI, (/sup 3/H)EPI, and (/sup 125/I)IPIN with high affinity and Scatchard plots revealed densities of 222 +/- 23, 111 +/- 7, and 325 +/- 37 fmol/mg of protein, respectively. Binding of (/sup 3/H)HBI and (/sup 3/H)EPI was inhibited allosterically by guanine nucleotides. Membranes prepared from wild-type S49 lymphoma cells bound (/sup 3/H)HBI and (/sup 125/I)IPIN with high affinity and Scatchard plots revealed densities of 48.9 +/- 7.1 and 196 +/- 29 fmol/mg of protein, respectively. Binding of (/sup 3/H)HBI was inhibited allosterically by GTP. Similar results were obtained with membranes prepared from the adenylate cyclase deficient variant of S49 lymphoma cells (cyc-), which does not contain a functional stimulatory guanine nucleotide-binding protein (N/sub s/), but does contain a functional inhibitory guanine nucleotide-binding protein (N/sub i/). Binding of (/sup 3/H)HBI to membranes prepared from cyc- S49 cells was inhibited by pretreatment of cells with pertussis toxin. These results suggest that ..beta..-adrenergic receptors on membranes prepared from cyc- S49 cells interact with N/sub i/ to form a ternary complex composed of agonist, receptor, and N/sub i/.

  3. Blocking the beta-adrenergic system does not affect sweat gland function during heat acclimation.

    PubMed

    Martinez, Ricardo; Jones, Douglas; Hodge, Daniel; Buono, Michael J

    2012-08-16

    The purpose of the current study was to test the hypothesis that the beta-adrenergic innervation of the human eccrine sweat gland facilitates greater sweat production following heat acclimation. Eight healthy subjects (mean ± SD age: 25.1 ± 4.1 years, weight: 79.0 ± 16.1 kg, and VO(2)max: 48.5 ± 8.0 ml/kg/min) underwent active heat acclimation by walking at 40% of their VO(2)max for 8 days (90 min a day) in an environmental chamber (35.3 ± 0.8°C and 40.2 ± 2.1% rH). To test the hypothesis, the adrenergic component of sweat gland innervation was inhibited by continuously administering a 0.5% solution of the beta-adrenergic antagonist propranolol via iontophoresis to a 5 cm(2) area of one forearm during each 90-min exercise bout. The opposing control forearm underwent iontophoresis with a saline solution. Following heat acclimation, mean sweat rate in the inhibited and control forearm was 0.47 ± 0.30 mg/cm(2)/min and 0.44 ± 0.25mg/cm(2)/min, respectively. Findings of the current study fail to support the hypothesis that adrenergic innervation facilitates human eccrine sweat gland function during heat acclimation, as no significant differences in sweating were observed. In light of the above, the physiological significance of the dual cholinergic and adrenergic innervation of the eccrine sweat gland has yet to be determined.

  4. Structural analysis of beta-adrenergic and muscarinic cholinergic receptors

    SciTech Connect

    Kerlavage, A.R.; Fraser, C.M.; Venter, J.C.

    1987-05-01

    The authors have recently cloned the gene encoding the human brain beta-adrenergic receptor. Beta-adrenergic and muscarinic cholinergic receptors have also been cloned from other tissues. In order to correlate the primary structures of these receptors with their function, they have undertaken detailed mapping of their functionally important sites. Purified guinea pig lung beta receptor was radioiodinated and digested with trypsin. The resultant peptides were resolved by reverse phase HPLC into nine peaks containing /sup 125/I, corresponding exactly with the predicted number of tyrosine containing peptides in the beta receptor. Hamster lung beta receptor was labeled with (/sup 125/I)-iodocyanopindolol diazarine ((/sup 125/I)CYPD) and partially purified by SDS-PAGE. The (/sup 125/I)CYPD-labeled receptor was extracted from the gel, digested with either trypsin or CNBr and the digests were resolved by reverse phase HPLC. The tryptic digest contained one (/sup 125/I)CYPD-labeled peak and the CNBr digest contained two. Rat brain muscarinic receptor was specifically labeled with (/sup 3/H)-propylbenzilyl-choline mustard ((/sup 3/H)PrBCM) and partially purified by SDS-PABE. The (/sup 3/H)PrBCM-labeled receptor was extracted from the gel and digested with CNBr. The resultant HPLC profile revealed a single (/sup 3/H)PrBCM-labeled peak. These data yield information on the location of functional sites within the primary sequences of these receptors.

  5. Phospholemman and beta-adrenergic stimulation in the heart.

    PubMed

    Wang, JuFang; Gao, Erhe; Song, Jianliang; Zhang, Xue-Qian; Li, Jifen; Koch, Walter J; Tucker, Amy L; Philipson, Kenneth D; Chan, Tung O; Feldman, Arthur M; Cheung, Joseph Y

    2010-03-01

    Phosphorylation at serine 68 of phospholemman (PLM) in response to beta-adrenergic stimulation results in simultaneous inhibition of cardiac Na(+)/Ca(2+) exchanger NCX1 and relief of inhibition of Na(+)-K(+)-ATPase. The role of PLM in mediating beta-adrenergic effects on in vivo cardiac function was investigated with congenic PLM-knockout (KO) mice. Echocardiography showed similar ejection fraction between wild-type (WT) and PLM-KO hearts. Cardiac catheterization demonstrated higher baseline contractility (+dP/dt) but similar relaxation (-dP/dt) in PLM-KO mice. In response to isoproterenol (Iso), maximal +dP/dt was similar but maximal -dP/dt was reduced in PLM-KO mice. Dose-response curves to Iso (0.5-25 ng) for WT and PLM-KO hearts were superimposable. Maximal +dP/dt was reached 1-2 min after Iso addition and declined with time in WT but not PLM-KO hearts. In isolated myocytes paced at 2 Hz. contraction and intracellular Ca(2+) concentration ([Ca(2+)](i)) transient amplitudes and [Na(+)](i) reached maximum 2-4 min after Iso addition, followed by decline in WT but not PLM-KO myocytes. Reducing pacing frequency to 0.5 Hz resulted in much smaller increases in [Na(+)](i) and no decline in contraction and [Ca(2+)](i) transient amplitudes with time in Iso-stimulated WT and PLM-KO myocytes. Although baseline Na(+)-K(+)-ATPase current was 41% higher in PLM-KO myocytes because of increased alpha(1)- but not alpha(2)-subunit activity, resting [Na(+)](i) was similar between quiescent WT and PLM-KO myocytes. Iso increased alpha(1)-subunit current (I(alpha1)) by 73% in WT but had no effect in PLM-KO myocytes. Iso did not affect alpha(2)-subunit current (I(alpha2)) in WT and PLM-KO myocytes. In both WT and NCX1-KO hearts, PLM coimmunoprecipitated with Na(+)-K(+)-ATPase alpha(1)- and alpha(2)-subunits, indicating that association of PLM with Na(+)-K(+)-ATPase did not require NCX1. We conclude that under stressful conditions in which [Na(+)](i) was high, beta-adrenergic agonist

  6. Epinephrine administration increases neural impulses propagated along the vagus nerve: Role of peripheral beta-adrenergic receptors.

    PubMed

    Miyashita, T; Williams, C L

    2006-03-01

    A significant number of animal and human studies demonstrate that memories for new experiences are encoded more effectively under environmental or laboratory conditions which elevate peripheral concentrations of the hormone epinephrine and in turn, induce emotional arousal. Although this phenomenon has been replicated across several learning paradigms, understanding of how this arousal related hormone affects memory processing remains obscure because epinephrine does not freely enter into the central circulation to produce any direct effects on the brain. This study examined whether epinephrine's actions on the CNS may be mediated by the initial activation of peripheral vagal fibers that project to the brain. The vagus was selected as a candidate for this role since it is densely embedded with beta-adrenergic receptors and the peripheral endings of this nerve innervate a broad spectrum of sensory organs that are directly affected by epinephrine release. Electrophysiological recordings of cervical vagal activity was measured over 110 min in urethane-anesthetized Sprague-Dawley rats given saline, epinephrine (0.3 mg/kg), the peripherally acting beta-adrenergic antagonist sotalol (2.0 mg/kg), or a combination of sotalol followed 15 min later by an injection of epinephrine. Epinephrine produced a significant increase in vagal nerve firing 10 min post-injection (p < .05) relative to controls and neural impulses recorded from the vagus remained significantly elevated for the remaining 55 min collection period. The excitatory actions of epinephrine were not observed in groups given an identical dose of the hormone after peripheral beta-adrenergic receptor blockade with sotalol. These findings demonstrate that neural discharge in vagal afferent fibers is increased by elevations in peripheral concentrations of epinephrine and the significance of these findings in understanding how epinephrine modulates brain limbic structures to encode and store new information into memory

  7. Visualization of the turkey erythrocyte beta-adrenergic receptor.

    PubMed

    Durieu-Trautmann, O; Delavier-Klutchko, C; Vauquelin, G; Strosberg, A D

    1980-01-01

    We have recently described the affinity chromatography purification of the turkey erythrocyte beta-adrenergic receptor. The minute amounts obtained initially precluded extensive biochemical characterization. To improve the yield of the receptor, the erythrocyte membranes have been prepared by a new method. This procedure resulted in a 10-fold higher receptor density in comparison with the membrane preparation used previously. The new membranes also contained a catecholamine-sensitive guanine triphosphatase and an adenylate cyclase sensitive to Gpp(NH)p and l-epinephrine. Solubilization by a double digitonin extraction resulted in a preparation containing 4-6 pmoles of 3H-dihydroalprenolol binding sites per mg of membrane protein. A single step of affinity chromatography on alprenolol-sepharose of the soluble digitonin extract resulted in an additional 1,000-fold purification of the receptor. The overall purification factor was 20,000 relative to the binding activity of the crude membrane preparations. Electrophoresis is SDS-polyacrylamide of iodinated purified beta-receptors revealed, after autoradiography, the presence of four major components. Three of these, corresponding to molecular weights of 170,000, 33,000, and 30,000, respectively, were not affected by reduction with beta-mercaptoethanol and were not observed when the digitonin extracts were loaded on the affinity gel in the presence of an excess of l-propranolol. A fourth 52,000-dalton component (60,000 daltons after reduction with beta-mercaptoethanol) remained apparent even when affinity purification was prevented by addition of l-propranolol. Our results suggest that the beta-adrenergic receptor is composed of at least three subunits that interact by noncovalent bonds.

  8. Mood states, sympathetic activity, and in vivo beta-adrenergic receptor function in a normal population.

    PubMed

    Yu, Bum-Hee; Kang, Eun-Ho; Ziegler, Michael G; Mills, Paul J; Dimsdale, Joel E

    2008-01-01

    The purpose of this study was to examine the relationship between mood states and beta-adrenergic receptor function in a normal population. We also examined if sympathetic nervous system activity is related to mood states or beta-adrenergic receptor function. Sixty-two participants aged 25-50 years were enrolled in this study. Mood states were assessed using the Profile of Mood States (POMS). Beta-adrenergic receptor function was determined using the chronotropic 25 dose isoproterenol infusion test. Level of sympathetic nervous system activity was estimated from 24-hr urine norepinephrine excretion. Higher tension-anxiety, depression-dejection, and anger-hostility were related to decreased beta-adrenergic receptor sensitivity (i.e., higher chronotropic 25 dose values), but tension-anxiety was the only remaining independent predictor of beta-adrenergic receptor function after controlling for age, gender, ethnicity, and body mass index (BMI). Urinary norepinephrine excretion was unrelated to either mood states or beta-adrenergic receptor function. These findings replicate previous reports that anxiety is related to decreased (i.e., desensitized) beta-adrenergic receptor sensitivity, even after controlling for age, gender, ethnicity, and body mass index.

  9. Direct analysis of beta-adrenergic receptor subtypes on intact adult ventricular myocytes of the rat

    SciTech Connect

    Buxton, I.L.; Brunton, L.L.

    1985-01-01

    beta 1- and beta 2-Adrenergic receptors co-exist in the adult rat ventricle. Radioligand binding and cell purification techniques have been employed to determine the cellular origin of these receptors. The beta-adrenergic antagonist ligand (+/-)-(/sup 125/I) iodocyanopindolol binds to 2 X 10(5) receptors per purified adult rat cardiomyocyte, with a dissociation constant of 70 pM. The subtype-selective antagonists betaxolol (beta 1), practolol (beta 1), and zinterol (beta 2) compete for (/sup 125/I)iodocyanopindolol-binding sites on intact myocytes in monophasic manners with dissociation constants of 46, 845, and 923 nM, respectively. (/sup 125/I)iodocyanopindolol binding to membranes prepared from nonmyocyte elements of rat ventricle occurs with a dissociation constant of 43 pM and a capacity of 88 fmol/mg membrane protein. Computer analysis of competition of (/sup 125/I)iodocyanopindolol binding by betaxolol, practolol, and zinterol in nonmyocyte membranes demonstrates biphasic curves that comprise binding to both beta 1- and beta 2-receptors. These data demonstrate that purified adult ventricular myocytes possess only beta 1-receptors, and that the beta 2-receptors found in rat ventricle are located on nonmyocyte cell types.

  10. Beta-adrenergic receptors on murine lymphocytes: density varies with cell maturity and lymphocyte subtype and is decreased after antigen administration

    SciTech Connect

    Fuchs, B.A.; Albright, J.W.; Albright, J.F.

    1988-07-01

    beta-Adrenergic receptors were assayed on intact, viable, murine splenocytes and thymocytes using the labeled adrenergic antagonists (3H)-dihydroalprenolol l-(ring propyl-3H(N)) ((3H)DHA) and 4-(3-t-butylamino-2-hydroxypropoxy)-(5,7-3H)benzimidazol-2-one ((3H)CGP 12177). The sites detected by (3H)DHA did not always possess the characteristics of beta-adrenergic receptors and were demonstrated to be stereospecific only after the addition of the binding assay. Populations of cells from C57Bl/6 inbred and CF1 outbred mice were compared. Purified T cells from C57Bl/6 mice had fewer receptors than did either whole spleen or B cells. Thymocytes from either strain had significantly fewer receptors than did the other lymphocyte populations. However, mature medullary thymocytes purified from C57Bl/6 mice had higher numbers of receptors per cell which were comparable to those of the splenic T cell. Radiation-resistant splenocytes recovered from CF1 mice 24 hr after 700 rad of irradiation possessed greatly increased numbers of receptors per cell. Immunization with sheep red blood cells caused a significant reduction in the density of receptors on splenocytes from C57Bl/6 mice. The wide variations observed in the density of beta-adrenergic receptors, possibly related to cell maturity or state of activation, seem to provide opportunities for differential modulation of cell functions by either endogenous or exogenous adrenergic agents.

  11. Beta-adrenergic receptors of lymphocytes in children with allergic respiratory diseases

    SciTech Connect

    Bittera, I.; Gyurkovits, K.; Falkay, G.; Eck, E.; Koltai, M.

    1988-01-01

    The beta-adrenergic receptor binding sites on peripheral lymphocytes in children with bronchial asthma (n = 16) and seasonal allergic rhinitis (n = 8) were examined in comparison with normal controls (n = 18) by means of /sup 124/I-cyanopindolol. The number of beta-adrenergic receptors was significantly lower in the asthmatic group (858 +/- 460/lymphocyte) than in the controls (1564 +/- 983/lymphocyte). The value (1891 +/- 1502/lymphocyte in children with allergic rhinitis was slightly higher than that in healthy controls. Of the 24 patients suffering from allergic diseases of the lower or upper airways, the bronchial histamine provocation test was performed in 21; 16 gave positive results, while 5 were negative. No difference in beta-adrenergic receptor count was found between the histamine-positive and negative patients. Neither was there any correlation between the number of beta-adrenergic receptors and the high (16/24) and low (8/24) serum IgE concentrations found in allergic patients. The significant decrease in beta-adrenergic receptor count in asthmatic children lends support to Szentivanyi's concept. Further qualitative and quantitative analysis of lymphocyte beta-adrenergic receptors may provide an individual approach to the treatment of bronchial asthma with beta-sympathomimetic drugs.

  12. Characterization of beta-adrenergic receptors through the replicative life span of IMR-90 cells

    SciTech Connect

    Scarpace, P.J.

    1987-01-01

    Beta-adrenergic receptor number and receptor affinity for isoproterenol were assessed at various in vitro ages of the human diploid fibroblast cell line IMR-90. From population doubling level (PDL) 33 to 44, there was a positive correlation between beta-adrenergic receptor density and PDL. Beta-adrenergic receptors, assessed by Scatchard analysis of (/sup 125/I)-iodocyanopindolol (ICYP) binding, increased from 15 fmol/mg protein at PDL 33 to 36 fmol/mg protein at PDL 44. In contrast, from PDL 44 to 59, there was a negative correlation between beta-adrenergic receptor density and PDL. Receptor density declined to 12 fmol/mg protein at PDL 59. When the density of beta-adrenergic receptors was expressed as receptor per cell, the findings were similar. Receptor agonist affinity for isoproterenol was determined from Hill plots of (/sup 125/I)-ICYP competition with isoproterenol. There was no change in the dissociation constant for isoproterenol with in vitro age. In humans, serum norepinephrine concentrations increase with age. This increase in serum norepinephrine may be partially responsible for the decreased beta-adrenergic receptor-agonist affinity observed with age in human lymphocytes and rat heart and lung. The present findings are consistent with the hypothesis that the decreases in receptor agonist affinity in rat and man with age are secondary to increases in catecholamine concentrations.

  13. Modulation of. beta. -adrenergic response in rat brain astrocytes by serum and hormones

    SciTech Connect

    Wu, D.K.; Morrison, R.S.; de Vellis, J.

    1985-01-01

    Purified astrocyte cultures from neonatal rat cerebrum respond to isoproterenol, a ..beta..-adrenergic agonist, with a transient rise in cAMP production. This astroglial property was regulated by serum, a chemically defined medium (serum-free medium plus hydrocortisone, putrescine, prostaglandin F/sub 2/, insulin, and fibroblast growth factor) and epidermal growth factor. Compared to astrocytes grown in serum-supplemented medium, astrocytes grown in the chemically defined medium were nonresponsive to isoproterenol stimulation, and this difference did not appear to be due to selection of a subpopulation of cells by either medium. The data suggest that a decreased ..beta..-adrenergic receptor number and an increased degradation of cAMP may account for the reduced response to ..beta..-adrenergic stimulation. The nonresponsive state of astrocytes in the defined medium was reversible when the medium was replaced with serum-supplemented medium. An active substance(s) in serum was responsible for restoring the responsiveness of astrocytes. Each of the five components of the defined medium had little effect by itself; however, together they acted synergistically to desensitize astrocytes to ..beta..-adrenergic stimulation. On the other hand, epidermal growth factor, a potent mitogen for astrocytes, was very competent by itself in reducing the cAMP response of astrocytes to ..beta..-adrenergic stimulation. Thus purified astrocytes grown in the chemically defined medium appear to be a good model for the study of hormonal interactions and of serum factors which may modulate the ..beta..-adrenergic response.

  14. beta. -adrenergic relaxation of smooth muscle: differences between cells and tissues

    SciTech Connect

    Scheid, C.R.

    1987-09-01

    The present studies were carried out in an attempt to resolve the controversy about the Na/sup +/ dependence of ..beta..-adrenergic relaxation in smooth muscle. Previous studies on isolated smooth muscle cells from the toad stomach had suggested that at least some of the actions of ..beta..-adrenergic agents, including a stimulatory effect on /sup 45/Ca efflux, were dependent on the presence of a normal transmembrane Na/sup +/ gradient. Studies by other investigators using tissues derived from mammalian sources had suggested that the relaxing effect of ..beta..-adrenergic agents was Na/sup +/ independent. Uncertainty remained as to whether these discrepancies reflected differences between cells and tissues or differences between species. Thus, in the present studies, the authors utilized both tissues and cells from the same source, the stomach muscle of the toad Bufo marinus, and assessed the Na/sup +/ dependence of ..beta..-adrenergic relaxation. They found that elimination of a normal Na/sup +/ gradient abolished ..beta..-adrenergic relaxation of isolated cells. In tissues, however, similar manipulations had no effect on relaxation. The reasons for this discrepancy are unclear but do not appear to be attributable to changes in smooth muscle function following enzymatic dispersion. Thus the controversy concerning the mechanisms of ..beta..-adrenergic relaxation may reflect inherent differences between tissues and cells.

  15. Amiloride interacts with renal. cap alpha. - and. beta. -adrenergic receptors

    SciTech Connect

    Howard, M.J.; Mullen, M.D.; Insel, P.A.

    1987-07-01

    The authors have used radioligand binding techniques to assess whether amiloride and certain analogues of amiloride (ethylisopropyl amiloride and benzamil) can bind to adrenergic receptors in the kidney. They found that amiloride could compete for (/sup 3/H)rauwolscine (..cap alpha../sub 2/-adrenergic receptors), (/sup 3/H)prazosin (..cap alpha../sub 1/-adrenergic receptors), and (/sup 125/I)iodocyanopindolol (..beta..-adrenergic receptors) binding in rat renal cortical membranes with inhibitor constants of 13.6 /plus minus/ 5.7, 24.4 /plus minus/ 7.4, and 8.36 /plus minus/ 13.5 ..mu..M, respectively. Ethylisopropyl amiloride and benzamil were from 2- to 25-fold more potent than amiloride in competing for radioligand binding sites in studies with these membranes. In addition, amiloride and the two analogues competed for (/sup 3/H)prazosin sites on intact Madin-Darby canine kidney cells and amiloride blocked epinephrine-stimulated prostaglandin E/sub 2/ production in these cells. They conclude that amiloride competes for binding to several classes of renal adrenergic receptors with a rank order of potency of ..cap alpha../sub 2/ > ..cap alpha../sub 1/ > ..beta... Binding to, and antagonism of, adrenergic receptors occurs at concentrations of amiloride that are lower than previously observed nonspecific interactions of this agent.

  16. Beta-adrenergic blockade and atrio--ventricular conduction impairment.

    PubMed

    Giudicelli, J F; Lhoste, F; Boissier, J R

    1975-04-01

    Atrio--ventricular conduction and its modifications induced by six Beta-adrenergic blocking agents have been investigated in the dog. Premature atrial stimuli (St2) were applied at variable intervals following regular stimuli (St1) ensuring atrial pacing; atrial (AERP), nodoventricular (NERP) and global (GERP) effective refractory periods as well as global functional refractory period (GFRP) were determined before and after administration of each of the six drugs. When Beta-blockade was produced with d,1-propranolol which hwas membrane stabilizing effects (MSE) but no intrinsic sympathomimetic activity (ISA) or with sotalol, which has neither MSE nor ISA, all parameters were significantly increased. When Beta-blockade was achieved with pindolol or practolol, which have only a poor Beta-adrenolytic potency and no ISA. Alprenolol showed intermediate effects. Thus, it appears that Beta-blockade and not MSE, is responsible for the onset of A-V conduction impairment but that ISA, probably through a metabolic mechanism, affords protection against this impairment. On the other hand, measurement of ventricular effective refractory period (VERP) has shown that at the Purkinje-free junction, it is MSE which is mainly involved in conduction impairment.

  17. Beta-adrenergic blocking agents and dental vasoconstrictors.

    PubMed

    Hersh, Elliot V; Giannakopoulos, Helen

    2010-10-01

    A clinically significant interaction between epinephrine or levonordefrin with nonselective beta-adrenergic blocking agents, although apparently rare in the dental setting, is potentially serious and can lead to significant hypertension with a concomitant reflex bradycardia. Based on the results of epinephrine infusion studies, the severity of the interaction seems dose related; small epinephrine doses cause less of a pressor response than larger doses. The interaction can be seen after intraoral submucosal injections but is generally of a smaller magnitude, at least with only 1 or 2 cartridges of lidocaine plus 1:100,000 epinephrine. However as demonstrated by 1 case report, some individuals are hypersensitive to this interaction. Inadvertent intravascular injections of local anesthetic plus vasoconstrictor and the use of high doses of vasoconstrictor are likely to result in a more pronounced response. Patients with significant cardiovascular disease may be especially vulnerable to the most serious sequelae resulting from the pressor reactions of the drug combination. Copyright © 2010 Elsevier Inc. All rights reserved.

  18. Purification and molecular characterization of the cardiac beta-adrenergic receptor

    SciTech Connect

    Robinson, D.A.; Venter, J.C.; Fraser, C.M.

    1986-05-01

    The porcine ventricle cardiac beta-adrenergic receptor (..beta..AR) is predominantly of the ..beta../sub 2/ subtype. Sucrose density gradient purified porcine ventricle membranes exhibit a high ..beta..AR density of 1 pmol per mg and a K/sub d/ for /sup 125/I-iodocyanopindolol of 180 pM. Digitonin solubilized receptor exhibits ligand binding characteristics identical to those of membrane bound receptor. Stability studies indicate that the solubilized cardiac ..beta..AR has a t/sub 1/2/ of 92 hours. Solubilized receptor is stabilized by occupation with antagonists. Isoelectric focusing indicates a pI = 5.0, in agreement with results obtained for both ..beta../sub 1/AR and ..beta../sub 2/AR isolated from other sources. The cardiac ..beta../sub 1/AR has been purified to homogeneity by affinity chromatography and size exclusion HPLC (2 TSK 2000, 1 TSK 3000). Autoradiograms of purified, radioiodinated receptor preparations subjected to SDS-PAGE revealed a single band with an apparent subunit molecular mass (M/sub r/) of 68 kDa. This subunit M/sub r/ was confirmed in membranes photoaffinity labeled with /sup 125/I-iodocyanopindolol diazirine. A single band was specifically labeled, as evidenced by blocking of photoincorporation by (-) and (+) propranolol with typical ..beta..AR stereoselectivity.

  19. Iontophoretic beta-adrenergic stimulation of human sweat glands: possible assay for cystic fibrosis transmembrane conductance regulator activity in vivo.

    PubMed

    Shamsuddin, A K M; Reddy, M M; Quinton, P M

    2008-08-01

    With the advent of numerous candidate drugs for therapy in cystic fibrosis (CF), there is an urgent need for easily interpretable assays for testing their therapeutic value. Defects in the cystic fibrosis transmembrane conductance regulator (CFTR) abolished beta-adrenergic but not cholinergic sweating in CF. Therefore, the beta-adrenergic response of the sweat gland may serve both as an in vivo diagnostic tool for CF and as a quantitative assay for testing the efficacy of new drugs designed to restore CFTR function in CF. Hence, with the objective of defining optimal conditions for stimulating beta-adrenergic sweating, we have investigated the components and pharmacology of sweat secretion using cell cultures and intact sweat glands. We studied the electrical responses and ionic mechanisms involved in beta-adrenergic and cholinergic sweating. We also tested the efficacy of different beta-adrenergic agonists. Our results indicated that in normal subjects the cholinergic secretory response is mediated by activation of Ca(2+)-dependent Cl(-) conductance as well as K(+) conductances. In contrast, the beta-adrenergic secretory response is mediated exclusively by activation of a cAMP-dependent CFTR Cl(-) conductance without a concurrent activation of a K(+) conductance. Thus, the electrochemical driving forces generated by beta-adrenergic agonists are significantly smaller compared with those generated by cholinergic agonists, which in turn reflects in smaller beta-adrenergic secretory responses compared with cholinergic secretory responses. Furthermore, the beta-adrenergic agonists, isoproprenaline and salbutamol, induced sweat secretion only when applied in combination with an adenylyl cyclase activator (forskolin) or a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, aminophylline or theophylline). We surmise that to obtain consistent beta-adrenergic sweat responses, levels of intracellular cAMP above that achievable with a beta-adrenergic agonist alone are

  20. Expression of mammalian beta-adrenergic receptors in Xenopus laevis oocytes

    SciTech Connect

    Bahouth, S.W.; Malbon, C.C.

    1987-05-01

    Xenopus laevis oocytes are a useful transcription and expression system for DNA and RNA, respectively. Total cellular RNA was extracted from mouse lymphoma S49 cells and poly(A)/sup +/mRNA prepared by affinity chromatography of RNA on oligo(dT) cellulose. The membranes of S49 cells contain beta-adrenergic receptors that display pharmacological characteristics of beta/sub 2/-subtype. Xenopus laevis oocytes were injected with 50 ng of mRNA/oocyte. Expression of beta-adrenergic receptors in oocytes incubated for 30 hr after microinjection was assessed in membranes by radioligand binding using (/sup 3/H) dihydroalprenolol. The injected oocytes displayed 0.34 fmol receptor/oocyte as compared to 0.02 fmol receptor/oocyte in the control oocytes. The affinity of beta-adrenergic receptors in injected oocytes for this radioligand was 2 nM, a value similar to the affinity of beta-adrenergic receptors for DHA in S49 cell membranes. The potency of beta-adrenergic agonists in competing for DHA binding to oocytes membranes was isoproterenol > epinephrine > norepineprine, indicating that the expressed beta-adrenergic receptors were of the beta/sub 2/-subtype. The K/sub I/ of these agonists for the beta-adrenergic receptor in oocyte membranes was 0.03, 0.15 and 1.2 ..mu..M, respectively. The role of post-translational modification in dictating receptor subtype is analyzed using mRNA of beta/sub 1/- as well as beta/sub 2/-adrenergic receptors.

  1. Interaction of sarcolysine with. beta. -adrenergic receptors of tumor cells

    SciTech Connect

    Belousova, A.K.; Solntseva, T.I.; Khabarov, S.V.

    1986-05-20

    The sites of specific binding of (L-/sup 3/H)dihydroalprenolol ((/sup 3/H)DHA), possessing the properties of ..beta..-adrenergic receptors, coupled with adenylate cyclase, were detected by methods of competitive displacement and binding of ..beta..-adrenoblockers: (/sup 3/H)-DHA and L-propranolol on the surface of ascites sarcoma 37 cells. Specific binding of the ligand occurs rapidly and with saturation. The total number of binding sites in the case of total saturation is (30-40) x 10/sup 3/ per cell. An analysis of the results by the Scatchard method permitted the detection of two types of ..beta..-adrenoreceptors with high (K/sub d/ = 0.9-1.0 mM) and low (K/sub d/ = 15-20 nM) affinity for (/sup 3/H)DHA. The number of receptors of the first type is (5.0-7.5) x 10/sup 3/, and of the second (20-30) x 10/sup 3/ per cell. Sarcolysine in 1-10 ..mu..M concentrations is capable of displacing (/sup 3/H)DHA bound to the ..beta..-adrenoreceptors, competing with it for common binding sites, and, like isoproterenol, inducing a brief increase in the content of cAMP in the tumor cells. Since sarcolysine noncompetitively inhibits cAMP phosphodiesterase of the plasma membranes of ascites sarcoma 37 cells in the same concentration range (2.5-25 ..mu..M), a possible functional association between the ..beta..-adrenoreceptors, adenylate cyclase, and the membrane cAMP phosphodiesterase and the participation of this complex in the antitumor effect of the cytostatic are suggested.

  2. The rush to adrenaline: drugs in sport acting on the beta-adrenergic system.

    PubMed

    Davis, E; Loiacono, R; Summers, R J

    2008-06-01

    Athletes attempt to improve performance with drugs that act on the beta-adrenergic system directly or indirectly. Of three beta-adrenoceptor (AR) subtypes, the beta(2)-AR is the main target in sport; they have bronchodilator and anabolic actions and enhance anti-inflammatory actions of corticosteroids. Although demonstrable in animal experiments and humans, there is little evidence that these properties can significantly improve performance in trained athletes. Their actions may also be compromised by receptor desensitization and by common, naturally occurring receptor mutations (polymorphisms) that can influence receptor signalling and desensitization properties in individuals. Indirectly acting agents affect release and reuptake of noradrenaline and adrenaline, thereby influencing all AR subtypes including the three beta-ARs. These agents can have potent psychostimulant effects that provide an illusion of better performance that does not usually translate into improvement in practice. Amphetamines and cocaine also have considerable potential for cardiac damage. beta-AR antagonists (beta-blockers) are used in sports that require steadiness and accuracy, such as archery and shooting, where their ability to reduce heart rate and muscle tremor may improve performance. They have a deleterious effect in endurance sports because they reduce physical performance and maximum exercise load. Recent studies have identified that many beta-AR antagonists not only block the actions of agonists but also activate other (mitogen-activated PK) signalling pathways influencing cell growth and fate. The concept that many compounds previously regarded as 'blockers' may express their own spectrum of pharmacological properties has potentially far-reaching consequences for the use of drugs both therapeutically and illicitly.

  3. Targeting of Beta Adrenergic Receptors Results in Therapeutic Efficacy against Models of Hemangioendothelioma and Angiosarcoma

    PubMed Central

    Stiles, Jessica M.; Amaya, Clarissa; Rains, Steven; Diaz, Dolores; Pham, Robert; Battiste, James; Modiano, Jaime F.; Kokta, Victor; Boucheron, Laura E.; Mitchell, Dianne C.; Bryan, Brad A.

    2013-01-01

    Therapeutic targeting of the beta-adrenergic receptors has recently shown remarkable efficacy in the treatment of benign vascular tumors such as infantile hemangiomas. As infantile hemangiomas are reported to express high levels of beta adrenergic receptors, we examined the expression of these receptors on more aggressive vascular tumors such as hemangioendotheliomas and angiosarcomas, revealing beta 1, 2, and 3 receptors were indeed present and therefore aggressive vascular tumors may similarly show increased susceptibility to the inhibitory effects of beta blockade. Using a panel of hemangioendothelioma and angiosarcoma cell lines, we demonstrate that beta adrenergic inhibition blocks cell proliferation and induces apoptosis in a dose dependent manner. Beta blockade is selective for vascular tumor cells over normal endothelial cells and synergistically effective when combined with standard chemotherapeutic or cytotoxic agents. We demonstrate that inhibition of beta adrenergic signaling induces large scale changes in the global gene expression patterns of vascular tumors, including alterations in the expression of established cell cycle and apoptotic regulators. Using in vivo tumor models we demonstrate that beta blockade shows remarkable efficacy as a single agent in reducing the growth of angiosarcoma tumors. In summary, these experiments demonstrate the selective cytotoxicity and tumor suppressive ability of beta adrenergic inhibition on malignant vascular tumors and have laid the groundwork for a promising treatment of angiosarcomas in humans. PMID:23555867

  4. Effects of ovarian hormones on beta-adrenergic and muscarinic receptors in rat heart

    SciTech Connect

    Klangkalya, B.; Chan, A.

    1988-01-01

    The in vitro and in vivo effects of estrogen and progesterone on muscarinic and ..beta..-adrenergic receptors of cardiac tissue were studied in ovariectomized (OVX) rats. The binding assay for muscarinic receptors was performed under a nonequilibrium condition; whereas the binding assay for ..beta..-adrenergic receptors, under an equilibrium condition. Estrogenic compounds and progesterone were found to have no effect on the binding of the radioligand, (/sup 3/H)-dihydroalprenolol, to ..beta..-adrenergic receptors in vitro. However, progestins but not estrogenic compounds inhibited the binding of the radioligand, (/sup 3/H)-quinuclidinyl benzilate, to muscarinic receptors in vitro, with progesterone as the most potent inhibitor. Progesterone was found to decrease the apparent affinity of muscarinic receptors for (/sup 3/H)(-)QNB in vitro. Daily treatment of OVX rats with estradiol benzoate or progesterone for 4 days had no effect on the muscarinic or ..beta..-adrenergic receptors with respect to the binding affinity and receptor density. However, administrations of these hormones together for 4 days caused an increase in the receptor density of muscarinic receptors without a significant effect on their apparent binding affinity; also these hormones induced a decrease in the binding affinity and an increase in the receptor density of ..beta..-adrenergic receptors.

  5. Beta-Adrenergic Receptor Expression in Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, Ronald B.; Bridge, K.; Vaughn, J. R.

    1999-01-01

    beta-adrenergic receptor (bAR) agonists presumably exert their physiological action on skeletal muscle cells through the bAR. Since the signal generated by the bAR is cyclic AMP (cAMP), experiments were initiated in primary chicken muscle cell cultures to determine if artificial elevation of intracellular cAMP by treatment with forskolin would alter the population of bAR expressed on the surface of muscle cells. Chicken skeletal muscle cells after 7 days in culture were employed for the experiments because muscle cells have attained a steady state with respect to muscle protein metabolism at this stage. Cells were treated with 0-10 uM forskolin for a total of three days. At the end of the 1, 2, and 3 day treatment intervals, the concentration of cAMP and the bAR population were measured. Receptor population was measured in intact muscle cell cultures as the difference between total binding of [H-3]CGP-12177 and non-specific binding of [H-3]CGP-12177 in the presence of 1 uM propranolol. Intracellular cAMP concentration was measured by radioimmunoassay. The concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. Increasing concentrations of forskolin also led to an increase in (beta)AR population, with a maximum increase of approximately 50% at 10 uM. This increase in (beta)AR population was apparent after only 1 day of treatment, and the pattern of increase was maintained for all 3 days of the treatment period. Thus, increasing the intracellular concentration of cAMP leads to up-regulation of (beta)AR population. Clenbuterol and isoproterenol gave similar effects on bAR population. The effect of forskolin on the quantity and apparent synthesis rate of the heavy chain of myosin (mhc) were also investigated. A maximum increase of 50% in the quantity of mhc was observed at 0.2 UM forskolin, but higher concentrations of forskolin reduced the quantity of mhc back to control levels.

  6. Beta-Adrenergic Receptor Expression in Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, Ronald B.; Bridge, K.; Vaughn, J. R.

    1999-01-01

    beta-adrenergic receptor (bAR) agonists presumably exert their physiological action on skeletal muscle cells through the bAR. Since the signal generated by the bAR is cyclic AMP (cAMP), experiments were initiated in primary chicken muscle cell cultures to determine if artificial elevation of intracellular cAMP by treatment with forskolin would alter the population of bAR expressed on the surface of muscle cells. Chicken skeletal muscle cells after 7 days in culture were employed for the experiments because muscle cells have attained a steady state with respect to muscle protein metabolism at this stage. Cells were treated with 0-10 uM forskolin for a total of three days. At the end of the 1, 2, and 3 day treatment intervals, the concentration of cAMP and the bAR population were measured. Receptor population was measured in intact muscle cell cultures as the difference between total binding of [H-3]CGP-12177 and non-specific binding of [H-3]CGP-12177 in the presence of 1 uM propranolol. Intracellular cAMP concentration was measured by radioimmunoassay. The concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. Increasing concentrations of forskolin also led to an increase in (beta)AR population, with a maximum increase of approximately 50% at 10 uM. This increase in (beta)AR population was apparent after only 1 day of treatment, and the pattern of increase was maintained for all 3 days of the treatment period. Thus, increasing the intracellular concentration of cAMP leads to up-regulation of (beta)AR population. Clenbuterol and isoproterenol gave similar effects on bAR population. The effect of forskolin on the quantity and apparent synthesis rate of the heavy chain of myosin (mhc) were also investigated. A maximum increase of 50% in the quantity of mhc was observed at 0.2 UM forskolin, but higher concentrations of forskolin reduced the quantity of mhc back to control levels.

  7. The orphan nuclear receptor, NOR-1, is a target of beta-adrenergic signaling in skeletal muscle.

    PubMed

    Pearen, Michael A; Ryall, James G; Maxwell, Megan A; Ohkura, Naganari; Lynch, Gordon S; Muscat, George E O

    2006-11-01

    beta-Adrenergic receptor (beta-AR) agonists induce Nur77 mRNA expression in the C2C12 skeletal muscle cell culture model and elicit skeletal muscle hypertrophy. We previously demonstrated that Nur77 (NR4A1) is involved in lipolysis and gene expression associated with the regulation of lipid homeostasis. Subsequently it was demonstrated by another group that beta-AR agonists and cold exposure-induced Nur77 expression in brown adipocytes and brown adipose tissue, respectively. Moreover, NOR-1 (NR4A3) was hyperinduced by cold exposure in the nur77(-/-) animal model. These studies underscored the importance of understanding the role of NOR-1 in skeletal muscle. In this context we observed 30-480 min of beta-AR agonist treatment significantly and transiently increased expression of the orphan nuclear receptor NOR-1 in both mouse skeletal muscle tissue (plantaris) and C2C12 skeletal muscle cells. Specific beta(2)- and beta(3)-AR agonists had similar effects as the pan-agonist and were blocked by the beta-AR antagonist propranolol. Moreover, in agreement with these observations, isoprenaline also significantly increased the activity of the NOR-1 promoter. Stable exogenous expression of a NOR-1 small interfering RNA (but not the negative control small interfering RNA) in skeletal muscle cells significantly repressed endogenous NOR-1 mRNA expression and led to changes in the expression of genes involved in the control of lipid use and muscle mass underscored by a dramatic increase in myostatin mRNA expression. Concordantly the myostatin promoter was repressed by NOR-1 expression. In conclusion, NOR-1 is highly responsive to beta-adrenergic signaling and regulates the expression of genes controlling fatty acid use and muscle mass.

  8. Timolol. A beta-adrenergic blocking agent for the treatment of glaucoma.

    PubMed

    Zimmerman, T J; Kaufman, H E

    1977-04-01

    Timolol maleate, a beta-adrenergic blocking agent, was studied in 30 patients with glaucoma. Significant intraocular pressure lowering was achieved with 0.5% and 1.5% solution of the drug. At seven hours following treatment, the IOP was lowered 50% from the pretreatment pressure with both strengths of timolol. There were no subjective or objective ocular or systemic side effects detected. Visual acuity and pupil response were unchanged from pretreatment levels throughout the study. beta-Adrenergic blocking agents and specifically timolol may be an important breakthrough for the medical management of glaucoma.

  9. Mechanisms of action and the clinical pharmacology of beta-adrenergic blocking drugs.

    PubMed

    Lowenthal, D T; Saris, S D; Packer, J; Haratz, A; Conry, K

    1984-10-05

    At present more than 20 beta-adrenergic blocking drugs are commercially available in Western Europe, and six are available in the United States. The clinical indications for their usage include hypertension, arrhythmias, ischemic heart disease, thyrotoxicosis, migraine headaches, glaucoma, and anxiety states. We will review the mechanisms suggested for the antihypertensive action of beta-adrenergic blocking drugs as well as these agents' clinical pharmacologic aspects. In general, the pharmacodynamic effects of the beta blocking drugs are quite similar, yet the properties of biotransformation, including pharmacokinetics, tend to be distinguishing features.

  10. Characterization of beta-adrenergic receptors and adenylate cyclase activity in rat brown fat

    SciTech Connect

    Baresi, L.A.; Morley, J.E.; Scarpace, P.J.

    1986-03-01

    Catecholamines stimulate thermogenesis in rat brown fat through a mechanism which involves binding to the beta-adrenergic receptor (BAR), stimulation of adenylate cyclase (AC) and culminating with uncoupling of mitochondrial respiration from ATP synthesis. The authors characterized BAR, AC and cytochrome (cyt) c oxidase in CDF (F-344) interscapular brown fat. Scatchard analysis of (/sup 125/)Iodopindolol binding yields a straight line consistent with a single class of antagonist binding sites with 41.8 +/- 12.0 fmol BAR/mg protein and a K/sub d/ of 118 +/- 15 pM. Binding was both specific and stereospecific. Competition with 1-propranolol (K/sub d/ = 6.7 nM) was 15 times more potent than d-propranolol (K/sub d/ = 103 nM). Competition with isoproterenol (K/sub d/ = 79 nM) was 10 times more potent than epinephrine (K/sub d/ = 820 nM) which was 35 times more potent than norepinephrine (K/sub d/ = 2.9 x 10/sup -5/ M) suggesting predominate beta/sub 2/-type BAR. Cyt c oxidase activity was assessed in brown fat mitochrondrial preparations. The ratio of BAR to cyt c activity was 959 +/- 275 nmol BAR/mol cyc c/min. Isoproterenol (0.1 mM) stimulated AC activity was 24 times GTP (0.1 mM) stimulated AC (98.5 vs 40.7 pmol cAMP/min/mg). NaF-stimulated AC was nine times basal activity (90.5 vs 11.3 pmol cAMP/min/mg). These data demonstrate the presence of a beta-/sub 2/-type BAR coupled to adenylate cyclase in rat brown fat.

  11. Robust experiment design for estimating myocardial {beta} adrenergic receptor concentration using PET

    SciTech Connect

    Salinas, Cristian; Muzic, Raymond F. Jr.; Ernsberger, Paul; Saidel, Gerald M.

    2007-01-15

    Myocardial {beta} adrenergic receptor ({beta}-AR) concentration can substantially decrease in congestive heart failure and significantly increase in chronic volume overload, such as in severe aortic valve regurgitation. Positron emission tomography (PET) with an appropriate ligand-receptor model can be used for noninvasive estimation of myocardial {beta}-AR concentration in vivo. An optimal design of the experiment protocol, however, is needed for sufficiently precise estimates of {beta}-AR concentration in a heterogeneous population. Standard methods of optimal design do not account for a heterogeneous population with a wide range of {beta}-AR concentrations and other physiological parameters and consequently are inadequate. To address this, we have developed a methodology to design a robust two-injection protocol that provides reliable estimates of myocardial {beta}-AR concentration in normal and pathologic states. A two-injection protocol of the high affinity {beta}-AR antagonist [{sup 18}F]-(S)-fluorocarazolol was designed based on a computer-generated (or synthetic) population incorporating a wide range of {beta}-AR concentrations. Timing and dosage of the ligand injections were optimally designed with minimax criterion to provide the least bad {beta}-AR estimates for the worst case in the synthetic population. This robust experiment design for PET was applied to experiments with pigs before and after {beta}-AR upregulation by chemical sympathectomy. Estimates of {beta}-AR concentration were found by minimizing the difference between the model-predicted and experimental PET data. With this robust protocol, estimates of {beta}-AR concentration showed high precision in both normal and pathologic states. The increase in {beta}-AR concentration after sympathectomy predicted noninvasively with PET is consistent with the increase shown by in vitro assays in pig myocardium. A robust experiment protocol was designed for PET that yields reliable estimates of {beta

  12. Identification of beta-adrenergic receptors on cultured human fibroblast IMR-90 cells

    SciTech Connect

    Scarpace, P.J.

    1986-03-05

    Fibroblast cultures derived from normal human tissue undergo a finite number of population doublings when serial subcultivated in vitro. IMR-90 cells derived from human embryonic lung tissue undergo approximately 60 population doublings. Beta-adrenergic receptor (BAR) characteristics and isoproterenol-stimulated adenylate cyclase activity were assessed in IMR-90 cells at various population doublings (PDL). Scatchard analysis of /sup 125/I-Iodocyanopindolol (ICYP) binding yields a straight line consistent with a single class of antagonist binding sites with 452 +/- 35 sites/cell and a dissociation constant of 18.7 +/- 1.3 pM. There were no changes in BAR density between PDL 32 to PDL 46. Binding was both stereospecific and specific. Competition with epinephrine was 7.4 times more potent than with norepinephrine, suggesting predominate beta/sub 2/-type BAR. Competition with isoproterenol (Hill plots) indicated an apparent K/sub d/ of 1.3 +/- 0.1 x 10/sup -8/ M. Competition curves were resolved into high and low affinity binding sites yielding K/sub d/-high = 3.6 +/- 1.3 nM and k/sub d/-low = 1.6 +/- 0.7 x 10/sup -7/ M with 49.9 +/- 6.6% of the receptors in the high affinity state at PDL 31 to PDL 37. Cultures demonstrate isoproterenol-stimulated adenylate cyclase activity with a concentration of 1 x 10/sup -6/ M producing half-maximal stimulation and a maximum stimulation of 2 pmol cAMP/mg/min. Forskolin-stimulated was 10 pmol/cAMP/mg/min at PDL 46.

  13. Beta-adrenergic receptor function is acutely altered in surgical patients.

    PubMed

    Marty, J; Nimier, M; Rocchiccioli, C; Mantz, J; Luscombe, F; Henzel, D; Loiseau, A; Desmonts, J M

    1990-07-01

    Catecholamine-induced desensitization of beta-adrenergic receptors resulting in hyporesponsiveness to further stimulation has been frequently reported after an increase in endogenous catecholamines. To examine the possibility of beta-adrenoceptor desensitization due to intraoperative adrenergic activation (surgical stress), the alterations of human lymphocyte beta-adrenergic receptor density and affinity observed after anesthesia and surgery were studied using (-)125I-iodocyanopindolol binding in 19 patients undergoing noncardiac surgical procedures with general anesthesia (thiopental, fentanyl, and halothane or isoflurane). In 13 patients, repeated determinations of plasma levels of norepinephrine and epinephrine showed an increase during the surgical procedure (norepinephrine +60%; epinephrine +60%); this change was not observed in the remaining patients. A significant postoperative increase in receptor density (Bmax +25%) and a significant decrease of receptor affinity for isoproterenol (IC50 +22%) were found in the patients who experienced intraoperative adrenergic activation. By contrast, no significant change in beta-receptor density or affinity was found in the patients who had normal intraoperative adrenergic activation. In addition, heart rate responses to the postoperative changes in plasma catecholamines (an index of cardiac sensitivity to agonist) were significantly attenuated in patients who experienced both intraoperative adrenergic activation and a decrease in affinity of beta-receptor for agonist, suggesting hyporesponsiveness to beta stimulation. We conclude that beta-adrenergic receptors and, consequently, beta-adrenergic responsiveness might be altered by perioperative adrenergic activation in surgical patients.

  14. Possible involvement of parotid beta-adrenergic receptors in the etiology of sialadenosis.

    PubMed

    Chilla, R; Witzemann, V; Opaitz, M; Arglebe, C

    1981-01-01

    The concentration of beta-adrenergic receptors was determined in rat and human parotid glands, in normal tissue as well as after sympathetic denervation of the rat, and in human sialadenosis. Receptor levels were clearly elevated after denervation of the rat and in sialadenosis. The possible implications of these findings for the etiology of human sialadenosis are discussed.

  15. Beta-adrenergic agonists inhibit corticosteroid-induced apoptosis of airway epithelial cells.

    PubMed

    Tse, Roberta; Marroquin, Bertha A; Dorscheid, Delbert R; White, Steven R

    2003-08-01

    Airway epithelial damage is a feature of persistent asthma. Treatment with inhaled and oral corticosteroids may suppress inflammation and gain clinical control despite continued epithelial damage. We have previously demonstrated that corticosteroids elicit apoptosis of airway epithelial cells in culture. beta-Adrenergic receptor agonists are commonly used in asthma therapy and can inhibit corticosteroid-induced apoptosis of eosinophils. We tested the hypothesis that beta-adrenergic agonists would inhibit corticosteroid-induced airway epithelial cell apoptosis in cultured primary airway epithelial cells and in the cell line 1HAEo-. Albuterol treatment inhibited dexamethasone-induced apoptosis completely but did not inhibit apoptosis induced by Fas receptor activation. The protective effect of albuterol was duplicated by two different analogs of protein kinase A. The protective effect was not associated with increased translocation of the glucocorticoid receptor to the nucleus nor with changes in glucocorticoid receptor-mediated transcriptional activation or repression. We demonstrate that beta-adrenergic agonists can inhibit corticosteroid-induced apoptosis but not apoptosis induced by Fas activation. These data suggest that one potential deleterious effect of corticosteroid therapy in asthma can be prevented by concomitant beta-adrenergic agonist treatment.

  16. Beta Adrenergic Blocking Medications for Aggressive or Self-Injurious Mentally Retarded Persons.

    ERIC Educational Resources Information Center

    Ruedrich, Stephen L.; And Others

    1990-01-01

    Literature is reviewed and a case report is presented concerning blockers of the beta-adrenergic function of the sympathetic nervous system, postulated to have efficacy in treatment of aggressive or self-injurious syndromes in persons with mental retardation. Concerns are raised regarding endorsement of beta-blocking medications before they have…

  17. beta-Adrenergic and cholinergic receptors in hypertension-induced hypertrophy

    SciTech Connect

    Vatner, D.E.; Kirby, D.A.; Homcy, C.J.; Vatner, S.F.

    1985-05-01

    Perinephritic hypertension was produced in dogs by wrapping one kidney with silk and removing the contralateral kidney 1 week later. Mean arterial pressure rose from 104 +/- 3 to 156 +/- 11 mm Hg, while left ventricular free wall weight, normalized for body weight, was increased by 49%. Muscarinic, cholinergic receptor density measured with (/sup 3/H)-quinuclidinyl benzilate, fell in hypertensive left ventricles (181 +/- 19 fmol/mg, n = 6; p less than 0.01) as compared with that found in normal left ventricles (272 +/- 16 fmol/mg, n = 8), while receptor affinity was not changed. The beta-adrenergic receptor density, measured by binding studies with (/sup 3/H)-dihydroalprenolol, rose in the hypertensive left ventricles (108 +/- 10 fmol/mg, n = 7; p less than 0.01) as compared with that found in normal left ventricles (68.6 +/- 5.2 fmol/mg, n = 15), while beta-adrenergic receptor affinity decreased in the hypertensive left ventricles (10.4 +/- 1.2 nM) compared with that found in the normal left ventricles (5.0 +/- 0.7 nM). Plasma norepinephrine levels were similar in the two groups, but myocardial norepinephrine levels were depressed (p less than 0.05) in dogs with hypertension. Moderate left ventricular hypertrophy induced by long-term aortic banding in dogs resulted in elevations in beta-adrenergic receptor density (115 +/- 14 fmol/mg) and decreases in affinity (10.4 +/- 2.2 nM) similar to those observed in the dogs with left ventricular hypertrophy induced by hypertension. Thus, these results suggest that perinephritic hypertension in the dog induces divergent effects on cholinergic and beta-adrenergic receptor density. The increased beta-adrenergic receptor density and decreased affinity may be a characteristic of left ventricular hypertrophy rather than hypertension.

  18. Butyrate modulates the expression of. beta. -adrenergic receptor subtype in 3T3-L1 cells

    SciTech Connect

    Poksay, K.S.; Nakada, M.T.; Crooke, S.T.; Stadel, J.M.

    1986-03-05

    In mouse 3T3-L1 fibroblasts, the glucocorticoid dexamethasone (dex) affects a switch in ..beta..-adrenergic receptor (..beta..AR) subtype expression from ..beta../sub 1/AR to ..beta../sub 2/AR and increases total ..beta..AR number. They now demonstrate a similar effect by sodium butyrate (B) and find that the combined effect of these two gene-activating agents is greater than additive suggesting different mechanisms of action on the ..beta..AR. ..beta..AR are assayed in membranes prepared from 3T3-L1 cells using the radiolabeled ..beta..AR-specific antagonist (/sup 125/I)-cyanopindolol. ..beta..AR subtype is determined by competition binding of the ..beta../sub 2/AR-selective antagonist ICI 118.551 for the radioligand. B (2-10mM) causes a dose-dependent increase in total ..beta..AR number (up to 2-fold over control) and the proportion of ..beta../sub 2/AR. B (5mM) causes a time-dependent increase in total ..beta..AR number (2-fold) and the proportion of ..beta../sub 2/AR up to 24 hr. Dex maximally increases total ..beta..AR number (2-fold) when treated for 48 hr at concentrations greater than or equal to 100nM. B (2 or 5mM) together with dex (250nM) have a greater than additive effect on total ..beta..AR number at 24 hr (1.7-fold) and at 48 hr (1.4-2.4-fold, using 5 or 10mM B and dex greater than or equal to 10nM). The proportion of ..beta../sub 2/AR is also greater when both compounds are added together. In comparison with proprionate and valerate, B increases total ..beta..AR number and the proportion of ..beta../sub 2/AR to a greater extent and at lower concentrations. To determine a functional correlate to these findings, cells were pre-treated for 48 hr with B and/or dex, intracellular ATP labeled with /sup 3/H-adenine, followed by treatment with forskolin (10..mu..M) and ..beta..AR agonists. B caused a dramatic increase in /sup 3/H-cAMP produced compared to control and dex treatments and a greater than additive effect was again achieved when B and dex were

  19. Mechanisms altered beta-adrenergic responsiveness in the hyperthyroid and hypothyroid turkey erythrocyte.

    PubMed

    Bilezikian, J P; Loeb, J N

    Studies on the relationship between thyroid hormone and the beta-adrenergic catecholamines have been carried out in the turkey erythrocyte. Conditions of thyroid hormone excess and deficiency were examined with respect to their effects on the beta receptor itself, as well as to their effects on associated biochemical and physiological indices of beta receptor function, including agonist stimulated adenylate cyclase activity, cellular cyclic AMP generation, and catecholamine-induced stimulation of potassium ion influx. Erythrocytes obtained from hypothyroid turkeys showed a marked (approximately 50%) reduction in beta receptor number without any change in receptor affinity for agonists or antagonists. Catecholamine-sensitive adenylate cyclase activity and cellular cyclic AMP levels were similarly reduced. The sensitivity of these cells to agonist-stimulated potassium influx was significantly decreased, but maximal agonist-stimulated transport rate was unchanged. Analysis of the quantitative relationship between beta receptor number, agonist concentration, and level of catecholamine-stimulated potassium influx indicates that, at any given absolute level of receptor occupancy, the level of agonist-stimulated potassium influx is identical in hypothyroid and normal erythrocytes, and that the diminished physiological sensitivity of the hypothyroid cell is attributable in its entirety to a reduction in beta receptor number per se. The results obtained in the hyperthyroid turkey erythrocyte were strikingly different. Here, beta receptor number, binding affinity for agonists and antagonists, catecholamine-sensitive adenylate cyclase activity, and maximal cyclic AMP levels were all unchanged. In contrast, maximal agonist-stimulated potassium ion transport was markedly reduced, while the concentration of isoproterenol required for half-maximal stimulation was only slightly increased. Analysis of the relationship between beta receptor number, agonist concentration, and

  20. [Anti-arrhythmic effect of acupuncture pretreatment in the rat of myocardial ischemia the post-receptor signaling pathway of beta-adrenergic receptor].

    PubMed

    Gao, Jun-hong; Fu, Wei-xing; Jin, Zhi-gao; Yu, Xiao-chun

    2006-06-01

    To observe anti-arrhythmic effect of acupuncture pretreatment in the rat of myocardial ischemia and reperfusion (MIR) and to explore the role of cAMP and Gsa protein in beta-adrenergic receptor signaling. MIR was produced by ligation and reperfusion of the left anterior descending coronary artery in the rat. Arrhythmic score, content of cAMP and Gsalpha protein in ischemic myocardium were compared among the normal control (NC), ischemia and reperfusion (IR), electroacupuncture (EA) and EA plus propranolol (EAP) groups. The arrhythmic score in the IR group at 10 min after reperfusion was higher than the NC group (P < 0.01); in the EA group the score was decreased (P < 0.01 vs the IR group); the score in the EAP group was similar to the IR group, much higher than the EA group (P < 0.01). The similar results for the contents of cAMP and Gsalpha protein were found in the ischemic myocardium. It is suggested that EA pretreatment significantly attenuates the arrhythmic incidence rate and the enhancement of the contents of myocardial cAMP and Gsalpha protein induced by MIR, and the attenuating effect is significantly inhibited by the intraperitoneal pretreatment of propranolol, a specific beta-adrenoceptor antagonist. Pretreatment of EA can produce anti-arrhythmic effect in the rat of MIR, which is mediated by the post-receptor signaling pathway of beta-adrenergic receptor.

  1. The effects of a new ultra-short-acting beta-adrenergic blocker, ONO-1101, on cardiac function during and after cardiopulmonary bypass.

    PubMed

    Ahmet, I; Fukushima, N; Sawa, Y; Masai, T; Kadoba, K; Kagisaki, K; Chang, J C; Yamaguchi, T; Matsuda, H

    1999-01-01

    The administration of an ultra-short-acting beta-adrenergic antagonist, esmolol, has been introduced as a novel method for beating-heart surgery. In the present study, a new ultra-short-acting beta-blocker, ONO-1101, was administered during cardiopulmonary bypass (CPB) to investigate its effects on cardiac function and hemodynamics. Nine adult mongrel dogs underwent 60 min of CPB during which they were given either ONO-1101 (ONO group; n = 4) or saline (control group; n = 5). In the ONO group, the hearts became flaccid enough for surgery to be performed without cardiac standstill within 10 min after the commencement of ONO-1101 with significant decreases in the heart rate, the preload recruitable stroke work (PRSW), and the slope of the end-systolic left ventricular pressure-volume relationship (Emax). The mean arterial pressure and systemic vascular resistance also decreased, but were maintained above 50 mmHg during CPB without catecholamine. These indices increased to the control group level 20 min after the discontinuation of ONO-1101. The serum concentration of ONO-1101 decreased from the maximum level of 121 +/- 15 microg/ml soon after infusion to 11 +/- 5 microg/ml within 30 min after discontinuation. These data suggest that ONO-1101 may be useful to enable beating-heart surgery to be performed without aortic cross-clamp as an ultra-short-acting beta-adrenergic blocker.

  2. Properties of rat erythrocyte membrane cytoskeletal structures produced by digitonin extraction: digitonin-insoluble beta-adrenergic receptor, adenylate cyclase, and cholera toxin substrate.

    PubMed

    LeVine, H; Sahyoun, N E; Cuatrecasas, P

    1982-01-01

    Rat erythrocyte plasma membranes have been extracted exhaustively with digitonin at low temperature, and the residual, detergent-extracted membrane cytoskeletal material is compared to that prepared with Triton X-100 with respect to protein, glycoprotein, phospholipid, and cholesterol content. Digitonin, a weaker detergent than Triton X-100, solubilizes only 26% of the phospholipids and none of the cholesterol. SDS-polyacrylamide gel electrophoresis reveals that differences between the proteins extracted by the two detergents are primarily quantitative. In terms of functional preservation, digitonin retains in the cytoskeleton 28% of the beta-adrenergic receptor binding activity (with the balance accounted for in the supernatant), greater than 90% of the adenylate cyclase and greater than 90% of the 45,000 mol wt polypeptide cholera toxin substrate. The cytoskeletal-associated beat-adrenergic receptor retains binding properties for antagonist and agonist which are identical to those of the native membrane receptor. The digitonin-extracted cytoskeleton containing the beta-adrenergic receptor may provide a useful vehicle for the reconstitution of a hormone-sensitive adenylate cyclase.

  3. Cardiac beta-adrenergic receptors and coronary hemodynamics in the conscious dog during hypoxic hypoxia.

    NASA Technical Reports Server (NTRS)

    Erickson, H. H.; Stone, H. L.

    1972-01-01

    The mechanisms by which acute hypoxia (10% and 5% oxygen) mediates changes in coronary blood flow and cardiac function were investigated in the conscious dog. When the dogs breathed hypoxic gas mixtures through a tracheostomy, both arterial and coronary sinus oxygen tensions were significantly decreased. With 5% oxygen, there were significant increases in heart rate (25%), maximum left ventricular dP/dt (39%), left circumflex coronary artery blood flow (163%), and left ventricular oxygen consumption (52%), which were attenuated by beta-adrenergic blockage with propranolol. When electrical pacing was used to keep the ventricular rate constant during hypoxia, there was no significant difference in coronary blood flow before and after beta blockade. Beta-adrenergic receptor activity in the myocardium participates in the integrated response to hypoxia although it may not cause active vasodilation of the coronary vessels.

  4. Cardiac beta-adrenergic receptors and coronary hemodynamics in the conscious dog during hypoxic hypoxia.

    NASA Technical Reports Server (NTRS)

    Erickson, H. H.; Stone, H. L.

    1972-01-01

    The mechanisms by which acute hypoxia (10% and 5% oxygen) mediates changes in coronary blood flow and cardiac function were investigated in the conscious dog. When the dogs breathed hypoxic gas mixtures through a tracheostomy, both arterial and coronary sinus oxygen tensions were significantly decreased. With 5% oxygen, there were significant increases in heart rate (25%), maximum left ventricular dP/dt (39%), left circumflex coronary artery blood flow (163%), and left ventricular oxygen consumption (52%), which were attenuated by beta-adrenergic blockage with propranolol. When electrical pacing was used to keep the ventricular rate constant during hypoxia, there was no significant difference in coronary blood flow before and after beta blockade. Beta-adrenergic receptor activity in the myocardium participates in the integrated response to hypoxia although it may not cause active vasodilation of the coronary vessels.

  5. Receptor-Mediated Enhancement of Beta Adrenergic Drug Activity by Ascorbate In Vitro and In Vivo

    PubMed Central

    Dillon, Patrick F.; Root-Bernstein, Robert; Robinson, N. Edward; Abraham, William M.; Berney, Catherine

    2010-01-01

    Rationale Previous in vitro research demonstrated that ascorbate enhances potency and duration of activity of agonists binding to alpha 1 adrenergic and histamine receptors. Objectives Extending this work to beta 2 adrenergic systems in vitro and in vivo. Methods Ultraviolet spectroscopy was used to study ascorbate binding to adrenergic receptor preparations and peptides. Force transduction studies on acetylcholine-contracted trachealis preparations from pigs and guinea pigs measured the effect of ascorbate on relaxation due to submaximal doses of beta adrenergic agonists. The effect of inhaled albuterol with and without ascorbate was tested on horses with heaves and sheep with carbachol-induced bronchoconstriction. Measurements Binding constants for ascorbate binding to beta adrenergic receptor were derived from concentration-dependent spectral shifts. Dose- dependence curves were obtained for the relaxation of pre-contracted trachealis preparations due to beta agonists in the presence and absence of varied ascorbate. Tachyphylaxis and fade were also measured. Dose response curves were determined for the effect of albuterol plus-and-minus ascorbate on airway resistance in horses and sheep. Main Results Ascorbate binds to the beta 2 adrenergic receptor at physiological concentrations. The receptor recycles dehydroascorbate. Physiological and supra-physiological concentrations of ascorbate enhance submaximal epinephrine and isoproterenol relaxation of trachealis, producing a 3–10-fold increase in sensitivity, preventing tachyphylaxis, and reversing fade. In vivo, ascorbate improves albuterol's effect on heaves and produces a 10-fold enhancement of albuterol activity in “asthmatic” sheep. Conclusions Ascorbate enhances beta-adrenergic activity via a novel receptor-mediated mechanism; increases potency and duration of beta adrenergic agonists effective in asthma and COPD; prevents tachyphylaxis; and reverses fade. These novel effects are probably caused by a

  6. Biomarker Identification in Breast Cancer: Beta-Adrenergic Receptor Signaling and Pathways to Therapeutic Response

    PubMed Central

    Kafetzopoulou, Liana E.; Boocock, David J.; Dhondalay, Gopal Krishna R.; Powe, Desmond G.; Ball, Graham R.

    2013-01-01

    Recent preclinical studies have associated beta-adrenergic receptor (β-AR) signaling with breast cancer pathways such as progression and metastasis. These findings have been supported by clinical and epidemiological studies which examined the effect of beta-blocker therapy on breast cancer metastasis, recurrence and mortality. Results from these studies have provided initial evidence for the inhibition of cell migration in breast cancer by beta-blockers and have introduced the beta-adrenergic receptor pathways as a target for therapy. This paper analyzes gene expression profiles in breast cancer patients, utilising Artificial Neural Networks (ANNs) to identify molecular signatures corresponding to possible disease management pathways and biomarker treatment strategies associated with beta-2-adrenergic receptor (ADRB2) cell signaling. The adrenergic receptor relationship to cancer is investigated in order to validate the results of recent studies that suggest the use of beta-blockers for breast cancer therapy. A panel of genes is identified which has previously been reported to play an important role in cancer and also to be involved in the beta-adrenergic receptor signaling. PMID:24688711

  7. Brain beta-adrenergic receptor binding in rats with obesity induced by a beef tallow diet.

    PubMed

    Matsuo, T; Suzuki, M

    1997-01-01

    We have previously reported that compared with safflower oil diet, feeding a beef tallow diet leads to a greater accumulation of body fat by reducing sympathetic activities. The present study examined the effects of dietary fats consisting of different fatty acids on alpha1- and beta-adrenergic receptor binding in the hypothalamus and cerebral cortex. Male Sprague-Dawley rats were meal-fed isoenergetic diets based on safflower oil (rich in n-6 polyunsaturated fatty acids) or beef tallow (rich in saturated fatty acids) for 8 weeks. Binding affinities of the beta-adrenergic receptor in the hypothalamus and cortex were significantly lower in the beef tallow diet group, but those of the alpha1-receptor did not differ between the two groups. The polyunsaturated to saturated fatty acid (P/S) ratio and fluidities of plasma membranes in the hypothalamus and cortex were lower in the beef tallow diet group than in the safflower oil diet group. These results suggest that the beef tallow diet decreases membrane fluidity by altering the fatty acid composition of plasma membranes in the hypothalamus and cerebral cortex of rat. Consequently, beta-adrenergic receptor binding affinities in the brain were lower in rats fed the beef tallow diet than in rats fed the safflower oil diet. We recognized that there is possible link between the membrane fluidity and the changes in affinity of beta-adrenoceptors in rat brain.

  8. Allosteric equilibrium model explains steady-state coupling of beta-adrenergic receptors to adenylate cyclase in turkey erythrocyte membranes.

    PubMed Central

    Ugur, O; Onaran, H O

    1997-01-01

    We used a simple experimental approach to clarify some contradictory predictions of the collision coupling and equilibrium models (e.g. ternary complex, two-state ternary complex or quinternary complex), which describe G-protein-mediated beta-adrenergic receptor signalling in essentially different manners. Analysis of the steady-state coupling of beta-adrenoceptors to adenylate cyclase in turkey erythrocyte membranes showed that: (1) in the absence of an agonist, Gpp(NH)p (a hydrolysis-resistant analogue of GTP) can activate adenylate cyclase very slowly; (2) this activity reaches a steady state in approx. 5 h, the extent of activity depending on the concentration of the nucleotide; (3) isoprenaline-activated steady-state adenylate cyclase can be inactivated by propranolol (a competitive antagonist that relaxes the receptor activation), in the presence of Gpp(NH)p (which provides a virtual absence of GTPase) and millimolar concentrations of Mg2+ (the rate of this inactivation is relatively fast); (4) increasing the concentration of Gpp(NH)p can saturate the steady-state activity of adenylate cyclase. The saturated enzyme activity was lower than that induced by isoprenaline under the same conditions. This additional agonist-induced activation was reversible. In the light of these results, we conclude that agonist can also activate the guanine nucleotide-saturated system in the absence of GTPase by a mechanism other than guanine nucleotide exchange. We explain these phenomena in the framework of a quinternary complex model as an agonist-induced and receptor-mediated dissociation of guanine nucleotide-saturated residual heterotrimer, the equilibrium concentration of which is not necessarily zero. These results, which suggest a continuous interaction between receptor and G-protein, can hardly be accommodated by the collision coupling model that was originally suggested for the present experimental system and then applied to many other G-protein systems. Therefore we

  9. Allosteric equilibrium model explains steady-state coupling of beta-adrenergic receptors to adenylate cyclase in turkey erythrocyte membranes.

    PubMed

    Ugur, O; Onaran, H O

    1997-05-01

    We used a simple experimental approach to clarify some contradictory predictions of the collision coupling and equilibrium models (e.g. ternary complex, two-state ternary complex or quinternary complex), which describe G-protein-mediated beta-adrenergic receptor signalling in essentially different manners. Analysis of the steady-state coupling of beta-adrenoceptors to adenylate cyclase in turkey erythrocyte membranes showed that: (1) in the absence of an agonist, Gpp(NH)p (a hydrolysis-resistant analogue of GTP) can activate adenylate cyclase very slowly; (2) this activity reaches a steady state in approx. 5 h, the extent of activity depending on the concentration of the nucleotide; (3) isoprenaline-activated steady-state adenylate cyclase can be inactivated by propranolol (a competitive antagonist that relaxes the receptor activation), in the presence of Gpp(NH)p (which provides a virtual absence of GTPase) and millimolar concentrations of Mg2+ (the rate of this inactivation is relatively fast); (4) increasing the concentration of Gpp(NH)p can saturate the steady-state activity of adenylate cyclase. The saturated enzyme activity was lower than that induced by isoprenaline under the same conditions. This additional agonist-induced activation was reversible. In the light of these results, we conclude that agonist can also activate the guanine nucleotide-saturated system in the absence of GTPase by a mechanism other than guanine nucleotide exchange. We explain these phenomena in the framework of a quinternary complex model as an agonist-induced and receptor-mediated dissociation of guanine nucleotide-saturated residual heterotrimer, the equilibrium concentration of which is not necessarily zero. These results, which suggest a continuous interaction between receptor and G-protein, can hardly be accommodated by the collision coupling model that was originally suggested for the present experimental system and then applied to many other G-protein systems. Therefore we

  10. beta-Adrenergic modulation of the inwardly rectifying potassium channel in isolated human ventricular myocytes. Alteration in channel response to beta-adrenergic stimulation in failing human hearts.

    PubMed Central

    Koumi, S; Backer, C L; Arentzen, C E; Sato, R

    1995-01-01

    The beta-adrenergic modulation of the inwardly-rectifying K+ channel (IK1) was examined in isolated human ventricular myocytes using patch-clamp techniques. Isoproterenol (ISO) reversibly depolarized the resting membrane potential and prolonged the action potential duration. Under the whole-cell C1- -free condition, ISO applied via the bath solution reversibly inhibited macroscopic IdK1. The reversal potential of the ISO-sensitive current was shifted by approximately 60 mV per 10-fold change in the external K+ concentration and was sensitive to Ba2+. The ISO-induced inhibition of IK1 was mimicked by forskolin and dibutyrl cAMP, and was prevented by including a cAMP-dependent protein kinase (PKA) inhibitor (PKI) in the pipette solution. In single-channel recordings from cell-attached patches, bath applied ISO could suppress IK1 channels by decreasing open state probability. Bath application of the purified catalytic sub-unit of PKA to inside-out patches also inhibited IK1 and the inhibition could be antagonized by alkaline phosphatase. When beta-adrenergic modulation of IK1 was compared between ventricular myocytes isolated from the failing and the nonfailing heart, channel response to ISO and PKA was significantly reduced in myocytes from the failing heart. Although ISO inhibited IK1 in a concentration-dependent fashion in both groups, a half-maximal concentration was greater in failing (0.12 microM) than in nonfailing hearts (0.023 microM). These results suggest that IK1 in human ventricular myocytes can be inhibited by a PKA-mediated phosphorylation and the modulation is significantly reduced in ventricular myocytes from the failing heart compared to the nonfailing heart. Images PMID:8675658

  11. Electrical Stimulation Decreases Coupling Efficiency Between Beta-Adrenergic Receptors and Cyclic AMP Production in Cultured Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.

    1999-01-01

    Electrical stimulation of skeletal muscle cells in culture is an effective way to simulate the effects of muscle contraction and its effects on gene expression in muscle cells. Expression of the beta-adrenergic receptor and its coupling to cyclic AMP synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this project was to determine if electrical stimulation altered the beta-adrenergic response in muscle cells. Chicken skeletal muscle cells that had been grown for seven days in culture were subjected to electrical stimulation for an additional two days at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. At the end of this two-day stimulation period, beta-adrenergic receptor population was measured by the binding of tritium-labeled CGP-12177 to muscle cells, and coupling to cAMP synthesis was measured by Radioimmunoassay (RIA) after treating the cells for 10 min with the potent (beta)AR agonist, isoproterenol. The number of beta adrenergic receptors and the basal levels of intracellular cyclic AMP were not affected by electrical stimulation. However, the ability of these cells to synthesize cyclic AMP was reduced by approximately 50%. Thus, an enhanced level of contraction reduces the coupling efficiency of beta-adrenergic receptors for cyclic AMP production.

  12. Electrical Stimulation Decreases Coupling Efficiency Between Beta-Adrenergic Receptors and Cyclic AMP Production in Cultured Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.

    1999-01-01

    Electrical stimulation of skeletal muscle cells in culture is an effective way to simulate the effects of muscle contraction and its effects on gene expression in muscle cells. Expression of the beta-adrenergic receptor and its coupling to cyclic AMP synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this project was to determine if electrical stimulation altered the beta-adrenergic response in muscle cells. Chicken skeletal muscle cells that had been grown for seven days in culture were subjected to electrical stimulation for an additional two days at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. At the end of this two-day stimulation period, beta-adrenergic receptor population was measured by the binding of tritium-labeled CGP-12177 to muscle cells, and coupling to cAMP synthesis was measured by Radioimmunoassay (RIA) after treating the cells for 10 min with the potent (beta)AR agonist, isoproterenol. The number of beta adrenergic receptors and the basal levels of intracellular cyclic AMP were not affected by electrical stimulation. However, the ability of these cells to synthesize cyclic AMP was reduced by approximately 50%. Thus, an enhanced level of contraction reduces the coupling efficiency of beta-adrenergic receptors for cyclic AMP production.

  13. Modeling beta-adrenergic control of cardiac myocyte contractility in silico

    NASA Technical Reports Server (NTRS)

    Saucerman, Jeffrey J.; Brunton, Laurence L.; Michailova, Anushka P.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)

    2003-01-01

    The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.

  14. Role of hormone-sensitive lipase in beta-adrenergic remodeling of white adipose tissue.

    PubMed

    Mottillo, Emilio P; Shen, Xiang Jun; Granneman, James G

    2007-11-01

    Free fatty acids (FFA) are important extracellular and intracellular signaling molecules and are thought to be involved in beta-adrenergic-induced remodeling of adipose tissue, which involves a transient inflammatory response followed by mitochondrial biogenesis and increased oxidative capacity. This work examined the role of hormone-sensitive lipase (HSL), a key enzyme of acylglycerol metabolism, in white adipose tissue (WAT) remodeling using genetic inactivation or pharmacological inhibition. Acute treatment with the beta(3)-adrenergic agonist CL-316,243 (CL) induced expression of inflammatory markers and caused extravasation of myeloid cells in WAT of wild-type (WT) mice. HSL-knockout (KO) mice had elevated inflammatory gene expression in the absence of stimulation, and acute injection of CL did not further recruit myeloid cells, nor did it further elevate inflammatory gene expression. Acute pharmacological inhibition of HSL with BAY 59-9435 (BAY) had no effect on inflammatory gene expression in WAT or in cultured 3T3-L1 adipocytes. However, BAY prevented induction of inflammatory cytokines by beta-adrenergic stimulation in WAT in vivo and in cultured 3T3-L1 adipocytes. Chronic CL treatment stimulated mitochondrial biogenesis, expanded oxidative capacity, and increased lipid droplet fragmentation in WT mice, and these effects were significantly impaired in HSL-KO mice. In contrast to HSL-KO mice, mice with defective signaling of Toll-like receptor 4, a putative FFA receptor, showed normal beta-adrenergic-induced remodeling of adipose tissue. Overall, results reveal the importance of HSL activity in WAT metabolic plasticity and inflammation.

  15. Cyclic Adenosine Monophosphate Accumulation and beta-Adrenergic Binding in Unweighted and Denervated Rat Soleus Muscle

    NASA Technical Reports Server (NTRS)

    Kirby, Christopher R.; Woodman, Christopher R.; Woolridge, Dale; Tischler, Marc E.

    1992-01-01

    Unweighting, but not denervation, of muscle reportedly "spares" insulin receptors, increasing insulin sensitivity. Unweighting also increases beta-adrenergic responses of carbohydrate metabolism. These differential characteristics were studied further by comparing cyclic adenosine monophosphate (cAMP) accumulation and beta-adrenergic binding in normal and 3-day unweighted or denervated soleus muscle. Submaximal amounts of isoproterenol, a p-agonist, increased cAMP accumulation in vitro and in vivo (by intramuscular (IM) injection) to a greater degree (P less than .05) in unweighted muscles. Forskolin or maximal isoproterenol had similar in vitro effects in all muscles, suggesting increased beta-adrenergic sensitivity following unweighting. Increased sensitivity was confirmed by a greater receptor density (B(sub max)) for iodo-125(-)-pindolol in particulate preparations of unweighted (420 x 10(exp -18) mol/mg muscle) than of control or denervated muscles (285 x 10(exp-18) mol/mg muscle). The three dissociation constant (Kd) values were similar (20.3 to 25.8 pmol/L). Total binding capacity (11.4 fmol/muscle) did not change during 3 days of unweighting, but diminished by 30% with denervation. This result illustrates the "sparing" and loss of receptors, respectively, in these two atrophy models. In diabetic animals, IM injection of insulin diminished CAMP accumulation in the presence of theophylline in unweighted muscle (-66% +/- 2%) more than in controls (-42% +'- 6%, P less than .001). These results show that insulin affects CAMP formation in muscle, and support a greater in vivo insulin response following unweighting atrophy. These various data support a role for lysosomal proteolysis in denervation, but not in unweighting, atrophy.

  16. Modeling beta-adrenergic control of cardiac myocyte contractility in silico

    NASA Technical Reports Server (NTRS)

    Saucerman, Jeffrey J.; Brunton, Laurence L.; Michailova, Anushka P.; McCulloch, Andrew D.; McCullough, A. D. (Principal Investigator)

    2003-01-01

    The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.

  17. Beta adrenergic receptor blockade of feline myocardium. Cardiac mechanics, energetics, and beta adrenoceptor regulation.

    PubMed Central

    Cooper, G; Kent, R L; McGonigle, P; Watanabe, A M

    1986-01-01

    Myocardial oxygen consumption is regulated by interrelated mechanical and inotropic conditions; there is a parallel increase in the aerobic metabolism and inotropic state during beta-adrenergic stimulation under fixed mechanical conditions. In contrast, there is some evidence that beta-blockade may reduce oxygen consumption through effects independent of its influence on mechanical conditions and contractile state, and that prolonged beta-blockade may sensitize the myocardium to beta-adrenergic stimulation. To clarify these two points, the present study examined the relationship of myocardial energetics to mechanics and inotropism during acute beta-blockade and after the withdrawal of long-term beta-blockade, whereupon the basis for any effect observed was sought by characterizing the number, affinity, and affinity states of the beta-receptors as well as the coupling of activated beta-receptors to cyclic AMP generation. Studies of right ventricular papillary muscles from control and chronically beta-blocked cats demonstrated contractile and energetic properties as well as dose-response behavior and inotropic specificity suggestive of an increase in myocardial sensitivity to beta-adrenoceptor stimulation in the latter group. Assays of cardiac beta-adrenoceptors from further groups of control and pretreated cats, both in cardiac tissue and in isolated cardiac muscle cells, failed to define a difference between the two groups either in terms of receptor number and affinity or in terms of the proportion of receptors in the high-affinity state. However, coupling of the activated beta-adrenoceptors to cyclic AMP generation was enhanced in cardiac muscle cells from chronically beta-blocked cats. These data demonstrate that beta-adrenoceptor blockade (a) produces parallel effects on inotropic state and oxygen consumption without an independent effect on either and (b) increases myocardial sensitivity to beta-adrenergic stimulation after beta-blockade withdrawal, not by "up

  18. Differences in affinity of cardiac beta-adrenergic receptors for (3H)dihydroalprenolol

    SciTech Connect

    Muntz, K.H.; Calianos, T.A.; Vandermolen, D.T.; Willerson, J.T.; Buja, L.M.

    1986-03-01

    We performed quantitative light microscopic autoradiography of (3H)dihydroalprenolol (DHA) binding to frozen sections of canine myocardium to test the hypothesis that there are differences in the density or affinity of beta-adrenergic receptors on various tissue compartments. In one study, with concentrations of (3H)DHA from 0.34 to 5.1 nM, specific binding to cardiac myocytes was saturable, whereas nonspecific binding was linear with ligand concentration. Arterioles had more specific grain counts than muscle cells (P less than 0.0001), and Scatchard analysis showed that the arterioles had a much higher affinity for (3H)DHA than myocytes. In a second study with lower concentrations of (3H)DHA (0.19-1.98 nM), binding to the arterioles saturated, whereas binding to the cardiac myocytes did not. Specific binding to arterioles was significantly higher (P less than 0.0001) than binding to myocytes at all concentrations of (3H)DHA. The dissociation constants for the subendocardial and subepicardial myocytes were 1.57 and 1.71 nM, respectively, while the dissociation constant for the arterioles was 0.26 nM. The maximum number of binding sites was 911 grains/0.9 X 10(-2) mm2 for subepicardial myocytes, 936 for subendocardial myocytes, and 986 for arterioles. The large nerves accompanying an epicardial artery also demonstrated specific (3H)DHA binding. Thus this study has demonstrated major differences in the distribution and affinity of beta-adrenergic receptors, which may help to explain various physiological responses to beta-adrenergic stimulation.

  19. beta-adrenergic effects on carbohydrate metabolism in the unweighted rat soleus muscle

    NASA Technical Reports Server (NTRS)

    Kirby, Christopher R.; Tischler, Marc E.

    1990-01-01

    The effect of unweighting on the response of the soleus-muscle carbohydrate metabolism to a beta-adrenergic agonist (isoproterenol) was investigated in rats that were subjected to three days of tail-cast suspension. It was found that isoproterenol promoted glycogen degradation in soleus from suspended rats to a higher degree than in weighted soleus from control rats, and had no effect in unweighted digitorum longus. However, isoproterenol did not have a greater inhibitory effect on the net uptake of tritium-labeled 2-deoxy-glucose by the unweighted soleus and that isoproterenol inhibited hexose phosphorylation less in the unweighted than in the control muscle.

  20. Improved myocardial beta-adrenergic responsiveness and signaling with exercise training in hypertension.

    PubMed

    MacDonnell, Scott M; Kubo, Hajime; Crabbe, Deborah L; Renna, Brian F; Reger, Patricia O; Mohara, Jun; Smithwick, L Ashley; Koch, Walter J; Houser, Steven R; Libonati, Joseph R

    2005-06-28

    Cardiac responses to beta-adrenergic receptor stimulation are depressed with pressure overload-induced cardiac hypertrophy. We investigated whether exercise training could modify beta-adrenergic receptor responsiveness in a model of spontaneous hypertension by modifying the beta-adrenergic receptor desensitizing kinase GRK2 and the abundance and phosphorylation of some key Ca2+ cycling proteins. Female spontaneously hypertensive rats (SHR; age, 4 months) were placed into a treadmill running (SHR-TRD; 20 m/min, 1 h/d, 5 d/wk, 12 weeks) or sedentary group (SHR-SED). Age-matched Wistar Kyoto (WKY) rats were controls. Mean blood pressure was higher in SHR versus WKY (P<0.01) and unaltered with exercise. Left ventricular (LV) diastolic anterior and posterior wall thicknesses were greater in SHR than WKY (P<0.001) and augmented with training (P<0.01). Langendorff LV performance was examined during isoproterenol (ISO) infusions (1x10(-10) to 1x10(-7) mol/L) and pacing stress (8.5 Hz). The peak LV developed pressure/ISO dose response was shifted rightward 100-fold in SHR relative to WKY. The peak ISO LV developed pressure response was similar between WKY and SHR-SED and increased in SHR-TRD (P<0.05). SHR-TRD showed the greatest lusitropic response to ISO (P<0.05) and offset the pacing-induced increase in LV end-diastolic pressure and the time constant of isovolumic relaxation (tau) observed in WKY and SHR-SED. Improved cardiac responses to ISO in SHR-TRD were associated with normalized myocardial levels of GRK2 (P<0.05). SHR displayed increased L-type Ca2+ channel and sodium calcium exchanger abundance compared with WKY (P<0.001). Training increased ryanodine receptor phosphorylation and phospholamban phosphorylation at both the Ser16 and Thr17 residues (P<0.05). Exercise training in hypertension improves the inotropic and lusitropic responsiveness to beta-adrenergic receptor stimulation despite augmenting LV wall thickness. A lower GRK2 abundance and an increased

  1. [Study of a beta-adrenergic stimulant and its antidepressant activity in man].

    PubMed

    Jouvent, R; Lecrubier, Y; Puech, A J; Simon, H F; Widlocher, D

    1977-01-01

    In animals, the psychopharmacological profile of beta-adrenergic stimulants is very similar to that of tricyclic antidepressants. In patients, more particularly in endogenous depressive patients, the antidepressant effect of salbutamol was very clear. A definite improvement was observed in all of the 22 studied patients after 1 to 3 days of intermittent venous infusion. The place of salbutamol in the therapeutic armamentarium of depressive states has still to be defined exactly. It is speculated that the antidepressant effect of imipramine-like derivatives is related to the stimulation of central beta 2-adrenergic receptors.

  2. Fluid transfer from skeletal muscle to blood during hemorrhage. Importance of beta adrenergic vascular mechanisms.

    PubMed

    Lundvall, J; Hillman, J

    1978-04-01

    Vascular reactions in the cat lower leg in response to short-term (10 min) hemorrhagic hypotension (approximately 80 mmHg) were studied before and after regional blockade of the beta-adrenoceptors. In the muscle region with intact beta-adrenoceptors, hemorrhage raised vascular resistance by about 80% and caused a dilatation of the precapillary sphincters, the latter effect evidenced in terms of a 35% increase of the capillary filtration coefficient. Concomitantly, an absorption of extravascular fluid to the blood stream occurred, a process tending to compensate for the reduction of intravascular fluid volume. After regional beta-blockade there was quite a marked augmentation of the hemorrhage induced increase of vascular resistance whereas the inhibition of precapillary sphincter tone and the transcapillary fluid absorption were almost abolished. These observations indicate that bleeding is associated with a significant beta-adrenergic dilator influence in both the resistance vessels and precapillary sphincters of skeletal muscle and that the beta-dilator mechanism may be essential for the important, compensatory fluid gain from the extravascular to the intravascular space during hemorrhage. The observed beta-adrenergic mediation of the net transcapillary fluid absorption could be ascribed to resetting of the pre-/postcapillary resistance ratio, leading to decreased capillary hydrostatic pressure, and to the dilator influence in the precapillary sphincters, leading to an increased number of the patent capillaries available for the transcapillary fluid exchange.

  3. Variability in Beta-Adrenergic Receptor Population in Cultured Chicken Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, Ronald B; Bridge, Kristin Y.; Vaughn, Jeffrey R.

    1998-01-01

    Investigations into expression of the beta-adrenergic receptor (bAR) in chicken skeletal muscle cells in culture were initiated because several beta-adrenergic receptor agonists are known to increase skeletal muscle protein deposition in avian and mammalian species. During initial attempts to study the bAR population on the surface of chicken skeletal muscle cells, we observed a high degree of variability that was later found to be the result of using different batches of horse serum in the cell culture media. The separation between total binding and nonspecific binding in cells grown in two serum samples was approximately two-fold The number of nuclei within multinucleated myotubes was not significantly different in cells grown in the two serum samples. To investigate whether these two sera had an effect on coupling efficiency between bAR population and cAMP production, the ability of these cells to synthesize cAMP was also assessed. Despite the two-fold difference in receptor population, the ability of these cells to synthesize cAMP was not significantly different. Because of the possible link between bAR population and muscle protein, we also determined if the quantity of the major skeletal muscle protein, myosin, was affected by conditions that so drastically affected the bAR population. The quantity of myosin heavy chain was not significantly different.

  4. Variability in Beta-Adrenergic Receptor Population in Cultured Chicken Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, Ronald B; Bridge, Kristin Y.; Vaughn, Jeffrey R.

    1998-01-01

    Investigations into expression of the beta-adrenergic receptor (bAR) in chicken skeletal muscle cells in culture were initiated because several beta-adrenergic receptor agonists are known to increase skeletal muscle protein deposition in avian and mammalian species. During initial attempts to study the bAR population on the surface of chicken skeletal muscle cells, we observed a high degree of variability that was later found to be the result of using different batches of horse serum in the cell culture media. The separation between total binding and nonspecific binding in cells grown in two serum samples was approximately two-fold The number of nuclei within multinucleated myotubes was not significantly different in cells grown in the two serum samples. To investigate whether these two sera had an effect on coupling efficiency between bAR population and cAMP production, the ability of these cells to synthesize cAMP was also assessed. Despite the two-fold difference in receptor population, the ability of these cells to synthesize cAMP was not significantly different. Because of the possible link between bAR population and muscle protein, we also determined if the quantity of the major skeletal muscle protein, myosin, was affected by conditions that so drastically affected the bAR population. The quantity of myosin heavy chain was not significantly different.

  5. Food restriction modulates. beta. -adrenergic-sensitive adenylate cyclase in rat liver during aging

    SciTech Connect

    Katz, M.S. Audie L. Murphy Memorial Veterans Hospital, San Antonio, TX )

    1988-01-01

    Adenylate cyclase activities were studied in rat liver during postmaturational aging of male Fischer 344 rats fed ad libitum or restricted to 60% of the ad libitum intake. Catecholamine-stimulated adenylate cyclase activity increased by 200-300% between 6 and 24-27 mo of age in ad libitum-fed rats, whereas in food-restricted rats catecholamine response increased by only 58-84% between 6 and 30 mo. In ad libitum-fed rats, glucagon-stimulated enzyme activity also increased by 40% between 6 and 12 mo and in restricted rats a similar age-related increase was delayed until 18 mo. {beta}-Adrenergic receptor density increased by 50% between 6 and 24 mo in livers from ad libitum-fed but not food-restricted rats and showed a highly significant correlation with maximal isoproterenol-stimulated adenylate cyclase activity over the postmaturational life span. Age-related increases in unstimulated (basal) adenylate cyclase activity and nonreceptor-mediated enzyme activation were retarded by food restriction. The results demonstrate that food restriction diminishes a marked age-related increase in {beta}-adrenergic-sensitive adenylate cyclase activity of rat liver. Alterations of adrenergic-responsive adenylate cyclase with age and the modulatory effects of food restriction appear to be mediated by changes in both receptor and nonreceptor components of adenylate cyclase.

  6. Comparison of annual cost between brand and generic ocular beta-adrenergic blockers.

    PubMed

    Ikeda, Hiroaki; Tsukamoto, Hidetoshi; Sawa, Akihiro; Sugimoto, Ayako; Mishima, Hiromu; Kihira, Kenji

    2005-05-01

    We conducted a study of the annual cost of various ophthalmic products used in Japan for treating glaucoma including six of brands and generic ocular beta-adrenergic blockers (38 products). The total number of drops in one bottle of each solution was counted drop by drop. The cost per drop was calculated by dividing the government-controlled standard prices by the total number of drops in one bottle. The annual cost of ophthalmic solution was calculated by multiplying the cost per drop by the number of drops typically used per day. The total number of drops of the ophthalmic solutions in one bottle ranged from 108 to 168. The yearly cost of the beta-adrenergic blockers studied ranged widely, from yen 5392 to yen 27236. Differences in the total number of drops and the usage effect on the annual cost of ophthalmic solutions were found. The annual cost depended on not only the price of the products but also on the total number of drops in one bottle and the usage. Annual cost data may be helpful in selecting ophthalmic products for treating glaucoma in Japan.

  7. Effect of beta-adrenergic stimulants on cytotoxicity of mitomycin C in HeLa cells.

    PubMed

    Miyamoto, K; Sanae, F; Iwasaki, M; Koshiura, R

    1982-12-01

    Effects of several autonomic agents on the cytotoxicity of mitomycin C in HeLa cells were studied. When beta-adrenergic stimulants such as isoproterenol, epinephrine, terbutaline and turobuterol were added at concentrations over 10(-14) M 15 to 60 min before mitomycin C, the colony-forming ability of HeLa cells was significantly inhibited more than by mitomycin C alone. The action of isoproterenol and epinephrine on the colony-forming ability of the cells was abolished by propranolol. The intracellular cyclic AMP level of HeLa cells reached the peak of about two-fold the basal level at 30 min after the addition of 10(-8) M isoproterenol. In combination with mitomycin C, the high level of intracellular cyclic AMP induced by isoproterenol was maintained for a significantly longer period in comparison with that by isoproterenol alone, while mitomycin C alone caused essentially no change in the cyclic AMP level. The pretreatment with dibutyryl cyclic AMP also enhanced the effect of mitomycin C. From these findings, it is strongly suggested that the synergistic effect of beta-adrenergic stimulants on the cytotoxicity of mitomycin C is mediated via stimulation of the beta-adrenoceptors of HeLa cells which elevates the intracellular cyclic AMP for a long time in combination with mitomycin C.

  8. ( sup 3 H)protein secretion in rat parotid gland: Substance P-. beta. -adrenergic synergism

    SciTech Connect

    Dreux, C.; Imhoff, V.; Rossignol, B. )

    1987-12-01

    In parotid fragment ({sup 3}H)protein, secretion induced by substance P was moderate, but strongly Ca dependent. However, secretion induced by isoproterenol was large and Ca independent. Potentiation of protein secretion was observed when substance P (SP) and isoproterenol (ISO) acted together. Addition of 10{sup {minus}8} M SP caused a shift to the left in the secretion dose-response curve caused by ISO, but did not enhance ISO-induced maximal response. The potentiating effect seems to be a postreceptor event, since it can be mimicked by forskolin (FK), known to induce directly cAMP accumulation, thus bypassing the {beta}-adrenergic receptor. The synergism described above was, therefore, investigated at the second messenger production level. Stimulation of parotid gland fragments by simultaneous addition of SP plus ISO or FK did not modify cAMP nor inositol trisphosphate (IP{sub 3}) accumulation induced independently by each secretagogue alone. The ionophore A23187 was also able to potentiate secretion induced by a {beta}-adrenergic agonist, this effect being totally abolished by external calcium omission, thus suggesting a role for external calcium in this potentiation phenomenon. These results suggest that the potentiation phenomenon observed is a postreceptor event that occurs at a step distal from the second messenger production.

  9. Elevated level of. beta. -adrenergic receptors in hepatocytes from regenerating rat liver

    SciTech Connect

    Sandnes, D.; Sand, T.E.; Sager, G.; Broenstad, G.O.; Refsnes, M.R.; Gladhaug, I.P.; Jacobsen, S.; Christoffersen, T.

    1986-01-01

    Hepatocytes from regenerating rat liver show an enhanced epinephrine-sensitive adenylate cyclase activity and cAMP response, which may be involved in triggering of the cell proliferation. We have determined adrenergic receptors and adenylate cyclase activity in hepatocytes isolated at various time points after partial hepatectomy. The number of ..beta..-adrenergic receptors, measured by binding of (/sup 125/I)iodocyanopindolol ((/sup 125/I)CYP) to a particulate fraction prepared from isolated hepatocytes, increased rapidly after partial hepatectomy as compared with sham-operated or untreated controls. The maximal increase, which was observed at 48 h, was between 5- and 6-fold (from approx.1800 to approx.10,500 sites per cell). Thereafter, the number of ..beta..- adrenergic receptors decreased gradually. Competition experiments indicated ..beta../sub 2/-type receptors. Parallelism was found between the change in the number of ..beta../sub 2/-adrenergic receptors and the isoproterenol-responsive adenylate cyclase activity. The number of ..cap alpha../sub 1/-adrenergic receptors, determined by binding of (/sup 3/H)prazosin, was transiently lowered by about 35% at 18-24 h. with no significant change in K/sub d/. Although the results of this study do not exclude the possibility of post-receptor events, they suggest that the increased number of..beta../sub 2/-adrenergic receptors is a major factor responsible for the enhanced catecholamine-responsive adenylate cyclase activity in regenerating liver.

  10. Beta-adrenergic agonist therapy accelerates the resolution of hydrostatic pulmonary edema in sheep and rats.

    PubMed

    Frank, J A; Wang, Y; Osorio, O; Matthay, M A

    2000-10-01

    To determine whether beta-adrenergic agonist therapy increases alveolar liquid clearance during the resolution phase of hydrostatic pulmonary edema, we studied alveolar and lung liquid clearance in two animal models of hydrostatic pulmonary edema. Hydrostatic pulmonary edema was induced in sheep by acutely elevating left atrial pressure to 25 cmH(2)O and instilling 6 ml/kg body wt isotonic 5% albumin (prepared from bovine albumin) in normal saline into the distal air spaces of each lung. After 1 h, sheep were treated with a nebulized beta-agonist (salmeterol) or nebulized saline (controls), and left atrial pressure was then returned to normal. beta-Agonist therapy resulted in a 60% increase in alveolar liquid clearance over 3 h (P < 0.001). Because the rate of alveolar fluid clearance in rats is closer to human rates, we studied beta-agonist therapy in rats, with hydrostatic pulmonary edema induced by volume overload (40% body wt infusion of Ringer lactate). beta-Agonist therapy resulted in a significant decrease in excess lung water (P < 0.01) and significant improvement in arterial blood gases by 2 h (P < 0.03). These preclinical experimental studies support the need for controlled clinical trials to determine whether beta-adrenergic agonist therapy would be of value in accelerating the resolution of hydrostatic pulmonary edema in patients.

  11. alpha. - and. beta. -adrenergic receptors in proximal tubules of rat kidney

    SciTech Connect

    Sundaresan, P.R.; Fortin, T.L.; Kelvie, S.L. )

    1987-11-01

    Proximal tubules were isolated from the rat kidney by collagenase digestion of the cortical tissue followed by Percoll gradient centrifugation. Microscopic and hormone-stimulated adenylate cyclase activity studies proved the purity of the preparation. ({sup 3}H)Prazosin, ({sup 3}H)rauwolscine, and ({sup 125}I)iodocyanopindolol were used to identify and quantitate respectively the {alpha}{sub 1}-, {alpha}{sub 2}- and {beta}-adrenergic receptors. Proximal tubular (F{sub 4}) particulate fraction was compared against other cortical nephron segment (F{sub 1},F{sub 2}) fractions and the total collagenase-digested cortex particulate suspension (F{sub t}). Proximal tubules were enriched in {alpha}{sub 1}- and {alpha}{sub 2}-adrenergic receptors compared with. The fractions enriched in glomeruli and distal tubular segments had relatively low concentrations of {alpha}{sub 1}- and {alpha}{sub 2}-adrenergic receptors. Isoproterenol-stimulated adenylate cyclase activities in the different fractions corroborated well with the pattern suggested by the ({sup 125}I)iodocyanopindolol binding studies. The results suggest that whole-cortex preparation radioligand binding studies may reflect proximal tubular {alpha}{sub 1}- and {alpha}{sub 2}-adrenergic receptor changes quite well. They may, however, miss or give erroneous impressions about {beta}-adrenergic receptor changes occurring in different cortical nephron segments.

  12. Post-retrieval beta-adrenergic receptor blockade: effects on extinction and reconsolidation of cocaine-cue memories.

    PubMed

    Fricks-Gleason, Ashley N; Marshall, John F

    2008-09-01

    Contexts and discrete cues associated with drug-taking are often responsible for relapse among addicts. Animal models have shown that interference with the reconsolidation of drug-cue memories can reduce seeking of drugs or drug-paired stimuli. One such model is conditioned place preference (CPP) in which an animal is trained to associate a particular environment with the rewarding effects of a drug. Previous work from this laboratory has shown that intra-nucleus accumbens core infusions of a MEK inhibitor can interfere with reconsolidation of these drug-cue memories. A question that remains is whether post-retrieval drug effects on subsequent memories represent an interference with reconsolidation processes or rather a facilitation of extinction. In this experiment, we explore the effect of post-retrieval injections of propranolol, a beta-adrenergic receptor antagonist, on reconsolidation and extinction of cocaine CPP. After acquisition of cocaine CPP, animals were given post-retrieval propranolol injections once or each day during a protocol of unreinforced preference tests, until the animals showed no preference for the previously cocaine-paired environment. Following a cocaine priming injection, the animals that received daily post-test propranolol injections did not reinstate their preference for the drug-paired side. In contrast, a single post-retrieval propranolol injection followed by multiple days of unreinforced preference tests failed to blunt subsequent cocaine reinstatement of the memory. These data suggest that daily post-retrieval systemic injections of propranolol decrease the conditioned preference by interfering with reconsolidation of the memory for the association between the drug-paired side and the reinforcing effects of the drug, rather than facilitating new extinction learning.

  13. Distribution of beta-adrenergic receptors in failing human myocardium. Implications for mechanisms of down-regulation

    SciTech Connect

    Murphree, S.S.; Saffitz, J.E.

    1989-06-01

    The density of beta-adrenergic receptors is reduced in crude membranes prepared from failing human myocardium. We used quantitative autoradiography of radioligand binding sites in intact tissue slices to determine whether the total tissue content of receptors is reduced and to characterize the transmural distribution of receptors in cardiac myocytes and the coronary vasculature in hearts obtained from nine cardiac transplant patients with severe congestive failure. Binding of (125Iodo)cyanopindolol to transmural slices of human myocardium was rapid, saturable, stereoselective, and displaceable by agonists and antagonists with an appropriate rank order of potency. Binding isotherms in four normal and nine failing ventricles showed a significant reduction in the total tissue content of beta-receptors in failing myocardium (38.3 +/- 2.0 fmol/mg protein) compared with normal tissue (52.4 +/- 1.7 fmol/mg protein, p = 0.038). In the normal ventricles, the greatest receptor density was observed autoradiographically in myocytic regions of the subendocardium. Receptor density of the coronary arterioles was approximately 70% of that in adjacent myocytic regions. The density of binding sites in both myocytic regions and arterioles was diminished in all regions of the failing ventricles, but down-regulation was due primarily to a selective reduction of beta-receptors of subendocardial myocytes (63 +/- 5% of subepicardial receptor density vs. 115 +/- 6% in controls, p less than 0.0001). These observations indicate that down-regulation occurs nonuniformly in the transmural distribution and thus is likely not related simply to elevated circulating catecholamine levels.

  14. Severe hyperkalemia as a complication of timolol, a topically applied beta-adrenergic antagonist

    SciTech Connect

    Swenson, E.R.

    1986-06-01

    Severe hyperkalemia occurred in a patient with radiation pneumonitis and glaucoma shortly after beginning prednisone therapy. There was no evidence of renal failure, diabetes, acidosis, increased potassium intake, or significant tissue trauma. Medications having adverse effects on potassium metabolism were considered, and the patient's use of timolol maleate eyedrops was discontinued. His serum potassium level normalized despite continuation of the prednisone therapy. He became hyperkalemic on rechallenge with timolol and normokalemic following its withdrawal. This case indicates that the potential for beta-blocker-induced hyperkalemia exists even with topical appreciation.

  15. Reconsolidation of Appetitive Memories for Both Natural and Drug Reinforcement Is Dependent on [beta]-Adrenergic Receptors

    ERIC Educational Resources Information Center

    Milton, Amy L.; Lee, Jonathan L. C.; Everitt, Barry J.

    2008-01-01

    We have investigated the neurochemical mechanisms of memory reconsolidation and, in particular, the functional requirement for intracellular mechanisms initiated by [beta]-adrenergic signaling. We show that propranolol, given in conjunction with a memory reactivation session, can specifically disrupt the conditioned reinforcing properties of a…

  16. Altered beta-adrenergic receptor-stimulated cAMP formation in cultured skin fibroblasts from Alzheimer donors.

    PubMed

    Huang, H M; Gibson, G E

    1993-07-15

    An alteration in signal transduction systems in Alzheimer's disease would likely be of pathophysiological significance, because these steps are critical to normal brain function. Since dynamic processes are difficult to study in autopsied brain, the current studies utilized cultured skin fibroblasts. The beta-adrenergic-stimulated increase in cAMP was reduced approximately 80% in fibroblasts from Alzheimer's disease compared with age-matched controls. The deficit in Alzheimer fibroblasts in response to various adrenergic agonists paralleled their beta-adrenergic potency, and enhancement of cAMP accumulation by a non-adrenergic agonist, such as prostaglandin E1, was similar in Alzheimer and control fibroblasts. Diminished adenylate cyclase activity did not underlie these abnormalities, since direct stimulation of adenylate cyclase by forskolin elevated cAMP production equally in Alzheimer and control fibroblasts. Cholera toxin equally stimulated cAMP formation in Alzheimer and control fibroblasts. Moreover, cholera toxin partially reduced isoproterenol-induced cAMP deficit in Alzheimer fibroblasts. Pertussis toxin, on the other hand, did not alter the Alzheimer deficits. The results suggest either that the coupling of the GTP-binding protein(s) to the beta-adrenergic receptor is abnormal or that the sensitivity of receptor is altered with Alzheimer's disease. Further, any hypothesis about Alzheimer's disease must explain why a reduced beta-adrenergic-stimulated cAMP formation persists in tissue culture.

  17. Reconsolidation of Appetitive Memories for Both Natural and Drug Reinforcement Is Dependent on [beta]-Adrenergic Receptors

    ERIC Educational Resources Information Center

    Milton, Amy L.; Lee, Jonathan L. C.; Everitt, Barry J.

    2008-01-01

    We have investigated the neurochemical mechanisms of memory reconsolidation and, in particular, the functional requirement for intracellular mechanisms initiated by [beta]-adrenergic signaling. We show that propranolol, given in conjunction with a memory reactivation session, can specifically disrupt the conditioned reinforcing properties of a…

  18. Participation of beta-adrenergic activity in modulation of GLUT4 expression during fasting and refeeding in rats

    USDA-ARS?s Scientific Manuscript database

    Through in vitro studies, several factors have been reported as modulators of GLUT4 gene expression. However, the role(s) of each potential GLUT4 modulator is not completely understood in the in vivo setting. The present study has investigated the hypothesis that beta-adrenergic stimulation particip...

  19. beta. -adrenergic receptor binding characteristics and responsiveness in cultured Wistar-Kyoto rat arterial smooth muscle cells

    SciTech Connect

    Jazayeri, A.; Meyer, W.J. III

    1988-01-01

    The tone of arterial blood vessels is regulated by the catecholamines through their receptors on arterial smooth muscle cells (ASMC). ..beta..-/sub 2/-adrenergic receptors of ASMC mediate vasodilation through agonist mediated c-AMP production. Previous reports have described these receptors on freshly isolated blood vessels. This study demonstrates the presence of ..beta../sub 2/-adrenergic receptors on cultured rat ASMC and that these receptors are functional. ..beta..-adrenergic receptor binding was measured using (/sup 3/H)-dihydroalprenolol (DHA) binding to the membrane of cultured ASMC from normotensive Wistar-Kyoto rats. The ASMC ..beta..-adrenergic receptors have a Kd of 0.56 +/- 0.16 nM and a Bmax of 57.2 +/- 21.7 fmol/mg protein. Competition binding studies revealed a much greater affinity of these receptors for epinephrine than norepinephrine, indicating the preponderance of a ..beta../sub 2/-adrenergic receptor subtype. Isoproterenol stimulation of cultured ASMC resulted in a 14 +/- 7 fold increase in intracellular c-AMP content of these cells indicating these receptors are functional. ..beta..-adrenergic receptors of cultured ASMC provide an excellent system in which the association between hypertension and observed ..beta..-adrenergic receptor differences can be further explored.

  20. Diabetes reduces right atrial beta-adrenergic signaling but not agonist stimulation of heart rate in swine.

    PubMed

    Stanley, W C; Dore, J J; Hall, J L; Hamilton, C D; Pizzurro, R D; Roth, D A

    2001-04-01

    This study assessed the effects of streptozotocin diabetes in swine on the heart rate response to beta-adrenergic stimulation the adenylyl cyclase signal transduction pathway. Diabetic animals (n = 9) were hyperglycemic compared to the control group (n = 10) (12.6 +/- 1.0 vs. 3.53 +/- 0.29 mM). There were no significant differences between the diabetic and nondiabetic groups in the heart rate response to isoproterenol, however, there was a significant reduction (14%) in beta-adrenergic receptor density in the right atrium in the diabetic (61 +/- 3 fmol/mg protein) versus the nondiabetic group (71 +/- 3) (P < 0.05). The content of guanosine triphosphate binding regulatory proteins (Gs and Gi) in the right atrium was not affected by diabetes, nor was adenylyl cyclase activity under unstimulated conditions or with receptor-dependent stimulation with isoproterenol. On the other hand, adenylyl cyclase activity was 34% lower when directly stimulated with forskolin, and it was reduced by 23% when stimulated through Gs with Gpp(NH)p. In conclusion, beta-adrenergic stimulation of heart rate with isoproteronol and the receptor-dependent signal transduction pathway remained intact in the right atrium of diabetic swine despite reduced beta-adrenergic receptor density, G-protein content, and direct stimulation of adenylyl cyclase activity.

  1. Ocular hypotensive effect of atenolol (Tenormin, I.C.I.). A new beta-adrenergic blocker.

    PubMed Central

    Elliot, M J; Cullen, P M; Phillips, C I

    1975-01-01

    Atenolol (Tenormin or I.C.I. 66082) is a new beta-adrenergic blocking drug, unique in being cardio-selective and in having no intrinsic sympathomimetic or membrane activity. In a controlled double-blind study, a single 50 mg oral dose produced a significant fall in ocular tension for about 7 hours in five patients with definite or suspected glaucoma. The average maximum fall was 35 per cent of the initial pressure; it occurred at 5 hours after oral ingestion. Accordingly neither intrinsic sympathomimetic nor membrane activity can account for all the ocular hypotensive effect of beta blockers in humans. The practical implications for treatment of glaucoma require longer-term investigations some of which are in progress. PMID:240378

  2. Rat Sertoli cells acquire a beta-adrenergic response during primary culture.

    PubMed Central

    Kierszenbaum, A L; Spruill, W A; White, M G; Tres, L L; Perkins, J P

    1985-01-01

    Two-dimensional polyacrylamide gel electrophoresis and the radioligand (-)-[125I]iodopindolol (125I-Pin) have been used to study isoproterenol-dependent protein phosphorylation and beta-adrenergic receptor availability, respectively, in cultured Sertoli cells and freshly isolated seminiferous tubular segments of sexually immature and mature rats. Sertoli cells prepared from sexually immature rats show progressive 125I-Pin binding in primary cultures that correlates with isoproterenol-induced cell shape changes, redistribution of immunoreactive vimentin, and phosphorylation of this intermediate filament protein. The development of 125I-Pin binding to Sertoli cell lysates is blocked by cycloheximide. Seminiferous tubules do not show significant isoproterenol-dependent vimentin phosphorylation nor 125I-Pin binding. However, vimentin phosphorylation can be induced by follicle-stimulating hormone or a cyclic nucleotide analog. This study stresses the need for correlating pharmacological-induced responses observed in Sertoli cell primary cultures with those in the intact seminiferous tubule. Images PMID:2984678

  3. Mitigation of caffeine-induced fetopathy in mice by pretreatment with beta-adrenergic blocking agents.

    PubMed

    Fujii, T

    1976-12-01

    In a previous experiment, fetopathic effects of caffeine were significantly reduced by pretreatment with propranolol at dosage levels of 2.5 to 10 mg/kg. The present experiments were undertaeken to investigate the relation between time intervals of propranolol pretreatment and its effect on reducing fetopathy. Furthermore, the effect of timolol, another beta-adrenergic blocking agent, on reducing fetopathy was compared with that of propranolol. Propranolol (5 mg/kg) administered 15, 30 or 60 minutes before caffeine treatment significantly reduced the caffeine-induced fetopathy. The optimal effect was found when propranolol was given 30 minutes before caffine. The reduction in fetopathy by timolol pretreatment was comparable to that of propranolol. The results lend support to the hypothesis that the fetopathic effect of caffeine is linked with released catecholamines in material or fetal issues of mice.

  4. Glaucoma, capillaries and pericytes. 4. Beta-adrenergic activation of cultured retinal pericytes.

    PubMed

    Zschauer, A O; Davis, E B; Anderson, D R

    1996-01-01

    To characterize the relaxation of pericytes induced by beta-adrenergic stimulation, changes in the contractile tone of pericytes were quantified as a change in the wrinkling of an elastic silicone surface on which they were cultured. Isoproterenol produced relaxation of pericytes in a dose-dependent manner over a range of 5 nM to 1 microM. Low concentrations of the nonselective beta-blockers propanolol and timolol blocked the relaxation produced by isoproterenol. The specific beta 2-adrenergic component of isoproterenol-induced relaxation was shown by blockage with bromoacetyl alprenolol menthane. In contrast, atenolol and betaxolol, as relatively selective beta 1-adrenergic blockers, had no effect on the isoproterenol-induced relaxation.

  5. [Influence of endogenous catecholamines on responses of rat lung to beta-adrenergic agonists].

    PubMed

    Candenas, M L; Anselmi, E

    1988-12-01

    Relaxation responses to the beta-adrenoceptor agonists: isoprenaline (non selective), salbutamol (beta 2-selective) and noradrenaline (plus phentolamine 10(-5) M) (beta 1-selective) have been obtained on rat lung parenchymal strips in the absence and presence of pargyline and tropolone (monoamino-oxidase and catechol-O-methyltransferase inhibitors), cocaine (neuronal uptake blocking agent), corticosterone (extraneuronal uptake inhibitor) as well as in reserpinized rat. Responses to these beta-adrenergic agonists were not potentiated in the presence of any of these inhibitors. This indicates that endogenous catecholamines, enzymatic or uptake processes, do not modulate beta-adrenoceptor mediated responses of rat lung strip and demonstrates that there is no correlation between neuronal uptake/beta 1-adrenoceptors and extraneuronal uptake/beta 2-adrenoceptor mediated responses, as had previously been suggested.

  6. Uncoupling of the beta-adrenergic receptor as a mechanism of in vitro neutrophil desensitization

    SciTech Connect

    Galant, S.P.; Britt, S.

    1984-02-01

    Human leukocytes have been useful in studying desensitization phenomena to beta-adrenergic agonists in a number of clinical conditions. In the present in vitro study the authors have explored the mechanism for beta-adrenergic desensitization and have compared conditions for homologous and heterologous desensitization, using the intact PMN model. PMN preincubated with isoproterenol (10/sup -4/M), washed thoroughly, then restimulated, desensitized rapidly so that within 10 min 80% of control isoproterenol-induced cyclic AMP stimulation is lost. Cells washed free of isoproterenol recover full responsiveness in 1 to 2 hr. The estimated isoproterenol desensitization EC/sub 50/ in cells washed and then restimulated is 1 x 10/sup -5/M, and EC/sub 50/ in unwashed cells that are restimulated is 9 x 10/sup -8/M. Rank-order potency studies of catecholamine desensitization show isoproterenol > epinephrine > norepinephrine, a beta-2 pattern. Isoproterenol-induced desensitization results in a small reduction in (/sup 3/H)DHA binding sites, which becomes statistically significant (p < 0.05) from control values at 1 hr (67% of control) and 3 hr (64%). In the absence of GTP, isoproterenol binding is characterized by an EC/sub 50/ of 6.6 +/- 2.6 x 10/sup -/(M, which is significantly different (p < 0.05) from the EC/sub 50/ of 38.1 +/- 9.1 x 10/sup -1/M found when cells are previously desensitized with isoproterenol for 10 min. GTP does not affect the EC/sub 50/ of desensitized cells. Finally, prolonged (3 hr) isoproterenol preincubation results in a small but significant (p < 0.05) loss of cyclic AMP responsiveness to histamine (67.7% +/- 11.7 of control) and PGE/sub 1/ (59.3% +/- 7.4), suggesting heterologous desensitization. These studies suggest that the human PMN is a suitable model to study both homologous and heterologous desensitization in vitro. 22 references. 6 figures. 3 tables.

  7. Downregulation of CuZn-superoxide dismutase contributes to beta-adrenergic receptor-mediated oxidative stress in the heart.

    PubMed

    Srivastava, Sanjay; Chandrasekar, Bysani; Gu, Yan; Luo, Jianzhu; Hamid, Tariq; Hill, Bradford G; Prabhu, Sumanth D

    2007-06-01

    Sustained beta-adrenergic receptor (beta-AR) activation augments oxidative stress in the heart; whether alterations in antioxidant enzymes contribute to this effect is unknown. Adult male Wistar rats were implanted with osmotic minipumps to infuse either l-isoproterenol (ISO, 25 microg/kg/h) or saline (SAL). After 7-days, ISO-treated hearts exhibited significant (p<0.005): 1) concentric hypertrophy and augmentation of systolic function, 2) reductions of end-systolic wall stress, and 3) augmentation of oxidative stress, with a approximately 3-fold increase in 4-hydroxy-2-nonenal-and malondialdehyde-protein adducts. ISO-treated hearts also exhibited significant (p<0.01) reductions of CuZn-superoxide dismutase (SOD) enzyme activity (30%), protein (40%), and mRNA (60%), without changes in Mn-SOD, catalase, or glutathione peroxidase. Elk-1 and YinYang1 (YY1) are transcription factors that positively and negatively regulate CuZn-SOD expression, respectively. ISO-treated hearts exhibited a 3-fold increase in YY1 and a 2-fold reduction in Elk-1 DNA binding activity, strongly favoring CuZn-SOD gene repression. In isolated cardiomyocytes, sustained (24 h) ISO stimulation significantly (p<0.01) increased reactive oxygen species (ROS), an effect blocked by CGP20712A, a beta1-AR antagonist, but not by ICI118,551, a beta2-AR antagonist. CuZn-SOD downregulation paralleled the increase in ROS, and were similarly blocked by beta1- but not beta2-AR blockade. There were no changes in CuZn-SOD mRNA stability or myocyte size with ISO treatment. However, nuclear run-on revealed a 40% reduction in CuZn-SOD mRNA expression (p<0.01), consistent with transcriptional repression. ISO also depressed total cellular antioxidant capacity, reduced glutathione (GSH) levels, and the GSH:GSSG ratio. Moreover, CuZn-SOD siRNA transfection of H9c2 cardiomyocytes to suppress CuZn-SOD protein by approximately 40-50% (analogous to the in vivo changes) induced cellular apoptosis. Sustained beta

  8. The receptor kinase family: primary structure of rhodopsin kinase reveals similarities to the beta-adrenergic receptor kinase.

    PubMed Central

    Lorenz, W; Inglese, J; Palczewski, K; Onorato, J J; Caron, M G; Lefkowitz, R J

    1991-01-01

    Light-dependent deactivation of rhodopsin as well as homologous desensitization of beta-adrenergic receptors involves receptor phosphorylation that is mediated by the highly specific protein kinases rhodopsin kinase (RK) and beta-adrenergic receptor kinase (beta ARK), respectively. We report here the cloning of a complementary DNA for RK. The deduced amino acid sequence shows a high degree of homology to beta ARK. In a phylogenetic tree constructed by comparing the catalytic domains of several protein kinases, RK and beta ARK are located on a branch close to, but separate from the cyclic nucleotide-dependent protein kinase and protein kinase C subfamilies. From the common structural features we conclude that both RK and beta ARK are members of a newly delineated gene family of guanine nucleotide-binding protein (G protein)-coupled receptor kinases that may function in diverse pathways to regulate the function of such receptors. Images PMID:1656454

  9. The influence of hyperthyroidism and hypothyroidism on alpha- and beta-adrenergic receptor systems and adrenergic responsiveness.

    PubMed

    Bilezikian, J P; Loeb, J N

    1983-01-01

    A detailed review has been conducted of studies addressing dressing the subject of the influence of thyroid hormone on alpha- and beta-adrenergic receptors and adrenergic responsiveness in a wide range of experimental animals and tissues. The studies summarized in the present article have been restricted to those in which explicit measurements of receptor number were made by the use of appropriate radioligands. Particular emphasis is given to an examination of the relationship between thyroid hormone-induced changes in alpha- and beta-adrenergic receptor number and accompanying changes in adenylate cyclase activity and more distal adrenergic responses. Although in many instances thyroid hormone-induced changes in receptor number are reflected in coordinate changes in adrenergic sensitivity, this is shown to be by no means uniformly the case. In contrasting instances, modifications at other more distal sites in the sequence of events mediating catecholamine hormone action are responsible for biochemical and physiological changes in catecholamine responsiveness induced by thyroid hormone.

  10. Multiple effects of long-term morphine treatment on postsynaptic beta-adrenergic receptor function in hippocampus: an intracellular analysis.

    PubMed

    Ackerman, J M; Womble, M D; Moises, H C

    1994-09-12

    We previously reported that beta-adrenergic receptors are increased in cerebral cortex and hippocampus in rats treated chronically with morphine and subsequently down-regulated after morphine withdrawal [22,23]. The changes in receptor density in hippocampus were accompanied by a corresponding super- and subsensitivity, respectively, in beta-adrenergic responsiveness, as assessed electrophysiologically by measuring the ability of isoproterenol to augment population spike responses in the slice. In this study, we compared the ability of isoproterenol to reduce the Ca(2+)-activated K+ slow afterhyperpolarization (slow AHP) in pyramidal neurons in hippocampal slices from opiate-naive and chronic morphine-treated rats to determine whether such changes in beta-adrenergic receptor function are localized postsynaptically. Chronic treatment of rats with morphine produced a 3.5-fold parallel shift to the left in the concentration-response curve for isoproterenol and reduced the EC50 from 4.8 +/- 1.3 to 1.4 +/- 0.5 nM. In contrast, sensitivity and maximal responsiveness to isoproterenol was markedly decreased in pyramidal neurons recorded in slices from morphine withdrawn animals. The concentration-response curves for inhibition of the slow AHP by carbachol or forskolin were not affected by chronic morphine treatment. However, blockade of the slow AHP by forskolin was significantly reduced in pyramidal neurons studied after morphine withdrawal. These data suggest that the increase in electrophysiological responsiveness to beta-adrenergic receptor stimulation found in hippocampus after chronic morphine treatment most likely resulted from an up-regulation in postsynaptic membrane receptors, whereas alterations occurring beyond the receptor level may be involved in the desensitization that is associated with morphine withdrawal.

  11. Antibodies with beta-adrenergic activity from chronic chagasic patients modulate the QT interval and M cell action potential duration

    PubMed Central

    Medei, Emiliano Horacio; Nascimento, José H.M.; Pedrosa, Roberto C.; Barcellos, Luciane; Masuda, Masako O.; Sicouri, Serge; Elizari, Marcelo V.; Campos de Carvalho, Antonio C.

    2009-01-01

    Aims The aim of this study was to investigate whether the sera from chronic chagasic patients (CChPs) with beta-1 adrenergic activity (Ab-β) can modulate ventricular repolarization. Beta-adrenergic activity has been described in CChP. It increases the L-type calcium current and heart rate in isolated hearts, but its effects on ventricular repolarization has not been described. Methods and results In isolated rabbit hearts, under pacing condition, QT interval was measured under Ab-β perfusion. Beta-adrenergic activity was also tested in guinea pig ventricular M cells. Furthermore, the immunoglobulin fraction (IgG-β) of the Ab-β was tested on Ito, ICa, and Iks currents in rat, rabbit, and guinea pig myocytes, respectively. Beta-adrenergic activity shortened the QT interval. This effect was abolished in the presence of propranolol. In addition, sera from CChP without beta-adrenergic activity (Ab-β) did not modulate QT interval. The M cell action potential duration (APD) was reversibly shortened by Ab-β. Atenolol inhibited this effect of Ab-β, and Ab- did not modulate the AP of M cells. Ito was not modulated by isoproterenol nor by IgG-β. However, IgG-β increased ICa and IKs. Conclusion The shortening of the QT interval and APD in M cells and the increase of IKs and ICa induced by IgG-β contribute to repolarization changes that may trigger malignant ventricular arrhythmias observed in patients with chronic chagasic or idiopathic cardiomyopathy. PMID:18515284

  12. Muscarinic cholinergic inhibition of beta-adrenergic stimulation of phospholamban phosphorylation and CaS transport in guinea pig ventricles

    SciTech Connect

    Lindemann, J.P.; Watanabe, A.M.

    1985-10-25

    The effects of muscarinic cholinergic stimulation on beta-adrenergic induced increases in phospholamban phosphorylation and CaS transport were studied in intact myocardium. Isolated guinea pig ventricles were perfused via the coronary arteries with TSPi, after which membrane vesicles were isolated from individual hearts. Isoproterenol produced reversible increases in TSP incorporation into phospholamban. Associated with the increases in TSP incorporation were increases in the initial rate of phosphate-facilitated CaS uptake measured in aliquots of the same membrane vesicles isolated from the perfused hearts. The increases in TSP incorporation and calcium transport were significantly attenuated by the simultaneous administration of acetylcholine. Acetylcholine also attenuated increases in phospholamban phosphorylation and CaS uptake produced by the phosphodiesterase inhibitor isobutylmethylxanthine and forskolin. The contractile effects of all agents which increased cAMP levels (increased contractility and a reduction in the t1/2 of relaxation) were also attenuated by acetylcholine. The inhibitory effects of acetylcholine were associated with attenuation of the increases in cAMP levels produced by isoproterenol and isobutylmethylxanthine but not by forskolin. Acetylcholine also increased the rate of reversal of the functional and biochemical effects of isoproterenol by propranolol without affecting cAMP levels. These results suggest that cholinergic agonists inhibit the functional effects of beta-adrenergic stimulation in part by inhibition of phospholamban phosphorylation. This inhibition may be mediated by two potential mechanisms: inhibition of beta-adrenergic activation of adenylate cyclase and stimulation of dephosphorylation.

  13. Alkaline phosphatase relieves desensitization of adenylate cyclase-coupled beta-adrenergic receptors in avian erythrocyte membranes

    SciTech Connect

    Stadel, J.M.; Rebar, R.; Crooke, S.T.

    1987-05-01

    Desensitization of adenylate cyclase-coupled ..beta..-adrenergic receptors in avian erythrocytes results in 40-65% decrease in agonist-stimulated adenylate cyclase activity and correlates with increased phosphorylation of ..beta..-adrenergic receptors. To assess the role of phosphorylation in desensitization, membranes from isoproterenol- and cAMP-desensitized turkey erythrocytes were incubated with alkaline phosphatase for 30 min at 37/sup 0/C, pH = 8.0. In both cases alkaline phosphatase treatment significantly reduced desensitization of agonist-stimulated adenylate cyclase activity by 40-60%. Similar results were obtained following alkaline phosphatase treatment of membranes from isoproterenol- and cAMP-desensitized duck erythrocytes. In addition, alkaline phosphatase treatment of membranes from duck erythrocytes desensitized with phorbol 12-mystrate 13-acetate returned adenylate cyclase activity to near control values. In all experiments inclusion of 20 mM NaPO/sub 4/ to inhibit alkaline phosphatase during treatment of membranes blocked the enzyme's effect on agonist-stimulated adenylate cyclase activity. These results demonstrate a role for phosphorylation in desensitization of adenylate cyclase-coupled ..beta..-adrenergic receptors in avian erythrocytes.

  14. Mechanism of the attenuated cardiac response to beta-adrenergic stimulation in chronic hypoxia.

    PubMed

    Maher, J T; Deniiston, J C; Wolfe, D L; Cymerman, A

    1978-05-01

    A blunting of the chronotropic and inotropic responses of the heart to beta-adrenergic stimulation occurs following chronic exposure to hypobaric hypoxia. To pursue the mechanism(s) involved, observations were made in six intact, conscious goats at sea level and in another six goats maintained in a decompression chamber at 445 Torr (approximately 4,300m) for 10 days (Pao2 = 43 Torr). No significant group differences in cardiac frequency and various indices of myocardial performance (peak dP/dt, time-to-peak dP/dt, Vmax) were demonstrable either before or after cholinergic blockade with intravenous atropine methyl bromide, 1 mg/kg. Following hemodynamic studies, thoracotomies were performed and full-thickness biopsies were obtained from the free wall of each of the cardiac chambers. Neither monoamine oxidase activity nor norepinephrine level of any region of the heart was altered by chronic hypoxia. However, a twofold increase (P less than 0.001) in catechol O-methyltransferase activity above sea-level values was found in both the atria and ventricles of the hypoxic animals. Thus, the attenuation in cardiac responsiveness to beta-adrenoceptor stimulation in chronic hypoxia appears unrelated to the level of vagal activity, but may be attributable to enhanced enzymatic inactivation of catecholamines.

  15. Peptide YY antagonizes beta-adrenergic-stimulated release of insulin in dogs

    SciTech Connect

    Greeley, G.H. Jr.; Lluis, F.; Gomex, G.; Ishizuka, J.; Holland, B.; Thompson, J.C. )

    1988-04-01

    Peptide YY (PYY) and neuropeptide Y (NPY) are peptides of 36 amino acids that share structural homologies with pancreatic polypeptide (PP). PP is predominantly found in the endocrine pancreas. PYY is primarily found in mucosal endocrine cells of the distal ileum, colon, and rectum, whereas NPY is found in both the peripheral and central nervous system. Previous studies indicate that these peptides can interact with the autonomic nervous system. The objective of the present experiments was to study the effect of PYY on neurally stimulated insulin release in conscious dogs. Intravenous administration of PYY (100, 200, and 400 pmol{center dot}kg{sup {minus}1} {center dot}h{sup {minus}1}) reduced 2-DG-stimulated insulin release in a dose-dependent manner (P <0.05) without affecting plasma glucose levels. Administration of NPY, but not PP, reduced 2-DG-stimulated release of insulin. The inhibitory action of PYY on 2-DG-stimulated insulin release persisted in the presence of atropine or phentolamine treatment; however, hexamethonium alone or phentolamine plus propranolol treatment blocked the inhibitory action of PYY. Release of insulin stimulated by the {beta}-agonist isoproterenol was also inhibited by PYY. These results indicate that PYY can inhibit autonomic neurotransmission by a mechanism that may involve ganglionic or postganglionic inhibition of {beta}-adrenergic stimulation. The findings suggest a role for PYY and NPY in the autonomic regulation of insulin release.

  16. Beta-Adrenergic blockers as antiarrhythmic and antifibrillatory compounds: an overview.

    PubMed

    Singh, Bramah N

    2005-06-01

    Beta-Adrenergic blockers have a wide spectrum of action for controlling cardiac arrhythmias that is larger than initially thought. Data from the past several decades indicate that, as an antiarrhythmic class, beta-blockers remain among the very few pharmacologic agents that reduce the incidence of sudden cardiac death, prolong survival, and ameliorate symptoms caused by arrhythmias in patients with cardiac disease. As a class of compounds, beta-blockers have a fundamental pharmacologic property that attenuates the effects of competitive adrenergic receptors. However, the net clinical effects of the different beta-receptor blockers may vary quantitatively because of variations in associated intrinsic sympathomimetic agonism and in their intrinsic potency for binding to beta-receptors. These individual compounds also differ in their selectivity for beta(1)- and beta(2)-receptors. Metoprolol is a beta(1)-selective blocker, whereas carvedilol is a nonselective beta(1)- and beta(2)-blocker, an antioxidant, and has a propensity to inhibit alpha(1)-receptors and endothelin. Evolving data from controlled and uncontrolled clinical trials suggest that there are clinically significant differences among this class of drugs. Recent evidence also suggests that the antiarrhythmic actions of certain beta-receptor blockers such as carvedilol and metoprolol extend beyond the ventricular tissue to encompass atrial cells and help maintain sinus rhythm in patients with atrial fibrillation, especially in combination with potent antifibrillatory agents such as amiodarone. This introduction provides a current perspective on these newer developments in the understanding of the antiarrhythmic and antifibrillatory actions of beta-blockers.

  17. Studies on leukocyte. beta. -adrenergic receptors in depression: A critical appraisal

    SciTech Connect

    Werstiuk, E.S.; Steiner, M.; Burns, T. )

    1990-01-01

    Alterations in {beta}adrenergic receptors (BAR) of human mononuclear leukocytes (MNL) are considered to reflect changes in central noradrenergic function and have been studied in a number of diseases. This paper critically reviews the results of recent studies on MNL-BAR in depression, with particular emphasis on the biochemical and clinical methodologies used. Despite considerable differences in these methods, a number of laboratories report consistent decreases in MNL-BAR density and significantly reduced functional response in patients as compared to controls. These studies used MNL, isolated from patients who had a >14 day drug washout, and BAR-densities were measured in membrane preparations, using full Scatchard analyses, and {sup 125}I-ICYP or {sup 3}H-DHA as the ligand. Functional response of MNL-BARs was assessed by the determination of isoproterenol-stimulated cyclic AMP accumulation. A comparison of methods used by these groups further indicates that additional biochemical parameters such as lymphocyte preparation and standardized experimental conditions for the binding assays are also important for obtaining consistent results.

  18. Studies of the stimulation and desensitization of beta adrenergic receptors in the human lymphocyte

    SciTech Connect

    Borst, S.E.

    1985-01-01

    Lymphocytes, were employed in radioligand binding studies of beta-adrenergic receptor density and affinity for agonists and in studies of isoproterenol stimulated adenylate cyclase activity. Studies of isoproterenol stimulation of adenylate cyclase activity demonstrated a role for extracellular calcium ions but not for extracellular magnesium ions in this process. Responses were diminished by chelation or by removal of extracellular calcium, as well as by lanthanum ion which competes with calcium for membrane binding sites. Initial studies using /sup 3/H-dihydroalprenolol (/sup 3/H-DHA) indicated that 40% of cell surface beta receptors are lost during exposure of lymphocytes to isoproterenol and that the remaining receptors have a reduced affinity for beta agonists. Results from studies with /sup 125/iodocyanopindolol (/sup 125/ICYP) are consistent with the view that beta receptors lost from the cell surface during isoproterenol treatment are present in a internal compartment of the cell. In mild asthmatic patients receiving a three week regimen of oral terbutaline a 40% reduction in the total receptor population was observed, suggesting that degradation of internalized receptors had occurred.

  19. Beta-adrenergic receptors are differentially expressed in distinct interneuron subtypes in the rat hippocampus.

    PubMed

    Cox, David J; Racca, Claudia; LeBeau, Fiona E N

    2008-08-20

    Noradrenaline (NA) acting via beta-adrenergic receptors (betaARs) plays an important role in the modulation of memory in the hippocampus. betaARs have been shown to be expressed in principal cells, but their distribution across different interneuron classes is unknown. We have used specific interneuron markers including calcium binding proteins (parvalbumin, calbindin, and calretinin) and neuropeptides (somatostatin, neuropeptide Y, and cholecystokinin) together with either beta1AR or beta2AR to determine the distribution of these receptors in all major subfields of the hippocampus. We found that beta1AR-expressing interneurons were more prevalent in the CA3 and CA1 regions of the hippocampus than in the dentate gyrus, where they were relatively sparse. beta2AR-expressing interneurons were more uniformly distributed between all three regions of the hippocampus. A high proportion of neuropeptide Y-containing interneurons in the dentate gyrus co-expressed beta2AR. beta1AR labeling was common in interneurons expressing somatostatin and parvalbumin in the CA3 and CA1 regions, particularly in the stratum oriens of these regions. beta2AR labeling was more likely to be found than beta1AR labeling in cholecystokinin-expressing interneurons. In contrast, calretinin-containing interneurons were virtually devoid of beta1AR or beta2AR labeling. These regional and interneuron type-specific differences suggest functionally distinct roles for NA in modulating hippocampal activity via activation of betaARs.

  20. Responses of calves to treadmill exercise during beta-adrenergic agonist administration.

    PubMed

    Bruckmaier, R M; Blum, J W

    1992-09-01

    Calves perorally administered the beta-adrenergic agonist (beta-A) clenbuterol for 28 d were studied before, during, and after a 12-min treadmill exercise. During exercise on d 1 of clenbuterol administration, respiratory rate, respiratory minute volume, and heart rate and blood glucose, lactate, and insulin concentrations increased more in beta-A-treated calves than in controls. Oxygen extraction rate and growth hormone concentrations were lower in clenbuterol-treated calves, whereas oxygen consumption, carbon dioxide production, and blood cortisol concentration increased similarly in the absence and presence of the beta-A. After 2 wk of daily clenbuterol administration, respiratory rate and respiratory minute volume during exercise were still higher and oxygen extraction was still lower, whereas all other measures were similar to those in controls. The increased heart rate in response to isoproterenol after 3 wk of clenbuterol administration was reduced markedly in resting but only slightly in exercising animals, whereas heart rate reduction by propranolol during exercise was similar to that in controls. Seven days after withdrawal of clenbuterol, newly administered clenbuterol evoked the same effects as on d 1. In conclusion, there were marked reactions to the first clenbuterol treatment that were in part enhanced during treadmill exercise. After 2 wk of beta-A administration, animals responded much less to the beta-A and changes were not different from those in controls. Resensitization to the beta-A was observed 7 d after its withdrawal.

  1. Molecular and biological interaction between major histocompatibility complex class I antigens and luteinizing hormone receptors or beta-adrenergic receptors triggers cellular response in mice.

    PubMed Central

    Solano, A R; Cremaschi, G; Sánchez, M L; Borda, E; Sterin-Borda, L; Podestá, E J

    1988-01-01

    Purified IgG from BALB/c mouse anti-C3H serum exerts positive inotropic and chronotropic effects in C3H mouse atria and induces testosterone synthesis in C3H mouse Leydig cells. The effect depends on IgG concentration and can be abolished by beta-adrenergic-receptor and luteinizing hormone-receptor antagonists. IgG interferes with the binding of dihydroalprenolol and luteinizing hormone. Monoclonal antibodies against major histocompatibility complex class I antigens were active on the Leydig cells of C3H and BALB/c mice. There was a parallelism between the effect of each individual monoclonal antibody with specificity for a particular haplotype and the response of the target cell from the strains carrying such haplotypes. These antibodies could precipitate the soluble luteinizing hormone-receptor complex. The results suggested that bound hormone triggers the association of major histocompatibility class I antigen with the receptor, thereby activating the respective target cells. PMID:2839829

  2. D-1 dopaminergic and beta-adrenergic stimulation of adenylate cyclase in a clone derived from the human astrocytoma cell line G-CCM.

    PubMed

    Balmforth, A J; Ball, S G; Freshney, R I; Graham, D I; McNamee, H B; Vaughan, P F

    1986-09-01

    Clones have been isolated from the human astrocytoma cell line G-CCM. Homogenates of clone D384 contain an adenylate cyclase that is stimulated by 3,4-dihydroxyphenylethylamine (dopamine), noradrenaline, and isoprenaline with Ka apparent values of 4, 56, and 2.7 microM, respectively. The Ka apparent value for dopamine was increased by the D-1 antagonist cis-flupenthixol, 25 and 100 nM, to 23 and 190 microM, respectively, but was unaffected by propranolol (1 microM). Noradrenaline stimulation of adenylate cyclase was only partially inhibited by either propranolol (10 microM) or cis-flupenthixol (1 microM). Propranolol (10 microM), but not cis-flupenthixol (1 microM), prevented stimulation by isoprenaline. The stimulation of adenylate cyclase by dopamine and noradrenaline remained unchanged in the presence of phentolamine (1 microM) and sulpiride (1 microM). These results suggest that clone D384 contains both D-1 dopaminergic and beta-adrenergic receptors coupled to adenylate cyclase. Dopamine stimulates D384 adenylate cyclase through D-1 receptors, isoprenaline via beta-receptors, and noradrenaline through both receptors.

  3. Production and characterization of a monoclonal antibody against the beta-adrenergic agonist ractopamine.

    PubMed

    Shelver, W L; Smith, D J; Berry, E S

    2000-09-01

    A monoclonal antibody was generated toward the beta-adrenergic agonist ractopamine hydrochloride ¿(1R,3R),(1R, 3S)-4-hydroxy-alpha-[[[3-(4-hydroxyphenyl)-1-methylpropyl]amino]methy l]benzenemethanol hydrochloride¿. Ractopamine-glutarate-keyhole limpet hemocyanin (KLH) was used as the antigen for antibody generation in mice. Clone 5G10, secreted antibody with isotype IgG1kappa, was used for the development of an immunoassay. The selected antibody was specific for racemic ractopamine with an IC(50) of 2.69 +/- 0.36 ng/mL (n = 15). Antibody binding toward ractopamine was stereoselective with (1R,3R)-ractopamine having an IC(50) of 0.55 +/- 0.09 ng/mL (n = 3). IC(50) values for the (1S, 3R)-, (1S,3S)-, and (1R,3S)-ractopamine stereoisomers were 2.00 +/- 0.37, 140 +/- 23, and 291+/- 32 ng/mL (n = 3), respectively. Phenethanolamine beta-agonists showed low cross-reactivity. Studies using a series of ractopamine metabolites and ractopamine analogues demonstrated structural requirements for the antibody binding. A free phenolic group on the N-butylphenol moiety was required for high-affinity binding because methoxylated analogues and metabolites glucuronidated at this phenol generally had IC(50) values greater than 200 ng/mL. Ractopamine analogues methoxylated or glucuronidated at the ethanolamine phenol had IC(50) values of 0.7-2.6 ng/mL. Lack of a benzylic hydroxyl group was of less importance to antibody binding than was the correct stereochemical orientation (3R) of ractopamine's N-phenylalkyl group. In conclusion, a highly specific monoclonal antibody to ractopamine hydrochloride was developed that could be of potential utility in screening assays.

  4. Effects of cholinergic and beta-adrenergic blockade on orthostatic tolerance in healthy subjects

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Sather, T. M.

    2000-01-01

    Cardiovascular responses during a graded lower body negative pressure (LBNP) protocol were compared before and after atropine and propranolol administration to test the hypothesis that both sympathetic and parasympathetic control of cardio-acceleration are associated with syncopal predisposition to orthostatic stress in healthy subjects. Eleven men were categorized into two groups having high (HT, N = 6) or low (LT, N = 5) tolerance based on their total time before the onset of presyncopal symptoms. HT and LT groups were similar in physical characteristics, fitness, and baseline cardiovascular measurements. Atropine treatment had no effect on LBNP tolerance or mean arterial pressure at presyncope, despite an atropine-induced increase in heart rate. Propranolol treatment reduced (p<0.05) LBNP tolerance in both groups. Diminished LBNP tolerance after propranolol administration was associated with reductions in cardiac output, whereas increase in systemic peripheral resistance from baseline to presyncope was unaffected by propranolol. Reduction in cardiac output and LBNP tolerance after beta blockade reflected a chronotropic effect because lower LBNP tolerance for the HT (-50%) and LT (-39%) groups was associated with dramatic reductions (p <0.05) in the magnitude of LBNP-induced tachycardia without significant effects on stroke volume at presyncope. Absence of an atropine-induced difference in cardiac output and systemic peripheral resistance between HT and LT groups failed to support the notion that cardiac vagal withdrawal represents a predominant mechanism that could account for differences in orthostatic tolerance. Because a reduction in LBNP tolerance in both HT and LT groups after propranolol treatment was most closely associated with reduced tachycardia, the data suggest that a primary autonomically mediated mechanism for maintenance of mean arterial pressure and orthostatic tolerance in healthy subjects is beta adrenergic-induced tachycardia.

  5. Ontogenic loss of brown adipose tissue sensitivity to beta-adrenergic stimulation in the ovine.

    PubMed

    Lomax, Michael A; Sadiq, Fouzia; Karamanlidis, Georgios; Karamitri, Angeliki; Trayhurn, Paul; Hazlerigg, David G

    2007-01-01

    In ruminants and other large animals, expression of uncoupling protein-1 (UCP1) in brown adipose tissue (BAT) is confined to the perinatal period when it plays a key role in nonshivering thermogenesis. This study determined whether loss of expression of the BAT phenotype was due to reduced response to a beta-agonist, isoprenaline, and expression of the peroxisome proliferator-activated receptor (PPAR) family [PPARalpha, PPARgamma, PPAR coactivator 1alpha (PGC-1alpha)], which regulates UCP1 gene expression. Perirenal adipose tissue (PAT) was sampled from ovine fetuses, newborn lambs, and lambs on d 1, 5, 7, and 21 of life. UCP1 mRNA and protein in PAT increased from d 123 of fetal life to reach a maximum at birth followed by a rapid decrease over the first 5 d of life. Expression of the coactivator, PGC-1alpha and PPAR alpha, peaked between fetal day 123 and birth, and then declined to undetectable levels in the first days of life. In vivo administration of isoprenaline was able to induce expression of UCP1, PGC-1alpha, and PPARalpha in BAT up to 5 d of age but thereafter was ineffective. In vitro addition of beta-receptor, PPARalpha, and PPARgamma agonists were unable to overcome the suppression of UCP1, PPARalpha, and PPARgamma expression observed in differentiated adipocytes prepared from 30-d-old compared with 1-d-old lambs. These data are consistent with a model in which postnatal loss of UCP1 expression and beta-adrenergic induction of the brown adipocyte phenotype is due to loss of expression of PGC-1alpha and PPARalpha.

  6. Cross-talk of opioid peptide receptor and beta-adrenergic receptor signalling in the heart.

    PubMed

    Pepe, Salvatore; van den Brink, Olivier W V; Lakatta, Edward G; Xiao, Rui-Ping

    2004-08-15

    Opioid peptide receptor (OPR) and beta-adrenergic receptor (beta-AR) are well-established members of G-protein-coupled receptor (GPCR) superfamily and are involved in regulating cardiac contractility, energy metabolism, myocyte survival or death. OPRs are typical Gi/Go-coupled receptors and activated by opioid peptides derived from the endorphin, dynorphin and enkephalin families, whereas beta-AR stimulated by catecholamines is the model system for Gs-coupled receptors. While it is widely accepted that beta-AR stimulation serves as the most powerful means to increase cardiac output in response to stress or exercise, we have only begun to appreciate functional roles of OPR stimulation in regulating cardiovascular performance. Cardiovascular regulatory effects of endogenous opioids were initially considered to originate from the central nervous system and involved the pre-synaptic co-release of norepinephrine with enkephalin from sympathetic neuronal terminals in the heart. However, opioid peptides of myocardial origin have been shown to play important roles in local regulation of the heart. Notably, OPR stimulation not only inhibits cardiac excitation-contraction coupling, but also protects the heart against hypoxic and ischemic injury via activation of Gi-mediated signalling pathways. Further, OPRs functionally and physically cross-talk with beta-ARs via multiple hierarchical mechanisms, including heterodimerization of these receptors, counterbalance of functional opposing G protein signalling, and interface at downstream signalling events. As a result, the beta-AR-mediated positive inotropic effect and increase in cAMP are markedly attenuated by OPR activation in isolated cardiomyocytes as well as sympathectomized intact rat hearts. This brief review will focus on the interaction between beta-AR and OPR and its potential physiological and pathophysiological relevance in the heart. Copryright 2004 European Society of Cardiology

  7. beta-Adrenergic activation reveals impaired cardiac calcium handling at early stage of diabetes.

    PubMed

    op den Buijs, Jorn; Miklós, Zsuzsanna; van Riel, Natal A W; Prestia, Christina M; Szenczi, Orsolya; Tóth, András; Van der Vusse, Ger J; Szabó, Csaba; Ligeti, László; Ivanics, Tamás

    2005-01-21

    Cardiac function is known to be impaired in diabetes. Alterations in intracellular calcium handling have been suggested to play a pivotal role. This study aimed to test the hypothesis that beta-adrenergic activation can reveal the functional derangements of intracellular calcium handling of the 4-week diabetic heart. Langendorff perfused hearts of 4-week streptozotocin-induced diabetic rats were subjected to the beta-adrenoceptor agonist isoproterenol. Cyclic changes in [Ca(2+)](i) levels were measured throughout the cardiac cycle using Indo-1 fluorescent dye. Based on the computational analysis of the [Ca(2+)](i) transient the kinetic parameters of the sarcoplasmic reticulum Ca(2+)-ATPase and the ryanodine receptor were determined by minimizing the squared error between the simulated and the experimentally obtained [Ca(2+)](i) transient. Under unchallenged conditions, hemodynamic parameters were comparable between control and diabetic hearts. Isoproterenol administration stimulated hemodynamic function to a greater extent in control than in diabetic hearts, which was exemplified by more pronounced increases in rate of pressure development and decline. Under unchallenged conditions, [Ca(2+)](i) amplitude and rate of rise and decline of [Ca(2+)](i) as measured throughout the cardiac cycle were comparable between diabetic and control hearts. Differences became apparent under beta-adrenoceptor stimulation. Upon beta-activation the rate-pressure product showed a blunted response, which was accompanied by a diminished rise in [Ca(2+)](i) amplitude in diabetic hearts. Computational analysis revealed a reduced function of the sarcoplasmic reticulum Ca(2+)-ATPase and Ca(2+)-release channel in response to beta-adrenoceptor challenge. Alterations in Ca(2+)(i) handling may play a causative role in depressed hemodynamic performance of the challenged heart at an early stage of diabetes.

  8. Beta-adrenergic regulation of the blood lymphocyte phenotype distribution in normal subjects and splenectomized patients.

    PubMed

    Landmann, R; Dürig, M; Gudat, F; Wesp, M; Harder, F

    1985-01-01

    The beta-adrenergic effect on the release of immunoregulatory cells from the spleen was investigated by physical stress testing (bicycle ergometry up to submaximal work capacity) in 19 normal subjects (15 males, median 21 years) and in 10 male patients splenectomized for trauma (median 29 years). It was repeated in 6 subjects of each group during beta-blockade with 80 mg oxprenolol. Blood samples for leucocyte analysis were taken before and at the end of the test. Leucocyte subpopulations were analyzed in a cytofluorograph after staining of buffy coat cells by direct (B cells) or indirect immunofluorescence with monoclonal antibodies directed against the phenotypes of T- (Leu-1), T helper- (Leu-3a), T suppressor/cytotoxic (Leu-2a) cells and natural killer (OKM1+ lymphocytes) cells. In the controls all leucocyte subsets increased at ergometry, but B-, Leu-2a- and OKM1-cells increased more than Leu-3a cells. During beta-blockade the leucocyte changes reached only 50% of the value without treatment; the B- and Leu-2a cell mobilization was reduced more than the Leu-3a-, OKM1 cell- and monocyte changes. In splenectomized patients the proportional cellular changes were only half of those found in normal subjects, except for the Leu-3a cells which were not released. Beta-blockade during ergometry had no effect on Leu-3a cells, a similar effect on B- and Leu-2a cells as in normal subjects and a stronger effect on granulocytes, monocytes and OKM1 cells than in controls. In conclusion, the B- and Leu-2a cell mobilization from the spleen (50%) was beta-adrenoceptor dependent, while the one from other lymphoid organs was beta-adrenoceptor independent. The strongly spleen dependent Leu-3a cell changes were not beta-adrenoceptor mediated. Granulocyte-, monocyte- and OKM1 cell changes were only partly spleen dependent. The spleen independent changes however were strongly beta-adrenoceptor dependent.

  9. Effects of cholinergic and beta-adrenergic blockade on orthostatic tolerance in healthy subjects

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Sather, T. M.

    2000-01-01

    Cardiovascular responses during a graded lower body negative pressure (LBNP) protocol were compared before and after atropine and propranolol administration to test the hypothesis that both sympathetic and parasympathetic control of cardio-acceleration are associated with syncopal predisposition to orthostatic stress in healthy subjects. Eleven men were categorized into two groups having high (HT, N = 6) or low (LT, N = 5) tolerance based on their total time before the onset of presyncopal symptoms. HT and LT groups were similar in physical characteristics, fitness, and baseline cardiovascular measurements. Atropine treatment had no effect on LBNP tolerance or mean arterial pressure at presyncope, despite an atropine-induced increase in heart rate. Propranolol treatment reduced (p<0.05) LBNP tolerance in both groups. Diminished LBNP tolerance after propranolol administration was associated with reductions in cardiac output, whereas increase in systemic peripheral resistance from baseline to presyncope was unaffected by propranolol. Reduction in cardiac output and LBNP tolerance after beta blockade reflected a chronotropic effect because lower LBNP tolerance for the HT (-50%) and LT (-39%) groups was associated with dramatic reductions (p <0.05) in the magnitude of LBNP-induced tachycardia without significant effects on stroke volume at presyncope. Absence of an atropine-induced difference in cardiac output and systemic peripheral resistance between HT and LT groups failed to support the notion that cardiac vagal withdrawal represents a predominant mechanism that could account for differences in orthostatic tolerance. Because a reduction in LBNP tolerance in both HT and LT groups after propranolol treatment was most closely associated with reduced tachycardia, the data suggest that a primary autonomically mediated mechanism for maintenance of mean arterial pressure and orthostatic tolerance in healthy subjects is beta adrenergic-induced tachycardia.

  10. Localization of beta-adrenergic receptors in transmural slices of myocardium with quantitative autoradiography

    SciTech Connect

    Murphree, S.S.; Saffitz, J.E.

    1986-03-01

    Alterations in the density of myocardial ..beta..-adrenergic receptors (..beta..AR) induced by ischemia may be important in the pathophysiology of acute ischemic heart disease. Conventional binding assays in tissue homogenates lack the anatomic resolution required for cell-specific analysis of early alterations in receptor density induced by ischemia. Accordingly, the authors have developed methods for localization of ..beta..AR in transmural slices of feline left ventricle with quantitative autoradiography. Frozen sections were incubated with /sup 125/I-iodocyanopindolol (ICYP) +/- Z-propranolol for 60 min at 37/sup 0/. Non-specifically bound radioactivity was removed by rinsing the sections for 60 min at 22/sup 0/. At saturating concentrations of ICYP, > 90% specific binding was achieved. Specific binding was rapid, saturable, of high affinity and proportional to section thickness (B/sub max/ = 26.5 +/- 6.4 fmol/mg tissue protein; K/sub d/ = 10.0 +/- 2.1 pM; N = 14). Agonist binding showed the rank order of potency expected for ..beta..AR (IC/sub 50/ = 0.12 ..mu..M, isoproterenol; .18 ..mu..M, norepinephrine; .54 ..mu..M, epinephrine) and demonstrated stereo-selectivity (IC/sub 50/ = .013 ..mu..M, Z-isoproterenol; 9.5 ..mu..M, d-isoproterenol). Quantitative autoradiography with both film and emulsion methods will permit regional analysis of ..beta..AR density in large transmural sections as well as cell-specific analysis at the microscopic level.

  11. Specific beta-adrenergic receptor binding of carazolol measured with PET

    SciTech Connect

    Berridge, M.S.; Nelson, A.D.; Zheng, L.

    1994-10-01

    Carazolol is a promising high-affinity beta-adrenergic receptor ligand for the noninvasive determination of beta receptor status using PET> Earlier investigations demonstrated specific receptor binding of carazolol in mice. These PET studies with S(-)-[2{double_prime}-{sup 11}C]carazolol in pigs were performed to explore the utility of the tracer for PET receptor studies. Tracer uptake in the heart and lung was measured by PET as a function of time. Receptors were blocked with propranolol and different doses of ICI 118,551 to estimate specific binding. Fluorine-18-1{double_prime}-Fluorocarazolol and the less active R-enantiomer of [{sup 11}C]-carazolol were also studied. Specific receptor binding was 75% of the total uptake in the heart, preventable and displaceable by propranolol. Dose-dependent competition showed that carazolol binds in vivo to {beta}{sub 1} and to {beta}{sub 2} subtypes. Uptake of the labeled R(=) enantiomer of carazolol was not receptor-specific. Carazolol labeled with {sup 11}C or {sup 18}F is a strong candidate for use in receptor estimation with PET. The in vivo observations were consistent with its known high affinity and slow receptor dissociation rate. Its high specific receptor uptake and low metabolism allow existing kinetic models to be applied for receptor measurements. The {sup 11}C label is convenient for repeated administrations, though {sup 13}F allowed the long observation periods necessary for measurement of the receptor dissociation rate. If needed, nonspecific uptake can be estimated without pharmacologic intervention by using the labeled R enantiomer. 32 refs., 11 figs.

  12. Exercise intensity-dependent contribution of beta-adrenergic receptor-mediated vasodilatation in hypoxic humans.

    PubMed

    Wilkins, Brad W; Pike, Tasha L; Martin, Elizabeth A; Curry, Timothy B; Ceridon, Maile L; Joyner, Michael J

    2008-02-15

    We previously reported that hypoxia-mediated reductions in alpha-adrenoceptor sensitivity do not explain the augmented vasodilatation during hypoxic exercise, suggesting an enhanced vasodilator signal. We hypothesized that beta-adrenoceptor activation contributes to augmented hypoxic exercise vasodilatation. Fourteen subjects (age: 29 +/- 2 years) breathed hypoxic gas to titrate arterial O(2) saturation (pulse oximetry) to 80%, while remaining normocapnic via a rebreath system. Brachial artery and antecubital vein catheters were placed in the exercising arm. Under normoxic and hypoxic conditions, baseline and incremental forearm exercise (10% and 20% of maximum) was performed during control (saline), alpha-adrenoceptor inhibition (phentolamine), and combined alpha- and beta-adrenoceptor inhibition (phentolomine/propranolol). Forearm blood flow (FBF), heart rate, blood pressure, minute ventilation, and end-tidal CO(2) were determined. Hypoxia increased heart rate (P < 0.05) and minute ventilation (P < 0.05) at rest and exercise under all drug infusions, whereas mean arterial pressure was unchanged. Arterial adrenaline (P < 0.05) and venous noradrenaline (P < 0.05) were higher with hypoxia during all drug infusions. The change (Delta) in FBF during 10% hypoxic exercise was greater with phentolamine (Delta306 +/- 43 ml min(-1)) vs. saline (Delta169 +/- 30 ml min(-1)) or combined phentolamine/propranolol (Delta213 +/- 25 ml min(-1); P < 0.05 for both). During 20% hypoxic exercise, DeltaFBF was greater with phentalomine (Delta466 +/- 57 ml min(-1); P < 0.05) vs. saline (Delta346 +/- 40 ml min(-1)) but was similar to combined phentolamine/propranolol (Delta450 +/- 43 ml min(-1)). Thus, in the absence of overlying vasoconstriction, the contribution of beta-adrenergic mechanisms to the augmented hypoxic vasodilatation is dependent on exercise intensity.

  13. Effect of maturation and aging on beta-adrenergic signal transduction in rat kidney and liver.

    PubMed

    Fraeyman, N; Van de Velde, E; Van Ermen, A; Bazan, A; Vanderheyden, P; Van Emmelo, J; Vandekerckhove, J

    2000-12-15

    The characteristics of the beta-adrenergic signal transduction system were analyzed in kidney and liver membrane preparations from neonatal (2-3 days), mature (2 months), and old (2 years) rats. When comparing kidneys from adult to neonatal rats, we found a higher beta-receptor density and a higher percentage of beta(1)-receptor subtype, lower immunoreactive G(salpha)-protein, a lower ratio between the high and low molecular weight splice variant of G(salpha), lower immunoreactive G(ialpha)-protein, and lower basal adenylate cyclase activity. When comparing livers from adult to neonatal rats, we found lower beta-receptor density and basal adenylate cyclase activity. Very few differences could be detected when comparing mature to old kidneys or livers. Stimulated adenosine 3',5'-cyclic monophosphate (cAMP) synthesis was tissue- and age-dependent. In liver, G-protein- and beta-receptor-stimulated cAMP synthesis mirrored basal adenylate cyclase activity and was highest in liver from neonatal animals. In contrast, cAMP synthesis was significantly more stimulated in kidneys from mature animals than from neonatal and senescent rats. We conclude that: (i) the stoichiometry of the components within the beta-receptor/G-protein/adenylate cyclase complex is not fixed but is both tissue- and age-dependent; (ii) adenylate cyclase enzyme activity is possibly but not necessarily the rate-limiting step in the beta-receptor-mediated synthesis of cAMP; and (iii) there is in vivo evidence for a preferential co-expression of the large splice variant of the G(s)-protein and beta(2)-receptor subtype. It is speculated that this could have important physiological consequences for the development of the kidney.

  14. Biochemical characterization of phosphorylated beta-adrenergic receptors from catecholamine-desensitized turkey erythrocytes.

    PubMed

    Stadel, J M; Rebar, R; Shorr, R G; Nambi, P; Crooke, S T

    1986-06-17

    Isoproterenol-induced desensitization of turkey erythrocyte adenylate cyclase is accompanied (1) by a decrease in the mobility of beta-adrenergic receptor proteins, specifically photoaffinity labeled with 125I-(p-azidobenzyl)carazolol (125I-PABC), on sodium dodecyl sulfate (SDS)-polyacrylamide gels and (2) by a 2-3-fold increase in phosphate incorporation into the beta receptor [Stadel, J.M., Nambi, P., Shorr, R. G. L., Sawyer, D. F., Caron, M. G., & Lefkowitz, R. J. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 3173]. Analysis of 32P-labeled beta receptors partially purified by affinity chromatography and subsequently hydrolyzed in 6 N HCl revealed that the beta receptor from control erythrocytes contained only phosphoserine and that agonist-promoted phosphorylation of the receptor in desensitized cells occurred on serine residues. Comparison of limited-digest peptide maps of 125I-PABC-labeled beta receptors from control and desensitized erythrocytes reveals distinctly different sensitivities of the two beta receptors to cleavage by chymotrypsin and Staphylococcus aureus protease. The altered mobility of the 125I-PABC-labeled beta receptor from desensitized erythrocytes was eliminated when 5 M urea was included in the SDS-polyacrylamide gels. Limited-digest peptide mapping of 32P-labeled beta receptors from control and desensitized cells with the protease papain identified a unique phosphorylated peptide in desensitized preparations. Our results are consistent with the hypothesis that the altered mobility of beta-receptor proteins on SDS gels following desensitization is due to changes in conformation promoted by prolonged exposure to agonists.

  15. Heterogeneous response of J-wave syndromes to beta-adrenergic stimulation.

    PubMed

    Roten, Laurent; Derval, Nicolas; Sacher, Frédéric; Pascale, Patrizio; Scherr, Daniel; Komatsu, Yuki; Ramoul, Khaled; Daly, Matthew; Denis, Arnaud; Shah, Ashok J; Hocini, Mélèze; Jaïs, Pierre; Haïssaguerre, Michel

    2012-12-01

    Inferolateral early repolarization (ER) and Brugada syndrome manifest with J waves. Isoproterenol suppresses recurrent ventricular arrhythmias while reducing J waves in both disorders. To characterize the effect of isoproterenol on J waves. We analyzed the impact of isoproterenol on J waves in 20 patients with Brugada-type electrocardiogram (Br group) and 38 patients with ER (ER group). In the ER group, J waves were present in inferior leads in 32 patients (84%) and in lateral leads in 23 patients (61%). Isoproterenol increased the heart rate by 75 beats/min in the ER group and by 71 beats/min in the Br group (P = .20). The incidences of persistent (≤ 0.05-mV decrease), decreased, and normalized J waves (residual J wave ≤ 0.05 mV) were 20%, 80%, and 0% for Br group patients and 29%, 8%, and 63% for ER group patients, respectively (P <.001). Within the ER group, inferior J waves persisted in 34% of the cases, decreased in 9%, and normalized in 56% whereas lateral J waves always normalized (P <.001). Baseline QRS width was broader in ER group patients with persistent J waves (90 ms vs 80 ms; P = .003) and was unchanged with isoproterenol (90 ms; P = .19), whereas it decreased in the remaining patients (75 ms; P <.001). J-wave syndromes have distinct regional sensitivity to beta-adrenergic stimulation. J waves may persist in a subset of patients with right precordial and inferior J waves but never in lateral location. This heterogeneous response to isoproterenol may indicate distinctive mechanisms for Brugada and ER patterns, including depolarization abnormalities or ion channel sensitivity. Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  16. Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induce cyclooxygenase-2 activity in human gastric cancer cells: Involvement of nicotinic acetylcholine receptor (nAChR) and {beta}-adrenergic receptor signaling pathways

    SciTech Connect

    Shin, Vivian Yvonne; Jin, H.C.; Ng, Enders K.O.; Yu Jun; Leung, W.K.; Cho, C.H.; Sung, J.J.Y.

    2008-12-01

    Induction of cyclooxygenase-2 (COX-2) associates with cigarette smoke exposure in many malignancies. Nicotine and its derivative, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are the two important components in cigarette smoke that contributes to cancer development. However, the molecular mechanism(s) by which nicotine or NNK promotes gastric carcinogenesis remains largely unknown. We found that nicotine and NNK significantly enhanced cell proliferation in AGS cells that expressed both alpha7 nicotinic acetylcholine receptor ({alpha}7 nAChR) and {beta}-adrenergic receptors. Treatment of cells with {alpha}-bungarotoxin ({alpha}-BTX, {alpha}7nAChR antagonist) or propranolol ({beta}-adrenergic receptor antagonist) blocked NNK-induced COX-2/PGE{sub 2} and cell proliferation, while nicotine-mediated cell growth and COX-2/PGE{sub 2} induction can only be suppressed by propranolol, but not {alpha}-BTX. Moreover, in contrast to the dependence of growth promoting effect of nicotine on Erk activation, inhibitor of p38 mitogen-activated protein kinase (MAPK) repressed NNK-induced COX-2 upregulation and resulted in suppression of cell growth. In addition, nicotine and NNK mediated COX-2 induction via different receptors to modulate several G1/S transition regulatory proteins and promote gastric cancer cell growth. Selective COX-2 inhibitor (SC-236) caused G1 arrest and abrogated nicotine/NNK-induced cell proliferation. Aberrant expression of cyclin D1 and other G1 regulatory proteins are reversed by blockade of COX-2. These results pointed to the importance of adrenergic and nicotinic receptors in gastric tumor growth through MAPK/COX-2 activation, which may perhaps provide a chemoprevention strategy for cigarette smoke-related gastric carcinogenesis.

  17. Regulation of the beta-adrenergic receptor-adenylate cyclase complex of 3T3-L1 fibroblasts by sodium butyrate

    SciTech Connect

    Stadel, J.M.; Poksay, K.S.; Nakada, M.T.; Crooke, S.T.

    1986-05-01

    Mouse 3T3-L1 fibroblasts contain beta-adrenergic receptors (BAR), predominantly of the B/sub 1/ subtype. Incubation of these cells with 2-10 mM sodium butyrate (SB) for 24-48 hr results in a switch in the BAR subtype from B/sub 1/ to B/sub 2/ and promotes a 1.5 to 2.5 fold increase in total BAR number. Other short chain acids were not as effective as SB in promoting changes in BAR. BAR were assayed in membranes prepared from the 3T3-L1 cells using the radiolabeled antagonist (/sup 125/I)-cyanopindolol and the B/sub 2/ selective antagonist ICI 118.551. BAR subtype switch was confirmed functionally by measuring cellular cAMP accumulation in response to agonists. The structure and amount of the alpha subunits of the guanine nucleotide regulatory proteins N/sub s/ and N/sub i/ were determined by ADP-ribosylation using /sup 32/P-NAD and either cholera toxin or pertussis toxin for labeling of the respective subunits. Preincubation of cells with 5 mM SB for 48 hr resulted in a 2-3 fold increase in the labeling of the alpha subunits of both N/sub s/ and N/sub i/. A protein of M/sub r/ = 44,000 showed enhanced labeling by cholera toxin following SB treatment of the cells. These data indicate SB concomitantly regulates expression of BAR subtype and components of the adenylate cyclase in 3T3-L1 cells.

  18. Desensitization of the insulin receptor by antireceptor antibodies in vivo is blocked by treatment of mice with beta-adrenergic agonists.

    PubMed

    Elias, D; Rapoport, M; Cohen, I R; Shechter, Y

    1988-06-01

    In previous studies we reported that immunization of mice with ungulate insulins induced the development of antiinsulin antibodies, which include an idiotype that appeared to recognize the part of the insulin molecule recognized by the hormone receptor. The antiinsulin antibodies of this idiotype were replaced spontaneously by antiidiotypic antibodies. The antiidiotypic antibodies, which persisted for about 14 d, mimicked insulin and functioned as antibodies to the insulin receptor. They induced down regulation, desensitization and refractoriness of the insulin receptor and disturbances in glucose homeostasis in vivo (Shechter, Y., D. Elias, R. Maron, and I.R. Cohen., 1984; Elias, D., R. Maron, I.R. Cohen, and Y. Shechter. 1984, J. Biol. Chem. 259: 6411-6419). We now report that effects of the antiidiotypic antibodies on the insulin receptor effector system can be modified pharmacologically. Administration of the beta-adrenergic agonist isoproterenol during the period of insulin resistance (days 26-40 after primary immunization), largely restored fat cell responsiveness to insulin, and eliminated the appearance of fasting hyperglycemia. This restoration appeared to be caused by inhibition of both insulin receptor desensitization and refractoriness. In contrast, down regulation of insulin receptors was not reversed by isoproterenol treatment in vivo. The effects of treatment with isoproterenol persisted for 2-4 d after termination of treatment. The beta-antagonist, propranolol and more so, the beta 1a-antagonist metoprolol, specifically blocked the effect of isoproterenol at a molar ratio of 3-10:1. Oral administration of the cAMP phosphodiesterase inhibitor, aminophylline, was also effective in inhibiting the development of desensitization in fat cells. These results indicate that treatment with beta 1-adrenergic agonists in vivo, or other agents that elevate cellular cAMP levels, can inhibit the development of the "postbinding" defects induced by insulin

  19. Meta-analysis of the effect of heart rate achieved by perioperative beta-adrenergic blockade on cardiovascular outcomes.

    PubMed

    Biccard, B M; Sear, J W; Foëx, P

    2008-01-01

    Acute perioperative beta-adrenergic blockade may be cardioprotective in the high-risk cardiac patient for major non-cardiac surgery. We have investigated the association between the heart rate achieved with perioperative beta-blockade and the incidence of perioperative cardiac complications. We identified eight randomized studies (1931 patients) reporting acute perioperative beta-blockade and major perioperative cardiovascular outcomes after non-cardiac surgery. The mean heart rates within the first 72 h after operation were analysed. A meta-analysis of means was conducted using a random effects model. A bivariate correlation analysis was conducted using Spearman's correlation coefficient to assess for an association between the mean postoperative heart rate and the 30 day cardiac outcomes. Acute perioperative beta-blockade did not significantly reduce 30 day cardiac death [odds ratio (OR) 0.35, 95% confidence interval (CI) 0.08-1.52] or non-fatal myocardial infarction (OR 0.90, 95% CI 0.52-1.56) in the studies with adequate methodology. The mean (95% CI) heart rate was 73 (71-74) beats min(-1) in the beta-blockade group, which was significantly lower than the placebo group (mean heart rate 82, P=0.0001). There was no correlation between heart rate and 30 day cardiac complications (P=0.848). The reduction in heart rate was associated with increased drug-associated adverse events (OR 2.53, 95% CI 2.05-3.13, P<0.0001). A major limitation of this analysis may be that postoperative heart rate was not a primary outcome in any of the studies identified and the mean postoperative heart rate achieved may be too high to realize optimal cardioprotection. This meta-analysis cannot confirm that heart rate control with beta-adrenergic blockade is cardioprotective. A randomized controlled trial examining the effect of tight perioperative heart rate control with beta-adrenergic blockade on clinically important outcomes and adverse events is warranted.

  20. Slowing of shortening velocity of rat cardiac myocytes by adenosine receptor stimulation regardless of beta-adrenergic stimulation.

    PubMed Central

    Strang, K T; Mentzer, R M; Moss, R L

    1995-01-01

    1. Single ventricular myocytes were enzymatically isolated, incubated with the A1-purinergic and beta-adrenergic receptor-specific agonists N6-cyclopentyladenosine (CPA) and isoprenaline (Iso), and then rapidly skinned. Ca2+ sensitivity of isometric tension and unloaded shortening velocity (Vo) were measured, and protein kinase A (PKA)-specific phosphorylations of troponin I (TnI) and C-protein were assessed by back-phosphorylation of cell suspensions with [gamma-32P]-ATP. 2. Isoprenaline treatment decreased the Ca2+ sensitivity of isometric tension relative to propranolol-treated controls, as did simultaneous stimulation with Iso and CPA (Iso + CPA). CPA alone had no effect on Ca2+ sensitivity. Vo was greater in Iso-treated cells than in paired controls, while Vo was significantly less than control in both Iso + CPA-treated and CPA-treated cells. 3. Phosphorylation of TnI and C-protein was increased by Iso treatment and also when Iso and CPA were simultaneously applied. CPA alone caused a significant decrease in the phosphorylation state of these two proteins. 4. From these results we conclude that A1-purinergic receptor stimulation does not inhibit beta-adrenergic receptor-mediated phosphorylation of myofilament proteins, nor does it alter the Ca2+ sensitivity of isometric tension at the level of the myofilaments. However, A1-receptor stimulation does decrease Vo at the level of the myofilaments by a mechanism that is independent of beta-adrenergically mediated phosphorylation of TnI and C-protein. Images Figure 1 Figure 4 PMID:7473228

  1. Rate dependency of beta-adrenergic modulation of repolarizing currents in the guinea-pig ventricle.

    PubMed

    Rocchetti, M; Freli, V; Perego, V; Altomare, C; Mostacciuolo, G; Zaza, A

    2006-07-01

    Beta-adrenergic stimulation modulates ventricular currents and sinus cycle length (CL). We investigated how changes in CL affect the current induced by isoprenaline (Iso) during the action potential (AP) of guinea-pig ventricular myocytes. Action-potential clamp was applied at CLs of 250 and 1000 ms to measure: (1) the net current induced by 0.1 microm Iso (I(Iso)); (2) the L-type Ca2+ current I(CaL) and slow delayed rectifier current I(Ks) components of I(Iso) (I(IsoCa) and I(IsoK)), identified as the Iso-induced current sensitive to nifedipine and HMR1556, respectively; and (3) I(Iso) persisting after inhibition of both I(Ca) and I(Ks) (I(isoR)). The pause dependency of I(Ks) and its modulation were evaluated in voltage-clamp experiments. The rate dependency of the duration of the action potential at 90% repolarization (APD90) and its modulation by isoprenaline were tested in current-clamp experiments. At a CL of 250 ms I(Iso) was inward during initial repolarization and reversed at 59% of APD90. At a CL of 1000 ms I(Iso) became mostly inward in all cells. Switching to shorter CL did not change I(IsoCa) and I(IsoK) amplitudes, but moved their peak amplitudes to earlier repolarization; I(IsoR) was independent of CL. Acceleration of I(IsoK) at shorter CL was based on faster pause dependency of I(Ks) activation rate. The 'restitution' of activation rates was modulated by isoprenaline. The APD90-CL relation was rotated anticlockwise by isoprenaline and crossed the control curve at a CL of 150 ms (400 beats min(-1)). We conclude that: (1) isoprenaline induced markedly different current profiles according to pacing rate, involving CL-dependent I(Ca) and I(Ks) modulation; (2) the effect of isoprenaline on APD90 was CL dependent, and negligible during tachycardia; and (3) during sympathetic activation, repolarization stability may involve matched modulation of sinus rate and repolarizing currents.

  2. Permanent effects of postnatal administration of beta-adrenergic ligands on the volume of sexually dimorphic nucleus of the preoptic area (SDN-POA) in rats.

    PubMed

    Izdebska-Straszak, Grazyna; Gubala, Elzbieta; Jedrzejowska-Szypulka, Halina; Klencki, Mariusz; Wiczkowski, Andrzej; Jarzab, Barbara

    2006-01-01

    beta-adrenergic ligands have been shown to influence sexual differentiation of the brain. In the present study we document that short postnatal treatment with beta-adrenergic agonists or antagonists may permanently reverse the morphological sex of the brain, as judged by the volume of sexually dimorphic nucleus of the preoptic area (SDN-POA). Female rats treated by beta(2)-adrenergic stimulating ligands exhibit an increased, male type SDN-POA volume while male rats treated by beta1-adrenergic antagonists show a decreased, female type of SDN-POA volume. To analyze the volume of SDN-POA of adult rats after postnatal administration of betaadrenergic ligands. From the second day of life, over 5 consecutive days, all the neonates were injected subcutaneously with the following drugs: isoproterenol, salbutamol, metoprolol alprenolol or saline. SDN-POA volumes were estimated planimetrically on serial brain slides. In male rats the mean volume of SDN-POA was 9.97 +/- 1.66 x 10(-3) mm(3), in female rats the respective volume reached 4.02 +/- 1.26 x 10(-3) mm(3) only and was 2.5 times lower, the difference being highly statistically significant. Postnatal administration of isoproterenol remained without effect in male rats but diminished the SDN-POA volume in female rats, thus increasing the sexual dimorphism. The disappearance of sexual dimorphism was noted in rats treated postnatally with salbutamol. This effect was due to the increase in SDN-POA volumes in female rats, up to 9.81 +/- 2.64 x 10(-3) mm(3), the levels approaching the male type of POA differentiation. Postnatal alprenolol treatment influenced the sexual dimorphism of the brain by decreasing the SDN-POA volume reached by adult males. In fact, in rats treated postnatally with alprenolol, the volume of the nucleus reached only 4,44 +/- 1,61 x 10(-3) mm(3), being not statistically different from female nuclei. The effect of metoprolol pretreatment was similar to alprenolol. Male volumes of SDN-POA were restored

  3. [Interrelation between cardiac pump function disturbances and cardiac contractility after beta-adrenergic hyperstimulation of the heart in rats].

    PubMed

    Kuz'menko, M O; Pavliuchenko, V B; Tumanovs'ka, L V; Dosenko, V Ie; Moĭbenko, O O

    2011-01-01

    The complex of structural and functional changes of myocardium was investigated in experiments with rats with chronic beta-adrenergic activation for 1 month. We observed substantial attenuation of myocardial pump function, particularly reduction of stroke volume by 38.50% (P < 0.01), cardiac output by 42.38% (P < 0.01), and ejection fraction by 35.61% (P < 0.01). Furthermore, 2-fold increase of end-diastolic left ventricular pressure (P < 0.01) and rise of active relaxation constant Tau by 12.91% (P < 0.05) were observed. This indicates on an impaired diastolic function of the heart that is associated with accumulation of connective tissue elements in myocardium and increase of its end-diastolic stiffness that finally leads to cardiac pump function disturbances. Surprisingly, myocardial contractility was considerably augmented not only after the treatment with beta-adrenergic agonist but also on the 26th day after drug cessation. This phenomenon is associated with elevation of dP/dt(max) by 49.9% (P < 0.01), 2.5-fold increase of end-systolic elastance (P < 0.01) as well as maximal myocardial elastance by 42.53% (P < 0.05). It can be explained by compensatory influence of increased contractility that nevertheless failed to maintain adequate cardiac pump function and furthermore it may result in depletion of cardiac energy resource.

  4. Hydrocortisone increases the responsiveness of mast cells to beta-adrenergic agonists by an action distal to the beta-adrenoreceptors.

    PubMed Central

    Tolone, G.; Bonasera, L.; Sajeva, R.

    1979-01-01

    Hydrocortisone in pharmacologically attainable concentrations potentiates beta-adrenergic-stimulated cyclic AMP accumulation in rat peritoneal mast cells. Direct binding studies using 3H-dihydroalprenolol indicated no significant changes in the number of beta-adrenoreceptors or in the kinetics of the interaction of the radio-ligand with receptors after treatment of mast cells with the corticosteroid. Competition binding studies with epinephrine revealed no hydrocortisone-induced change in Kd values for this agonist. It is concluded that hydrocortisone-induced stimulation of cyclic AMP synthesis results from an effect that occurs beyond the interaction of the beta-adrenergic agonist with its receptor. PMID:38825

  5. Beta-adrenergic receptors support attention to extinction learning that occurs in the absence, but not the presence, of a context change

    PubMed Central

    André, Marion Agnès Emma; Wolf, Oliver T.; Manahan-Vaughan, Denise

    2015-01-01

    The noradrenergic (NA)-system is an important regulator of cognitive function. It contributes to extinction learning (EL), and in disorders where EL is impaired NA-dysfunction has been postulated. We explored whether NA acting on beta-adrenergic-receptors (β-AR), regulates EL that depends on context, but is not fear-associated. We assessed behavior in an “AAA” or “ABA” paradigm: rats were trained for 3 days in a T-maze (context-A) to learn that a reward is consistently found in the goal arm, despite low reward probability. This was followed on day 4 by EL (unrewarded), whereby in the ABA-paradigm, EL was reinforced by a context change (B), and in the AAA-paradigm, no context change occurred. On day 5, re-exposure to the A-context (unrewarded) occurred. Typically, in control “AAA” animals EL occurred on day 4 that progressed further on day 5. In control “ABA” animals, EL also occurred on day 4, followed by renewal of the previously learned (A) behavior on day 5, that was succeeded (on day 5) by extinction of this behavior, as the animals realised that no food reward would be given. Treatment with the β-AR-antagonist, propranolol, prior to EL on day 4, impaired EL in the AAA-paradigm. In the “ABA” paradigm, antagonist treatment on day 4, had no effect on extinction that was reinforced by a context change (B). Furthermore, β-AR-antagonism prior to renewal testing (on day 5) in the ABA-paradigm, resulted in normal renewal behavior, although subsequent extinction of responses during day 5 was prevented by the antagonist. Thus, under both treatment conditions, β-AR-antagonism prevented extinction of the behavior learned in the “A” context. β-AR-blockade during an overt context change did not prevent EL, whereas β-AR were required for EL in an unchanging context. These data suggest that β-AR may support EL by reinforcing attention towards relevant changes in the previously learned experience, and that this process supports extinction

  6. Beta-Adrenergic Receptor Activation during Distinct Patterns of Stimulation Critically Modulates the PKA-Dependence of LTP in the Mouse Hippocampus

    ERIC Educational Resources Information Center

    Gelinas, Jennifer N.; Tenorio, Gustavo; Lemon, Neal; Abel, Ted; Nguyen, Peter V.

    2008-01-01

    Activation of Beta-adrenergic receptors (Beta-ARs) enhances hippocampal memory consolidation and long-term potentiation (LTP), a likely mechanism for memory storage. One signaling pathway linked to Beta-AR activation is the cAMP-PKA pathway. PKA is critical for the consolidation of hippocampal long-term memory and for the expression of some forms…

  7. Obesity-induced p53 activation in insulin-dependent and independent tissues is inhibited by beta-adrenergic agonist in diet-induced obese rats.

    PubMed

    Zand, Hamid; Homayounfar, Reza; Cheraghpour, Makan; Jeddi-Tehrani, Mahmood; Ghorbani, Arman; Pourvali, Katayoun; Soltani, Sama Reza

    2016-02-15

    The purpose of this study was to assay the role of beta-adrenergic receptor signaling in the regulation of obesity-induced p53 in high fat feeding obese rats. The role of beta-adrenergic receptor/cyclic AMP in the regulation of p53 and its downstream mediators was evaluated by western blot and real-time quantitative RT-PCR among diet induced rats. Beta-adrenergic receptor agonist, isoproterenol, and an adenylate cyclase activator, forskolin, at a single dose significantly reduced insulin resistance consistent with a decrease in total and phospho-p53 levels in insulin and non-insulin metabolic target tissues. The decrease of p53 signaling was consistent with the elevation of AKT and subsequent activation. Obese rats exposed to fasting also exhibited improvement in insulin action despite a slight effect on p53 level. Results of the present study obviously showed that beta-adrenergic receptor agonist/cAMP prevented obesity-induced p53 activation. Although this effect in metabolic insulin target tissues tempted us to consider them as insulin sensitizers in obesity-related diabetes, p53 inhibition in non-insulin target tissues warned about the impairment of anti-cancer mechanisms in obese subjects. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Association between Selective Beta-adrenergic Drugs and Blood Pressure Elevation: Data Mining of the Japanese Adverse Drug Event Report (JADER) Database.

    PubMed

    Ohyama, Katsuhiro; Inoue, Michiko

    2016-01-01

    Selective beta-adrenergic drugs are used clinically to treat various diseases. Because of imperfect receptor selectivity, beta-adrenergic drugs cause some adverse drug events by stimulating other adrenergic receptors. To examine the association between selective beta-adrenergic drugs and blood pressure elevation, we reviewed the Japanese Adverse Drug Event Reports (JADERs) submitted to the Japan Pharmaceuticals and Medical Devices Agency. We used the Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms extracted from Standardized MedDRA queries for hypertension to identify events related to blood pressure elevation. Spontaneous adverse event reports from April 2004 through May 2015 in JADERs, a data mining algorithm, and the reporting odds ratio (ROR) were used for quantitative signal detection, and assessed by the case/non-case method. Safety signals are considered significant if the ROR estimates and lower bound of the 95% confidence interval (CI) exceed 1. A total of 2021 reports were included in this study. Among the nine drugs examined, significant signals were found, based on the 95%CI for salbutamol (ROR: 9.94, 95%CI: 3.09-31.93) and mirabegron (ROR: 7.52, 95%CI: 4.89-11.55). The results of this study indicate that some selective beta-adrenergic drugs are associated with blood pressure elevation. Considering the frequency of their indications, attention should be paid to their use in elderly patients to avoid adverse events.

  9. Role of postsynaptic alpha-adrenergic receptors in the beta-adrenergic stimulation of melatonin production in the Syrian hamster pineal gland in organ culture.

    PubMed

    Santana, C; Guerrero, J M; Reiter, R J; Menendez-Pelaez, A

    1989-01-01

    The role played by postsynaptic alpha-adrenergic receptors in the stimulation of pineal melatonin production was investigated in the Syrian hamster. The studies were conducted using organ cultured pineal glands collected from both anatomically intact and superior cervical ganglionectomized hamsters. Results obtained indicate that phenylephrine, an alpha-adrenergic agonist, by itself has no effect in promoting melatonin production; however, it potentiates the stimulatory effects of isoproterenol, a beta-adrenergic agonist, on pineal melatonin production in nonoperated hamsters. Similar observations were obtained with pineal glands whose presynaptic terminals were removed by prior superior cervical ganglionectomy. However, a longer incubation time was required (4-6 hours vs. 2 hours) with pineal glands taken from ganglionectomized animals. Apparently, beta-adrenergic activation is an absolute requirement to stimulate pineal melatonin production, and an alpha-adrenergic receptor mechanism potentiates beta-adrenergic activation. In addition, the findings obtained with denervated pineal glands suggest that the regulation of pineal melatonin production by both alpha- and beta-adrenergic mechanisms is through receptors located on postsynaptic structures.

  10. Timing of parturition in two species of viviparous lizard: influences of beta-adrenergic stimulation and temperature upon uterine responses to arginine vasotocin (AVT).

    PubMed

    Atkins, Natalia; Jones, Susan M; Guillette, Louis J

    2006-11-01

    The southern snow skink Niveoscincus microlepidotus is a viviparous alpine lizard with biennial reproduction, in which embryos are fully developed before winter but parturition is delayed until spring. We aimed to determine whether, in this species, in vitro uterine preparations are responsive to arginine vasotocin (AVT) and prostaglandin (PGF(2alpha)) in autumn and spring, and whether pre-treatment with the beta-adrenergic agonist isoproterenol decreases the effectiveness of AVT in stimulating uterine contractions. Using the spotted snow skink (Niveoscincus ocellatus), an annually breeding species, we aimed to determine influences of temperature and the beta-adrenergic system upon the response to AVT in vivo. In both N. microlepidotus and N. ocellatus females are more responsive to AVT than to PGF(2alpha), and that the response to AVT is decreased, but not prevented, by beta-adrenergic stimulation. In N. microlepidotus, uteri are equally responsive in both seasons to the hormones administered. In N. ocellatus environmental conditions, specifically, temperature, modulate the response to AVT in vivo with the time to parturition increasing as temperature decreases. We conclude that in these viviparous squamates the endocrine cascade leading to parturition is modulated by the beta-adrenergic system, and that this may reflect the mechanism by which the timing of parturition is tied to suitable environmental conditions.

  11. [The immune-enzyme analysis based on chimeric molecule and oligopeptide fragmentations to detect autoantibodies to beta-adrenergic receptor in patients with dilation cardiomyopathy].

    PubMed

    Afanas'eva, O I; Klesareva, E A; Efremov, E E; Sidorova, M V; Bespalova, Zh D; Levashov, P A; Ezhov, M V; Adamova, I Iu; Pokrovskiĭ, S N

    2013-04-01

    The article deals with specification of technique of immune-enzyme analysis to detect autoantibodies to beta-adrenergic receptors (beta1-AP) using compound of oligopeptids representing the fragmentations of extracellular sites beta1-AP and chimeric molecule of extracellular section of receptor This technique significantly exceeds the analogues defined in publications by its sensitivity and correlation with diagnosis.

  12. Retrieval-induced forgetting under psychosocial stress: no reduction by delayed stress and beta-adrenergic blockade.

    PubMed

    Dreifus, Laura; Engler, Harald; Kissler, Johanna

    2014-04-01

    Retrieval-induced forgetting (RIF) is the phenomenon that 'retrieval-practice', the repeated retrieval of a subset of initially learned material, can impair the recall of episodically related memories. Previous studies showed that RIF is eliminated when retrieval-practice is carried out under psycho-social stress, anxiety, or in negative mood. However, pharmacological manipulation by hydrocortisone did not eliminate the effect. This study investigated the effect of beta-adrenergic blockade on stress-induced modulations of RIF, addressing possible interactive effects of the glucocorticoid and sympatho-adrenomedullary systems. Participants learned categorized word lists and then received either 60 mg propranolol or a placebo. After 90 min they were exposed to the TSST. A third group did not receive any medication and performed a non-stressful control task with the same timing as the other two groups. Finally, all participants underwent retrieval-practice and final recall. Both TSST groups exhibited a stress-induced increase in cortisol-levels, and the placebo group also exhibited large increases in markers of sympathetic nervous system activity and more psychological distress at the time of retrieval-practice. Although, overall recall was poorer under stress, an overall RIF effect emerged irrespective of group and showed no clear modulation by stress with or without beta-adrenergic blockade. In previous demonstrations of RIF elimination by negative emotion, state induction and retrieval-practice followed very briefly after initial learning. Given that both the previous study of hydrocortisone effects on RIF and the present study used longer delays between learning and retrieval-practice, the possibility that stress effects on retrieval-practice eliminate RIF only relatively briefly after learning is discussed.

  13. Validity of pulse pressure and augmentation index as surrogate measures of arterial stiffness during beta-adrenergic stimulation.

    PubMed

    Lemogoum, Daniel; Flores, Gabriella; Van den Abeele, Wouter; Ciarka, Agnieszka; Leeman, Marc; Degaute, Jean Paul; van de Borne, Philippe; Van Bortel, Luc

    2004-03-01

    Increased arterial stiffness is a determinant of cardiovascular mortality. Pulse wave velocity (PWV) is a direct measure of arterial stiffness. Aortic augmentation index (AI) and pulse pressure (PP) are surrogate measures of arterial stiffness. Both PWV, AI and PP increase with cardiovascular risk factors. The aim of this study was to test the validity of AI and PP as surrogate measures of arterial stiffness compared with PWV, during beta-adrenergic stimulation with Isoprenaline (Iso). A total of 41 healthy volunteers entered a randomized, double-blind, placebo-controlled, cross-over study. In random order, subjects were given intravenous infusion in equal volume of Iso 8 microg/kg per min (dissolved in glucose 5%) and placebo (glucose 5%). A wash-out period of 25 min was observed between the infusions. Measurements included blood pressure (BP), heart rate (HR), PWV, and AI. PWV were determined using complior (Complior, Artech-Medical, Paris, France). AI and aortic PP were obtained from pulse wave analysis of radial applanation tonometry, using transfer function (SphygmoCor Windows software). Baseline AI increased (P < 0.05) with aging, a lower height and a larger diastolic BP (DBP). Iso increased (P < 0.0001) HR, brachial SBP, brachial and aortic PP as compared with placebo. In contrast, Iso decreased (P < 0.05) AI, brachial DBP, peripheral PWV, but not aortic PWV. Decrease of AI induced by Iso was not related to PWV. In stepwise multiple regression changes in HR, brachial SBP and DBP were independent determinants of AI response to Iso (r = 0.78, P < 0.0001). Our findings show that AI and PP fail as surrogate measures of arterial stiffness during beta-adrenergic stimulation.

  14. Beta-adrenergic receptors and enzymes in rat myocardial membranes: implications of fractionation procedures and beta-adrenoceptor antagonists.

    PubMed

    Schrader, E; Inczédy-Marcsek, M; Grobecker, H

    1988-06-01

    1. We performed an enzymatic characterization of two different fractionation procedures of ventricles from rat hearts. The enzymatic assays covered succinic dehydrogenase as a marker for inner mitochondrial membranes, monoamine oxidase as a marker for outer mitochondrial membranes, NADPH-cytochrome c reductase and RNA as endoplasmatic reticular markers, acid phosphatase as a lysosomal marker, and lactic dehydrogenase as a marker for the "soluble" compartment; DNA was estimated for nuclear contamination. 2. The plasma membrane markers 5'-nucleotidase, Ca2+-ATPase, Mg2+-ATPase, Na+-K+-ATPase, and adenylate cyclase were determined. 3. The roughly prepared membrane fractions showed increased yields of the membrane markers; the number of beta receptors, determined with (-)-[3H] dihydroalprenolol and DL-propranolol, amounted to 68 +/- 6 fmol/mg protein (KD = 3390 +/- 450 pmol, Hill coefficient = 1.5). 4. The membrane fraction prepared with a linear sucrose gradient showed an increased inner mitochondrial membrane marker; presumably the outer mitochondrial membrane was stripped off. The beta-receptor number was 39 +/- 3 fmol/mg protein (KD = 6250 +/- 300 pmol; Hill coefficient = 1.2).

  15. Contralateral effect of topical beta-adrenergic antagonists in initial one-eyed trials in the ocular hypertension treatment study.

    PubMed

    Piltz, J; Gross, R; Shin, D H; Beiser, J A; Dorr, D A; Kass, M A; Gordon, M O

    2000-10-01

    To evaluate the magnitude of the contralateral effect of topically administered beta-blockers on intraocular pressure. The Ocular Hypertension Treatment Study enrolled 1,636 subjects. Of these, 817 subjects were randomized to receive topical ocular hypotensive medication and 819 subjects were randomized to close observation (i.e., no topical medication). We compared the intraocular pressure of the contralateral eye of subjects at the baseline visit and after an initial one-eyed therapeutic trial of topical beta-blockers. We examined differences between baseline and follow-up intraocular pressure in untreated eyes of subjects randomized to close observation. The mean reduction in intraocular pressure in the beta-blocker-treated eyes was -5.9 +/- 3. 4 mm Hg (-22% +/- 12%; Student t test, P <.0001). In the contralateral eyes, mean intraocular pressure reduction was -1.5 +/- 3.0 mm Hg (-5.8% +/- 12%; P <.0001). Of the contralateral eyes, 35% showed a reduction of 3 mm Hg or more, and 10% showed a reduction of 6 mm Hg or more. The contralateral effect of the relatively selective beta-blocker betaxolol did not differ from that of any of the nonselective beta-blockers. Factors associated with the magnitude of the contralateral effect were the degree of intraocular pressure reduction in the treated eye and baseline intraocular pressure of the contralateral eye. In the close observation group, no significant reduction in intraocular pressure was noted between the baseline and follow-up visit. The contralateral effect is important in clinical practice and in clinical trials when the hypotensive effect of a topical beta-blocker is evaluated by means of a one-eyed therapeutic trial.

  16. Beta-adrenergic antagonist propranolol inhibits mammalian cell lysosome spreading and invasion by Trypanosoma cruzi metacyclic forms.

    PubMed

    Macedo, Silene; Rodrigues, João Paulo Ferreira; Schenkman, Sergio; Yoshida, Nobuko

    2017-01-19

    The involvement of β-adrenergic receptor (β-AR) in host cell invasion by Trypanosoma cruzi metacyclic trypomastigote (MT) is not known. We examined whether isoproterenol, an agonist of β-AR, or nonselective β-blocker propranolol affected MT internalization mediated the stage-specific surface molecule gp82. Treatment of HeLa cells with propranolol significantly inhibited MT invasion whereas isoproterenol had no effect. Propranolol, but not isoproterenol, also inhibited the lysosome spreading required for gp82-dependent MT invasion. The effect of propranolol in inhibiting MT internalization was not due to the prevention of gp82 interaction with β-AR. It was mainly associated with its ability to impair lysosome spreading.

  17. Coexistence of alpha1 and beta adrenergic receptors in the liver of the frog Rana esculenta, the toad Bufo bufo, the lizard Podarcis sicula campestris, and the turtle Pseudemys picta elegans.

    PubMed

    Fabbri, E; Barbin, L; Capuzzo, A

    1997-09-01

    In mammals and birds the characteristics of alpha1 adrenergic receptors and their biological role in liver metabolism have been clearly described, although the predominance of receptor subtypes varies with species. In contrast, the actual presence of hepatic alpha1 adrenergic receptors in fish, amphibians, and reptiles has been questioned. Only recently has their existence been demonstrated in some fish species and also in the wood frog Rana sylvatica. The present study assessed the presence of alpha1 adrenergic binding sites on hepatic membranes of frogs, toads, lizards, and turtles using the specific alpha1 adrenergic receptor antagonist [3H]prazosin; for comparison, the binding of the specific beta adrenergic receptor antagonist [3H]CGP-12177A was evaluated in the same preparations. alpha1 Adrenergic receptors are indeed present in the liver of the ectotherms examined. Specific binding is saturable, reversible, and linear as a function of tissue concentration. The binding data indicated the presence of two classes of binding sites displaying high and low affinities with Kds in the nanomolar and micromolar ranges, respectively. The present study provides the first evidence for the presence of alpha1 adrenergic receptors in the liver of toad, lizard, and turtle while confirming their existence in another species of frog, Rana esculenta.

  18. Cross-talk between cardiac kappa-opioid and beta-adrenergic receptors in developing hypertensive rats.

    PubMed

    Yu, X C; Wang, H X; Zhang, W M; Wong, T M

    1999-03-01

    effects of NE and forskolin on the electrically induced [Ca2+]i transient was attenuated in SHR aged from 8 weeks when the blood pressure was rapidly increasing. The different time courses of altered responses to U50,488H, and NE and forskolin suggest that the attenuated negative modulation of kappa-receptor stimulation on the beta-adrenergic receptor is not due to the signal transduction pathway activated by beta-adrenergic stimulation. In 13-week-old SHR with the arterial blood pressure restored to normal by pharmacological manipulations, the blunted responses to NE, U50,488H and forskolin still occurred, indicating that the altered responses to activation of beta-adrenergic and kappa-opioid receptors and adenylate cyclase are not secondary to hypertension.

  19. Beta-Adrenergic Blockade Does not Prevent Polycythemia or Decrease in Plasma Volume in Men at 4300 m Altitude

    NASA Technical Reports Server (NTRS)

    Grover, R. F.; Selland, M. A.; McCullough, R. G.; Dahms, T. E.; Wolfel, E. E.; Butterfield, G. E.; Reeves, J. T.; Greenleaf, J. E.

    1998-01-01

    When humans ascend to high altitude (ALT) their plasma volume (PV) and total blood volume (BV) decrease during the first few days. With continued residence over several weeks, the hypoxia-induced stimulation of erythropoietin increases red cell production which tends to restore BV. Because hypoxia also activates the beta-adrenergic system, which stimulates red blood cell production, we investigated the effect of adrenergic beta-receptor inhibition with propranolol on fluid volumes and the polycythemic response in 11 healthy unacclimatized men (21-33 years old exposed to an ALT of 4300 m (barometric pressure 460 Torr) for 3 weeks on Pikes Peak, Colorado. PV was determined by the Evans blue dye method (PV(sub EB)), BV by the carbon monoxide method (BV(sub CO)), red cell volume (RCV)was calculated from hematocrit (Hct) and BV(sub CO), and serum erythropoietin concentration ([EPO]) and reticulocyte count, were also determined. All determinations were made at sea level and after 9-11 (ALT-10) and 9-20 (ALT-20) days at ALT. At sea level and ALT, six men received propranolol (pro, 240 mg/day), and five received a placebo (pla). Effective beta-blockade did not modify the mean (SE) maximal values of [EPO] [pla: 24.9 (3.5) vs pro: 24.5 (1.5) mU/ml] or reticulocyte count [pla: 2.7 (0.7) vs pro: 2.2 (0.5)%]; nor changes in PV(sub EB)[pla: -15.8 (3.8) vs pro: -19.9 (2.8)%], RCV(sub CO) [pla: +7.0 (6.7) vs pro: +10.1 (6.1)%], or BV(sub CO) [pla: -7.3 (2.3) vs pro: -7.1 (3.9)%]. In the absence of weight loss, a redistribution of body water with no net loss is implied. Hence, activation of the beta-adrenergic system did not appear to affect the hypovolemic or polycythemic responses that occurred during 3 weeks at 4300 m ALT in these subjects.

  20. Effects of two beta-adrenergic agonists on finishing performance, carcass characteristics, and meat quality of feedlot steers.

    PubMed

    Avendaño-Reyes, L; Torres-Rodríguez, V; Meraz-Murillo, F J; Pérez-Linares, C; Figueroa-Saavedra, F; Robinson, P H

    2006-12-01

    The impact of using 2 beta-adrenergic agonists in feedlot cattle fed finishing diets was evaluated using 54 steers (45 crossbred Charolais and 9 Brangus) initially weighing 424 +/- 26.6 kg in a randomized complete block design with 3 treatments and 6 blocks (i.e., 18 pens with 3 steers per pen). Response variables were feedlot performance, carcass characteristics, and meat quality. Treatments were 1) control (no supplement added); 2) zilpaterol hydrochloride (ZH; 60 mg.steer(-1).d(-1)); and 3) ractopamine hydrochloride (RH; 300 mg.steer(-1).d(-1)). The beta-agonists were added to the diets during the final 33 d of the experiment. The groups of steers fed ZH or RH improved (P < 0.01) ADG by 26 or 24%, respectively, compared with control steers. Steers supplemented with RH consumed less (P = 0.03) DM (8.37 kg) than control steers (8.51 kg), whereas intake was similar (P = 0.37) for ZH and control steers. Addition of either beta-agonist to the diet considerably improved (P < 0.01) the G:F (ZH, 0.253 and RH, 0.248 vs. control, 0.185). Hot carcass weight and carcass yield were enhanced (P < 0.05) with both beta-agonists. The LM area was increased (P = 0.026) by ZH (75.2 cm(2)), but that of RH (72.2 cm(2)) was similar (P = 0.132) to the control steers (66.8 cm(2)). Meat from the ZH- (P = 0.0007) and RH- (P = 0.0267) supplemented steers had greater shear force values than control steers (ZH = 5.11; RH = 4.83; control = 4.39 kg/cm(2)). Variables related to meat color indicated that both beta-agonists led to a similar redness of the LM area related to the control group. In general, feedlot performance was greatly enhanced by beta-adrenergic agonists, and meat tenderness from treated animals was classified as intermediate. Furthermore, meat color was not altered by beta-agonist supplementation.

  1. Beta-Adrenergic Receptors and Isoproterenol-stimulated Potassium Transport in Erythrocytes from Normal and Hypothyroid Turkeys

    PubMed Central

    Furukawa, Haruyasu; Loeb, John N.; Bilezikian, John P.

    1980-01-01

    We have previously reported that in hypothyroid turkeys the number of beta-adrenergic receptors in intact erythrocytes is reduced by ∼50% without any changes in the affinity of the receptor for the agonist, isoproterenol. In view of the physiological action of the catecholamines to stimulate bidirectional ion fluxes in these cells, we have now examined the possibility that the decrease in beta receptor number might be associated with concomitant changes in catecholamine-dependent potassium ion transport. Hypothyroid turkey erythrocytes display decreased sensitivity to isoproterenol-stimulated potassium influx. Half-maximal stimulation of potassium influx occurs at 9.2±1.7 nM in hypothyroid cells as opposed to only 3.8±0.4 nM in normal cells (P < 0.005). A maximal stimulatory concentration of isoproterenol (100 nM) leads to the same increment in ion flux in erythrocytes from hypothyroid and normal turkeys. Analysis of the quantitative relationship between isoproterenol concentration, receptor occupancy, and associated effects upon potassium influx shows that at low levels of isoproterenol, where occupancy is linear with agonist concentration, occupation of a given number of beta receptors leads to a stimulation of potassium transport that is identical in erythrocytes from normal and hypothyroid turkeys. Thus, decreased sensitivity to catecholamine-stimulated potassium transport in hypothyroidism can be attributed to the decrease in receptor number and the resulting two- to threefold higher isoproterenol concentration required for occupancy of the same number of beta receptors. Once a single receptor is occupied, however, the more distal components of the sequence of events mediating the physiological response to beta-adrenergic agonists in the hypothyroid cell function as they do under normal circumstances. It would appear, therefore, that the decrease in sensitivity to isoproterenol-dependent ion flux in the hypothyroid turkey erythrocyte can be accounted for

  2. Beta-Adrenergic Blockade Does not Prevent Polycythemia or Decrease in Plasma Volume in Men at 4300 m Altitude

    NASA Technical Reports Server (NTRS)

    Grover, R. F.; Selland, M. A.; McCullough, R. G.; Dahms, T. E.; Wolfel, E. E.; Butterfield, G. E.; Reeves, J. T.; Greenleaf, J. E.

    1998-01-01

    When humans ascend to high altitude (ALT) their plasma volume (PV) and total blood volume (BV) decrease during the first few days. With continued residence over several weeks, the hypoxia-induced stimulation of erythropoietin increases red cell production which tends to restore BV. Because hypoxia also activates the beta-adrenergic system, which stimulates red blood cell production, we investigated the effect of adrenergic beta-receptor inhibition with propranolol on fluid volumes and the polycythemic response in 11 healthy unacclimatized men (21-33 years old exposed to an ALT of 4300 m (barometric pressure 460 Torr) for 3 weeks on Pikes Peak, Colorado. PV was determined by the Evans blue dye method (PV(sub EB)), BV by the carbon monoxide method (BV(sub CO)), red cell volume (RCV)was calculated from hematocrit (Hct) and BV(sub CO), and serum erythropoietin concentration ([EPO]) and reticulocyte count, were also determined. All determinations were made at sea level and after 9-11 (ALT-10) and 9-20 (ALT-20) days at ALT. At sea level and ALT, six men received propranolol (pro, 240 mg/day), and five received a placebo (pla). Effective beta-blockade did not modify the mean (SE) maximal values of [EPO] [pla: 24.9 (3.5) vs pro: 24.5 (1.5) mU/ml] or reticulocyte count [pla: 2.7 (0.7) vs pro: 2.2 (0.5)%]; nor changes in PV(sub EB)[pla: -15.8 (3.8) vs pro: -19.9 (2.8)%], RCV(sub CO) [pla: +7.0 (6.7) vs pro: +10.1 (6.1)%], or BV(sub CO) [pla: -7.3 (2.3) vs pro: -7.1 (3.9)%]. In the absence of weight loss, a redistribution of body water with no net loss is implied. Hence, activation of the beta-adrenergic system did not appear to affect the hypovolemic or polycythemic responses that occurred during 3 weeks at 4300 m ALT in these subjects.

  3. cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta-adrenergic agonists.

    PubMed Central

    Jurevicius, J; Fischmeister, R

    1996-01-01

    The role of cAMP subcellular compartmentation in the progress of beta-adrenergic stimulation of cardiac L-type calcium current (ICa) was investigated by using a method based on the use of whole-cell patch-clamp recording and a double capillary for extracellular microperfusion. Frog ventricular cells were sealed at both ends to two patch-clamp pipettes and positioned approximately halfway between the mouths of two capillaries that were separated by a 5-micron thin wall. ICa could be inhibited in one half or the other by omitting Ca2+ from one solution or the other. Exposing half of the cell to a saturating concentration of isoprenaline (ISO, 1 microM) produced a nonmaximal increase in ICa (347 +/- 70%; n = 4) since a subsequent application of ISO to the other part induced an additional effect of nearly similar amplitude to reach a 673 +/- 130% increase. However, half-cell exposure to forskolin (FSK, 30 microM) induced a maximal stimulation of ICa (561 +/- 55%; n = 4). This effect was not the result of adenylyl cyclase activation due to FSK diffusion in the nonexposed part of the cell. To determine the distant effects of ISO and FSK on ICa, the drugs were applied in a zero-Ca solution. Adding Ca2+ to the drug-containing solutions allowed us to record the local effect of the drugs. Dose-response curves for the local and distant effects of ISO and FSK on ICa were used as an index of cAMP concentration changes near the sarcolemma. We found that ISO induced a 40-fold, but FSK induced only a 4-fold, higher cAMP concentration close to the Ca2+ channels, in the part of the cell exposed to the drugs, than it did in the rest of the cell. cAMP compartmentation was greatly reduced after inhibition of phosphodiesterase activity with 3-isobutyl-methylxanthine, suggesting the colocalization of enzymes involved in the cAMP cascade. We conclude that beta-adrenergic receptors are functionally coupled to nearby Ca2+ channels via local elevations of cAMP. PMID:8552625

  4. [Arterial hypertension. Density of alpha 1 and alpha 2 adrenergic receptors in blood platelets, beta adrenergic receptors in the lymphocytes and serum catecholamine levels].

    PubMed

    Halawa, B

    1991-01-01

    The influence of the sympathetic nervous system on blood pressure is mediated predominantly by catecholamines norepinephrine and epinephrine acting on alpha- and beta-adrenoceptors. The study of human alpha-adrenergic and beta-adrenergic receptors in hypertension is hampered by the lack of easily accessible cardiovascular tissues. Therefore numerous investigators have used platelets as a model system to study alpha-adrenergic receptors and lymphocytes to study beta-adrenergic receptors in humans. During the last decade some studies with small patient numbers have been published, that generally did not detect significant differences in platelet alpha 2-adrenergic receptor density between normotensive and hypertensive subjects, however, most investigators have described higher density of beta-receptors in lymphocytes from hypertensive patients than in cells from normotensive control subjects. This study was carried out to analyse density of alpha 1- and alpha 2-adrenoceptors in platelet membrane preparations and beta-adrenoreceptors in lymphocytes before and after physiological increase in plasma catecholamines. It was found that density of alpha 1- and alpha 2-adrenoreceptors in platelet membranes of patients with stable blood hypertension was similar to that in the healthy individuals while beta-adrenergic receptors density in lymphocytes was higher. In normotensives posture induced rise in plasma catecholamines correlated with reduced alpha 1- and alpha 2-adrenoreceptors density as well as beta-adrenoreceptor density. Hypertensive subjects had similar rise in plasma catecholamines with upright posture, but no changes in receptor density was observed. These suggest that in hypertension alpha-adrenergic and beta-adrenergic regulation by agonist may be disturbed.

  5. Vitamins C and E attenuate apoptosis, beta-adrenergic receptor desensitization, and sarcoplasmic reticular Ca2+ ATPase downregulation after myocardial infarction.

    PubMed

    Qin, Fuzhong; Yan, Chen; Patel, Ravish; Liu, Weimin; Dong, Erdan

    2006-05-15

    Oxidative stress plays an important role in mediating ventricular remodeling and dysfunction in heart failure (HF), but its mechanism of action has not been fully elucidated. In this study we determined whether a combination of antioxidant vitamins reduced myocyte apoptosis, beta-adrenergic receptor desensitization, and sarcoplasmic reticular (SR) Ca2+ ATPase downregulation in HF after myocardial infarction (MI) and whether these effects were associated with amelioration of left ventricular (LV) remodeling and dysfunction. Vitamins (vitamin C 300 mg and vitamin E 300 mg) were administered to rabbits 1 week after MI or sham operation for 11 weeks. The results showed that MI rabbits exhibited cardiac dilation and LV dysfunction measured by fractional shortening and the maximal rate of pressure rise (dP/dt), an index of contractility. These changes were associated with elevation of oxidative stress, decreases of mitochondrial Bcl-2 and cytochrome c proteins, increases of cytosolic Bax and cytochrome c proteins, caspase 9 and caspase 3 activities and myocyte apoptosis, and downregulation of beta-adrenergic receptor sensitivity and SR Ca2+ ATPase. Combined treatment with vitamins C and E diminished oxidative stress, increased mitochondrial Bcl-2 protein, decreased cytosolic Bax, prevented cytochrome c release from mitochondria to cytosol, reduced caspase 9 and caspase 3 activities and myocyte apoptosis, blocked beta-adrenergic receptor desensitization and SR Ca2+ ATPase downregulation, and attenuated LV dilation and dysfunction in HF after MI. The results suggest that antioxidant therapy may be beneficial in HF.

  6. Central beta-adrenergic receptors play an important role in the enhancing effect of voluntary exercise on learning and memory in rat.

    PubMed

    Ebrahimi, Shima; Rashidy-Pour, Ali; Vafaei, Abbas A; Akhavan, Maziar M

    2010-03-17

    The beneficial effects of physical activity and exercise on brain functions such as improvement in learning and memory are well documented. The aim of this study was to examine the role of the beta-adrenergic system in voluntary exercise-induced enhancement of learning and memory in rat. In order to block the beta-adrenergic receptors, the animals were received propranolol (a beta-blocker), or nadolol (a peripherally acting beta-blocker) before each night of five consecutive nights of exercise. Then their learning and memory were tested on the water maze task using a two-trials-per-day for 5 consecutive days. A probe trial was performed 2 days after the last training day. Our results showed that propranolol, but not nadolol reversed the exercise-induced improvement in learning and memory in rat. Our findings indicate that central beta-adrenergic receptors play an important role in mediating the beneficial effects of voluntary exercise on learning and memory.

  7. Phosphatidic acid phosphatase in neonatal rat lung: effects of prenatal dexamethasone or terbutaline treatment on basal activity and on responsiveness to beta adrenergic stimulation.

    PubMed

    Kudlacz, E M; Navarro, H A; Slotkin, T A

    1989-07-01

    Phosphatidic acid phosphatase (PAPase) is a key enzyme in the synthesis of lung surfactant. This study compares the effects of prenatal exposure (gestational days 17, 18 and 19) to two drugs which enhance surfactant synthesis: dexamethasone (0.2 mg/kg) and terbutaline (2 or 10 mg/kg). Maternal dexamethasone treatment did not cause an initial stimulation of lung PAPase but did eventually evoke a small increase after the 1st postnatal week. The effect was selective in that brain PAPase activity was generally unaffected; liver PAPase was stimulated during the early neonatal period only. Dexamethasone also prolonged the developmental period of peak reactivity of lung PAPase to beta developmental period of peak reactivity of lung PAPase to beta adrenergic stimulation (tested with acute isoproterenol challenge), which ordinarily accompanies genesis of alveoli in the 2nd to 3rd postnatal week. Significant growth retardation was present even at this low dose of dexamethasone. In contrast, maternal administration of the beta adrenergic agonist, terbutaline, resulted in a large increase in basal enzyme activity in the lung during the immediate perinatal period and enhanced the responsiveness to isoproterenol challenge. The effect of terbutaline was accompanied by little or no growth impairment. Thus, although prenatal administration of either glucocorticoids or beta adrenergic agonists can enhance lung PAPase activity and reactivity to stimulation, the two classes of drugs differ substantially in time course of effect and in the propensity to retard growth.

  8. Comparison of. beta. -adrenergic receptors between different strains of rat with different susceptibility to hypertension: a survey of binding characteristics, responsiveness and corticosteroid induced modulation

    SciTech Connect

    Jazayeri, A.

    1987-01-01

    The objective of this research was two fold: the first objective was to measure ..beta..-adrenergic receptor characteristics (Bmax and Kd) and responsiveness (isoproterenol induced c-AMP production) between different strains of rat with different susceptibility to hypertension. The second objective of this research was to determine if ..beta..-adrenergic receptors of arterial smooth muscle cells (ASMC) can be modulated by corticosteroids. These studies were done under controlled conditions using ASMC grown in culture from the rat aorta. (/sup 3/H)-dihydroalprenolol (DHA) was used to measure ..beta..-adrenergic receptor binding characteristics (Kd and Bmax). Scatchard analysis of (/sup 3/H)-DHA binding revealed one class of binding sites with affinity in the range of 100 pM. (/sup 3/H)-DHA binding comparison between Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) revealed that the Bmax for SHR was significantly lower than WKY. However, isoproterenol stimulated c-AMP production by SHR, is significantly higher than WKY. Fischer 344 rats, showed similar Bmax, Kd, and responsiveness as WKY rats. Dahl-sensitive and Dahl-resistant rats had equal Bmax and Kd measured by (/sup 3/H)-DHA binding.

  9. New beta-adrenergic agonists used illicitly as growth promoters in animal breeding: chemical and pharmacodynamic studies.

    PubMed

    Mazzanti, Gabriela; Daniele, Claudia; Boatto, Gianpiero; Manca, Giuliana; Brambilla, Gianfranco; Loizzo, Alberto

    2003-05-03

    Clenbuterol and beta-adrenergic receptor agonist drugs are illegally used as growth promoters in animal production. Pharmacologically active residues in edible tissues led to intoxication outbreaks in several countries. Pressure of official controls pulsed synthesis of new compounds to escape analytical procedures. We report two new compounds named 'A' and 'G4', found in feeding stuffs. Chemical structure was studied through nuclear magnetic resonance-imaging and infrared spectroscopy, and beta(1)- and beta(2)-adrenergic activity was evaluated on isolated guinea-pig atrium and trachea in comparison with clenbuterol. Both compounds share with clenbuterol an halogenated aromatic ring with a primary amino group. Main modifications consisted of substitution of secondary amino group with an alkyl chain in compound A and substitution of the ter-butyl group with a benzene ring in compound G4. In guinea-pig trachea these compounds showed myorelaxant potency lower than clenbuterol (EC(50) was 43.8 nM for clenbuterol, 11700 nM for compound A, 2140 nM for G4). On the contrary, in the guinea-pig atrium (heart-beat rate stimulant effect) the compounds were more potent than clenbuterol (EC(50) was 15.2 nM for clenbuterol, 3.4 nM for compound A, 2.8 nM for G4). These pharmacodynamic properties, and stronger lipophilic properties shown by the two compounds may result in increased cardiovascular risk for consumers of illicitly treated animals.

  10. Developmental Changes is Expression of Beta-Adrenergic Receptors in Cultures of C2C12 Skeletal Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, Ronald B.; Bridge, K. Y.; Vaughn, J. R.

    2000-01-01

    beta-Adrenergic receptor (bAR) agonists have been reported to modulate growth in several mammalian and avian species, and bAR agonists presumably exert their physiological action on skeletal muscle cells through this receptor. Because of the importance of bAR regulation on muscle protein metabolism in muscle cells, the objectives of this study were to determine the developmental expression pattern of the bAR population in C2C12 skeletal muscle cells, and to analyze changes in both the quantity and isoform expression of the major muscle protein, myosin. The number of bAR in mononucleated C2C12 cells was approximately 8,000 bAR per cell, which is comparable with the population reported in several other nonmuscle cell types. However, the bar population increased after myoblast fusion to greater than 50,000 bAR per muscle cell equivalent. The reasons for this apparent over-expression of bAR in C2C12 cells is not known. The quantity of myosin also increased after C2C12 myoblast fusion, but the quantity of myosin was less than that reported in primary muscle cell cultures. Finally, at least five different isoforms of myosin heavy chain could be resolved in C2C12 cells, and three of these exhibited either increased or decreased developmental regulation relative to the others. Thus, C2C12 myoblasts undergo developmental regulation of bAR population and myosin heavy chain isoform expression.

  11. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.

    2003-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

  12. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.; Cureri, Peter A. (Technical Monitor)

    2002-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of cAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of cAMP by either epinephrine or isoproterenol.

  13. Duality of G protein-coupled mechanisms for beta-adrenergic activation of NKCC activity in skeletal muscle.

    PubMed

    Gosmanov, Aidar R; Wong, Jennifer A; Thomason, Donald B

    2002-10-01

    Skeletal muscle Na(+)-K(+)-2Cl(-) cotransporter (NKCC) activity provides a potential mechanism for regulated K(+) uptake. beta-Adrenergic receptor (beta-AR) activation stimulates skeletal muscle NKCC activity in a MAPK pathway-dependent manner. We examined potential G protein-coupled pathways for beta-AR-stimulated NKCC activity. Inhibition of G(s)-coupled PKA blocked isoproterenol-stimulated NKCC activity in both the slow-twitch soleus muscle and the fast-twitch plantaris muscle. However, the PKA-activating agents cholera toxin, forskolin, and 8-bromo-cAMP (8-BrcAMP) were not sufficient to activate NKCC in the plantaris and partially stimulated NKCC activity in the soleus. Isoproterenol-stimulated NKCC activity in the soleus was abolished by pretreatment with pertussis toxin (PTX), indicating a G(i)-coupled mechanism. PTX did not affect the 8-BrcAMP-stimulated NKCC activity. PTX treatment also precluded the isoproterenol-mediated ERK1/2 MAPK phosphorylation in the soleus, consistent with NKCC's MAPK dependency. Inhibition of isoproterenol-stimulated ERK activity by PTX treatment was associated with an increase in Akt activation and phosphorylation of Raf-1 on the inhibitory residue Ser(259). These results demonstrate a novel, muscle phenotype-dependent mechanism for beta-AR-mediated NKCC activation that involves both G(s) and G(i) protein-coupled mechanisms.

  14. Exercise performance and beta-adrenergic blockade in patients with complete heart block treated with ventricular inhibited pacing.

    PubMed

    Wikner, J; Larsen, F F; Nordlander, R; Pehrsson, K; Aström, H

    1991-09-01

    The effect of beta-adrenergic blockade (propranolol) on exercise performance was studied in 15 patients (12 men and 3 women, mean age 70 years) with complete heart block treated with a ventricular-inhibited pacemaker (VVI). In a double-blind procedure, the patients were randomly given either 0.1 mg/kg of propranolol or saline solution i.v. before a first exercise test and vice versa before a second test. The interval between the tests was 24 hours. Nine patients were in sinus rhythm, 4 patients had atrial flutter, and 2 others had atrial fibrillation. The exercise capacity was on an average 11% lower with propranolol than with placebo (p less than 0.001). The most marked reductions (20 and 33%) were found in the two patients with atrial fibrillation. The atrial rate in patients with sinus rhythm was significantly lower with propranolol than placebo both at rest (68 vs. 83 beats/min, p less than 0.001) and at maximal work load (91 vs. 141 beats/min, p less than 0.001). The present findings show that beta blockade has negative effects on exercise capacity in patients with complete heart block treated with VVI pacemakers. This finding should be considered in the selection of drug treatment in patients with fixed rate pacing and concomitant hypertension and/or ischemic heart disease.

  15. Effect of beta-ADrenergic Agonist on Cyclic AMP Synthesis in Chicken Skeletal Muscle Cells in Culture

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.; Rose, M. Franklin (Technical Monitor)

    2000-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Because it seems logical that these agonists exert their action on muscle through stimulation of cAMP synthesis, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax levels were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. In addition, the EC50 values for isoproterenol, cimaterol, clenbuterol, epinephrine, and albuterol were 360 nM, 630 nM, 900 nM, 2,470 nM, and 3,650 nM, respectively. Finally, dose response curves show that the concentrations of cimaterol and clenbuterol in culture media at concentrations known to cause significant muscle hypertrophy in animals had no detectable effect on stimulation of CAMP accumulation in chicken skeletal muscle cells.

  16. Developmental Changes is Expression of Beta-Adrenergic Receptors in Cultures of C2C12 Skeletal Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, Ronald B.; Bridge, K. Y.; Vaughn, J. R.

    2000-01-01

    beta-Adrenergic receptor (bAR) agonists have been reported to modulate growth in several mammalian and avian species, and bAR agonists presumably exert their physiological action on skeletal muscle cells through this receptor. Because of the importance of bAR regulation on muscle protein metabolism in muscle cells, the objectives of this study were to determine the developmental expression pattern of the bAR population in C2C12 skeletal muscle cells, and to analyze changes in both the quantity and isoform expression of the major muscle protein, myosin. The number of bAR in mononucleated C2C12 cells was approximately 8,000 bAR per cell, which is comparable with the population reported in several other nonmuscle cell types. However, the bar population increased after myoblast fusion to greater than 50,000 bAR per muscle cell equivalent. The reasons for this apparent over-expression of bAR in C2C12 cells is not known. The quantity of myosin also increased after C2C12 myoblast fusion, but the quantity of myosin was less than that reported in primary muscle cell cultures. Finally, at least five different isoforms of myosin heavy chain could be resolved in C2C12 cells, and three of these exhibited either increased or decreased developmental regulation relative to the others. Thus, C2C12 myoblasts undergo developmental regulation of bAR population and myosin heavy chain isoform expression.

  17. Regulation of beta-adrenergic receptor signaling by S-nitrosylation of G-protein-coupled receptor kinase 2.

    PubMed

    Whalen, Erin J; Foster, Matthew W; Matsumoto, Akio; Ozawa, Kentaro; Violin, Jonathan D; Que, Loretta G; Nelson, Chris D; Benhar, Moran; Keys, Janelle R; Rockman, Howard A; Koch, Walter J; Daaka, Yehia; Lefkowitz, Robert J; Stamler, Jonathan S

    2007-05-04

    beta-adrenergic receptors (beta-ARs), prototypic G-protein-coupled receptors (GPCRs), play a critical role in regulating numerous physiological processes. The GPCR kinases (GRKs) curtail G-protein signaling and target receptors for internalization. Nitric oxide (NO) and/or S-nitrosothiols (SNOs) can prevent the loss of beta-AR signaling in vivo, but the molecular details are unknown. Here we show in mice that SNOs increase beta-AR expression and prevent agonist-stimulated receptor downregulation; and in cells, SNOs decrease GRK2-mediated beta-AR phosphorylation and subsequent recruitment of beta-arrestin to the receptor, resulting in the attenuation of receptor desensitization and internalization. In both cells and tissues, GRK2 is S-nitrosylated by SNOs as well as by NO synthases, and GRK2 S-nitrosylation increases following stimulation of multiple GPCRs with agonists. Cys340 of GRK2 is identified as a principal locus of inhibition by S-nitrosylation. Our studies thus reveal a central molecular mechanism through which GPCR signaling is regulated.

  18. How effortful is cognitive control? Insights from a novel method measuring single-trial evoked beta-adrenergic cardiac reactivity.

    PubMed

    Kuipers, Mithras; Richter, Michael; Scheepers, Daan; Immink, Maarten A; Sjak-Shie, Elio; van Steenbergen, Henk

    2017-09-01

    The ability to adjust attentional focus to varying levels of task demands depends on the adaptive recruitment of cognitive control processes. The present study investigated for the first time whether the mobilization of cognitive control during response-conflict trials in a flanker task is associated with effort-related sympathetic activity as measured by changes in the RZ-interval at a single-trial level, thus providing an alternative to the pre-ejection period (PEP) which can only be reliably measured in ensemble-averaged data. We predicted that response conflict leads to a physiological orienting response (i.e. heart rate slowing) and increases in effort as reflected by changes in myocardial beta-adrenergic activity (i.e. decreased RZ interval). Our results indeed showed that response conflict led to cardiac deceleration and decreased RZ interval. However, the temporal overlap of the observed heart rate and RZ interval changes suggests that the effect on the latter reflects a change in cardiac pre-load (Frank-Starling mechanism). Our study was thus unable to provide evidence for the expected link between cognitive control and cardiovascular effort. However, it demonstrated that our single-trial analysis enables the assessment of transient changes in cardiac sympathetic activity, thus providing a promising tool for future studies that aim to investigate effort at a single-trial level. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Effect of beta-ADrenergic Agonist on Cyclic AMP Synthesis in Chicken Skeletal Muscle Cells in Culture

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.; Rose, M. Franklin (Technical Monitor)

    2000-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Because it seems logical that these agonists exert their action on muscle through stimulation of cAMP synthesis, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax levels were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. In addition, the EC50 values for isoproterenol, cimaterol, clenbuterol, epinephrine, and albuterol were 360 nM, 630 nM, 900 nM, 2,470 nM, and 3,650 nM, respectively. Finally, dose response curves show that the concentrations of cimaterol and clenbuterol in culture media at concentrations known to cause significant muscle hypertrophy in animals had no detectable effect on stimulation of CAMP accumulation in chicken skeletal muscle cells.

  20. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.

    2003-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate CAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of CAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of CAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of CAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of CAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of CAMP by either epinephrine or isoproterenol.

  1. Activation of Cyclic AMP Synthesis by Full and Partial Beta-Adrenergic Receptor Agonists in Chicken Skeletal Muscle Cells

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.; Cureri, Peter A. (Technical Monitor)

    2002-01-01

    Several beta-adrenergic receptor (bAR) agonists are known to cause hypertrophy of skeletal muscle tissue. Accordingly, five bAR agonists encompassing a range in activity from strong to weak were evaluated for their ability to stimulate cAMP accumulation in embryonic chicken skeletal muscle cells in culture. Two strong agonists (epinephrine and isoproterenol), one moderate agonist (albuterol), and two weak agonists known to cause hypertrophy in animals (clenbuterol and cimaterol) were studied. Dose response curves were determined over six orders of magnitude in concentration for each agonist, and values were determined for their maximum stimulation of cAMP synthesis rate (Bmax) and the agonist concentration at which 50% stimulation of cAMP synthesis (EC50) occurred. Bmax values decreased in the following order: isoproterenol, epinephrine, albuterol, cimaterol, clenbuterol. Cimaterol and clenbuterol at their Bmax concentrations were approximately 15-fold weaker than isoproterenol in stimulating the rate of cAMP synthesis. When cimaterol and clenbuterol were added to culture media at concentrations known to cause significant muscle hypertrophy in animals, there was no detectable effect on stimulation of cAMP synthesis. Finally, these same levels of cimaterol and clenbuterol did not antagonize the stimulation of cAMP by either epinephrine or isoproterenol.

  2. Identification of the Cardiac Beta-Adrenergic Receptor Protein: Solubilization and Purification by Affinity Chromatography

    PubMed Central

    Lefkowitz, Robert J.; Haber, Edgar; O'Hara, Donald

    1972-01-01

    A protein that binds catecholamines with a specificity parallel to that of their in vivo effects on cardiac contractility (isoproterenol > epinephrine or norepinephrine > dopamine > dihydroxyphenylalanine) was solubilized from a microsomal fraction of canine ventricular myocardium. The binding protein was purified 500 to 800-fold by solubilization and subsequent affinity chromatography with conjugates of norepinephrine linked to agarose beads. Purified β-adrenergic binding protein exists in two forms, corresponding to molecular weights of 40,000 and 160,000. The purified material has a single association constant, 2.3 × 105 liters/mol (as compared to two association constants, 107 and 106 liters/mol, for the binding protein in particulate form) but retains the identical binding specificity for β-adrenergic drugs and antagonists. Images PMID:4507606

  3. Beta adrenergic blockade decreases the immunomodulatory effects of social disruption stress.

    PubMed

    Hanke, M L; Powell, N D; Stiner, L M; Bailey, M T; Sheridan, J F

    2012-10-01

    During physiological or psychological stress, catecholamines produced by the sympathetic nervous system (SNS) regulate the immune system. Previous studies report that the activation of β-adrenergic receptors (βARs) mediates the actions of catecholamines and increases pro-inflammatory cytokine production in a number of different cell types. The impact of the SNS on the immune modulation of social defeat has not been examined. The following studies were designed to determine whether SNS activation during social disruption stress (SDR) influences anxiety-like behavior as well as the activation, priming, and glucocorticoid resistance of splenocytes after social stress. CD-1 mice were exposed to one, three, or six cycles of SDR and HPLC analysis of the plasma and spleen revealed an increase in catecholamines. After six cycles of SDR the open field test was used to measure behaviors characteristic of anxiety and indicated that the social defeat induced increase in anxiety-like behavior was blocked by pre-treatment with the β-adrenergic antagonist propranolol. Pre-treatment with the β-adrenergic antagonist propranolol did not significantly alter corticosterone levels indicating no difference in activation of the hypothalamic-pituitary-adrenal axis. In addition to anxiety-like behavior the SDR induced splenomegaly and increase in plasma IL-6, TNFα, and MCP-1 were each reversed by pre-treatment with propranolol. Furthermore, flow cytometric analysis of cells from propranolol pretreated mice reduced the SDR-induced increase in the percentage of CD11b(+) splenic macrophages and significantly decreased the expression of TLR2, TLR4, and CD86 on the surface of these cells. In addition, supernatants from 18h LPS-stimulated ex vivo cultures of splenocytes from propranolol-treated SDR mice contained less IL-6. Likewise propranolol pre-treatment abrogated the glucocorticoid insensitivity of CD11b(+) cells ex vivo when compared to splenocytes from SDR vehicle-treated mice

  4. Beta-adrenergic effect of antibodies from chagasic patients and normal human lymphocytes on isolated rat atria

    PubMed Central

    Sterin-Borda, Leonor; Fink, Susana; Diez, C.; Cossio, Patricio; De E. De Bracco, María M.

    1982-01-01

    It was previously shown that fresh sera from chagasic patients that contained antibodies reacting with the plasma membrane of striated muscle and endothelial cells (EVI(+) serum) could act in co-operation with complement as a partial beta-agonist increasing the frequency of contraction of isolated rat atria. This activity was absent in EVI(-) chagasic serum or normal human serum and was lost upon heat-inactivation of EVI(+) serum. Also, IgG purified from EVI(+) serum was virtually devoid of activity. In this report we demonstrate that normal human lymphocytes can collaborate with EVI(+) IgG or heat-inactivated EVI(+) sera and induce both positive ino- and chronotropic effects on isolated rat atria. Depletion of phagocytic mononuclear cells from the effector cell population did not alter its activity, whereas blockade of the receptors for the Fc fragment of IgG with heat-aggregated IgG abrogated the effect. After fractionation of the T and non-T cell populations by sedimentation of E rosette forming cells the activity was present in the non-T cell fraction. The mechanism triggered involved a beta-adrenergic reaction that could be blocked by 10-7 M (-)-propanolol and not by inhibitors of prostaglandin synthesis (10-6 M indomethacin and 1·8 × 10-4 M acetyl salicylic acid) or an anti-histamine drug (10-6 M pyrilamine). Since positive EVI reactivity and myocardial lympho-mononuclear cell infiltrates are frequent in patients with chronic Chagas' cardiomyo-pathy, the possibility that they could interact influencing the rhythm and contractile activity of the heart should be taken into account. PMID:6819907

  5. Mechanism for desensitization of beta-adrenergic receptor-stimulated lipolysis in adipocytes from rats harboring pheochromocytoma.

    PubMed

    Prokocimer, P G; Maze, M; Vickery, R G; Hoffman, B B

    1988-07-01

    Prolonged stimulation of beta-adrenergic receptors with catecholamines leads to desensitization of their ability to activate cAMP accumulation. However, little is known about the relationship between these changes and possible alterations in physiological responses. We have used isolated adipocytes prepared from NEDH rats harboring pheochromocytomas, a norepinephrine-secreting tumor, to address this question. As expected, there was a decrease in the ability of isoproterenol to maximally activate cAMP accumulation in adipocytes from rat harboring pheochromocytoma [323 +/- 107 vs. 707 +/- 145 pmol/10(5) cells.min (mean +/- SD) in controls]. This change was associated with an increase in the EC50 of isoproterenol for activation of cAMP-dependent protein kinase (5.8 X 10(-8) vs. 2.4 X 10(-8) M in controls) and a decrease in maximal activation of the kinase (38 +/- 16% vs. 77 +/- 14% in controls). For lipolysis there was a loss in sensitivity to isoproterenol but no change in maximal lipolytic rate in the adipocytes from rats harboring pheochromocytoma. For both groups there was a similar relationship between kinase activation and lipolysis; maximal lipolysis had already occurred for protein kinase-A activity ratios less than 30%. Therefore, the blunted cAMP response in adipocytes from rats harboring pheochromocytoma did not impair the maximal lipolytic rate. These results demonstrate that adipocytes can efficiently maintain maximal lipolysis in a desensitized state because of considerable reserve in the biochemical cascade leading to the lipolytic response. In addition, our findings demonstrate that there are no regulatory changes induced by prolonged exposure to catecholamines that are distal to cAMP accumulation.

  6. Participation of beta-adrenergic activity in modulation of GLUT4 expression during fasting and refeeding in rats.

    PubMed

    Zanquetta, Melissa Moreira; Nascimento, Monalisa Edi Cabral; Mori, Rosana Cristina Tieko; D'Agord Schaan, Beatriz; Young, Martin E; Machado, Ubiratan Fabres

    2006-11-01

    Through in vitro studies, several factors have been reported as modulators of GLUT4 gene expression. However, the role(s) of each potential GLUT4 modulator is not completely understood in the in vivo setting. The present study has investigated the hypothesis that beta-adrenergic stimulation participates in modulation of GLUT4 expression during fasting and refeeding. As such, GLUT4 messenger RNA (mRNA) and protein were investigated in insulin-sensitive tissues during a 48-hour fast. In addition, the effects of 8-hour refeeding on GLUT4 mRNA in the gastrocnemius muscle and interscapular brown adipose tissue (BAT) were investigated. Whether beta-adrenoceptor blockade by propranolol (20 mg/kg) treatment influenced the responsiveness to fasting/refeeding was also investigated. The results show that fasting repressed GLUT4 gene and protein expression in BAT, white adipose tissue, and soleus muscle, but had no effect on the gastrocnemius muscle. Refeeding induced a rapid overexpression of GLUT4 mRNA in both gastrocnemius (approximately 25%, P < .05) and BAT (approximately 200%, P < .001). Propranolol treatment induced an increase (approximately 60%, P < .05) in GLUT4 mRNA at the end of the fasting period. In contrast, propranolol treatment attenuated GLUT4 mRNA induction after refeeding; the latter may be due to attenuation of postprandial insulin levels. These results suggest that sympathetic activity is important for the repression of GLUT4 gene expression during fasting. In contrast, sympathetic control of the GLUT4 gene seems to be overbalanced by metabolic/hormonal modulators during refeeding stage. Taken together, the results suggest that feeding behavior influences GLUT4 gene expression pattern through changes in sympathetic activity, especially during long-term starvation periods.

  7. Influence of beta-adrenoceptor agonists and antagonists on baclofen-induced memory impairment in mice.

    PubMed

    Zarrindast, M R; Haidari, H; Jafari, M R; Djahanguiri, B

    2004-07-01

    Post-training administration of different doses of baclofen (a GABAB agonist) has been shown to impair memory retention, in a step-down passive avoidance test in mice. We have studied the effects of beta-adrenergic agonists and antagonists on baclofen-induced memory impairment in mice. Dobutamine (a beta 1-agonist) or salbutamol (a beta 2-agonist) reversed the memory impairment induced by baclofen without exhibiting intrinsic actions on memory when administered alone. The administration of atenolol (a beta 1-antagonist) or propranolol (a beta-antagonist) produced a memory impairment. When co-administered with baclofen, both atenolol and propranolol exacerbated the memory impairment induced by the GABAB agonist. It is concluded that beta-adrenergic mechanisms may be involved in the modulation of memory via GABAB receptors.

  8. Differential involvement of cholinergic and beta-adrenergic systems during acquisition, consolidation, and retrieval of long-term memory of social and neutral odors.

    PubMed

    Miranda, María Isabel; Ortiz-Godina, Fatima; García, Dafne

    2009-08-24

    Acetylcholine and norepinephrine have been implicated during different kinds of social recognition that involves olfactory memory formation. For example, blockade of muscarinic and beta-adrenergic receptors has been shown to impair short-term memory of both socially relevant as well as of neutral odors. However, previous studies have not explicitly compared the role of cholinergic and adrenergic modulation in long-term memory for socially relevant odor vs. incidental odor stimuli. In this work, we studied the function of muscarinic and beta-adrenergic receptors during acquisition and/or consolidation of a novel odor and during the retrieval of a familiar odor. The effects of systemic injections of scopolamine and propranolol, before and after presentation of estrous urine odor or mint odor, were evaluated by a long-term odor habituation task. The results demonstrated that scopolamine disrupts memory acquisition and/or consolidation of mint odor, and did not have any effect during retrieval of mint odor memory. Conversely, scopolamine disrupts memory consolidation and retrieval of estrous odor, depending on the dose applied. Propranolol injections have no effect on acquisition or consolidation for mint or estrous odor, but disrupt memory retrieval of familiar odor regarding their social/sexual or neutral content. These results demonstrate that muscarinic receptors are required differentially during long-term odor memory formation and for familiar odor recognition depending on the socially relevant content of the stimulus. Furthermore, the beta-adrenergic system could play an important role in memory recognition for familiar odors, regardless of the sexual/social or neutral content of the stimuli.

  9. Functional interactions in smooth muscle: kinetic characterization of the relaxation and desensitization responses to a beta adrenergic agonist in the rabbit aorta.

    PubMed

    Keitz, S A; Osman, R; Clarke, W P; Goldfarb, J; Maayani, S

    1990-11-01

    Vascular smooth muscle tone is continuously modulated in vivo by the functional interaction of a variety of vasoconstrictor and vasodilator stimuli. Endogenous substances such as epinephrine simultaneously activate alpha adrenergic receptors that elicit muscle contraction and beta adrenergic receptors that relax the muscle. This study characterizes the beta adrenergic response in the isolated rabbit aorta precontracted with 1 microM phenylephrine. The beta adrenergic agonist isoproterenol (0.03-10 microM) produces a biphasic response that is composed of a rapid relaxation followed by a slower regaining of tension, which is identified as desensitization. An exploratory kinetic model that describes both the relaxation and the desensitization as first-order processes provides a good fit to the experimental data. The parameters used to describe the isoproterenol response are: 1) the observed rate constant for relaxation and its magnitude (krel and R, respectively), 2) the observed rate constant for desensitization and its magnitude (kdes and D, respectively) and 3) the observed delay in the onset of the desensitization response (td). Both the krel and the fractional relaxation were dependent on concentration of isoproterenol in a saturable manner (EC50 = 0.017 and 0.067 microM, respectively). No concentration dependence was observed for kdes, fractional desensitization and td (the average values +/- S.E.M. of these parameters are (4.7 +/- 0.2). 10(-3) sec-1, 0.83 +/- 0.02 and 191 +/- 6 sec, respectively). This work demonstrates that a kinetic approach is necessary to characterize the desensitization response and is also very useful in characterizing the kinetic and steady-state parameters of the relaxation response.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Contractile properties of early human embryonic stem cell-derived cardiomyocytes: beta-adrenergic stimulation induces positive chronotropy and lusitropy but not inotropy.

    PubMed

    Pillekamp, Frank; Haustein, Moritz; Khalil, Markus; Emmelheinz, Markus; Nazzal, Rewa; Adelmann, Roland; Nguemo, Filomain; Rubenchyk, Olga; Pfannkuche, Kurt; Matzkies, Matthias; Reppel, Michael; Bloch, Wilhelm; Brockmeier, Konrad; Hescheler, Juergen

    2012-08-10

    Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) provide the unique opportunity to study the very early development of the human heart. The aim of this study was to investigate the effect of calcium and beta-adrenergic stimulation on the contractile properties of early hESC-CMs. Beating clusters containing hESC-CMs were co-cultured in vitro with noncontractile slices of neonatal murine ventricles. After 5-7 days, when beating clusters had integrated morphologically into the damaged tissue, isometric force measurements were performed during spontaneous beating as well as during electrical field stimulation. Spontaneous beating stopped when extracellular calcium ([Ca²⁺](ec)) was removed or after administration of the Ca²⁺ channel blocker nifedipine. During field stimulation at a constant rate, the developed force increased with incremental concentrations of [Ca²⁺](ec). During spontaneous beating, rising [Ca²⁺](ec) increased beating rate and developed force up to a [Ca²⁺](ec) of 2.5 mM. When [Ca²⁺](ec) was increased further, spontaneous beating rate decreased, whereas the developed force continued to increase. The beta-adrenergic agonist isoproterenol induced a dose-dependent increase of the frequency of spontaneous beating; however, it did not significantly change the developed force during spontaneous contractions or during electrical stimulation at a constant rate. Force developed by early hESC-CMs depends on [Ca²⁺](ec) and on the L-type Ca²⁺ channel. The lack of an inotropic reaction despite a pronounced chronotropic response after beta-adrenergic stimulation most likely indicates immaturity of the sarcoplasmic reticulum. For cell-replacement strategies, further maturation of cardiac cells has to be achieved either in vitro before or in vivo after transplantation.

  11. Effects of tobacco constituents and psychological stress on the beta-adrenergic regulation of non-small cell lung cancer and pancreatic cancer: implications for intervention.

    PubMed

    Schuller, Hildegard M

    2013-01-01

    This review summarizes current preclinical and clinical evidence in support of the hypothesis that smoking and psychological stress have significant cancer promoting effects on non small cell lung cancer and pancreatic cancer via direct and indirect effects on nicotinic receptor-regulated beta-adrenergic signaling. Evidence is provided that targeted pharmacological interference with the resulting hyperactive cAMP-dependent signaling by beta-blockers or by γ-aminobutyric acid as well as positive psychological influences may be highly effective in preventing and improving clinical outcomes of these cancers, provided that appropriate diagnostic protocols are followed to monitor systemic levels of stress neurotransmitters and cAMP.

  12. Beta-adrenergic receptors link NO/sGC/PKG signaling to BDNF expression during the consolidation of object recognition long-term memory.

    PubMed

    Furini, Cristiane R; Rossato, Janine I; Bitencourt, Lucas L; Medina, Jorge H; Izquierdo, Iván; Cammarota, Martín

    2010-05-01

    The nitric oxide (NO)/soluble guanylyl cyclase (sGC)/protein kinase G (PKG) pathway is important for memory processing, but the identity of its downstream effectors as well as its actual participation in the consolidation of nonaversive declarative long-term memory (LTM) remain unknown. Here, we show that training rats in an object recognition (OR) learning task rapidly increased nitrites/nitrates (NOx) content in the CA1 region of the dorsal hippocampus while posttraining intra-CA1 microinfusion of the neuronal NO synthase (nNOS) inhibitor L-NN hindered OR LTM retention without affecting memory retrieval or other behavioral variables. The amnesic effect of L-NN was not state dependent, was mimicked by the sGC inhibitor LY83583 and the PKG inhibitor KT-5823, and reversed by coinfusion of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and the PKG activator 8-bromoguanosine 3',5'-cyclic monophosphate (8Br-cGMP). SNAP did not affect the amnesic effect of LY83583 and KT-5823. Conversely, 8Br-cGMP overturned the amnesia induced by LY83583 but not that caused by KT-5823. Intra-CA1 infusion of the beta-adrenergic receptor blocker timolol right after training hindered OR LTM and, although coadministration of noradrenaline reversed the amnesia caused by L-NN, LY83583, and KT5823, the amnesic effect of timolol was unaffected by coinfusion of 8Br-cGMP or SNAP, indicating that hippocampal beta-adrenergic receptors act downstream NO/sGC/PKG signaling. We also found that posttraining intra-CA1 infusion of function-blocking anti-brain-derived neurotrophic factor (BDNF) antibodies hampered OR LTM retention, whereas OR training increased CA1 BDNF levels in a nNOS- and beta-adrenergic receptor-dependent manner. Taken together, our results demonstrate that NO/sGC/PKG signaling in the hippocampus is essential for OR memory consolidation and suggest that beta-adrenergic receptors link the activation of this pathway to BDNF expression during the consolidation of declarative

  13. Beta-Adrenergic Receptor Population is Up-Regulated in Chicken Skeletal Muscle Cells Treated with Forskolin

    NASA Technical Reports Server (NTRS)

    Bridge, K. Y.; Young, R. B.; Vaughn, J. R.

    1998-01-01

    Skeletal muscle hypertrophy is promoted by in vivo administration of beta-adrenergic receptor (betaAR) agonists. These compounds presumably exert their physiological action through the betaAR, and alterations in the population of betaAR could potentially change the ability of the cell to respond to the betaAR agonists. Since the intracellular chemical signal generated by the betaAR is cyclic AMP (cAMP), experiments were initiated in primary chicken muscle cell cultures to determine if artificial elevation of intracellular cAMP by treatment with forskolin would alter the population of functional betaAR expressed on the surface of muscle cells. Chicken skeletal muscle cells after 7 days in culture were employed for the experiments because muscle cells have attained a steady state with respect to muscle protein metabolism at this stage. Cells were treated with 0-10 microM forskolin for a total of three days. At the end of the 1, 2, and 3 day treatment intervals, the concentration of cAMP and the betaAR population were measured. Receptor population was measured in intact muscle cell cultures as the difference between total binding of [H-3]CGP-12177 and non-specific binding of [H-3]CGP-12177 in the presence of 1 microM propranolol. Intracellular cAMP concentration was measured by radioimmunoassay. The concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. Increasing concentrations of forskolin also led to an increase in betaAR population, with a maximum increase of approximately 50% at 10 microM. This increase in PAR population was apparent after only 1 day of treatment, and the pattern of increase was maintained for all 3 days of the treatment period. Thus, increasing the intracellular concentration of cAMP leads to up-regulation of betaAR population. The effect of forskolin on the quantity and apparent synthesis rate of the heavy chain of myosin (mhc) were also investigated. A maximum increase of 50% in the quantity of mhc

  14. Beta-Adrenergic Receptor Population is Up-Regulated in Chicken Skeletal Muscle Cells Treated with Forskolin

    NASA Technical Reports Server (NTRS)

    Bridge, K. Y.; Young, R. B.; Vaughn, J. R.

    1998-01-01

    Skeletal muscle hypertrophy is promoted by in vivo administration of beta-adrenergic receptor (betaAR) agonists. These compounds presumably exert their physiological action through the betaAR, and alterations in the population of betaAR could potentially change the ability of the cell to respond to the betaAR agonists. Since the intracellular chemical signal generated by the betaAR is cyclic AMP (cAMP), experiments were initiated in primary chicken muscle cell cultures to determine if artificial elevation of intracellular cAMP by treatment with forskolin would alter the population of functional betaAR expressed on the surface of muscle cells. Chicken skeletal muscle cells after 7 days in culture were employed for the experiments because muscle cells have attained a steady state with respect to muscle protein metabolism at this stage. Cells were treated with 0-10 microM forskolin for a total of three days. At the end of the 1, 2, and 3 day treatment intervals, the concentration of cAMP and the betaAR population were measured. Receptor population was measured in intact muscle cell cultures as the difference between total binding of [H-3]CGP-12177 and non-specific binding of [H-3]CGP-12177 in the presence of 1 microM propranolol. Intracellular cAMP concentration was measured by radioimmunoassay. The concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. Increasing concentrations of forskolin also led to an increase in betaAR population, with a maximum increase of approximately 50% at 10 microM. This increase in PAR population was apparent after only 1 day of treatment, and the pattern of increase was maintained for all 3 days of the treatment period. Thus, increasing the intracellular concentration of cAMP leads to up-regulation of betaAR population. The effect of forskolin on the quantity and apparent synthesis rate of the heavy chain of myosin (mhc) were also investigated. A maximum increase of 50% in the quantity of mhc

  15. Evaluation of the efficacy of Grofactor, a beta-adrenergic agonist based on zilpaterol hydrochloride, using feedlot finishing bulls.

    PubMed

    Avendaño-Reyes, L; Meraz-Murillo, F J; Pérez-Linares, C; Figueroa-Saavedra, F; Correa, A; Álvarez-Valenzuela, F D; Guerra-Liera, J E; López-Rincón, G; Macías-Cruz, U

    2016-07-01

    Beta-adrenergic agonists (β-AA) have been shown to positively impact finishing performance and some carcass traits of feedlot cattle. Our objective was to evaluate the efficacy of a β-AA on the basis of zilpaterol hydrochloride (Grofactor, Laboratorios Virbac México, Guadalajara, Mexico) on growth and DMI, carcass characteristics, and meat quality of finishing bulls. Forty-five bulls (75% 25% ) initially weighing 448.7 ± 2.58 kg were blocked by BW and randomly assigned to 1 of 3 diets, using pens of 3 animals, in a randomized complete block design: 1) daily feeding without β-AA in the basal diet (Control), 2) daily feeding with 0.15 mg/kg BW of Grofactor added to the basal diet (ZHG), or 3) daily feeding with 0.15 mg/kg BW of Zilmax (MSD Salud Animal México, Mexico City, Mexico) added to the basal diet (ZHZ). The duration of the feeding period was 30 d with a subsequent 4-d withdrawal period. Compared with Control bulls, the group fed ZHG had a 12% better ( < 0.025) G:F ratio, and their final BW ( 0.094) and ADG ( 0.084) tended to be enhanced. Feedlot performance of ZHG and ZHZ bulls was similar, although the DMI was ∼4% lower ( 0.05) in ZHG bulls vs. the ZHZ and Control groups. The HCW ( 0.001) and dressing percentage ( 0.015) were higher by 20 kg and 3%, respectively, in ZHG bulls vs. Control bulls. The KPH fat was lower ( 0.007) in bulls fed ZHG than in nonsupplemented bulls, but other carcass characteristics were not different in the ZHG and ZHZ bulls, and noncarcass components were not affected by ZHG or ZHZ supplementation. At 48 h postmortem, ZHG bulls had lower ( 0.007) water holding capacity and trended toward ( 0.06) increased chroma and reduced pH ( 0.09) compared to Control bulls. However, compared to ZHZ bulls, ZHG bulls had higher ( 0.02) chroma and a trend ( 0.08) toward increased hue angle. At 14 d postmortem, meat quality variables did not differ between the 3 groups of bulls. Supplementation of ZH Grofactor improved feedlot performance and

  16. [Determination of beta-adrenergic binding sites in the myocardium of young female chickens of various strains--a study for the clarification of frequent occurrence of sudden death and ascites in male broilers].

    PubMed

    Neubert, E; Huppke, S; Gründel, G

    1999-06-01

    The present investigations should contribute to clarify the importance of beta-adrenergic system in myocard for the triggering of sudden death syndrome and ascites in male broiler chickens. Therefore it should be verified if differences in density of beta-adrenergic receptors in myocard exist in several strains and sexes of chickens. We showed in both male and female broilers that the receptor density was significantly higher as in chickens of the laying strain. There were no significant differences in receptor density between sexes in both investigated strains as well as in KD-values between all groups. The latter finding is referred to the absence of differences in receptor affinity for 3H-dihydroalprenolol between the groups. Clarification of the question if chronic heart failure is in contrast to myocard hypertrophy accompanied with reduction of beta-adrenergic receptor density or receptor affinity in broilers too, as could be shown in other species, has to carried out in further investigations.

  17. Beta-Adrenergic Agonists

    PubMed Central

    Barisione, Giovanni; Baroffio, Michele; Crimi, Emanuele; Brusasco, Vito

    2010-01-01

    Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised. PMID:27713285

  18. Fluorescence histochemical study of the localisation and distribution of beta-adrenergic receptor sites in the spinal cord and cerebellum of the chicken.

    PubMed

    Bondok, A A; Botros, K G; el-Mohandes, E A

    1988-10-01

    The distribution of beta-adrenergic receptor sites has been studied in chicken spinal cord and cerebellum using a fluorescent analogue of propranolol, 9-amino-acridin-propranolol (9-AAP). In the cervical and lumbar regions of the spinal cord, beta-adrenoceptor sites were concentrated on cell bodies of alpha-motor neurons of the dorsolateral and ventrolateral nuclear groups of the ventral horn. In the thoracic region, they were present on cell bodies of the preganglionic sympathetic nucleus (dorsal commissural nucleus). In the dorsal horn, the receptor sites were present mainly on cell bodies of columna dorsalis magnocellularis. Sparse distribution of fluorescence was present in other regions of the gray matter. In the cerebellum, a dense distribution of beta-adrenergic receptor sites was observed on Purkinje cell bodies and their apical dendrites. Sparse distribution of receptor sites was present on fine ramifications of Purkinje cell dendrites in the molecular layer. Receptor sites were absent in the granule cell layer and the white matter. These observations indicate that alpha-motor neurons, preganglionic sympathetic neurons, neurons of columna dorsalis magnocellularis, and Purkinje cells are adrenoceptive, while granule cells are non-adrenoceptive.

  19. Fluorescence histochemical study of the localisation and distribution of beta-adrenergic receptor sites in the spinal cord and cerebellum of the chicken.

    PubMed Central

    Bondok, A A; Botros, K G; el-Mohandes, E A

    1988-01-01

    The distribution of beta-adrenergic receptor sites has been studied in chicken spinal cord and cerebellum using a fluorescent analogue of propranolol, 9-amino-acridin-propranolol (9-AAP). In the cervical and lumbar regions of the spinal cord, beta-adrenoceptor sites were concentrated on cell bodies of alpha-motor neurons of the dorsolateral and ventrolateral nuclear groups of the ventral horn. In the thoracic region, they were present on cell bodies of the preganglionic sympathetic nucleus (dorsal commissural nucleus). In the dorsal horn, the receptor sites were present mainly on cell bodies of columna dorsalis magnocellularis. Sparse distribution of fluorescence was present in other regions of the gray matter. In the cerebellum, a dense distribution of beta-adrenergic receptor sites was observed on Purkinje cell bodies and their apical dendrites. Sparse distribution of receptor sites was present on fine ramifications of Purkinje cell dendrites in the molecular layer. Receptor sites were absent in the granule cell layer and the white matter. These observations indicate that alpha-motor neurons, preganglionic sympathetic neurons, neurons of columna dorsalis magnocellularis, and Purkinje cells are adrenoceptive, while granule cells are non-adrenoceptive. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:2855328

  20. Paroxysmal beta-adrenergic receptor-mediated alterations in ventricular repolarization at rapid heart rates during inhibition of delayed rectifier currents.

    PubMed

    Overholser, Brian R; Zheng, Xiaomei; Tisdale, James E

    2009-09-01

    The contribution of the slow component of the delayed rectifier current (IKs) to ventricular repolarization is increased during rapid heart rates and prolonged repolarization. The objective was to characterize physiologically relevant paroxysmal beta-adrenergic receptor-mediated alterations on ventricular repolarization under these conditions. Paced guinea pig hearts were perfused with (1) control, (2) sparfloxacin (IKr inhibitor), or (3) sparfloxacin and HMR 1556 (IKs inhibitor). The mean +/- standard error of the mean epicardial action potential duration at 90% repolarization (APD90) increased from baseline with IKr inhibition (12.9% +/- 4.7%) and dual IKr/IKs inhibition (25.1% +/- 5.3). Paroxysmal isoproterenol (0.01 and 1.0 nM) significantly decreased APD90 in the presence of IKr inhibition but was attenuated with the addition of IKs inhibition. Spontaneous episodes of polymorphic ventricular tachycardia were observed with isoproterenol during dual IKr and IKs inhibition. The endocardial expression of KCNQ1 increased greater than 2-fold after exposure to IKr and dual IKr/IKs inhibition relative to control but was not altered in epicardial tissue. The beta-adrenergic receptor-mediated decrease in APD90 during IKr inhibition is reversed in the presence of IKs inhibition at rapid heart rates. IKs may serve as an important compensatory mechanism to protect against adrenergically induced arrhythmias when the repolarization reserve is depleted.

  1. Heart as a target organ in 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity: decreased. beta. -adrenergic responsiveness and evidence of increased intracellular calcium

    SciTech Connect

    Canga, L.; Levi, R.; Rifkind, A.B.

    1988-02-01

    The heart has not been regarded as a major target organ of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity notwithstanding that lethal cardiac dysfunction can occur in the absence of histopathological changes. To assess possible TCDD cardiotoxicity, the authors studied the effect of TCDD five days after treatment on the contractility of guinea pig right ventricular papillary muscle. TCDD treatment significantly decreased ..beta..-adrenergic responsiveness. In papillary muscles from TCDD-treated guinea pigs, the positive inotropic effect on isoproterenol was decreased by a mean of 65%, and the enhancement in the velocity of relaxation was 60% less than in the controls. On the other hand, TCDD treatment did not alter the positive inotropic effect of lower concentrations of isoproterenol. After TCDD, responsiveness to low-frequency stimulation was enhanced, responsiveness to increases in extracellular Ca/sup 2 +/ concentration was attenuated, and isoproterenol-elicited aftercontractions in K/sup +/-depolarized preparations were increased in magnitude. Collectively, the latter findings suggest that in addition to decreasing ..beta..-adrenergic responsiveness, TCDD increases the intracellular Ca/sup 2 +/ concentration in papillary muscle. The findings indicate that TCDD causes a specific pattern of cardiac dysfunction in a mammalian species, selectively augmenting or decreasing different cardiac responses. The cardiac changes are consistent with reported membrane effects of TCDD; further, they suggest that the heart may be a major target organ for TCDD toxicity.

  2. Site-directed mutagenesis of human beta-adrenergic receptors: substitution of aspartic acid-130 by asparagine produces a receptor with high-affinity agonist binding that is uncoupled from adenylate cyclase.

    PubMed Central

    Fraser, C M; Chung, F Z; Wang, C D; Venter, J C

    1988-01-01

    By using oligonucleotide-directed mutagenesis, we have produced a point mutation (guanine to adenine) at nucleotide 388 of the gene for human beta-adrenergic receptor (beta AR) that results in a substitution of asparagine for the highly conserved aspartic acid at position 130 in the putative third transmembrane domain of the human beta AR ([Asn130]beta AR). We have examined the functional significance of this mutation in B-82 cells continuously expressing the mutant [Asn130]beta AR. The mutant [Asn130]beta AR displayed normal antagonist binding but unusually high-affinity agonist binding (5- to 10-fold higher than wild-type beta AR), consistent with a single class of high-affinity binding sites. The mutant beta AR displayed guanine nucleotide-sensitive changes in agonist affinity (3- to 5-fold shift) implying an interaction between the beta AR and the stimulatory guanine nucleotide-binding regulatory protein; however, the ability of guanine nucleotides to alter agonist affinity was attenuated. Addition of saturating concentrations of isoproterenol to cell cultures expressing mutant [Asn130]-beta ARs had no effect on intracellular levels of cAMP, indicating that the mutant beta AR is unable to affect stimulation of adenylate cyclase. These results indicate that substitution of the aspartic acid with asparagine at residue 130 of the human beta AR dissociates the well-characterized guanine nucleotide effects on agonist affinity from those on activation of the stimulatory guanine nucleotide-binding regulatory protein and adenylate cyclase and suggests the existence of two distinct counterions for the amine portion of catecholamines that are associated with high- and low-affinity agonist binding states of beta AR. Images PMID:2840663

  3. Modulation of beta-adrenergic responses of chloride and calcium currents by external cations in guinea-pig ventricular cells.

    PubMed Central

    Tareen, F M; Yoshida, A; Ono, K

    1992-01-01

    1. The catecholamine-induced Cl- current and the Ca2+ current were recorded in the single ventricular cells of guinea-pig hearts, using the whole-cell patch clamp technique combined with internal perfusion. Dependence of the beta-adrenergic responses on external monovalent cations was investigated. The Cl- current was recognized by measuring the reversal potential of the agonist-induced current. 2. The amplitude of the Cl- current, activated by 1 microM adrenaline or 0.01-0.1 microM isoprenaline, was decreased when the external Na+ concentration ([Na+]o) was reduced by replacement with Tris+. The conductance of the catecholamine-induced Cl- current was proportional to the logarithm of the [Na+]o over a range of 15-140 mM. When the conductance was plotted against the concentration of Tris+, a dose-dependent inhibition of the Cl- response by Tris+ was suggested with a half-maximum concentration of 95 mM. 3. The inhibitory effect of the Na+ substitute TEA+ on the Cl- current was not affected by either increasing the buffer for the internal Ca2+ (10 mM BAPTA) or for the pH (50 mM HEPES). 4. In the relationship between agonist concentration and the Cl- conductance, the half-maximum concentration (K1/2) of isoprenaline was 0.013 microM in the control Na+ solution, and was shifted to 0.07, 0.08, 0.1 and 0.3 microM in the Li+, Cs+, TEA+ and Tris+ external solutions, respectively. The maximum slope conductance was not significantly affected, except for a slight depression on the Tris+ solution. When the current was induced by adrenaline, qualitatively the same finding was obtained; K1/2 was 0.15 and 3.2 microM in the Na+ and Tris+ solutions, respectively. 5. As a substitute for the external Na+, sucrose seemed to be inert. The activation of the inward Cl- current was conserved in the 300 mM sucrose solution ([Cl-]o = 8 mM) with a K1/2 value of 0.015 microM isoprenaline. 6. The Cl- current, when activated by either an external application of forskolin (0.2-10 microM) or an

  4. beta-adrenergic and cholinergic modulation of the inwardly rectifying K+ current in guinea-pig ventricular myocytes.

    PubMed Central

    Koumi, S; Wasserstrom, J A; Ten Eick, R E

    1995-01-01

    1. Whole-cell patch-clamp technique was used to study the beta-adrenergic and cholinergic regulation of the inwardly rectifying K+ conductance (gK1) in isolated guinea-pig ventricular myocytes. 2. In Cl(-)-free solutions or in the presence of 9-anthracenecarboxylic acid or Co2+, bath-applied isoprenaline (Iso) partially inhibited the steady-state whole-cell conductance (gss) calculated from the steady-state current (Iss)-voltage (Iss-V) curve at membrane voltages (Vm) negative to the equilibrium potential for potassium (EK). Iss was also inhibited at Vm positive to EK when the extracellular [K+] was 20 mM. The Iso-sensitive component of gss exhibited the characteristics of the inwardly rectifying K+ conductance (gK1). 3. The Iso-induced inhibition of gK1 was reversible, concentration dependent, blocked by propranolol, mimicked by both forskolin and dibutyryl cAMP, and prevented by including a cAMP-dependent protein kinase (PKA) inhibitor in the pipette solution. These findings suggest that PKA mediates the Iso-induced inhibition of gK1. 4. The apparent dissociation constant (KD) for the concentration dependence of Iso-induced inhibition was 0.035 microM and the Hill coefficient was approximately 1.0. A maximal Iso concentration (1 microM) inhibited gK1 by 40 +/- 4.1% (mean +/- S.E.M.; n = 13). 5. Bath application of acetylcholine (ACh, 0.1 microM or more) antagonized the Iso-induced (1 microM) inhibition of gK1; [ACh] > 1.0 microM antagonized 88 +/- 2.1% (n = 10) of the inhibition. ACh increased the KD for Iso to inhibit Iso-sensitive gK1 and also reduced the maximal Iso-induced inhibition. 6. ACh-induced antagonism could be abolished by pre-incubating myocytes with pertussis toxin (PTX), suggesting that a muscarinic receptor-coupled, PTX-sensitive G protein, Gi, is involved. 7. ACh (10 microM) also antagonized approximately 70% of the dibutyryl cyclic AMP (1 mM)-induced inhibition of gK1 (n = 3), suggesting that the ACh-induced antagonism involves more than simply

  5. Phospholemman-mediated activation of Na/K-ATPase limits [Na]i and inotropic state during beta-adrenergic stimulation in mouse ventricular myocytes.

    PubMed

    Despa, Sanda; Tucker, Amy L; Bers, Donald M

    2008-04-08

    Cardiac Na/K-ATPase (NKA) regulates intracellular Na ([Na](i)), which in turn affects intracellular Ca and thus contractility via Na/Ca exchange. Recent evidence shows that phosphorylation of the NKA-associated small transmembrane protein phospholemman (PLM) mediates beta-adrenergic-induced NKA stimulation. Here, we tested whether PLM phosphorylation during beta-adrenergic activation limits the rise in [Na](i), Ca transient amplitude, and triggered arrhythmias in mouse ventricular myocytes. In myocytes from wild-type (WT) mice, [Na](i) increased on field stimulation at 2 Hz from 11.1+/-1.8 mmol/L to a plateau of 15.2+/-1.5 mmol/L. Isoproterenol induced a decrease in [Na](i) to 12.0+/-1.2 mmol/L. In PLM knockout (PLM-KO) mice in which beta-adrenergic stimulation does not activate NKA, [Na](i) also increased at 2 Hz (from 10.4+/-1.2 to 17.0+/-1.5 mmol/L) but was unaltered by isoproterenol. The PLM-mediated decrease in [Na](i) in WT mice could limit the isoproterenol-induced inotropic state. Indeed, the isoproterenol-induced increase in the amplitude of Ca transients was significantly smaller in the WT mice (5.2+/-0.4- versus 7.1+/-0.5-fold in PLM-KO mice). This also was the case for the sarcoplasmic reticulum Ca content, which increased by 1.27+/-0.09-fold in WT mice versus 1.53+/-0.09-fold in PLM-KO mice. The higher sarcoplasmic reticulum Ca content in PLM-KO versus WT mice was associated with an increased propensity for spontaneous Ca transients and contractions in PLM-KO mice. These data suggest that PLM phosphorylation and NKA stimulation are an integral part of the sympathetic fight-or-flight response, tempering the rise in [Na](i) and cellular Ca loading and perhaps limiting Ca overload-induced arrhythmias.

  6. cAMP-mediated beta-adrenergic signaling negatively regulates Gq-coupled receptor-mediated fetal gene response in cardiomyocytes.

    PubMed

    Patrizio, Mario; Vago, Valerio; Musumeci, Marco; Fecchi, Katia; Sposi, Nadia Maria; Mattei, Elisabetta; Catalano, Liviana; Stati, Tonino; Marano, Giuseppe

    2008-12-01

    The treatment with beta-blockers causes an enhancement of the norepinephrine-induced fetal gene response in cultured cardiomyocytes. Here, we tested whether the activation of cAMP-mediated beta-adrenergic signaling antagonizes alpha(1)-adrenergic receptor (AR)-mediated fetal gene response. To address this question, the fetal gene program, of which atrial natriuretic peptide (ANP) and the beta-isoform of myosin heavy chain are classical members, was induced by phenylephrine (PE), an alpha(1)-AR agonist. In cultured neonatal rat cardiomyocytes, we found that stimulation of beta-ARs with isoproterenol, a beta-AR agonist, inhibited the fetal gene expression induced by PE. Similar results were also observed when cardiomyocytes were treated with forskolin (FSK), a direct activator of adenylyl cyclase, or 8-CPT-6-Phe-cAMP, a selective activator of protein kinase A (PKA). Conversely, the PE-induced fetal gene expression was further upregulated by H89, a selective PKA inhibitor. To evaluate whether these results could be generalized to Gq-mediated signaling and not specifically to alpha(1)-ARs, cardiomyocytes were treated with prostaglandin F(2)alpha, another Gq-coupled receptor agonist, which is able to promote fetal gene expression. This treatment caused an increase of both ANP mRNA and protein levels, which was almost completely abolished by FSK treatment. The capability of beta-adrenergic signaling to regulate the fetal gene expression was also evaluated in vivo conditions by using beta1- and beta2-AR double knockout mice, in which the predominant cardiac beta-AR subtypes are lacking, or by administering isoproterenol (ISO), a beta-AR agonist, at a subpressor dose. A significant increase of the fetal gene expression was found in beta(1)- and beta(2)-AR gene deficient mice. Conversely, we found that ANP, beta-MHC and skACT mRNA levels were significantly decreased in ISO-treated hearts. Collectively, these data indicate that cAMP-mediated beta-adrenergic signaling

  7. Memory Enhancement Induced by Post-Training Intrabasolateral Amygdala Infusions of [beta]-Adrenergic or Muscarinic Agonists Requires Activation of Dopamine Receptors: Involvement of Right, but Not Left, Basolateral Amygdala

    ERIC Educational Resources Information Center

    LaLumiere, Ryan T.; McGaugh, James L.

    2005-01-01

    Previous findings indicate that the noradrenergic, dopaminergic, and cholinergic innervations of the basolateral amygdala (BLA) modulate memory consolidation. The current study investigated whether memory enhancement induced by post-training intra-BLA infusions of a [beta]-adrenergic or muscarinic cholinergic agonist requires concurrent activation…

  8. Memory Enhancement Induced by Post-Training Intrabasolateral Amygdala Infusions of [beta]-Adrenergic or Muscarinic Agonists Requires Activation of Dopamine Receptors: Involvement of Right, but Not Left, Basolateral Amygdala

    ERIC Educational Resources Information Center

    LaLumiere, Ryan T.; McGaugh, James L.

    2005-01-01

    Previous findings indicate that the noradrenergic, dopaminergic, and cholinergic innervations of the basolateral amygdala (BLA) modulate memory consolidation. The current study investigated whether memory enhancement induced by post-training intra-BLA infusions of a [beta]-adrenergic or muscarinic cholinergic agonist requires concurrent activation…

  9. Cardiovascular considerations in using topical, oral, and intravenous drugs for the treatment of glaucoma and ocular hypertension: focus on beta-adrenergic blockade.

    PubMed

    Frishman, W H; Kowalski, M; Nagnur, S; Warshafsky, S; Sica, D

    2001-01-01

    Glaucoma and ocular hypertension are highly prevalent conditions in individuals over the age of 40 and are commonly seen together in patients with cardiovascular disease. Many of the antiglaucoma medications, when systemically absorbed, affect the sympathetic and parasympathetic nervous systems of patients and can cause cardiovascular toxicity. Such adverse effects are frequently associated with the long-term use of potentially toxic agents in elderly people, who are most prone to chronic eye disease. Moreover, patients may not associate their symptoms with the topical eye medications, and consequently may not report adverse drug effects. Drug-drug interactions can also occur when patients are taking medications for both cardiovascular disease and glaucoma. This review focuses on beta-adrenergic blockers as topical antiglaucoma medications and other topical antiglaucoma drugs. The systemic toxicity of these agents is reviewed, along with the possible drug interactions. Brief mention is also made of other antiglaucoma medications used alone and in combination with topical beta-blockers.

  10. Activation of a GTP-binding protein and a GTP-binding-protein-coupled receptor kinase (beta-adrenergic-receptor kinase-1) by a muscarinic receptor m2 mutant lacking phosphorylation sites.

    PubMed

    Kameyama, K; Haga, K; Haga, T; Moro, O; Sadée, W

    1994-12-01

    A mutant of the human muscarinic acetylcholine receptor m2 subtype (m2 receptor), lacking a large part of the third intracellular loop, was expressed and purified using the baculovirus/insect cell culture system. The mutant was not phosphorylated by beta-adrenergic-receptor kinase, as expected from the previous assignment of phosphorylation sites to the central part of the third intracellular loop. However, the m2 receptor mutant was capable of stimulating beta-adrenergic-receptor-kinase-1-mediated phosphorylation of a glutathione S-transferase fusion protein containing the m2 phosphorylation sites in an agonist-dependent manner. Both mutant and wild-type m2 receptors reconstituted with the guanine-nucleotide-binding regulatory proteins (G protein), G(o) and G(i)2, displayed guanine-nucleotide-sensitive high-affinity agonist binding, as assessed by displacement of [3H]quinuclidinyl-benzilate binding with carbamoylcholine, and both stimulated guanosine 5'-3-O-[35S]thiotriphosphate ([35S]GTP[S]) binding in the presence of carbamoylcholine and GDP. The Ki values of carbamoylcholine effects on [3H]quinuclidinyl-benzilate binding were indistinguishable for the mutant and wild-type m2 receptors. Moreover, the phosphorylation of the wild-type m2 receptor by beta-adrenergic-receptor kinase-1 did not affect m2 interaction with G proteins as assessed by the binding of [3H]quinuclidinyl benzilate or [35S]GTP[S]. These results indicate that (a) the m2 receptor serves both as an activator and as a substrate of beta-adrenergic-receptor kinase, and (b) a large part of the third intracellular loop of the m2 receptor does not contribute to interaction with G proteins and its phosphorylation by beta-adrenergic-receptor kinase does not uncouple the receptor and G proteins in reconstituted lipid vesicles.

  11. Sympathetic nerve activity in normal and cystic follicles from isolated bovine ovary: local effect of beta-adrenergic stimulation on steroid secretion.

    PubMed

    Paredes, Alfonso H; Salvetti, Natalia R; Diaz, Ariel E; Dallard, Bibiana E; Ortega, Hugo H; Lara, Hernan E

    2011-05-16

    Cystic ovarian disease (COD) is an important cause of abnormal estrous behavior and infertility in dairy cows. COD is mainly observed in high-yielding dairy cows during the first months post-partum, a period of high stress. We have previously reported that, in lower mammals, stress induces a cystic condition similar to the polycystic ovary syndrome in humans and that stress is a definitive component in the human pathology. To know if COD in cows is also associated with high sympathetic activity, we studied isolated small antral (5 mm), preovulatory (10 mm) and cystic follicles (25 mm). Cystic follicles which present an area 600 fold greater compared with preovulatory follicles has only 10 times less concentration of NE as compared with small antral and preovulatory follicles but they had 10 times more NE in follicular fluid, suggesting a high efflux of neurotransmitter from the cyst wall. This suggestion was reinforced by the high basal release of recently taken-up 3H-NE found in cystic follicles. While lower levels of beta-adrenergic receptor were found in cystic follicles, there was a heightened response to the beta-adrenergic agonist isoproterenol and to hCG, as measured by testosterone secretion. There was however an unexpected capacity of the ovary in vitro to produce cortisol and to secrete it in response to hCG but not to isoproterenol. These data suggest that, during COD, the bovine ovary is under high sympathetic nerve activity that in addition to an increased response to hCG in cortisol secretion could participate in COD development.

  12. Beta-Adrenergic Blockade Therapy for Autonomic Dysfunction is Less Effective for Elderly Patients with Heart Failure and Reduced Left Ventricular Ejection Fraction

    PubMed Central

    Shimamoto, Ken; Kawana, Masatoshi

    2015-01-01

    OBJECTIVE Heart rate variability (HRV) has been reported to be an independent predictor of all-cause and sudden cardiac death in patients with heart failure. In the aging heart, however, both autonomic and cardiac functions appear to be altered. We assessed the relationship between aging and responsiveness of HRV and ventricular remodeling to beta-adrenergic blockade therapy in patients with heart failure and reduced ejection fraction (HFREF). METHODS Twenty-eight clinically stable patients with chronic heart failure, sinus rhythm, and left ventricular ejection fraction <50% as confirmed by echocardiography were included. At baseline and after carvedilol treatment, 24-hour ambulatory Holter monitor recording was used to analyze HRV indices by the maximum entropy method. Changes in these parameters were compared among three age groups. RESULTS HR decreased in all groups after carvedilol treatment, but was still highest in the youngest group despite the same treatment doses. Time and frequency domain variables improved. The response of time domain variables (the standard deviation of all normal sinus to normal sinus [NN] intervals and the standard deviation of the averages of NN intervals in all 5-minute or 30-minute segments) to carvedilol therapy significantly decreased with increasing age. Ventricular reverse remodeling induced by carvedilol therapy significantly decreased with increasing age. Increases in time domain variables and a low-frequency domain moderately correlated with left ventricular reverse remodeling. CONCLUSION Beta-adrenergic blockade therapy improved HRV variables and ventricular remodeling in HFREF patients; however, the response tended to be milder in the elderly. HRV improvement was associated with ventricular reverse remodeling. PMID:26483614

  13. Role of myocardial neuronal nitric oxide synthase-derived nitric oxide in beta-adrenergic hyporesponsiveness after myocardial infarction-induced heart failure in rat.

    PubMed

    Bendall, Jennifer K; Damy, Thibaud; Ratajczak, Philippe; Loyer, Xavier; Monceau, Virginie; Marty, Isabelle; Milliez, Paul; Robidel, Estelle; Marotte, Françoise; Samuel, Jane-Lise; Heymes, Christophe

    2004-10-19

    An emerging concept is that a neuronal isoform of nitric oxide synthase (NOS1) may regulate myocardial contractility. However, a role for NOS1-derived nitric oxide (NO) in heart failure (HF) has not been defined. Using a model of myocardial infarction-induced HF, we demonstrated that cardiac NOS1 expression and activity increased in HF rats (P<0.05 and P<0.001 versus shams, respectively). This was associated with translocation of NOS1 from the ryanodine receptor to the sarcolemma through interactions with caveolin-3 in HF hearts. With ex vivo and in vivo pressure-volume analysis, cardiac NOS1-derived NO was found to be negatively inotropic in shams but not HF hearts. Ventricular elastance (E(es)) was significantly reduced in HF rats (P<0.05), and tau, the time constant of left ventricular relaxation, was prolonged (both P<0.05). Acute NOS1 inhibition significantly increased E(es) by 33+/-3% and tau by 17+/-2% (P<0.05) in shams, although these effects were significantly attenuated in HF hearts. beta-Adrenergic stimulation induced a marked increase in systolic performance in sham hearts, with the responses being significantly blunted in HF hearts. E(es) increased by 163+/-42% (P<0.01) in sham hearts and 56+/-9% in HF hearts, and LV +dP/dt increased by 97+/-9% (P<0.01) in shams and 37+/-7% (P<0.05) in the HF group. Interestingly, preferential NOS1 inhibition enhanced the blunted responses of LV +dP/dt and E(es) to beta-adrenergic stimulation in HF rats but had no effect in shams. These results provide the first evidence that increased NOS1-derived NO production may play a role in the autocrine regulation of myocardial contractility in HF.

  14. The impact of beta-adrenergic blockade on daily rhythms of melatonin and body temperature of golden spiny mice Acomys russatus.

    PubMed

    Haim, A; Zisapel, N

    1997-01-01

    Beta-adrenergic stimulation induces melatonin synthesis and non-shivering thermogenesis (NST) in rodents. The golden spiny mouse, Acomys russatus is a nocturnal species capable of diurnal activity when coexisting with its congenitor the common spiny mouse A. cahirinus. We have investigated the impact of beta-adrenergic blockade on 6-sulphatoxymelatonin (6-SMT--a metabolite and index of melatonin production) and body temperature (Tb) daily rhythms in male A. russatus. Mice were acclimated to an ambient temperature (Ta) of 28 degrees C, under two photoperiod regimes (16L:8D; 8L:16D). The daily rhythms of Tb and urinary 6-SMT were measured for a period of 30 h at intervals of 4 h. Propranolol (4.5 mg/kg, i.p.) was administered one hour before lights went off (i.e. when beta blockade does not affect NST in this species) and both variables were measured for another 30 h. The beta blocker markedly augmented melatonin output of A. russatus under both photoperiod regimes. The elevation in melatonin secretion was accompanied with an increase in Tb of only 16L:8D-acclimated mice (i.e. shorten duration of melatonin peak). However, in 8L:16D-acclimated mice, a phase advance of about 4 h was noted in 6-SMT daily rhythm. These results indicate that the role of sympathetic innervation in regulation of melatonin synthesis in A. russatus differs from that in the rat. In addition, these data are compatible with the hyperthermic action of melatonin in this species. Therefore, it is suggested that in A. russatus, other neural pathways are involved in its pineal regulation.

  15. Adenylyl cyclase type 6 overexpression selectively enhances beta-adrenergic and prostacyclin receptor-mediated inhibition of cardiac fibroblast function because of colocalization in lipid rafts.

    PubMed

    Liu, Xiaoqiu; Thangavel, Muthusamy; Sun, Shu Qiang; Kaminsky, Joseph; Mahautmr, Penden; Stitham, Jeremiah; Hwa, John; Ostrom, Rennolds S

    2008-06-01

    Cardiac fibroblasts produce and degrade extracellular matrix and are critical in regulating cardiac remodeling and hypertrophy. Fibroblasts are activated by factors such as transforming growth factor beta and inhibited by agents that elevate 3',5'-cyclic adenosine monophosphate (cAMP) levels. cAMP signal generation and response is known to be compartmentalized in many cell types in part through the colocalization of receptors and specific adenylyl cyclase isoforms in lipid rafts and caveolae. The present study sought to define the localization of key G protein-coupled receptors with adenylyl cyclase type 6 (AC6) in lipid rafts of rat cardiac fibroblasts and to determine if this colocalization was functionally relevant. We found that cardiac fibroblasts produce cAMP in response to agonists for beta-adrenergic (isoproterenol), prostaglandin EP2 (butaprost), adenosine (adenosine-5'-N-ethylcarboxamide, NECA), and prostacyclin (beraprost) receptors. Overexpression of AC6 increased cAMP production stimulated by isoproterenol and beraprost but not by butaprost or NECA. A key function of fibroblasts is the production of collagen. Isoproterenol- and beraprostmediated inhibition of collagen synthesis was also enhanced by AC6 overexpression, while inhibition by butaprost and NECA were unaltered. Lipid raft fractions from cardiac fibroblasts contain the preponderance of beta-adrenergic receptors and AC6 but exclude EP2 receptors. While we could not determine the localization of native prostacyclin receptors, we were able to determine that epitope-tagged prostanoid IP receptors (IPR) expressed in COS7 cells did localize, in part, in lipid raft fractions. These findings indicate that IP receptors are expressed in lipid rafts and can activate raft-localized AC isoforms. AC6 is completely compartmentized in lipid raft domains where it is activated solely by coresident G protein-coupled receptors to regulate cardiac fibroblast function.

  16. Modulation of Photofrin II accumulation in C6 glioma cells by stimulation of beta-adrenergic receptors

    NASA Astrophysics Data System (ADS)

    Croce, Anna C.; Mares, V.; Lisa, V.; Krajci, D.; Bottiroli, Giovanni F.

    1997-12-01

    The influence of drugs acting as (beta) -receptors agonists or antagonists on the uptake of Photofrin II in C6 glioma cultured cells was studied by microspectrofluorometric analysis. The pharmacological effect was evaluated on the semiconfluently grown cells, characterized by a long lasting uptake process and higher values of fluorescence intensity with respect to the solitary ones. Isoproterenol treatments resulted in a significant enhancement (by 50%) of the intracellular fluorescence signal of Photofrin II. This effect was hindered by contemporary treatments with equimolar alprenolol or propranolol, two (beta) -receptor antagonists, indicating a specific effect of isoproterenol. Both pharmacological activation of vesicular transport and changes in the membrane physical-chemico properties can explain the effects induced by drugs interacting with (beta) -receptor.

  17. Beta-adrenergic receptors couple to CFTR chloride channels of intercalated mitochondria-rich cells in the heterocellular toad skin epithelium.

    PubMed

    Larsen, Erik Hviid; Amstrup, Jan; Willumsen, Niels J

    2003-12-30

    In the heterocellular toad skin epithelium the beta-adrenergic receptor agonist isoproterenol activates cyclic AMP-dependent Cl(-) channels that are not located in the principal cells. With four experimental approaches, in the present study, we tested the hypothesis that the signalling pathway targets cystic fibrosis transmembrane conductance regulator (CFTR)-chloride channels of mitochondria-rich cells. (i) Serosal application of isoproterenol (log(10)EC(50)=-7.1+/-0.2; Hill coefficient=1.1+/-0.2), as well as noradrenaline, activated an anion pathway with an apical selectivity sequence, G(Cl)>G(Br)> or =G(NO(3))>G(I), comparable to the published selectivity sequence of cloned human CFTR expressed in Xenopus oocytes. (ii) Known modulators of human CFTR, glibenclamide (200 micromol/l) and genistein (50 micromol/l), depressed and activated, respectively, the receptor-stimulated G(Cl). Genistein did not modify the anion selectivity. (iii) Transcellular voltage clamp studies of single isolated mitochondria-rich cells revealed functional beta-adrenergic receptors on the basolateral membrane. With approximately 60,000 mitochondria-rich cells per cm(2), the saturating activation of 11.9+/-1.6 nS/cell accounted for the measured isoproterenol-activated transepithelial conductance of 600-900 microS/cm(2). In forskolin-stimulated cells, glibenclamide (200 micromol/l) reversibly inhibited the transcellular conductance by 9.6+/-1.6 nS/cell. (iv) With primers constructed from cloned Xenopus CFTR and PCR amplification of reverse-transcribed mRNA from toad skin, full-length Bufo CFTR cDNA was generated. The derived protein of 1466 residues shows 86% homology with xCFTR and 89% homology with hCFTR. All major functional sequences, that is, the R- and the NBF1- and NBF2-domains are well-conserved as are the predicted transmembrane segments proposed to form the pore of the channel protein. These new results taken together with our previously identified small-conductance CFTR-like Cl

  18. Influence of androgenic status on the alpha 2/beta-adrenergic control of lipolysis in white fat cells: predominant alpha 2-antilipolytic response in testosterone-treated-castrated hamsters.

    PubMed

    Pecquery, R; Leneveu, M C; Giudicelli, Y

    1988-06-01

    The aim of this study was to evaluate the influence of castration with or without testosterone propionate (TP) administration (one daily injection of 1 mg for 10 days) on the fat cell lipolytic activity in male hamsters. Basal and maximal lipolytic responses to the pure beta-adrenergic agonist isoproterenol, the mixed alpha 2-and beta-adrenergic agonist epinephrine, and the nonadrenergic compounds ACTH and 3-isobutyl-1-methylxanthine were all reduced by half in castrated animals. TP treatment restored these defective responses to control values, except the response to epinephrine which remained paradoxically unchanged. Sensitivity of lipolysis to epinephrine was unimpaired by castration but markedly reduced (10-fold) in TP-treated castrated hamsters. The antilipolytic potencies of the alpha 2-component of epinephrine and of the two alpha 2-agonists, UK 14304 and clonidine, were reduced by half in castrated animals, and returned to a value slightly higher than control after TP treatment. These changes in lipolysis were accompanied by parallel alterations in the stimulated cAMP responses to isoproterenol and forskolin but not to epinephrine. The latter was either unimpaired by castration or was clearly inhibited after TP treatment. Castration also induced a 2-fold decrease in the inhibitory potency of clonidine toward forskolin-stimulated cAMP production. Finally, these changes in the potency of clonidine were accompanied by parallel variations of the number of fat cell alpha 2-adrenoreceptors. These results indicate that testosterone in vivo, while increasing the beta-adrenergic lipolytic action of catecholamines (possibly through enhancement of the adenylate cyclase activity), promotes, to a greater extent, their alpha 2-adrenoreceptor-mediated antilipolytic potency. By providing the first demonstration that the androgenic status controls the functional alpha 2/beta-adrenergic balance in fat cells, this study also emphasizes the potential importance of such a

  19. Alpha- and beta-adrenergic mediation of changes in metabolism and Na/K exchange in rat brown fat

    PubMed Central

    1985-01-01

    Double- and triple-barreled ion-sensitive microelectrodes were used to measure changes in extracellular K+ and Na+ concentrations ([K+]o, [Na+]o) in brown fat. Redox states of different respiratory enzymes were measured simultaneously in order to correlate ion movements with metabolic activity. Trains of stimuli applied to the efferent nerves evoked two distinct increases in [K+]o. A first, small, rapid increase occurred within 10 s and accompanied a first, rapid membrane depolarization. A second, slow increase of [K+]o occurred several minutes after stimulation and accompanied a second, slow depolarization. A few seconds after stimulation onset, while the membrane was repolarizing and shifts in redox states indicated increases in lipolysis and respiration, [K+]o decreased. The [K+]o decrease was accompanied by an increase in [Na+]o, and could be partly blocked by ouabain. Phentolamine, an alpha-antagonist that blocks the first depolarization, also blocked the first, rapid [K+]o increase and part of the subsequent decrease. Propranolol, a beta-antagonist, had little effect on the first depolarization and the first increase in [K+]o, but blocked part of the subsequent [K+]o decrease and the second, slow [K+]o increase. The changes in [K+]o were almost completely abolished in the presence of both antagonists. It is concluded that brown adipocytes take up K+ and simultaneously lose Na+ in response to the interaction of noradrenaline with alpha- and beta- receptors, and this indicates a very early stimulation of the Na+ pump. PMID:2864385

  20. In vitro histamine H/sub 2/-antagonist activity of the novel compound HUK 978

    SciTech Connect

    Coombes, J.D.; Norris, D.B.; Rising, T.J.; Ross, B.C.; Steward, A.

    1985-11-04

    Histamine stimulated adenylate cyclase from guinea-pig fundic mucosa and /sup 3/H-tiotidine binding in guinea-pig cerebral cortex were used to assess the in-vitro histamine H/sub 2/-activity of the novel H/sub 2/-antagonist HUK 978. The results showed that HUK 978 was a more potent H/sub 2/-antagonist than either cimetidine or ranitidine. HUK 978 was also shown to be devoid of activity at the histamine H-/sub 1/-receptor, the muscarinic receptor and the ..cap alpha.. and ..beta..-adrenergic receptors.

  1. Effect of Electrical Stimulation on Beta-Adrenergic Receptor Population and Cyclic AMP Production in Chicken and Rat Skeletal Muscle Cell Cultures

    NASA Technical Reports Server (NTRS)

    Young, Ronald B.; Bridge, Kristin Y.; Strietzel, Catherine J.

    2000-01-01

    Expression of the beta-adrenergic receptor (PAR) and its coupling to Adenosine 3'5' Cyclic Monophosphate (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the PAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for 7 d in culture, were subjected to electrical stimulation for an additional 2 d at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the PAR population was not significantly affected by electrical stimulation; however, the ability, of these cells to synthesize cyclic AMP was reduced by approximately one-half. In contrast, the PAR population in rat muscle cells was increased slightly but not significantly by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was increased by almost twofold. The basal levels of intracellular cyclic AMP in neither rat muscle cells nor chicken muscle cells were affected by electrical stimulation.

  2. Effect of electrical stimulation on beta-adrenergic receptor population and cyclic amp production in chicken and rat skeletal muscle cell cultures

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.; Strietzel, C. J.

    2000-01-01

    Expression of the beta-adrenergic receptor (betaAR) and its coupling to cyclic AMP (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the betaAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for 7 d in culture were subjected to electrical stimulation for an additional 2 d at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the betaAR population was not significantly affected by electrical stimulation; however, the ability of these cells to synthesize cyclic AMP was reduced by approximately one-half. In contrast, the betaAR population in rat muscle cells was increased slightly but not significantly by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was increased by almost twofold. The basal levels of intracellular cyclic AMP in neither rat muscle cells nor chicken muscle cells were affected by electrical stimulation.

  3. Exercise induced changes in lymphocyte beta adrenergic receptors correlate with peak exercise heart rates in healthy trained and sedentary human subjects

    SciTech Connect

    Eisinger, M.; Engelmeier, R.; Glisson, S.; Scanlon, P.

    1986-03-05

    Lymphocyte beta adrenergic receptors (lymph BAR) increase after maximal multistage treadmill exercise (TME) presumably by externalization from intracellular vesicles. Nine healthy subjects underwent symptom limited TME by the Bruce protocol. Heart rate was measured at the end of each 3 minute stage. Plasma norepinephrine (NE), plasma epinephrine (EPI) and lymph BAR were measured at rest and at peak exercise. Catecholamines were determined by high performance liquid chromatography. Lymph BAR were measured by separating cells from 25cc of whole blood across a Ficoll-Hypaque density gradient and incubating membrane preparations with 7 dilutions of I/sup 125/ cyanopindolol in the presence or absence of 1..mu..M(-) propranolol in a total assay volume of 450 ..mu..l. BAR was standardized to Lowry-Peterson protein at rest and exercise. The relationship of maximum heart rate versus peak plasma NE, EPI and lymph BAR was analyzed by linear regression. The following conclusions were reached: (1) there is a significant correlation between exercise induced changes in lymph BAR and peak heart rate; (2) this relationship does not exist between peak plasma NE or EPI and peak heart rate.

  4. Screening and confirmation analysis of stimulants, narcotics and beta-adrenergic agents in human urine by hydrophilic interaction liquid chromatography coupled to mass spectrometry.

    PubMed

    Mazzarino, Monica; Fiacco, Ilaria; de la Torre, Xavier; Botrè, Francesco

    2011-11-11

    The chromatographic behaviour of 44 polar compounds (23 beta-adrenergic agents, 11 stimulants, 4 narcotics and 6 phenolalkylamines) included in the list of prohibited substances and methods of the World Anti-Doping Agency, has been investigated under hydrophilic interaction liquid chromatography conditions by application of different mobile phase compositions (percentage of the organic solvent, type and amount of mobile phase additive and ionic strength) and column temperatures. Detection of analytes was performed by a triple quadrupole mass spectrometer in positive ionization mode and selected reaction monitoring acquisition mode after liquid/liquid extraction. Data collected using as stationary phase type-B silica materials from different producers, showed that the best chromatographic conditions in terms of peak shape, selectivity and chromatographic retention were obtained using an initial percentage of acetonitrile of 90%, a column temperature of 35 °C, a mobile phase pH of 4.5 and ammonium acetate (5 mM) and acetic acid (0.1%) as mobile phase additives. The selected chromatographic conditions were used to develop screening and confirmation analytical procedures to detect polar compounds in human urine for antidoping purpose. The developed methods were validated in terms of specificity, matrix effect, linearity, precision, accuracy, sensitivity, robustness and repeatability of retention times and relative ion abundances. Such methods offer attractive alternatives and considerable advantages over traditional approaches especially for the analysis of the phenolalkylamines. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Chromosome mapping of the human arrestin (SAG), {beta}-arrestin 2 (ARRB2), and {beta}-adrenergic receptor kinase 2 (ADRBK2) genes

    SciTech Connect

    Calabrese, G.; Sallese, M.; Stornaiuolo, A.

    1994-09-01

    Two types of proteins play a major role in determining homologous desensitization of G-coupled receptors: {beta}-adrenergic receptor kinase ({beta}ARK), which phosphorylates the agonist-occupied receptor and its functional cofactor, {beta}-arrestin. Both {beta}ARK and {beta}-arrestin are members of multigene families. The family of G-protein-coupled receptor kinases includes rhodopsin kinase, {beta}ARK1, {beta}ARK2, IT11-A (GRK4), GRK5, and GRK6. The arrestin/{beta}-arrestin gene family includes arrestin (also known as S-antigen), {beta}-arrestin 1, and {beta}-arrestin 2. Here we report the chromosome mapping of the human genes for arrestin (SAG), {beta}arrestin 2 (ARRB2), and {beta}ARK2 (ADRBK2) by fluorescence in situ hybridization (FISH). FISH results confirmed the assignment of the gene coding for arrestin (SAG) to chromosome 2 and allowed us to refine its localization to band q37. The gene coding for {beta}-arrestin 2 (ARRB2) was mapped to chromosome 17p13 and that coding for {beta}ARK2 (ADRBK2) to chromosome 22q11. 17 refs., 1 fig.

  6. Neutrophil beta-adrenergic receptor responses are potentiated by acute exposure to phorbol ester without changes in receptor distribution or coupling

    SciTech Connect

    Kilfeather, S.A.; Stein, M.; O'Malley, K. )

    1991-01-01

    Exposure to the phorbol ester, phorbol 12-myristate, 13-acetate for 10 minutes enhanced cyclic AMP accumulation in human neutrophils under basal conditions and in response to the beta-adrenergic receptor agonist isoproterenol (ISO, 1{mu}M) and the adenylate cyclase activator forskolin (FSK, 10mM). Potentiation of responses to ISO by PMA was dose-dependent between 0.1 and 100nM PMA. The diacylglycerol analogue, 1-oleoyl-2-actylgylcerol (OAG) (50 {mu}M) also elevated beta-receptor responses, but 4beta-phorbol (100nM), lacking the capacity to activate PMA, was ineffective. Short-term exposure to the peptide n-formylmethionine leucyl-phenylalanine (FMLP, 1 {mu}M) also elevated neutrophil cyclic AMP accumulation. All potentiating effects of PMA on cyclic AMP production were inhibited by the protein kinase inhibitor 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine (H{sub 7}). PMA had no apparent effect on beta-receptor agonist-affinity, distribution between cell-surface and internalized compartments, or the capacity of ISO to induce beta-receptor internalization. Responses to FSK or ISO in terms of fold-stimulation of basal cyclic AMP accumulation int he presence of PMA were not elevated by PMA.

  7. Calcium-linked increase in coupled cAMP synthesis and hydrolysis is an early event in cholinergic and. beta. -adrenergic stimulation of parotid secretion

    SciTech Connect

    Deeg, M.A.; Graeff, R.M.; Walseth, T.F.; Goldberg, N.D. )

    1988-11-01

    The dynamics and compartmental characteristics of cAMP metabolism were examined by {sup 18}O labeling of cellular adenine nucleotide {alpha} phosphoryls in rat parotid gland stimulated to secrete with {beta}-adrenergic and cholinergic agents. The secretory response occurred in association with a rapidly increased rate of cAMP hydrolysis apparently coordinated with an equivalent increase in the rate of cAMP synthesis, since the cellular concentration of cAMP remained unchanged. The magnitude of this metabolic response was equivalent to the metabolism of 10-75 times the cellular content of cAMP within the first minute of stimulation. This increased metabolic rate occurred only during the early (1-3 min) period of stimulation, in what appeared to be an exclusive cellular compartment distinguished by a unique distribution of {sup 18}O among adenine nucleotide {alpha} phosphoryls. This {sup 18}O distribution contrasted with that produced by forskolin, which increased cellular cAMP concentration and elicited only a delayed response missing the early secretory component. The early acceleration of cAMP metabolism appeared linked to a stimulus-induced increase in intracellular Ca{sup 2+} concentration, since the Ca{sup 2+} ionophore ionomycin produced the same metabolic response in association with secretion. These observations suggest that cAMP metabolism is involved in stimulus-secretion coupling by a Ca{sup 2+}-linked mechanism different from that in which cAMP plays the role of a second messenger.

  8. Effect of Electrical Stimulation on Beta-Adrenergic Receptor Population and Cyclic AMP Production in Chicken and Rat Skeletal Muscle Cell Cultures

    NASA Technical Reports Server (NTRS)

    Young, Ronald B.; Bridge, Kristin Y.; Strietzel, Catherine J.

    2000-01-01

    Expression of the beta-adrenergic receptor (PAR) and its coupling to Adenosine 3'5' Cyclic Monophosphate (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the PAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for 7 d in culture, were subjected to electrical stimulation for an additional 2 d at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the PAR population was not significantly affected by electrical stimulation; however, the ability, of these cells to synthesize cyclic AMP was reduced by approximately one-half. In contrast, the PAR population in rat muscle cells was increased slightly but not significantly by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was increased by almost twofold. The basal levels of intracellular cyclic AMP in neither rat muscle cells nor chicken muscle cells were affected by electrical stimulation.

  9. Effect of electrical stimulation on beta-adrenergic receptor population and cyclic amp production in chicken and rat skeletal muscle cell cultures

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Bridge, K. Y.; Strietzel, C. J.

    2000-01-01

    Expression of the beta-adrenergic receptor (betaAR) and its coupling to cyclic AMP (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the betaAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for 7 d in culture were subjected to electrical stimulation for an additional 2 d at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the betaAR population was not significantly affected by electrical stimulation; however, the ability of these cells to synthesize cyclic AMP was reduced by approximately one-half. In contrast, the betaAR population in rat muscle cells was increased slightly but not significantly by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was increased by almost twofold. The basal levels of intracellular cyclic AMP in neither rat muscle cells nor chicken muscle cells were affected by electrical stimulation.

  10. Myofibrillar calcium sensitivity of isometric tension is increased in human dilated cardiomyopathies: role of altered beta-adrenergically mediated protein phosphorylation.

    PubMed Central

    Wolff, M R; Buck, S H; Stoker, S W; Greaser, M L; Mentzer, R M

    1996-01-01

    To examine the role of alterations in myofibrillar function in human dilated cardiomyopathies, we determined isometric tension-calcium relations in permeabilized myocytesized myofibrillar preparations (n = 16) obtained from left ventricular biopsies from nine patients with dilated cardiomyopathy (DCM) during cardiac transplantation or left ventricular assist device implantation. Similar preparations (n = 10) were obtained from six normal hearts used for cardiac transplantation. Passive and maximal Ca2+-activated tensions were similar for the two groups. However, the calcium sensitivity of isometric tension was increased in DCM compared to nonfailing preparations ([Ca2+]50=2.46+/-0.49 microM vs 3.24+/-0.51 microM, P < 0.001). In vitro treatment with the catalytic subunit of protein kinase A (PKA) decreased calcium sensitivity of tension to a greater degree in failing than in normal preparations. Further, isometric tension-calcium relations in failing and normal myofibrillar preparations were similar after PKA treatment. These findings suggest that the increased calcium sensitivity of isometric tension in DCM may be due at least in part to a reduction of the beta-adrenergically mediated (PKA-dependent) phosphorylation of myofibrillar regulatory proteins such as troponin I and/or C-protein. PMID:8690789

  11. Regional myocardial downregulation of the inhibitory guanosine triphosphate-binding protein (Gi alpha 2) and beta-adrenergic receptors in a porcine model of chronic episodic myocardial ischemia.

    PubMed Central

    Hammond, H K; Roth, D A; McKirnan, M D; Ping, P

    1993-01-01

    Regional myocardial ischemia is associated with increased levels of adenosine and norepinephrine, factors that may alter activation of the beta-adrenergic receptor (beta AR)-G protein-adenylyl cyclase pathway in the heart. We have used the ameroid constrictor model to determine whether alterations in myocardial signal transduction through the beta AR-G protein-adenylyl cyclase pathway occur in the setting of chronic episodes of reversible ischemia. Pigs were instrumented with ameroid occluders placed around the left circumflex coronary artery. 5 wk later, after ameroid closure, flow and function were normal in the ischemic bed, but flow (P = 0.001) and function (P < 0.03) were abnormal when metabolic demands were increased. The ischemic bed showed a reduction in myocardial beta AR number (P < 0.005). Despite regional downregulation of myocardial beta AR number, adenylyl cyclase activity was similar in the ischemic and control beds. Quantitative immunoblotting showed that the cardiac inhibitory GTP-binding protein, Gi alpha 2, was decreased in the ischemic bed (P = 0.02). In contrast, the cardiac stimulatory GTP-binding protein, Gs alpha, was increased in endocardial sections from the ischemic bed (P = < 0.05). Decreased Gi alpha 2 content was associated with decreased inhibition of adenylyl cyclase. Reduced Gi alpha 2 content, in conjunction with increased Gs alpha content in the endocardium, may provide a means by which adrenergic activation is maintained in the setting of chronic episodic myocardial ischemia. Images PMID:8254020

  12. Effect of Increased Cyclic AMP Concentration on Muscle Protein Synthesis and Beta-Adrenergic Receptor Expression in Chicken Skeletal Muscle Cells in Culture

    NASA Technical Reports Server (NTRS)

    Young, R. B.; Vaughn, J. R.; Bridge, K. Y.; Smith, C. K.

    1998-01-01

    Analogies of epinephrine are known to cause hypertrophy of skeletal muscle when fed to animals. These compounds presumably exert their physiological action through interaction with the P-adrenergic receptor. Since the intracellular signal generated by the Beta-adrenergic receptor is cyclic AMP (cAMP), experiments were initiated in cell culture to determine if artificial elevation of cAMP by treatment with forskolin would alter muscle protein metabolism and P-adrenergic receptor expression. Chicken skeletal muscle cells after 7 days in culture were treated with 0.2-30 micrometers forskolin for a total of three days. At the end of the treatment period, both the concentration of cAMP and the quantity of myosin heavy chain (MHC) were measured. Concentration of cAMP in forskolin-treated cells increased up to 10-fold in a dose dependent manner. In contrast, the quantity of MHC was increased approximately 50% above control cells at 0.2 micrometers forskolin, but exhibited a gradual decline at higher levels of forskolin so that the quantity of MHC in cells treated with 30 micrometers forskolin was not significantly different from controls. Curiously, the intracellular concentration of cAMP which elicited the maximum increase in the quantity of MHC was only 40% higher than cAMP concentration in control cells.

  13. Demonstration of. beta. -adrenergic receptors and catecholamine-mediated effects on cell proliferation in embryonic palatal tissue

    SciTech Connect

    Pisano, M.M.

    1986-01-01

    The ability of catecholamines to modulate cell proliferation, differentiation and morphogenesis in other systems, and modulate adenylate cyclase activity in the developing palate during the period of cellular differentiation, made it of interest to determine their involvement in palatal ontogenesis. Catecholamines exert their physiologic effects via interaction with distinct membrane-bound receptors, one class being the B-adrenergic receptors which are coupled to stimulation of adenylate cyclase and the generation of cAMP. A direct radioligand binding technique utilizing the B-adrenergic antagonist (/sup 3/H)-dihydroalprenolol ((/sup 3/H)-DHA) was employed in the identification of B-adrenergic receptors in the developing murine secondary palate. Specific binding of (/sup 3/H)-DHA in embryonic (day 13) palatal tissue homogenates was saturable and of high affinity. The functionality of B-adrenergic receptor binding sites was assessed from the ability of embryonic palate mesenchmyal cells in vitro to respond to catecholamines with elevations of cAMP. Embryonic palate mesenchymal cells responded to various B-adrenergic catecholamine agonists with significant, dose-dependent accumulations of intracellular cAMP. Embryonic (day 13) maxillary tissue homogenates were analyzed for the presence of catecholamines by high performance liquid chromatography and radioenzymatic assay. Since normal palatal and craniofacial morphogenesis depends on proper temporal and spatial patterns of growth, the effect of B-adrenergic catecholamines on embryonic palate mesenchymal cell proliferation was investigated.

  14. Effect of Electrical Stimulation on Beta-Adrenergic Receptor Population and Coupling Efficiency in Chicken and Rat Skeleton Muscle Cell Cultures

    NASA Technical Reports Server (NTRS)

    Young, Ronald B.; Bridge, Kristin Y.; Strietzel, Catherine J.

    1999-01-01

    Expression of the beta-adrenergic receptor (bAR) and its coupling to cyclic AMP (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the bAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for seven days in culture were subjected to electrical stimulation for an additional two days at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the bAR population was not significantly affected by electrical stimulation; however, the ability of these cells to synthesize cyclic AMP was reduced by approximately one-half. Thus, in chicken muscle cells an enhanced level of contraction reduced the coupling efficiency of bAR for cyclic AMP production by approximately 55% compared to controls. In contrast, the bAR population in rat muscle cells was increased by approximately 25% by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was also increased by almost two-fold. Thus, in rat muscle cells an enhanced level of contraction increased the coupling efficiency of bAR for cyclic AMP production by approximately 50% compared to controls. The basal levels of intracellular cyclic AMP in both rat muscle cells and chicken muscle cells were not affected by electrical stimulation.

  15. Beta Adrenergic Receptor Stimulation Suppresses Cell Migration in Association with Cell Cycle Transition in Osteoblasts-Live Imaging Analyses Based on FUCCI System.

    PubMed

    Katsumura, Sakie; Ezura, Yoichi; Izu, Yayoi; Shirakawa, Jumpei; Miyawaki, Atsushi; Harada, Kiyoshi; Noda, Masaki

    2016-02-01

    Osteoporosis affects over 20 million patients in the United States. Among those, disuse osteoporosis is serious as it is induced by bed-ridden conditions in patients suffering from aging-associated diseases including cardiovascular, neurological, and malignant neoplastic diseases. Although the phenomenon that loss of mechanical stress such as bed-ridden condition reduces bone mass is clear, molecular bases for the disuse osteoporosis are still incompletely understood. In disuse osteoporosis model, bone loss is interfered by inhibitors of sympathetic tone and adrenergic receptors that suppress bone formation. However, how beta adrenergic stimulation affects osteoblastic migration and associated proliferation is not known. Here we introduced a live imaging system, fluorescent ubiquitination-based cell cycle indicator (FUCCI), in osteoblast biology and examined isoproterenol regulation of cell cycle transition and cell migration in osteoblasts. Isoproterenol treatment suppresses the levels of first entry peak of quiescent osteoblastic cells into cell cycle phase by shifting from G1 /G0 to S/G2 /M and also suppresses the levels of second major peak population that enters into S/G2 /M. The isoproterenol regulation of osteoblastic cell cycle transition is associated with isoproterenol suppression on the velocity of migration. This isoproterenol regulation of migration velocity is cell cycle phase specific as it suppresses migration velocity of osteoblasts in G1 phase but not in G1 /S nor in G2 /M phase. Finally, these observations on isoproterenol regulation of osteoblastic migration and cell cycle transition are opposite to the PTH actions in osteoblasts. In summary, we discovered that sympathetic tone regulates osteoblastic migration in association with cell cycle transition by using FUCCI system.

  16. Effect of Electrical Stimulation on Beta-Adrenergic Receptor Population and Coupling Efficiency in Chicken and Rat Skeleton Muscle Cell Cultures

    NASA Technical Reports Server (NTRS)

    Young, Ronald B.; Bridge, Kristin Y.; Strietzel, Catherine J.

    1999-01-01

    Expression of the beta-adrenergic receptor (bAR) and its coupling to cyclic AMP (cAMP) synthesis are important components of the signaling system that controls muscle atrophy and hypertrophy, and the goal of this study was to determine if electrical stimulation in a pattern simulating slow muscle contraction would alter the bAR response in primary cultures of avian and mammalian skeletal muscle cells. Specifically, chicken skeletal muscle cells and rat skeletal muscle cells that had been grown for seven days in culture were subjected to electrical stimulation for an additional two days at a pulse frequency of 0.5 pulses/sec and a pulse duration of 200 msec. In chicken skeletal muscle cells, the bAR population was not significantly affected by electrical stimulation; however, the ability of these cells to synthesize cyclic AMP was reduced by approximately one-half. Thus, in chicken muscle cells an enhanced level of contraction reduced the coupling efficiency of bAR for cyclic AMP production by approximately 55% compared to controls. In contrast, the bAR population in rat muscle cells was increased by approximately 25% by electrical stimulation, and the ability of these cells to synthesize cyclic AMP was also increased by almost two-fold. Thus, in rat muscle cells an enhanced level of contraction increased the coupling efficiency of bAR for cyclic AMP production by approximately 50% compared to controls. The basal levels of intracellular cyclic AMP in both rat muscle cells and chicken muscle cells were not affected by electrical stimulation.

  17. Repeated stressor exposure enhances contextual fear memory in a beta-adrenergic receptor-dependent process and increases impulsivity in a non-beta receptor-dependent fashion

    PubMed Central

    Camp, Robert M.; Johnson, John D.

    2015-01-01

    Memory formation is promoted by stress via the release of norepinephrine and stimulation of beta-adrenergic receptors (β-ARs). Previous data demonstrate that repeated stressor exposure increases norepinephrine turnover and β-AR signaling within the amygdala, which led to the hypothesis that some stress-induced behavioral changes are likely due to facilitated associative learning. To test this, Fischer rats were exposed to chronic mild stress for four days. On day 5, subjects (including non-stressed controls) were injected with the beta-blocker propranolol or vehicle prior to conditioning in an operant box (animals receive two mild foot shocks) or passive avoidance apparatus (animals received a foot shock upon entry into the dark chamber). Twenty-four hours later, subjects were returned to the operant box for measurement of freezing or returned to the passive avoidance apparatus for measurement of latency to enter the dark chamber. Subjects were also tested in an open field to assess context-independent anxiety-like behavior. Animals exposed to chronic stress showed significantly more freezing behavior in the operant box than did controls, and this exaggerated freezing was blocked by propranolol during the conditioning trial. There was no effect of stress on behavior in the open field. Unexpectedly, retention latency was significantly reduced in subjects exposed to chronic stress. These results indicate that chronic exposure to stress results in complex behavioral changes. While repeated stress appears to enhance the formation of fearful memories, it also results in behavioral responses that resemble impulsive behaviors that result in poor decision-making. PMID:25747320

  18. Autonomic modulation during acute myocardial ischemia by low-dose pirenzepine in conscious dogs with a healed myocardial infarction: a comparison with beta-adrenergic blockade.

    PubMed

    Pedretti, Roberto F E; Prete, Giovanna; Foreman, Robert D; Adamson, Philip B; Vanoli, Emilio

    2003-05-01

    Experimental and clinical evidence documents the beneficial effects of blocking sympathetic activity and modulating heart rate to reduce risk for lethal events in ischemic heart disease. Beside beta-adrenergic receptor blockade, vagal activation is a meaningful approach but not yet easily attainable. Promising results were shown with low-dose atropine and scopolamine, but no follow-up was done because of significant adverse side effects. Pirenzepine is an atropine analogue approved to treat peptic ulcer disease in Europe that is devoid of central actions, which are mostly responsible for anti-muscarinic agents side effects. The vagomimetic action of IV low-dose pirenzepine was studied at rest under control conditions, at rest during acute coronary artery occlusion, and during exercise in conscious dogs with a healed anterior myocardial infarction (MI). The effects of pirenzepine were then compared, by internal control analysis, with those of atenolol (1 mg/kg). Increasing doses of pirenzepine (from 0.01 to 1 mg/kg) were tested in 11 dogs at rest by measuring time and frequency domain heart rate variability (HRV). The most effective dose (0.1 mg/kg) was used in the study. At the most effective dose, pirenzepine increased all measures of time domain HRV by 40-50%. However, the vagomimetic action of pirenzepine was lost during exercise and brief ischemia and no anti-arrhythmic action was observed. Conversely, pirenzepine effectively modulated the heart rate increase during acute ischemia at rest with an effect comparable to that of atenolol. The vagomimetic action of pirenzepine in the acutely ischemic heart supports the possibility that this intervention may be helpful for chronic autonomic modulation in post-MI patients.

  19. Repeated stressor exposure enhances contextual fear memory in a beta-adrenergic receptor-dependent process and increases impulsivity in a non-beta receptor-dependent fashion.

    PubMed

    Camp, Robert M; Johnson, John D

    2015-10-15

    Memory formation is promoted by stress via the release of norepinephrine and stimulation of beta-adrenergic receptors (β-ARs). Previous data demonstrate that repeated stressor exposure increases norepinephrine turnover and β-AR signaling within the amygdala, which led to the hypothesis that some stress-induced behavioral changes are likely due to facilitated associative learning. To test this, Fischer rats were exposed to chronic mild stress for four days. On day 5, subjects (including non-stressed controls) were injected with the beta-blocker propranolol or vehicle prior to conditioning in an operant box (animals receive two mild foot shocks) or passive avoidance apparatus (animals received a foot shock upon entry into the dark chamber). Twenty-four hours later, subjects were returned to the operant box for measurement of freezing or returned to the passive avoidance apparatus for measurement of latency to enter the dark chamber. Subjects were also tested in an open field to assess context-independent anxiety-like behavior. Animals exposed to chronic stress showed significantly more freezing behavior in the operant box than did controls, and this exaggerated freezing was blocked by propranolol during the conditioning trial. There was no effect of stress on behavior in the open field. Unexpectedly, retention latency was significantly reduced in subjects exposed to chronic stress. These results indicate that chronic exposure to stress results in complex behavioral changes. While repeated stress appears to enhance the formation of fearful memories, it also results in behavioral responses that resemble impulsive behaviors that result in poor decision-making. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Regional brain distribution of noradrenaline uptake sites, and of alpha1-alpha2- and beta-adrenergic receptors in PCD mutant mice: a quantitative autoradiographic study.

    PubMed

    Strazielle, C; Lalonde, R; Hébert, C; Reader, T A

    1999-01-01

    The mouse "Purkinje cell degeneration" (pcd) is characterized by a primary loss of Purkinje cells, as well as by retrograde and secondary partial degeneration of cerebellar granule cells and inferior olivary neurons; this neurological mutant can be considered as an animal model of human degenerative ataxia. To determine the consequences of this cerebellar pathology on the noradrenergic system, noradrenaline transporters as well as alpha1-, alpha2- and beta-adrenergic receptors were evaluated by quantitative ligand binding autoradiography in adult control and pcd mice using, respectively, [3H]nisoxetine, [3H]prazosin, [3H]idazoxan and [3H]CGP12177. In cerebellar cortex and deep nuclei of pcd mutants, [3H]nisoxetine labelling of noradrenaline transporters was higher than in control mice. However, when binding densities were corrected by surface area, they remained unchanged in the cerebellar cortex but associated with 25% and 40% lower levels of labelling of alpha1 and beta receptors, as well as a very important increase (275%) of alpha2 receptors. In deep cerebellar nuclei, surface corrections did not reveal any changes either in transporter or in receptor densities. Higher densities of [3H]nisoxetine labelling were found in several regions related with the cerebellum, namely inferior olive, inferior colliculus, vestibular, reticular, pontine, raphe and red nuclei, as well as in primary motor and sensory cerebral cortex; they may reflect an increased noradrenergic innervation related to motor adjustments for the cerebellar dysfunction. Increased [3H]nisoxetine labelling was also measured in vegetative brainstem regions and in dorsal hypothalamus, implying altered autonomic functions and possible compensation in pcd mutants. Other changes found in extracerebellar regions affected by the mutation, such as thalamus and the olfactory system implicated both noradrenaline transporters and adrenergic receptors. In contrast to the important alterations of the noradrenergic

  1. Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice.

    PubMed

    Douris, Nicholas; Desai, Bhavna N; Fisher, Ffolliott M; Cisu, Theodore; Fowler, Alan J; Zarebidaki, Eleen; Nguyen, Ngoc Ly T; Morgan, Donald A; Bartness, Timothy J; Rahmouni, Kamal; Flier, Jeffrey S; Maratos-Flier, Eleftheria

    2017-08-01

    We have previously shown that the consumption of a low-carbohydrate ketogenic diet (KD) by mice leads to a distinct physiologic state associated with weight loss, increased metabolic rate, and improved insulin sensitivity [1]. Furthermore, we identified fibroblast growth factor 21 (FGF21) as a necessary mediator of the changes, as mice lacking FGF21 fed KD gain rather than lose weight [2]. FGF21 activates the sympathetic nervous system (SNS) [3], which is a key regulator of metabolic rate. Thus, we considered that the SNS may play a role in mediating the metabolic adaption to ketosis. To test this hypothesis, we measured the response of mice lacking all three β-adrenergic receptors (β-less mice) to KD feeding. In contrast to wild-type (WT) controls, β-less mice gained weight, increased adipose tissue depots mass, and did not increase energy expenditure when consuming KD. Remarkably, despite weight-gain, β-less mice were insulin sensitive. KD-induced changes in hepatic gene expression of β-less mice were similar to those seen in WT controls eating KD. Expression of FGF21 mRNA rose over 60-fold in both WT and β-less mice fed KD, and corresponding circulating FGF21 levels were 12.5 ng/ml in KD-fed wild type controls and 35.5 ng/ml in KD-fed β-less mice. The response of β-less mice distinguishes at least two distinct categories of physiologic effects in mice consuming KD. In the liver, KD regulates peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways through an action of FGF21 independent of the SNS and beta-adrenergic receptors. In sharp contrast, induction of interscapular brown adipose tissue (BAT) and increased energy expenditure absolutely require SNS signals involving action on one or more β-adrenergic receptors. In this way, the key metabolic actions of FGF21 in response to KD have diverse effector mechanisms.

  2. Influence of stroke volume and exercise tolerance on peak oxygen pulse in patients with and without beta-adrenergic receptor blockers in patients with heart disease.

    PubMed

    Murata, Makoto; Adachi, Hitoshi; Oshima, Shigeru; Kurabayashi, Masahiko

    2017-01-01

    In a given individual, a consistent relationship exists between oxygen uptake (V˙O2) and heart rate (HR) during exercise. The quotient of V˙O2 and HR (V˙O2/HR) is called the oxygen pulse (O2 pulse), and its value is dependent on stroke volume (SV). However, it is difficult to believe that the O2 pulse would indicate the SV when HR has been modified as with the use of beta-adrenergic receptor blockers (BB). Until now, the effect of BB on peak O2 pulse has not been precisely studied. We tried to clarify the effect of BB on the relationship between O2 pulse and SV. Of 699 consecutive heart disease subjects who performed cardiopulmonary exercise tests (CPX) from 2012 to 2014, we enrolled 430 subjects who had sinus rhythm and could perform CPX until exhaustion. One hundred and fifty-seven subjects were taking BB. SV was evaluated during CPX using impedance cardiography, and we compared the peak O2 pulse with peak SV between patients without BB (Group A) and with BB (Group B). The HRs at rest and peak exercise in Group A were greater than those in Group B (74.4±13.0/min vs. 71.8±11.3/min, p<0.01, 134.9±21.7/min vs. 124.9±23.6/min, p<0.01, respectively). The regression line of the peak O2 pulse against the peak SV was steeper in Group B than in Group A. When we divided the patients into two groups according to the average values of the peak SV and peak V˙O2, O2 pulse/SV ratio in Group B above the average was greater than that in Group A, whereas it was similar in the two groups that were below average. We found that the increase in the O2 pulse was disproportionately greater than the SV that was measured by impedance cardiography when a BB was used in patients with preserved SV and exercise tolerance. Copyright © 2016. Published by Elsevier Ltd.

  3. Increased sodium/calcium exchanger activity enhances beta-adrenergic-mediated increase in heart rate: Whole-heart study in a homozygous sodium/calcium exchanger overexpressor mouse model.

    PubMed

    Kaese, Sven; Bögeholz, Nils; Pauls, Paul; Dechering, Dirk; Olligs, Jan; Kölker, Katharina; Badawi, Sascha; Frommeyer, Gerrit; Pott, Christian; Eckardt, Lars

    2017-08-01

    The cardiac sodium/calcium (Na(+)/Ca(2+)) exchanger (NCX) contributes to diastolic depolarization in cardiac pacemaker cells. Increased NCX activity has been found in heart failure and atrial fibrillation. The influence of increased NCX activity on resting heart rate, beta-adrenergic-mediated increase in heart rate, and cardiac conduction properties is unknown. The purpose of this study was to investigate the influence of NCX overexpression in a homozygous transgenic whole-heart mouse model (NCX-OE) on sinus and AV nodal function. Langendorff-perfused, beating whole hearts of NCX-OE and the corresponding wild-type (WT) were studied ± isoproterenol (ISO; 0.2 μM). Epicardial ECG, AV nodal Wenckebach cycle length (AVN-WCL), and retrograde AVN-WCL were obtained. At baseline, basal heart rate was unaltered between NCX-OE and WT (WT: cycle length [CL] 177.6 ± 40.0 ms, no. of hearts [n] = 20; NCX-OE: CL 185.9 ± 30.5 ms, n = 18; P = .21). In the presence of ISO, NCX-OE exhibited a significantly higher heart rate compared to WT (WT: CL 133.4 ± 13.4 ms, n = 20; NCX-OE: CL 117.7 ± 14.2 ms, n = 18; P <.001). ISO led to a significant shortening of the anterograde and retrograde AVN-WCL without differences between NCX-OE and WT. This study is the first to demonstrate that increased NCX activity enhances beta-adrenergic increase of heart rate. Mechanistically, increased NCX inward mode activity may promote acceleration of diastolic depolarization in sinus nodal pacemaker cells, thus enhancing chronotropy in NCX-OE. These findings suggest a novel potential therapeutic target for heart rate control in the presence of increased NCX activity, such as heart failure. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  4. Studies on responsiveness of hepatoma cells to catecholamines. II. Comparison of beta-adrenergic responsiveness of rat ascites hepatoma cells with cultured normal rat liver cells.

    PubMed

    Miyamoto, K; Matsunaga, T; Takemoto, N; Sanae, F; Koshiura, R

    1985-05-01

    The pharmacological properties of beta-adrenoceptors in rat ascites hepatoma cells were compared with those in normal rat liver cells which were cultured for 24 hr after collagenase digestion. Adenylate cyclases in the homogenates of cultured normal rat liver cells and rat ascites hepatoma cells, AH44, AH66, AH109A, AH130 and AH7974, were all activated by isoproterenol or NaF to different degrees. The enzyme in rat liver cells was activated by several beta 2-agonists but those in all hepatoma cells hardly responded. Furthermore, salbutamol, a beta 2-partial agonist, antagonized the cyclase activation by isoproterenol in AH130 cells. The Kact value of isoproterenol for the activation of adenylate cyclase in AH130 cells was smaller than that in rat liver cells. A comparison of the Ki values of beta-antagonists for the inhibition of isoproterenol-stimulated cyclase activity shows that while the Ki values of propranolol and butoxamine in AH130 cells were similar to those in rat liver cells, a significant difference was observed in the values for beta 1-selective antagonists between AH130 cells and rat liver cells. The Ki values of metoprolol and atenolol for AH130 cells were 137- and 90-fold lower, respectively, than for normal rat liver cells. From these findings, it is strongly suggested that beta-adrenoceptors in rat ascites hepatoma cells including AH130 cells have similar properties to the mammalian beta 1-receptor.

  5. Differential effect of beta-adrenergic receptor antagonism in basolateral amygdala on reconsolidation of aversive and appetitive memories associated with morphine in rats.

    PubMed

    Wu, Yan; Li, Yonghui; Yang, Xiaoyan; Sui, Nan

    2014-01-01

    Positive and negative emotional experiences induced by addictive drugs play an important role in the development of dysfunctional drug-related memory, which becomes resistant to extinction and contributes to high rate of relapse. Those memories may undergo a process called reconsolidation that in some cases can be disrupted by pharmacological treatment. The basolateral amygdala (BLA) has been shown to mediate the reconsolidation of drug-related appetitive memory, but its role in withdrawal-related aversive memory remains elusive. The present study used conditioned place preference (CPP) and conditioned place aversion (CPA) paradigms to investigate the role of BLA and its noradrenergic receptors in reconsolidation of morphine-associated emotional memory in rats. We found that inhibition of protein synthesis in BLA disrupted the reconsolidation of morphine CPP (m-CPP) and CPA related to morphine withdrawal (m-CPA). A high dose of the β-noradrenergic receptor antagonist propranolol (3 µg) in BLA-impaired reconsolidation of m-CPA but not m-CPP, whereas a low dose (0.3 µg) was ineffective. In contrast, neither low nor high doses of the α-noradrenergic receptor antagonist phentolamine (1 or 10 µg) blocked the reconsolidation of m-CPP and m-CPA. In addition, infusion of propranolol (3 µg) into nucleus accumbens after retrieval of either m-CPP or m-CPA did not affect its reconsolidation. The findings indicate that appetitive and aversive addictive memories share common neural substrates in BLA, but the specific neurotransmitter mechanism on reconsolidation of morphine-associated negative and positive memories can be dissociable.

  6. Drug-induced regulation of 1,4-dihydropyridine Ca sup 2+ channel antagonist binding sites in the brain and heart

    SciTech Connect

    Ramkumar, V.

    1987-01-01

    The ability of drugs to regulate the voltage-sensitive Ca{sup 2+} channels were assessed by determining the bind of ({sup 3}H)dihydropyridine Ca{sup 2+} channel antagonists in the heart and brain following administration of these drugs to rats and mice. Mice and rats implanted with morphine pellets for 3 days showed an increase in dihydropyridine binding sites in the brain, compared to non-treated or placebo treated controls. No increase in dihydropyridine binding sites was observed in the heart. The significance of the increase in binding to physical dependence on morphine is implied from the findings that pretreatment with Ca{sup 2+} channel antagonist drugs led to an attenuation of naloxone-precipitated withdrawal signs in both dependent rats and mice. Administration of other drugs, known to depress the CNS, was undertaken to determine whether the changes observed with morphine was a nonspecific response of the brain to depressant drugs. Prolonged administration of reserpine to rats resulted in no changes in dihydropyridine binding sites in the brain, even though the {beta}-adrenergic receptors in this tissue are upregulated. However, reserpine decreased the density of ({sup 3}H)nimodipine binding sites in the heart of this is accompanied by concomitant increases in {beta}-adrenergic receptors.

  7. Early developmental 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure decreases chick embryo heart chronotropic response to isoproterenol but not to agents affecting signals downstream of the beta-adrenergic receptor.

    PubMed

    Sommer, Rebecca J; Hume, Adam J; Ciak, Jessica M; Vannostrand, John J; Friggens, Megan; Walker, Mary K

    2005-02-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) causes cardiovascular toxicity in laboratory animals, including alteration in several processes in which beta-adrenergic receptor (beta-AR) signaling plays important roles. Thus, our laboratory investigated the effects of TCDD on beta-AR expression and signal transduction. Fertile chicken eggs were injected with vehicle (corn oil), 0.24 or 0.3 pmol TCDD/g egg on incubation day 0 (D0) or D5. On D10, heart function was assessed by ECG in ovo. Exposure to TCDD increased the incidence of arrhythmias and decreased the positive chronotropic responsiveness of the heart to isoproterenol. The reduced beta-AR responsiveness was, in part, independent of any overt morphological changes in the heart as chick embryos exposed to TCDD on D5 displayed an intermediate responsiveness to beta-AR agonist in the absence of the dilated cardiomyopathy observed in chick embryos exposed to TCDD on D0. TCDD did not decrease the chronotropic response of the heart to agents that stimulate signals downstream of the beta-AR. In fact, TCDD-exposed embryos were more sensitive than controls to forskolin, increasing heart rates (HR) 21.8 +/- 3.5 beats per min (bpm) above baseline versus control values at 6.3 +/- 2.7 bpm above baseline. TCDD exposure also augmented the negative chronotropic response of the heart to verapamil, decreasing HR -23.2 +/- 7.4 bpm relative to baseline versus control embryos at -12.7 +/- 5.9 bpm below baseline. Finally, the mean cardiac beta1-AR mRNA expression in D10 embryos was not significantly altered by exposure to TCDD on D0. These findings establish that a functional end point of the developing chick heart is sensitive to TCDD exposure and that the TCDD-induced reduction in beta-AR responsiveness may result from alterations in signal transduction upstream of adenylyl cyclase.

  8. Cooperative regulation of non-small cell lung carcinoma by nicotinic and beta-adrenergic receptors: a novel target for intervention.

    PubMed

    Al-Wadei, Hussein A N; Al-Wadei, Mohammed H; Schuller, Hildegard M

    2012-01-01

    Lung cancer is the leading cause of cancer death; 80-85% of lung cancer cases are non-small cell lung cancer (NSCLC). Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI-H1299), we identified the cooperation of nicotinic acetylcholine receptors (nAChRs) and β-adrenergic receptors (β-ARs) as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the α7nAChR and α4nAChR, along with significant inductions of p-CREB and p-ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the α7nAChR antagonist α-BTX or the β-blocker propranolol. Nicotine treatment also down-regulated expression of the GABA synthesizing enzyme GAD 65 and the level of endogenous GABA, while treatment of NSCLC cells with GABA inhibited cell proliferation. Interestingly, GABA acts by reducing β-adrenergic activated cAMP signaling. Our findings suggest that nicotine-induced activation of this autocrine noradrenaline-initiated signaling cascade and concomitant deficiency in inhibitory GABA, similar to modulation of these neurotransmitters in the nicotine-addicted brain, may contribute to the development of NSCLC in smokers. Our data suggest that exposure to nicotine either by tobacco smoke or nicotine supplements facilitates growth and progression of NSCLC and that pharmacological intervention by β blocker may lower the risk

  9. beta-adrenergic receptors primarily are located on the dendrites of granule cells and interneurons but also are found on astrocytes and a few presynaptic profiles in the rat dentate gyrus.

    PubMed

    Milner, T A; Shah, P; Pierce, J P

    2000-06-01

    In the rat dentate gyrus, beta-adrenergic receptor (beta-AR) activation is thought to be important in mediating the effects of norepinephrine (NE). beta-AR-immunoreactivity (beta-AR-I) was localized in this study by light and electron microscopy in the rat dentate gyrus by using two previously characterized antibodies to the beta-AR. By light microscopy, dense beta-AR-I was observed in the somata of granule cells and a few hilar interneurons. Diffuse and slightly granular beta-AR-I was found in all laminae, although it was most noticeable in the molecular layer. Ultrastructurally, the cytoplasm of granule cell and interneuronal perikarya (some of which contained parvalbumin immunoreactivity) contained beta-AR-I. beta-AR-I was associated primarily with the endoplasmic reticula; however, a few patches were observed near the plasmalemma. Quantitative analysis revealed that the greatest proportion of beta-AR-labeled profiles was found in the molecular layer. The majority of beta-AR-labeled profiles were either dendritic or astrocytic. In dendritic profiles, beta-AR-I was prominent near postsynaptic densities in large dendrites, many of which originated from granule cell somata. Moreover, some beta-AR-I was found in dendritic spines, sometimes affiliated with the spine apparati. Astrocytic profiles with beta-AR-I were commonly found next to unlabeled terminals which formed asymmetric (excitatory-type) synapses with dendritic spines. Additionally, beta-AR-I was observed in a few unmyelinated axons and axon terminals, many of which formed synapses with dendritic spines. Dual-labeling studies revealed that axons and axon terminals containing tyrosine hydroxylase (TH), the catecholamine synthesizing enzyme, often were near both neuronal and glial profiles containing beta-AR-I. These studies demonstrate that hippocampal beta-AR-I is localized: 1) principally in postsynaptic sites on granule cells and a few interneurons (some of which were basket cells); and 2) in glial

  10. Beta-adrenergic blockade in clinical practice.

    PubMed

    Frishman, W H

    1982-09-01

    Although all beta-blocking agents have similar pharmacologic effects, they have vastly different pharmacokinetic properties, which can influence the clinical usefulness of a given beta blocker in an individual patient. The efficacy of these drugs in a host of disorders-both cardiovascular and noncardiovascular-and their modes of action in these clinical contexts are examined and discussed.

  11. The effect of adrenergic agonists and antagonists on cysteine-proteinase inhibitor (cystatin) in rat saliva.

    PubMed

    Bedi, G S

    1991-01-01

    The effect of a number of adrenergic agonists and antagonists on the induction of rat salivary cystatin was investigated. A highly sensitive and specific radioimmunoassay was used to determine cystatin in rat whole saliva. Treatment for 10 consecutive days with a non-specific beta-adrenergic agonist isoproterenol, or the beta 1-adrenergic agonists dobutamine or methoxyphenamine, resulted in the induction of the salivary cystatin. Induction was also found in rats treated for 10 days with arterenol. Only trace quantities of cystatin could be detected in saliva of rats treated with the beta 2-adrenergic agonists terbutaline or salbutamol. When isoproterenol was injected concomitantly with the mixed beta-antagonist propranolol or the beta 1-adrenergic antagonists metaprolol, proctocol or atenolol the production of cystatin was totally suppressed. However, the beta 2-antagonist, ICI 118551, produced only a partial reduction in salivary cystatin induction elicited by isoproterenol. The findings suggest that the induction of salivary cystatin is regulated, in part, by beta 1-adrenergic receptor stimulation.

  12. Human fat cell alpha-2 adrenoceptors. I. Functional exploration and pharmacological definition with selected alpha-2 agonists and antagonists

    SciTech Connect

    Galitzky, J.; Mauriege, P.; Berlan, M.; Lafontan, M.

    1989-05-01

    This study was undertaken to investigate more fully the pharmacological characteristics of the human fat cell alpha-2 adrenoceptor. Biological assays were performed on intact isolated fat cells while radioligand binding studies were carried out with (/sup 3/H)yohimbine in membranes. These pharmacological studies brought: (1) a critical definition of the limits of the experimental conditions required for the exploration of alpha-2 adrenergic responsiveness on human fat cells and membranes; (2) an improvement in the pharmacological definition of the human fat cell postsynaptic alpha-2 adrenoceptor. Among alpha-2 agonists, UK-14,304 was the most potent and the relative order of potency was: UK-14,304 greater than p-aminoclonidine greater than clonidine = B-HT 920 greater than rilmenidine. For alpha-2 antagonists, the potency order was: yohimbine greater than idazoxan greater than SK F-86,466 much greater than benextramine; (3) a description of the impact of benextramine (irreversible alpha-1/alpha-2 antagonist) on human fat cell alpha-2 adrenergic receptors and on human fat cell function; the drug inactivates the alpha-2 adrenergic receptors with a minor impact on beta adrenergic receptors and without noticeable alterations of fat cell function as assessed by preservation of beta adrenergic and Al-adenosine receptor-mediated lipolytic responses; and (4) a definition of the relationship existing between alpha-2 adrenergic receptor occupancy, inhibition of adenylate cyclase activity and antilipolysis with full and partial agonists. The existence of a receptor reserve must be taken into account when evaluating alpha-2 adrenergic receptor distribution and regulation of human fat cells.

  13. Kisspeptin antagonists.

    PubMed

    Roseweir, Antonia Kathryn; Millar, Robert P

    2013-01-01

    Kisspeptin is now known to be an important regulator of the hypothalamic--pituitary-gonadal axis and is the target of a range of regulators, such as steroid hormone feedback, nutritional and metabolic regulation. Kisspeptin binds to its cognate receptor, KISS1R (also called GPR54), on GnRH neurons and stimulates their activity, which in turn provides an obligatory signal for GnRH secretion-thus gating down-stream events supporting reproduction. The development of peripherally active kisspeptin antagonists could offer a unique therapeutic agent for treating hormone-dependent disorders of reproduction, including precocious puberty, endometriosis, and metastatic prostate cancer. The following chapter discusses the advances made in the search for both peptide and small molecule kisspeptin antagonists and their use in delineating the role of kisspeptin within the reproductive system. To date, four peptide antagonists and one small molecule antagonist have been designed.

  14. The beta-1 adrenergic antagonist, betaxolol, improves working memory performance in rats and monkeys.

    PubMed

    Ramos, Brian P; Colgan, Lesley; Nou, Eric; Ovadia, Shira; Wilson, Steven R; Arnsten, Amy F T

    2005-12-01

    Previous studies have indicated that beta adrenergic receptor stimulation has no effect on the cognitive functioning of the prefrontal cortex (PFC). Blockade of beta-1 and beta-2 receptors in the PFC with the mixed beta-1/beta-2 antagonist, propanolol, had no effect on spatial working memory performance. However, more selective blockade of beta-1 or beta-2 receptors might show efficacy if the two receptors have opposite effects on PFC function. The current study examined the effects of the selective beta-1 antagonist, betaxolol, on working memory in rats and monkeys. In rats, betaxolol (.0011-1.11 microg/.5 microL) was infused into the PFC 5 min before delayed alternation testing. Monkeys were systemically injected with betaxolol (.0000011-.11 mg/kg) 2 hours before delayed response testing. Betaxolol produced a dose-related improvement in working memory performance following either direct PFC infusion in rats, or systemic administration in monkeys. However, some aged monkeys developed serious pancreatic problems over the course of this study. These findings suggest that endogenous activation of the beta-1 adrenergic receptor impairs PFC cognitive function. These results may have therapeutic relevance to post-traumatic stress disorder or other disorders with excessive noradrenergic activity and PFC dysfunction. Pancreatic side effects in aged subjects taking betaxolol warrants further investigation.

  15. Effect of adrenergic agonists and antagonists on alanine amino transferase, fructose-1:6-bisphosphatase and glucose production in hepatocytes.

    PubMed

    Begum, N A; Datta, A G

    1992-08-18

    Using rat hepatocytes we confirmed our previous results that glucagon and beta-adrenergic agonists increased the enzyme activity of alanine aminotransferase (AAT) and propranolol abolished their effects. Only the enzyme activity was measured and other parameters like quantity of the enzyme or activation due to modification were not looked for. As in perfusion experiment phenylephrine and phenoxybenzamine (alpha-agonist and alpha-antagonist respectively) also alpha-antagonist respectively) also increased the AAT activity in isolated rat hepatocytes and propranolol reversed these effects. The additive effect of glucagon and phenoxybenzamine on AAT was also persistent in hepatocyte system. Fructose-1:6-bisphosphatase (Fru-P2-ase), another key enzyme in gluconeogenic pathway, was elevated by glucagon and other beta-adrenergic agonists both in liver perfusion and isolated hepatocyte experiments and was brought back to the normal level by propranolol. In this case also only the enzyme activity was measured and no other parameters were looked for. Unlike AAT this enzyme was not stimulated by phenylephrine or phenoxybenzamine. But AAT and Fru-P2-ase activities were increased significantly by adenylate cyclase activators like fluoride or forskolin. Thus, it appears that the regulation of fru-P2-ase by glucagon is purely a b-receptor mediated process whereas AAT activation shows a mixed type of regulation where some well known alpha-agonist and antagonists are behaving as beta-agonists. Results further indicate the presence of phosphodiesterase in hepatocyte membrane which was stimulated by glucagon and brought back to the normal level by propranolol. The different adrenergic compounds stated above, not only modified the activity of the above two enzymes but also stimulated glucose production by hepatocytes from alanine which was in turn abolished by propranolol as well as amino oxyacetate (AOA), a highly specified inhibitor of AAT. This confirm the participation of AAT in

  16. Beta adrenergic modulation of spontaneous microcontractions and electrical field-stimulated contractions in isolated strips of rat urinary bladder from normal animals and animals with partial bladder outflow obstruction.

    PubMed

    Gillespie, J I; Rouget, C; Palea, S; Granato, C; Korstanje, C

    2015-07-01

    Spontaneous microcontractions and electrical field stimulation (EFS)-evoked contractions in isolated rat bladder strips from normal and from 6 weeks partial bladder outflow obstruction (pBOO) animals were studied to identify the potential site of action for the β3-adrenoceptor (AR) agonist mirabegron in detrusor overactivity in rats. For this, effects of the β-AR agonist isoprenaline and mirabegron were tested in presence or absence of selective antagonists for β-AR subtypes, namely CGP-20712A for β1-AR, ICI-118,551 for β2-AR, and L-748,337 for β3-AR. In detrusor strips from both normal and obstructed animals, EFS-induced contractions were weakly affected by isoprenaline and even less so by mirabegron. In contrast, microcontraction activity was more potently reduced by isoprenaline (pIC50 7.3; Emax ±85 %), whereas mirabegron showed a small effect. In pBOO strips, concentration response curves for isoprenaline and mirabegron at inhibition of EFS and spontaneous microcontractions were similar to those in normal strips. Isoprenaline-induced inhibition of microcontractions and EFS was antagonized by the β1-AR antagonist, but not by the β2- and β3-AR antagonists. In the context of β3-AR-mediated bladder functions for mirabegron in other experiments, the current data question a role for effects at spontaneous microcontractions, or neurogenic detrusor stimulation in the mode of action for mirabegron in vivo, since functional bladder effects for mirabegron are reported to occur at much lower concentrations.

  17. Vaninolol: a new selective beta 1-adrenoceptor antagonist derived from vanillin.

    PubMed

    Wu, B N; Hwang, T L; Liao, C F; Chen, I J

    1994-07-05

    The beta-adrenoceptor blocking properties of vaninolol ((+/-)4-[4'-(2-hydroxy-3-tert-butyl-aminopropoxy)-3'-methoxyphenyl]- 3-buten-2-one), derived from vanillin, were first investigated under in vivo and in vitro conditions. Vaninolol (0.1, 0.5, 1.0 mg/kg, i.v.), as well as propranolol, produced a dose-dependent bradycardia response and a sustained pressor action in urethane-anesthetized normotensive rats. Vaninolol inhibited the tachycardia effects induced by (-)isoproterenol, but had no blocking effect on the arterial pressor responses induced by phenylephrine. These findings suggested that vaninolol possessed beta-adrenergic blocking activity, but was without alpha-adrenergic blocking activity. In isolated guinea-pig tissues, vaninolol antagonized (-)isoproterenol-induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses in a concentration-dependent manner. The parallel shift to the right of the concentration-response curve of (-)isoproterenol suggested that vaninolol was a beta-adrenoceptor competitive antagonist. The effect of vaninolol was more potent on the atria than on tracheal tissues, indicating it had some beta 1-adrenoceptor selectivity. On the other hand, the order of the hydrophilicity was atenolol > vaninolol > propranolol. In addition, vaninolol had a mild direct cardiac depression at high concentrations and was without intrinsic sympathomimetic activity (ISA). Furthermore, binding characteristics of vaninolol and other beta-adrenoceptor antagonists were evaluated in [3H]dihydroalprenolol binding to guinea-pig ventricular membranes. The order of potency of beta-adrenoceptor antagonists in competing for the binding sites was (-)propranolol > vaninolol > or = atenolol. In conclusion, vaninolol was found to be a selective beta 1-adrenoceptor antagonist with relatively low lipophilicity in comparison with propranolol, devoid of ISA, and had a mild myocardial depressant effect.

  18. Analysis of hydrophobic interactions of antagonists with the beta2-adrenergic receptor.

    PubMed

    Novoseletsky, V N; Pyrkov, T V; Efremov, R G

    2010-01-01

    The adrenergic receptors mediate a wide variety of physiological responses, including vasodilatation and vasoconstriction, heart rate modulation, and others. Beta-adrenergic antagonists ('beta-blockers') thus constitute a widely used class of drugs in cardiovascular medicine as well as in management of anxiety, migraine, and glaucoma. The importance of the hydrophobic effect has been evidenced for a wide range of beta-blocker properties. To better understand the role of the hydrophobic effect in recognition of beta-blockers by their receptor, we carried out a molecular docking study combined with an original approach to estimate receptor-ligand hydrophobic interactions. The proposed method is based on automatic detection of molecular fragments in ligands and the analysis of their interactions with receptors separately. A series of beta-blockers, based on phenylethanolamines and phenoxypropanolamines, were docked to the beta2-adrenoceptor binding site in the crystal structure. Hydrophobic complementarity between the ligand and the receptor was calculated using the PLATINUM web-server (http://model.nmr.ru/platinum). Based on the analysis of the hydrophobic match for molecular fragments of beta-blockers, we have developed a new scoring function which efficiently predicts dissociation constant (pKd) with strong correlations (r(2) approximately 0.8) with experimental data.

  19. ACTH Antagonists

    PubMed Central

    Clark, Adrian John; Forfar, Rachel; Hussain, Mashal; Jerman, Jeff; McIver, Ed; Taylor, Debra; Chan, Li

    2016-01-01

    Adrenocorticotropin (ACTH) acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R), is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP) for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1) Cushing’s disease and ectopic ACTH syndrome – especially while preparing for definitive treatment of a causative tumor, or in refractory cases, or (2) congenital adrenal hyperplasia – as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article, we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role. PMID:27547198

  20. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies.

    PubMed

    Graudins, Andis; Lee, Hwee Min; Druda, Dino

    2016-03-01

    Management of cardiovascular instability resulting from calcium channel antagonist (CCB) or beta-adrenergic receptor antagonist (BB) poisoning follows similar principles. Significant myocardial depression, bradycardia and hypotension result in both cases. CCBs can also produce vasodilatory shock. Additionally, CCBs, such as verapamil and diltiazem, are commonly ingested in sustained-release formulations. This can also be the case for some BBs. Peak toxicity can be delayed by several hours. Provision of early gastrointestinal decontamination with activated charcoal and whole-bowel irrigation might mitigate this. Treatment of shock requires a multimodal approach to inotropic therapy that can be guided by echocardiographic or invasive haemodynamic assessment of myocardial function. High-dose insulin euglycaemia is commonly recommended as a first-line treatment in these poisonings, to improve myocardial contractility, and should be instituted early when myocardial dysfunction is suspected. Catecholamine infusions are complementary to this therapy for both inotropic and chronotropic support. Catecholamine vasopressors and vasopressin are used in the treatment of vasodilatory shock. Optimizing serum calcium concentration can confer some benefit to improving myocardial function and vascular tone after CCB poisoning. High-dose glucagon infusions have provided moderate chronotropic and inotropic benefits in BB poisoning. Phosphodiesterase inhibitors and levosimendan have positive inotropic effects but also produce peripheral vasodilation, which can limit blood pressure improvement. In cases of severe cardiogenic shock and/or cardiac arrest post-poisoning, extracorporeal cardiac assist devices have resulted in successful recovery. Other treatments used in refractory hypotension include intravenous lipid emulsion for lipophilic CCB and BB poisoning and methylene blue for refractory vasodilatory shock.

  1. Compartmentalization of beta-adrenergic signals in cardiomyocytes.

    PubMed

    Xiang, Yang K

    2011-07-08

    Activation of adrenergic receptors (AR) represents the primary mechanism to increase cardiac performance under stress. Activated βAR couple to Gs protein, leading to adenylyl cyclase-dependent increases in secondary-messenger cyclic adenosine monophosphate (cAMP) to activate protein kinase A. The increased protein kinase A activities promote phosphorylation of diversified substrates, ranging from the receptor and its associated partners to proteins involved in increases in contractility and heart rate. Recent progress with live-cell imaging has drastically advanced our understanding of the βAR-induced cAMP and protein kinase A activities that are precisely regulated in a spatiotemporal fashion in highly differentiated myocytes. Several features stand out: membrane location of βAR and its associated complexes dictates the cellular compartmentalization of signaling; βAR agonist dose-dependent equilibrium between cAMP production and cAMP degradation shapes persistent increases in cAMP signals for sustained cardiac contraction response; and arrestin acts as an agonist dose-dependent master switch to promote cAMP diffusion and propagation into intracellular compartments by sequestrating phosphodiesterase isoforms associated with the βAR signaling cascades. These features and the underlying molecular mechanisms of dynamic regulation of βAR complexes with adenylyl cyclase and phosphodiesterase enzymes and the implication in heart failure are discussed.

  2. [Takotsubo cardiomyopathy: a novel beta-adrenergic blocker withdrawal syndrome].

    PubMed

    Tomcsányi, János; Jávor, Kinga; Arabadzisz, Hrisula; Zsoldos, András; Wagner, Vince; Sármán, Balázs

    2013-02-17

    The authors describe two cases of takotsubo cardiomyopathy developing after an abrupt withdrawal of carvedilol and bisoprolol. Takotsubo or stress cardiomyopathy is characterized by acute and reversible cardiac dysfunction without coronary artery disease. It is triggered by acute emotional or physical stress, drugs or drug withdrawal. The immediate discontinuation of the long acting vasodilator beta-blocker, carvedilol has not yet been described to cause takotsubo cardiomyopathy. The authors recommend cautious withdrawal of beta-blockers.

  3. beta-Adrenergic receptor modulation of wound repair.

    PubMed

    Pullar, Christine E; Manabat-Hidalgo, Catherine G; Bolaji, Ranti S; Isseroff, R Rivkah

    2008-08-01

    Adrenergic receptors and their downstream effector molecules are expressed in all cell types in the skin, and it is only recently that functionality of the catecholamine agonist activated signaling in the cutaneous repair process has been revealed. In addition to responding to systemic elevations in catecholamines (as in stress situations) or to pharmacologically administered adrenergic agonists, epidermal keratinocytes themselves can synthesize catecholamine ligands. They also respond to these systemic or self-generated agonists via receptor mediated signaling, resulting in altered migration, and changes in wound re-epithelialization. Endothelial cells, inflammatory cells, dermal fibroblasts, and mesenchymal stem cells, all cells that contribute to the wound repair process, express multiple subtypes of adrenergic receptors and exhibit responses that can be either contribute or impair healing-and occasionally, depending on the species and assay conditions, results can be conflicting. There is still much to be uncovered regarding how this self-contained autocrine and paracrine signaling system contributes to cutaneous wound repair.

  4. Illegal use of beta-adrenergic agonists: European Community.

    PubMed

    Kuiper, H A; Noordam, M Y; van Dooren-Flipsen, M M; Schilt, R; Roos, A H

    1998-01-01

    The use of veterinary medicinal products within the European Community is governed by a series of directives and regulations that describe the requirements for safety, quality, and efficacy of these products. Veterinary therapeutic use of beta-agonists has only been approved in the case of clenbuterol for bronchodilatation in horses and calves and for tocolysis in cows. No beta-agonists have been permitted in the European Community for growth-promoting purposes in farm animals. Surveillance for the presence of residues of veterinary agents in food-producing animals and meat is regulated by the Directive 86/469/EEC containing specific guidelines for sampling procedures on farms and in slaughterhouses. The level and frequency of sampling is dependent on the category of compounds and animal species. When positive samples have been identified (above certain action levels), sampling intensity is increased. Results of monitoring programs in EU member states during 1992 and 1993 for the occurrence of residues of beta-agonists in food-producing animals vary substantially with respect to the percentages of positive samples, ranging from 0 to 7%. The variability is partly explained by differences in sampling strategies, detection methods, and action levels applied. Identification of the proper matrices for sampling and detection of beta-agonists is important. In the case of clenbuterol, hair and choroid retinal tissue are appropriate tissues because clenbuterol accumulates in these matrices. A clear decrease in the use of clenbuterol in cattle has been observed in The Netherlands, Germany, Northern Ireland, and Spanish Basque Country over the last 3 yr. This is partly due to intensified surveillance activities at farms and slaughterhouses by governmental agencies and production sector organizations. There are data on human intoxication following consumption of liver or meat from cattle treated with beta-agonists. At the concentrations of clenbuterol measured in contaminated liver and meat samples, pharmacological effects may be expected in humans after consuming 100 to 200 g of product. The use of highly active beta-agonists as growth promoters is not appropriate because of the potential hazard for human and animal health, as was recently concluded at the scientific Conference on Growth Promotion in Meat Production (Nov. 1995, Brussels).

  5. Beta-Adrenergic Receptor Blockers in Hypertension: Alive and Well.

    PubMed

    Frishman, William H

    2016-10-27

    βeta-Adrenergic receptor blockers (β-blockers) are an appropriate treatment for patients having systemic hypertension (HTN) who have concomitant ischemic heart disease (IHD), heart failure, obstructive cardiomyopathy, aortic dissection or certain cardiac arrhythmias. β-blockers can be used in combination with other antiHTN drugs to achieve maximal blood pressure control. Labetalol can be used in HTN emergencies and urgencies. β-blockers may be useful in HTN patients having a hyperkinetic circulation (palpitations, tachycardia, HTN, and anxiety), migraine headache, and essential tremor. β-blockers are highly heterogeneous with respect to various pharmacologic properties: degree of intrinsic sympathomimetic activity , membrane stabilizing activity , β1 selectivity, α1-adrenergic blocking effects, tissue solubility, routes of systemic elimination, potencies and duration of action, and specific properties may be important in the selection of a drug for clinical use. β-blocker usage to reduce perioperative myocardial ischemia and cardiovascular (CV) complications may not benefit as many patients as was once hoped, and may actually cause harm in some individuals. Currently the best evidence supports perioperative β-blocker use in two patient groups: patients undergoing vascular surgery with known IHD or multiple risk factors for it, and for those patients already receiving β-blockers for known CV conditions.

  6. Doping control for beta-adrenergic compounds through hair analysis.

    PubMed

    Kintz, P; Dumestre-Toulet, V; Jamey, C; Cirimele, V; Ludes, B

    2000-01-01

    An original procedure was developed to simultaneously test beta2-agonists (salbutamol and clenbuterol) and beta-blockers (atenolol, acebutolol, pindolol, betaxolol, propranolol, timolol, sotalol, metoprolol, tertatolol, bisoprolol, labetalol and oxprenolol) in both human and animal hair. After decontamination with methylene chloride (2 times, 2 min), a 200 mg hair strand is pulverized in a ball mill. Then, a 100 mg portion is incubated overnight in 2 mL 0.1 N HCl, at 56 degrees C, in the presence of carteolol, which was used as an internal standard. After neutralization of the acid phase with 0.1 N NaOH, a 2 mL bicarbonate buffer (pH 8.6) is added to the preparation, which is then purified by solid-phase extraction with Isolute C18 columns. Drugs are derivatized using a mixture of trimethylboroxine-ethyl acetate for 15 min at 80 degrees C to form methaneboronate derivatives. Drugs are detected using GC/MS on an HP 6890-5973 system. A 4 microL portion of the derivatized extract is injected using a pulsed mode in a 30 m HP5 MS capillary column. Linearity was observed for all compounds in the range 25 pg/mg to 10 ng/mg. Limits of detection were in the range 2 to 10 pg/mg. At 1 ng/mg, recoveries were in the range from 37 to 100%, with a within-run precision of 5.9 to 14.1% (n = 8). The application of the method can be documented by the following examples: (1) Hair from asthmatic patients (n - 11), including two cases of asthma deaths, tested positive for salbutamol in the range of 27 to 210 pg/mg. (2) A 24-year-old swimmer who tested positive in urine for salbutamnol denied the results. Hair analysis confirmed salbutamol exposure, with a concentration of 71 pg/mg. (3) A shooting specialist was assumed to chronically use metoprolol (100 mg/daily during some periods). Hair concentration of metoprolol was 8.41 ng/mg. (4) An archery specialist was assumed to chronically use sotalol (80 mg/daily, during some periods). Hair concentration of sotalol was 261 pg/mg. (5) Hair from two calves revealed chronic exposure to clenbuterol, which was used to increase the mass of the animals at a concentration of 30 and 48 pg/mg.

  7. CGS 8216: receptor binding characteristics of a potent benzodiazepine antagonist.

    PubMed

    Czernik, A J; Petrack, B; Kalinsky, H J; Psychoyos, S; Cash, W D; Tsai, C; Rinehart, R K; Granat, F R; Lovell, R A; Brundish, D E; Wade, R

    1982-01-25

    CGS 8216 is a novel nonbenzodiazepine that inhibited 3H-flunitrazepam (3H-FLU) binding to rat synaptosomal membranes in vitro at subnanomolar concentrations. It prevented the in vivo labeling of brain benzodiazepine receptors by 3H-FLU with the same potency as diazepam when given orally to mice. Pharmacologic tests showed that it was devoid of benzodiazepine-like activity but it antagonized the actions of diazepam in these tests. It did not interact with alpha- or beta- adrenergic, H1-histaminergic or GABA receptors but it inhibited adenosine-activation of cyclic AMP formation. Studies with 3H-CGS 8216 demonstrated that it bound specifically and with high affinity to rat forebrain membranes and was displaced by drugs with an order of potencies similar to that observed when 3H-diazepam and 3H-FLU were used as radioligands. The regional distribution of 3H-CGS 8216 binding sites in the brain was also similar to that of 3H-FLU. Dissociation of 3H-CGS 8216 binding was slow at 0 degrees C but increased with temperature and was almost complete within 1 min at 37 degrees C. Scatchard analyses were linear, yielding KD values of 0.044, 0.11 and 0.18 nM at 0, 25 and 37 degrees C, respectively; the Bmax value did not change appreciably with temperature and was approximately 1000 fmoles/mg protein. Using 3H-FLU, the value for Bmax as well as for the KD increased with temperature. The total number of binding sites determined for 3H-FLU was greater than that for 3H-CGS 8216 at each temperature. CGS 8216 exhibited mixed-type inhibition of 3H-FLU binding. GABA did not stimulate 3H-CGS 8216 binding whereas it enhanced 3H-FLU binding. CGS 8216 may be a useful ligand for probing the antagonist properties of the benzodiazepine receptor and is likely to exhibit interesting therapeutic effects.

  8. G protein antagonists. A novel hydrophobic peptide competes with receptor for G protein binding.

    PubMed

    Mukai, H; Munekata, E; Higashijima, T

    1992-08-15

    A substance P (SP) analog, [D-Pro4,D-Trp7,9,10] SP4-11, is known to inhibit the actions of various structurally unrelated messenger molecules as well as SP. Our studies on the effects of this peptide on the regulation of purified G proteins by receptor showed that at least some of the biological effects of the peptide can be explained by the ability of the peptide to block the activation of G proteins by receptors. Here we report that a novel truncated SP-related peptide, pGlu-Gln-D-Trp-Phe-D-Trp-D-Trp-Met-NH2, inhibited the activation of G(i) or G(o) by M2 muscarinic cholinergic receptor (M2 mAChR) or of Gs by beta-adrenergic receptor in the reconstituted phospholipid vesicles, assayed by receptor-promoted GTP hydrolysis. The inhibition by the peptide was apparently reversible and competitive with respect to receptor binding to G proteins; the inhibition could be overcome by increasing the concentration of receptor in the vesicles and was not altered by changes in the concentration of G protein. The competing effects of the peptide were used to analyze the effect of agonist on receptor-G protein interaction. The concentration change of muscarinic agonist did not alter the inhibitory effects of the peptide on M2 mAChR-promoted GTPase by G(o), which is consistent with the idea that agonist increases the regulatory efficiency of the receptor but does not alter its affinity for G proteins. This new group of compounds (G protein antagonists) is a promising tool to study receptor-G protein interaction quantitatively.

  9. Electrostimulation of catecholamine release in the eel: modulation by antagonists and autocrine agonists.

    PubMed

    Abele, B; Hathaway, C B; Nibbio, B; Epple, A

    1998-03-01

    The innervated chromaffin cells of the eel (Anguilla rostrata) release norepinephrine (NE) and epinephrine (E), while a component of the macrovascular wall releases dopamine (DA). The release of the three catecholamines is governed by complex controls which include adrenergic, nicotinergic, muscarinergic, and opioid mechanisms. To gain insight into the interactions between neural and autocrine factors in stimulated catecholamine release, we investigated the effect of adrenergic (phentolamine and propranolol) and muscarinergic (atropine) receptor antagonists, and of autocrine opioids (met-enkephalin, codeine, and morphine) on electrostimulated catecholamine secretion in situ. The hind brain (close to the root of nerve IX) of anesthetized eels was stimulated at four different time points, and segments of the posterior cardinal vein or the caudal vein were perfused with a saline solution, with or without test substances. Electrostimulation (30 s) four times within a total study duration of 14 min increased the release of DA, NE, and E into the perfusate of the cardinal vein. The vessel contains the innervated adrenomedullary equivalent. In the noninnervated caudal vein electrical stimulation had no impact on total DA release, while there was a slight decrease of NE release and a slight increase of E release. In the cardinal vein, both the alpha-adrenergic receptor antagonist phentolamine and the beta-adrenergic receptor antagonist propranolol strongly reduced the effect of electrostimulation on catecholamine release. Met-enkephalin reduced the release of all three catecholamines to a similar degree; its impact on NE release was especially strong. Codeine reduced the catecholamine release moderately, while morphine had no effect. Atropine reduced the release of all three catecholamines in a pattern similar to that of met-enkephalin. The findings on the posterior cardinal vein indicate that neurally stimulated NE and E release (1) involves autocrine/paracrine adrenergic

  10. Muscarinic Receptor Antagonists.

    PubMed

    Matera, Maria Gabriella; Cazzola, Mario

    2017-01-01

    Parasympathetic activity is increased in patients with chronic obstructive pulmonary disease (COPD) and asthma and appears to be the major reversible component of airway obstruction. Therefore, treatment with muscarinic receptor antagonists is an effective bronchodilator therapy in COPD and also in asthmatic patients. In recent years, the accumulating evidence that the cholinergic system controls not only contraction by airway smooth muscle but also the functions of inflammatory cells and airway epithelial cells has suggested that muscarinic receptor antagonists could exert other effects that may be of clinical relevance when we must treat a patient suffering from COPD or asthma. There are currently six muscarinic receptor antagonists licenced for use in the treatment of COPD, the short-acting muscarinic receptor antagonists (SAMAs) ipratropium bromide and oxitropium bromide and the long-acting muscarinic receptor antagonists (LAMAs) aclidinium bromide, tiotropium bromide, glycopyrronium bromide and umeclidinium bromide. Concerns have been raised about possible associations of muscarinic receptor antagonists with cardiovascular safety, but the most advanced compounds seem to have an improved safety profile. Further beneficial effects of SAMAs and LAMAs are seen when added to existing treatments, including LABAs, inhaled corticosteroids and phosphodiesterase 4 inhibitors. The importance of tiotropium bromide in the maintenance treatment of COPD, and likely in asthma, has spurred further research to identify new LAMAs. There are a number of molecules that are being identified, but only few have reached the clinical development.

  11. CCR2 antagonists.

    PubMed

    Struthers, Mary; Pasternak, Alexander

    2010-01-01

    Inhibition of CCR2 has been considered as a target for multiple therapeutic diseases including autoimmune disease, atherosclerosis, pain, and metabolic disease, based in part on the critical role this receptor plays on monocyte migration. Numerous companies have reported programs to identify CCR2 antagonists. Common challenges to the development of CCR2 agents have included poor activity at the rodent receptor and selectivity for both other chemokine receptors and ion channels. This review summarizes the rationale for targeting CCR2 in disease, the recent progress in the identification of potent and select CCR2 antagonists, and the current status of clinical trials for CCR2 agents.

  12. Opioid Antagonist Impedes Exposure.

    ERIC Educational Resources Information Center

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

  13. Opioid Antagonist Impedes Exposure.

    ERIC Educational Resources Information Center

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

  14. Advantages of an antagonist: bicuculline and other GABA antagonists

    PubMed Central

    Johnston, Graham AR

    2013-01-01

    The convulsant alkaloid bicuculline continues to be investigated more than 40 years after the first publication of its action as an antagonist of receptors for the inhibitory neurotransmitter GABA. This historical perspective highlights key aspects of the discovery of bicuculline as a GABA antagonist and the sustained interest in this and other GABA antagonists. The exciting advances in the molecular biology, pharmacology and physiology of GABA receptors provide a continuing stimulus for the discovery of new antagonists with increasing selectivity for the myriad of GABA receptor subclasses. Interesting GABA antagonists not structurally related to bicuculline include gabazine, salicylidene salicylhydrazide, RU5135 and 4-(3-biphenyl-5-(4-piperidyl)-3-isoxazole. Bicuculline became the benchmark antagonist for what became known as GABAA receptors, but not all ionotropic GABA receptors are susceptible to bicuculline. In addition, not all GABAA receptor antagonists are convulsants. Thus there are still surprises in store as the study of GABA receptors evolves. PMID:23425285

  15. Indications for Opioid Antagonists.

    PubMed

    Coppes, O J Michael; Sang, Christine N

    2017-06-01

    As opioids have become more common in clinical practice for the treatment of both acute and chronic pain, so too has the need for a deeper understanding of the clinical applications of opioid antagonists. The purpose of this review is to present both the longstanding and potential new indications for the use of drugs that block the effects of opioid receptors. There is a growing body of data demonstrating the modulation of pain by opioid antagonists. Additional clinical studies that show their direct antinociceptive effects and/or enhancement of the analgesic potency of opioid agonists are warranted. We briefly discuss the well-established role that these agents play in the reversal of life-threatening opioid toxicity and explore both existing and expanding clinical applications, including their apparent paradox that they may themselves be associated with analgesia.

  16. alpha2-Adrenoreceptor antagonists.

    PubMed

    Mayer, P; Imbert, T

    2001-06-01

    A review of the literature relating to the therapeutic potential of alpha2-adrenoceptor antagonists published between 1990 and 2000 is presented. Although extensively studied since the early 1970s in a wide spectrum of therapeutic applications, the distinction of alpha2-adrenoceptor subtypes and some emerging evidence concerning new applications in neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, obesity and schizophrenia, have refreshed an interest in this class of agents.

  17. Calcium antagonists and vasospasm.

    PubMed

    Meyer, F B

    1990-04-01

    A critical review of the clinical data supports the conclusion that nimodipine decreases the severity of neurologic deficits and improves outcome after subarachnoid hemorrhage. The mechanisms by which mortality and morbidity are reduced are still controversial. First, the frequency of vasospasm is not altered (Figs. 5 and 6). Second, the consistent reversal of vasospasm once present has not been demonstrated either angiographically or by noninvasive cerebral blood flow studies. These observations suggest that there is either modification of microcirculatory flow (i.e., dilation of pial conducting vessels or decreased platelet aggregation) or a direct neuronal protective effect. As suggested previously, support for either mechanism is not resolute, and further investigation is necessary. Currently, nimodipine has been the most thoroughly investigated calcium antagonist both from an experimental and clinical perspective. Oral administration has had few reported complications. Therefore, the benefit/risk ratio clearly supports the prophylactic use of this calcium antagonist in patients of all clinical grades after subarachnoid hemorrhage. Evidence also indicates that starting nimodipine after the onset of delayed ischemic deficits is of benefit. Finally, it can be predicted that in the future additional calcium antagonists with more selective vascular or neuronal effects will be developed for use in neurologic disorders.

  18. Tetrahydroindolizinone NK1 antagonists.

    PubMed

    Bao, Jianming; Lu, Huagang; Morriello, Gregori J; Carlson, Emma J; Wheeldon, Alan; Chicchi, Gary G; Kurtz, Marc M; Tsao, Kwei-Lan C; Zheng, Song; Tong, Xinchun; Mills, Sander G; DeVita, Robert J

    2010-04-01

    A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles. 2010 Elsevier Ltd. All rights reserved.

  19. Small Molecule CXCR3 Antagonists.

    PubMed

    Andrews, Stephen P; Cox, Rhona J

    2016-04-14

    Chemokines and their receptors are known to play important roles in disease. More than 40 chemokine ligands and 20 chemokine receptors have been identified, but, to date, only two small molecule chemokine receptor antagonists have been approved by the FDA. The chemokine receptor CXCR3 was identified in 1996, and nearly 20 years later, new areas of CXCR3 disease biology continue to emerge. Several classes of small molecule CXCR3 antagonists have been developed, and two have shown efficacy in preclinical models of inflammatory disease. However, only one CXCR3 antagonist has been evaluated in clinical trials, and there remain many opportunities to further investigate known classes of CXCR3 antagonists and to identify new chemotypes. This Perspective reviews the known CXCR3 antagonists and considers future opportunities for the development of small molecules for clinical evaluation.

  20. A nonsteroidal glucocorticoid receptor antagonist.

    PubMed

    Miner, Jeffrey N; Tyree, Curtis; Hu, Junlian; Berger, Elaine; Marschke, Keith; Nakane, Masaki; Coghlan, Michael J; Clemm, Dave; Lane, Ben; Rosen, Jon

    2003-01-01

    Selective intracellular receptor antagonists are used clinically to ameliorate hormone-dependent disease states. Patients with Cushing's syndrome have high levels of the glucocorticoid, cortisol, and suffer significant consequences from this overexposure. High levels of this hormone are also implicated in exacerbating diabetes and the stress response. Selectively inhibiting this hormone may have clinical benefit in these disease states. To this end, we have identified the first selective, nonsteroidal glucocorticoid receptor (GR) antagonist. This compound is characterized by a tri-aryl methane core chemical structure. This GR-specific antagonist binds with nanomolar affinity to the GR and has no detectable binding affinity for the highly related receptors for mineralocorticoids, androgens, estrogens, and progestins. We demonstrate that this antagonist inhibits glucocorticoid-mediated transcriptional regulation. This compound binds competitively with steroids, likely occupying a similar site within the ligand-binding domain. Once bound, however, the compound fails to induce critical conformational changes in the receptor necessary for agonist activity.

  1. Agonist-independent effects of muscarinic antagonists on Ca2+ and K+ currents in frog and rat cardiac cells.

    PubMed

    Hanf, R; Li, Y; Szabo, G; Fischmeister, R

    1993-02-01

    1. The whole-cell patch clamp and intracellular perfusion techniques were used for studying the effects of atropine and other muscarinic acetylcholine receptor (mAChR) antagonists on the L-type calcium currents (ICa) in frog and rat ventricular myocytes, and on the mAChR-activated K+ current (IK(ACh)) in frog atrial myocytes. 2. In frog ventricular myocytes, atropine (0.1 nM to 1 microM) reversed the inhibitory effect of acetylcholine (ACh, 1 nM) on ICa previously stimulated by isoprenaline (Iso, 2 microM), a beta-adrenergic agonist. However, in the concomitant presence of Iso, ACh and atropine, ICa was > 50% larger than in Iso alone. 3. The effects of atropine were then examined in the absence of mAChR agonists. After a preliminary stimulation of ICa with Iso (0.1 or 2 microM), atropine induced a dose-dependent stimulation of ICa. EC50 (i.e. the concentration of atropine at which the response was 50% of the maximum) and Emax (i.e. maximal stimulation of ICa expressed as percentage increase in ICa with respect to the level in Iso alone) were respectively 0.6 nM and 35%. The stimulatory effect of atropine on ICa was not voltage dependent. 4. Atropine (1 microM) had no effect on frog ICa (i) under basal conditions, (ii) upon stimulation of ICa by the dihydropyridine agonist (-)-Bay K 8644 (1 microM), or (iii) when ICa had been previously stimulated by intracellular perfusion with cyclic AMP (3 microM). However, atropine increased ICa after a stimulation by forskolin (0.3 microM). Therefore, an increased adenylyl cyclase activity was required for atropine to produce its stimulatory effect on ICa. 5. The order of potency of mAChR antagonists to reverse the inhibitory effect of ACh on Iso elevated ICa in frog ventricle was atropine > AF-DX 116 > pirenzepine. In the absence of ACh, mAChR antagonists produced their stimulatory effect on Iso elevated ICa with the same order of potency. 6. Intracellular substitution of Gpp(NH)p (5'-guanylylimidiphosphate) for GTP (420 micro

  2. Platelet-activating factor antagonists.

    PubMed

    Negro Alvarez, J M; Miralles López, J C; Ortiz Martínez, J L; Abellán Alemán, A; Rubio del Barrio, R

    1997-01-01

    Platelet-activating factor (PAF), identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, exhibits potent proinflammatory properties. PAF is produced by numerous cell types, including endothelial cells, neutrophils, monocytes, macrophages, basophils, eosinophils and mastocytes. Since the discovery and identification of the chemical structure of PAF, a large variety of specific PAF-receptor antagonists, both natural and synthetic compounds, have been described. Intensive research has been conducted and development programs set up by more 25 pharmaceutical companies world-wide, studying the therapeutic interest of more than 50 PAF-receptors antagonists in various pathophysiological conditions. Medline (1966-1996), Embase (Excerpta Medica; 1974-1996), and other biomedical and drug directory databases were searched to identify English-language articles (basic science, clinical trial research, and review articles) and abstracts of conference proceedings on PAF receptor antagonists and related terms. The most important PAF receptor antagonists are reviewed with their effectiveness in various experimental tests. Fundamentally, PAF antagonists may be divided in two groups: natural and synthetic compounds. Natural (Ginkgolides, Kadsurenone, Chantancin, Phomactin, Swietemohonin A, Prehispalone, THC-7-oic acid, Aglafoline, FR 900452, PCA 4248 and SCH 37370), and synthetic antagonists (CV-3988, CV-6209, SRI 63-072, SRI 63-441, UR-10324, UR-11353, E-5880, CL 184005, 6-Mono and Bis-aryl phosphate antagonists, TCV-309, Ro-74719, WEB 2086, Y 24180, BN 50726, BN 50727, BN 50730, BN 50739, Ro 24-4736, Ro 24-0238, RP 55778, RP 59227, RP 66681, YM 264, YM 461, SM 10661, SR 27417, UK 74505, BB 182, BB 823, BB 654, SDZ 64-412, SDZ 65-123, L 652731, L 659898, L 668750, L 671284, L680573, L 680574, CIS 19, ABT-299 and Pinusolide) have a great variability in their chemical structure that might have importance in their different pharmacological profile. The great majority of these

  3. Immediate post-defeat infusions of the noradrenergic receptor antagonist propranolol impair the consolidation of conditioned defeat in male Syrian hamsters.

    PubMed

    Gray, Cloe Luckett; Krebs-Kraft, Desiree L; Solomon, Matia B; Norvelle, Alisa; Parent, Marise B; Huhman, Kim L

    2015-12-01

    Social defeat occurs when an animal is attacked and subjugated by an aggressive conspecific. Following social defeat, male Syrian hamsters fail to display species-typical territorial aggression and instead exhibit submissive or defensive behaviors even when in the presence of a non-aggressive intruder. We have termed this phenomenon conditioned defeat (CD). The mechanisms underlying CD are not fully understood, but data from our lab suggest that at least some of the mechanisms are similar to those that mediate classical fear conditioning. The goal of the present experiment was to test the hypothesis that noradrenergic signaling promotes the consolidation of CD, as in classical fear conditioning, by determining whether CD is disrupted by post-training blockade of noradrenergic activity. In Experiment 1, we determined whether systemic infusions of the noradrenergic receptor antagonist propranolol (0, 1.0, 10, or 20mg/kg) given immediately after a 15 min defeat by a resident aggressor would impair CD tested 48 h later. Hamsters that were given immediate post-training infusions of propranolol (1.0, but not 10 or 20mg/kg) showed significantly less submissive behavior than did those given vehicle infusions supporting the hypothesis that there is noradrenergic modulation of the consolidation of a social defeat experience. In Experiment 2, we demonstrated that propranolol (1.0mg/kg) given immediately, but not 4 or 24h, after defeat impaired CD tested 48 h after defeat indicating that the window within which the memory for social defeat is susceptible to beta-adrenergic modulation is temporary. In Experiment 3, we examined whether central blockade of noradrenergic receptors could recapitulate the effect of systemic injections by giving an intracerebroventricular infusion of propranolol immediately after defeat and examining the effect on CD 24h later. Centrally administered propranolol (20 μg/3 μl but not 2 μg/3 μl) was also effective in dose-dependently reducing

  4. Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats.

    PubMed

    Rudoy, C A; Van Bockstaele, E J

    2007-06-30

    Anxiety has been indicated as one of the main symptoms of the cocaine withdrawal syndrome in human addicts and severe anxiety during withdrawal may potentially contribute to relapse. As alterations in noradrenergic transmission in limbic areas underlie withdrawal symptomatology for many drugs of abuse, the present study sought to determine the effect of cocaine withdrawal on beta-adrenergic receptor (beta(1) and beta(2)) expression in the amygdala. Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that beta(1)-adrenergic receptor, but not beta(2)-adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with betaxolol, a highly selective beta(1)-adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 h following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 h following the last betaxolol injection. Following behavioral testing, betaxolol effects on beta(1)-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal. Animals treated with betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline. Furthermore

  5. Immediate post-defeat infusions of the noradrenergic receptor antagonist propranolol impair the consolidation of conditioned defeat in male Syrian hamsters

    PubMed Central

    Gray, Cloe Luckett; Krebs-Kraft, Desiree L.; Solomon, Matia B.; Norvelle, Alisa; Parent, Marise B.; Huhman, Kim. L.

    2015-01-01

    Summary Social defeat occurs when an animal is attacked and subjugated by an aggressive conspecific. Following social defeat, male Syrian hamsters fail to display species-typical territorial aggression and instead exhibit submissive or defensive behaviors even when in the presence of a non-aggressive intruder. We have termed this phenomenon conditioned defeat (CD). The mechanisms underlying CD are not fully understood, but data from our lab suggest that at least some of the mechanisms are similar to those that mediate classical fear conditioning. The goal of the present experiment was to test the hypothesis that noradrenergic signaling promotes the consolidation of CD, as in classical fear conditioning, by determining whether CD is disrupted by post-training blockade of noradrenergic activity. In Experiment 1, we determined whether systemic infusions of the noradrenergic receptor antagonist propranolol (0, 1.0, 10, or 20 mg/kg) given immediately after a 15 min defeat by a resident aggressor would impair CD tested 48h later. Hamsters that were given immediate post-training infusions of propranolol (1.0, but not 10 or 20 mg/kg) showed significantly less submissive behavior than those given vehicle infusions supporting the hypothesis that there is noradrenergic modulation of social defeat consolidation. In Experiment 2, we demonstrated that propranolol (1.0 mg/kg) given immediately, but not 4 or 24h, after defeat impaired CD tested 48h after defeat indicating that the window within which the memory for social defeat is susceptible to beta-adrenergic modulation is temporary. In Experiment 3, we examined whether central blockade of noradrenergic receptors could recapitulate the effect of systemic injections by giving an intracerebroventricular infusion of propranolol immediately after defeat and examining the effect on CD 24 h later. Centrally administered propranolol (20 μg/3μl but not 2 μg/3μl) was also effective in dose-dependently reducing consolidation of CD

  6. Role of selective alpha and beta adrenergic receptor mechanisms in rat jejunal longitudinal muscle contractility.

    PubMed

    Seiler, Roland; Rickenbacher, Andreas; Shaw, Sidney; Haefliger, Simon; Balsiger, Bruno M

    2008-06-01

    Gut motility is modulated by adrenergic mechanisms. The aim of our study was to examine mechanisms of selective adrenergic receptors in rat jejunum. Spontaneous contractile activity of longitudinal muscle strips from rat jejunum was measured in 5-ml tissue chambers. Dose-responses (six doses, 10(-7) -3 x 10(-5)M) to norepinephrine (NE, nonspecific), phenylephrine (PH, alpha1), clonidine (C, alpha2), prenalterol (PR, beta1), ritodrine (RI, beta2), and ZD7714 (ZD, beta3) were evaluated with and without tetrodotoxin (TTX, nerve blocker). NE(3 x 10(-5)M) inhibited 74 +/- 5% (mean +/- SEM) of spontaneous activity. This was the maximum effect. The same dose of RI(beta2), PH(alpha1), or ZD(beta(3)) resulted in an inhibition of only 56 +/- 5, 43 +/- 4, 33 +/- 6, respectively. The calculated concentration to induce 50% inhibition (EC50) of ZD(beta3) was similar to NE, whereas higher concentrations of PH(alpha1) or RI(beta2) were required. C(alpha2) and PR(beta1) had no effect. TTX changed exclusively the EC50 of RI from 4.4 +/- 0.2 to 2.7 +/- 0.8% (p < 0.04). Contractility was inhibited by NE (nonspecific). PH(alpha1), RI(beta2), and ZD(beta3) mimic the effect of NE. TTX reduced the inhibition by RI. Our results suggest that muscular alpha1, beta2, and beta3 receptor mechanisms mediate adrenergic inhibition of contractility in rat jejunum. beta2 mechanisms seem to involve also neural pathways.

  7. Beta-adrenergic stimulation reverses the IKr–IKs dominant pattern during cardiac action potential

    PubMed Central

    Banyasz, Tamas; Jian, Zhong; Horvath, Balazs; Khabbaz, Shaden; Izu, Leighton T.; Chen-Izu, Ye

    2014-01-01

    β-adrenergic stimulation differentially modulates different K+ channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of IKs, IKr, and IK1 current in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K+ current to the total repolarization reserve. In this study we used an innovative AP-clamp Sequential Dissection technique to directly record the dynamic –IKs, IKr, IK1– currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of IKs, IKr, IK1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca2+ homeostasis. We found that isoproterenol treatment significantly enhanced IKs, moderately increased IK1, but slightly decreased IKr in a dose-dependent manner. The dominance pattern of the K+ currents was IKr>IK1>IKs at the control condition, but reversed to IKr

  8. beta. -adrenergic receptor-mediated hepatic glycogenolysis is increased in aged male rats

    SciTech Connect

    Herring, P.A.; Graham, S.M.; Arinze, I.J.

    1986-03-05

    The effect of age on catecholamine-stimulated glycogenolysis was studied in isolated hepatocytes prepared from 3, 12, and 24 month-old rats. Glucose release was stimulated by epinephrine and norepinephrine, this was inhibited by phentolamine and prazosin. Isoproterenol (ISO) stimulated glycogenolysis only in cells from 24 month-old rats, this was blocked by propranolol. In liver plasma membranes, binding of (/sup 3/H)yohimbine (100-130 fmol/mg protein) did not change with age, whereas (/sup 3/H)prazosin binding decreased from 870 fmol/mg at 3 months to 435 fmol/mg at 12 months, but subsequently rose to 656 fmol/mg at 24 months. (/sup 125/I)Cyanopindolol binding increased from 8 fmol/mg at 3 months to 19 fmol/mg at 24 months. The proportion of ..beta..-receptors in the high affinity state increased from 28% at 3 months to 42% at 24 months. ISO stimulated adenylate cyclase at 24 months but not at 3 months. Basal, fluoride-, GTP-, and Gpp(NH)p-stimulated activities were 1.4- to 2.4-fold greater at 24 months than at 3 months. These results suggest an age-related increase in the sensitivity of adenylate cyclase to ..beta..-receptor stimulation.

  9. The Effect of Beta Adrenergic Blockade on Ratings of Perceived Exertion.

    DTIC Science & Technology

    1984-01-01

    of cardiac rehabil- itation and adult fitness programs. These programs have established the fact that most individuals can go through an aerobic...Medicine (12) provide for the safe attainment of improved cardiovascular and musculoskeletal function by specifying an optimal mode, frequency, duration...complica- tions. Most cardiac rehabilitation and adult fitness pro- grams prescribe exercise intensity by either the METS (1 MET=3.5 ml of oxygen per

  10. Shortterm "escape" and longterm "drift." The dissipation effects of the beta adrenergic blocking agents.

    PubMed

    Boger, W P

    1983-12-01

    The dissipation phenomena associated with timolol have important implications in the clinical management of glaucoma patients. Shortterm "escape" and longterm "drift" are clinical terms which describe the reduction of timolol's efficacy over a few days and over months and years, respectively. Recent physiological studies suggest a cellular explanation for these readjustments in tissue responsiveness to continued administration of timolol. While the precise location of the physiologically responding cells and the interactions of the various adrenergic responsive elements remain unclear, subsensitivity and supersensitivity may prove to be the most accurate designations for alterations in tissue responsiveness to adrenergic stimulation following "down regulation" or "up regulation" of beta receptor density on cell membranes.

  11. Increased beta-adrenergic responsiveness induced by 14 days exposure to simulated microgravity

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Polet, J. L.; Engelke, K. A.; Hoffler, G. W.; Lane, L. D.; Blomqvist, C. G.

    1995-01-01

    Increased sensitivity of end-organ responses to neuroendocrine stimuli as a result of prolonged exposure to the relative inactivity of microgravity has recently been hypothesized. This notion is based on the inverse relationship between circulating norepinephrine and beta-adrenoreceptor sensitivity. The beta-adrenoreceptor activity is reduced in individuals who have elevated plasma norepinephrine as a result of regular exposure to upright posture and physical exercise. In contrast, adrenoreceptor hypersensitivity has been reported in patients with dysautonomias in which circulating catecholamines are absent or reduced. Taken together, these studies and the observation that circulating plasma norepinephrine has been reduced during spaceflight and in groundbased simulations of microgravity prompt the suggestion that adrenoreceptor hypersensitivity may be a consequence of the adaptation to spaceflight. We conducted an experiment designed to measure cardiovascular responses to adrenoreceptor agonists in human subjects before and after prolonged exposure to 6 deg head-down tilt (HDT) to test the hypothesis that adaptation to microgravity increases adrenoreceptor responsiveness, and that this adaptation is associated with reduced levels of circulating norepinephrine.

  12. Thromboelastography After Murine TBI and Implications of Beta-Adrenergic Receptor Knockout.

    PubMed

    Liou, Douglas Z; Ko, Ara; Volod, Oksana; Barmparas, Galinos; Harada, Megan Y; Martin, Matthew J; Salim, Ali; Dhillon, Navpreet; Thomsen, Gretchen M; Ley, Eric J

    2016-08-01

    The source of coagulopathy in traumatic brain injury (TBI) is multifactorial and may include adrenergic stimulation. The aim of this study was to assess coagulopathy after TBI using thromboelastography (TEG), and to investigate the implications of β-adrenergic receptor knockout. Adult male wild type c57/bl6 (WT) and β1/β2-adrenergic receptor knockout (BKO) mice were assigned to either TBI (WT-TBI, BKO-TBI) or sham injury (WT-sham, BKO-sham). Mice assigned to TBI were subject to controlled cortical impact (CCI). At 24 h post-injury, whole blood samples were obtained and taken immediately for TEG. At 24 h after injury, a trend toward increased fibrinolysis was seen in WT-TBI compared to WT-sham although this did not reach significance (EPL 8.1 vs. 0 %, p = 0.18). No differences were noted in fibrinolysis in BKO-TBI compared to BKO-sham (LY30 2.6 vs. 2.5 %, p = 0.61; EPL 3.4 vs. 2.9 %, p = 0.61). In addition BKO-TBI demonstrated increased clot strength compared to BKO-sham (MA 76.6 vs. 68.6, p = 0.03; G 18.2 vs. 11.3, p = 0.03). In a mouse TBI model, WT mice sustaining TBI demonstrated a trend toward increased fibrinolysis at 24 h after injury while BKO mice did not. These findings suggest β-blockade may attenuate the coagulopathy of TBI and minimize progression of intracranial hemorrhage by reducing fibrinolysis and increasing clot strength.

  13. Beta-adrenergic receptor sensitivity, autonomic balance and serotonergic activity in practitioners of Transcendental Meditation

    SciTech Connect

    Hill, D.A.

    1989-01-01

    The aim of this thesis was to investigate the acute autonomic effects of the Transcendental Meditation Program (TM) and resolve the conflict arising from discrepant neurochemical and psychophysiological data. Three experimental investigations were performed. The first examined beta{sub 2}-adrenergic receptors (AR's) on peripheral blood lymphocytes, via (I{sup 125})iodocyanopindolol binding, in 10 male mediating and 10 age matched non-meditating control subjects, to test the hypothesis that the long-term practice of TM and the TM Sidhi Program (TMSP) reduces end organ sensitivity to adrenergic agonists. The second investigated respiratory sinus arrhythmia (an indirect measure of cardiac Parasympathetic Nervous System tone), and skin resistance (a measure of Sympathetic Nervous System tone) during periods of spontaneous respiratory apneusis, a phenomenon occurring during TM that is known to mark the subjective experience of transcending. The third was within subject investigation of the acute effects of the TMSP on 5-hydroxytryptamine (5-HT) activity. Platelet 5-HT was assayed by high pressure liquid chromatography with electrochemical detection, plasma prolactin (PL) and lutenizing hormone (LH) by radioimmunoassay, tryptophan by spectrofluorimetry, and alpha-1-acid glycoprotein (AGP, a modulator of 5-HT uptake) by radial immunodiffusion assay.

  14. Toxicity of select beta adrenergic receptor-blocking pharmaceuticals (B-blockers) on aquatic organisms.

    PubMed

    Huggett, D B; Brooks, B W; Peterson, B; Foran, C M; Schlenk, D

    2002-08-01

    One class of pharmaceutical compounds identified in U.S. and European waters are the B-adrenergic receptor blocking compounds (B-blockers). However, little information is available on the potential aquatic toxicity of these compounds. Therefore, Hyalella azteca, Daphnia magna, Ceriodaphnia dubia, and Oryias latipes (Japanese medaka) were exposed to metoprolol, nadolol, and propranolol to determine potential toxicity. Average 48-h LC(50) for propranolol to H. azteca was 29.8 mg/L. The no-observed-effects concentration (NOEC) and lowest-observed-effects concentration (LOEC) for propranolol affecting reproduction of H. azteca were 0.001 and 0.1 mg/L, respectively. The average propranolol and metoprolol 48-h LC(50)s for D. magna were 1.6 and 63.9 mg/L, respectively. C. dubia 48-h LC(50)s were 0.85 and 8.8 mg/L for propranolol and metoprolol, respectively. The NOEC and LOEC of propranolol affecting reproduction in C. dubia were 0.125 and 0.25 mg/L, respectively. In O. latipes, the propranolol 48-h LC(50) was 24.3 mg/L. Medaka growth was decreased at 0.5 mg/L propranolol. A 2-week medaka reproductive study indicated significant changes in plasma steroid levels; however, no changes in the average number of eggs produced or number of viable eggs which hatched was observed. In a 4-week follow-up propranolol exposure, the total number of eggs produced by medaka and the number of viable eggs that hatched were decreased at concentrations as low as 0.5 microg/L. Based on this study and the expected aqueous environmental exposure levels, adverse effects of propranolol to invertebrate populations is unlikely; however, further reproductive studies are need to elucidate the risk to teleosts.

  15. Greater Beta-Adrenergic Receptor Mediated Vasodilation in Women Using Oral Contraceptives

    PubMed Central

    Limberg, Jacqueline K.; Peltonen, Garrett L.; Johansson, Rebecca E.; Harrell, John W.; Kellawan, Jeremy M.; Eldridge, Marlowe W.; Sebranek, Joshua J.; Walker, Benjamin J.; Schrage, William G.

    2016-01-01

    Background: β-adrenergic receptors play an important role in mitigating the pressor effects of sympathetic nervous system activity in young women. Based on recent data showing oral contraceptive use in women abolishes the relationship between muscle sympathetic nervous system activity and blood pressure, we hypothesized forearm blood flow responses to a β-adrenergic receptor agonist would be greater in young women currently using oral contraceptives (OC+, n = 13) when compared to those not using oral contraceptives (OC–, n = 10). Methods: Women (18–35 years) were studied during the early follicular phase of the menstrual cycle (days 1–5) or placebo phase of oral contraceptive use. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured at baseline and during graded brachial artery infusion of the β-adrenergic receptor agonist, Isoproterenol (ISO), as well as Acetylcholine (ACH, endothelium-dependent vasodilation) and Nitroprusside (NTP, endothelium-independent vasodilation). Forearm vascular conductance was calculated (FVC = FBF/MAP, ml/min/100 mmHg) and the rise in FVC from baseline during infusion quantified vasodilation (ΔFVC = FVCinfusion − FVCbaseline). Results: ISO increased FVC in both groups (p < 0.01) and ISO-mediated ΔFVC was greater in OC+ compared to OC– (Main effect of group, p = 0.02). Expressing data as FVC and FBF resulted in similar conclusions. FVC responses to both ACH and NTP were also greater in OC+ compared to OC–. Conclusions: These data are the first to demonstrate greater β-adrenergic receptor-mediated vasodilation in the forearm of women currently using oral contraceptives (placebo phase) when compared to those not using oral contraceptives (early follicular phase), and suggest oral contraceptive use influences neurovascular control. PMID:27375493

  16. Cattle handling technique can induce fatigued cattle syndrome in cattle not fed a beta adrenergic agonist.

    PubMed

    Frese, D A; Reinhardt, C D; Bartle, S J; Rethorst, D N; Hutcheson, J P; Nichols, W T; Depenbusch, B E; Corrigan, M E; Thomson, D U

    2016-02-01

    Angus crossbred steers (n = 40; 563 ± 44 kg) were used to examine the effects of handling method and fat thickness on the blood chemistry and physiology of market steers. Steers were blocked by backfat (BF) thickness and were randomly assigned to treatment groups: low-stress handling (LSH) and aggressive handling (AH). Cattle were then ran¬domly assigned to one of 5 blocks containing 4 steers from the LSH and AH treatments. Steers in the LSH treatment were walked and AH cattle were run through a course of 1,540 m. Blood samples were obtained via jugular venipuncture before handling (BASE), at 770 m (LAP1), at 1,540 m (LAP2), and at1 h (1H) and 2 h (2H) after finishing the course. Blood samples were analyzed for plasma lactate (LAC), creatinine kinase (CK), base excess (BE), blood pH (pH), serum cortisol (CORT) concentrations, and venous carbon dioxide (PvCO2) and oxygen (PvO2) pressures. Heart rate (HR), respiratory rate (RR), and rectal temperature (TEMP) were measured at the same intervals. Cattle in the AH treatment had greater ( < 0.05) LAC than those in LSH at BASE (4.1 vs. 3.0 mmol/L), LAP1 (16.5 vs. 2.3 mmol/L), LAP2 (22.3 vs. 2.4 mmol/L), 1H (7.2 vs. 2.7 mmol/L), and 2H (4.0 vs. 2.5 mmol/L), respectively. Creatinine kinase and RR were not different (P > 0.14). Blood pH in AH cattle was decreased compared with that in LSH cattle ( < 0.05) at LAP1 (7.25 vs. 7.45) and LAP2 (7.19 vs. 7.48) but was not different ( > 0.13) at BASE, 1H, or 2H. Heart rate and TEMP were increased in AH cattle compared to LSH ( > 0.01). Serum cortisol was increased ( < 0.05) in AH compared to that in LSH cattle at LAP1 (87.5 vs. 58.9 nmol/L), LAP2 (144.4 vs. 93.1 nmol/L), and 1H (113.5 vs. 53.1 nmol/L). Although RR was not differ¬ent between LSH and AH, PvCO2 was decreased in AH compared to that in LSH ( < 0.05) at LAP2 (30.6 vs. 39.3 mmHg) and PvO2 was increased at LAP1 (42.7 vs. 33.5 mmHg) and at LAP2 (51.5 vs. 36.6 mmHg). Lactate was increased in AH cattle in the thicker BF group at 1H ( < 0.05), and blood pH was decreased at LAP1, LAP2, and 1H ( < 0.05) compared to the thinner BF cohorts. Four AH steers became exhausted (EXH) and did not complete the course. Increased CK, decreased PvCO2, and muscle tremors occurred in EXH steers compared to non-exhausted AH cohorts. Results of this study show that AH causes physiologic and blood chemistry changes in steers, which can be potentially detrimental to cattle, emphasizing the need for low-stress handling practices.

  17. Effect of beta adrenergic blockade on thallium-201 myocardial perfusion imaging.

    PubMed Central

    Hockings, B; Saltissi, S; Croft, D N; Webb-Peploe, M M

    1983-01-01

    Nine patients with stable angina (group 1) underwent maximal treadmill stress testing and thallium-201 (201T1) myocardial scintigraphy after intravenous propranolol hydrochloride, and after placebo. Though seven of the nine patients exercised longer after propranolol than after placebo, this difference did not reach statistical significance. Propranolol, however, significantly reduced the mean maximum rate pressure product. Comparison of the perfusion scans on and off propranolol showed that in 36 out of 90 of the myocardial segments recorded (nine patients, five segments scanned twice per patient), only one of the scans showed a defect. In 24 out of 36 of these the propranolol scan was negative, the defect appearing in the placebo scan. Defects present on both scans but differing significantly in size occurred in 22 out of 54 view pairs (nine patients, three views after exercise and three views after redistribution on propranolol and on placebo), and in 19 of these the smaller defect was seen in the propranolol scan. In one of the nine patients, the propranolol scan was normal (false negative), whereas defects corresponding to angiographically proven coronary artery lesions were seen on the placebo scan. Six patients (group 2) were maximally exercised after propranolol and then re-exercised to the same rate pressure product on placebo. Again 16 out of 60 of the segment pairs disagreed and in 10 of these the unmatched defect was present on the placebo scan. In 10 out of 14 discrepant view pairs, the smaller defect occurred on the propranolol scan. Thus in patients taking propranolol, negative results do not exclude coronary artery disease, and perfusion defects (if present) though accurately reflecting the presence of disease may underestimate its true extent. PMID:6821615

  18. The Use of Beta-Adrenergic Blockade in Preventing Trauma-Induced Hepatomegaly

    PubMed Central

    Barrow, Robert E.; Wolfe, Robert R.; Dasu, Mohan R.; Barrow, Laura N.; Herndon, David N.

    2006-01-01

    Objective: The objective of this study was to test the hypothesis that hepatomegaly in burned children can be attenuated or reversed by blocking lipolysis and reducing free fatty acids delivered to the liver. Summary Background Data: Accelerated lipolysis in severely burned children has been shown to play an important role in the accumulation of hepatic TGs. Severely burned children who survive 10 days or more after injury commonly have enlarged livers often twice or more normal size for their sex, age, and weight. Methods: Ninety-eight children, 2 to 18 years of age, with burns covering more than 40% of their body surface and who received either propranolol (β-adrenergic blockade) or placebo were studied. Liver weights were measured by ultrasonic scanning. Body composition changes were identified by dual-image x-ray absorptiometry and validated by whole-body potassium-40 scintillation counting. Discarded abdominal cutaneous adipose tissue was collected before and after propranolol or placebo for microarray analysis. Results: In 80% of severely burned children studied not receiving propranolol, liver sizes increased by 100% or more while 86% of burned children receiving propranolol showed a decrease or no change in liver size over the same period of time after injury. Gene expression patterns of adipose tissue after propranolol treatment showed that all of the identified genes related to lipid metabolism were down-regulated. Conclusions: Data reported here support the hypothesis that β-adrenergic blockade can reduce delivery of fatty acids to the liver and hepatic congestion commonly found in severely burned children by inhibiting lipolysis and reducing hepatic blood flow. PMID:16371745

  19. Quantification of beta adrenergic receptor subtypes in beta-arrestin knockout mouse airways.

    PubMed

    Hegde, Akhil; Strachan, Ryan T; Walker, Julia K L

    2015-01-01

    In allergic asthma Beta 2 adrenergic receptors (β2ARs) are important mediators of bronchorelaxation and, paradoxically, asthma development. This contradiction is likely due to the activation of dual signaling pathways that are downstream of G proteins or β-arrestins. Our group has recently shown that β-arrestin-2 acts in its classical role to desensitize and constrain β2AR-induced relaxation of both human and murine airway smooth muscle. To assess the role of β-arrestins in regulating β2AR function in asthma, we and others have utilized β-arrestin-1 and -2 knockout mice. However, it is unknown if genetic deletion of β-arrestins in these mice influences β2AR expression in the airways. Furthermore, there is lack of data on compensatory expression of βAR subtypes when either of the β-arrestins is genetically deleted, thus necessitating a detailed βAR subtype expression study in these β-arrestin knockout mice. Here we standardized a radioligand binding methodology to characterize and quantitate βAR subtype distribution in the airway smooth muscle of wild-type C57BL/6J and β-arrestin-1 and β-arrestin-2 knockout mice. Using complementary competition and single-point saturation binding assays we found that β2ARs predominate over β1ARs in the whole lung and epithelium-denuded tracheobronchial smooth muscle of C57BL/6J mice. Quantification of βAR subtypes in β-arrestin-1 and β-arrestin-2 knockout mouse lung and epithelium-denuded tracheobronchial tissue showed that, similar to the C57BL/6J mice, both knockouts display a predominance of β2AR expression. These data provide further evidence that β2ARs are expressed in greater abundance than β1ARs in the tracheobronchial smooth muscle and that loss of either β-arrestin does not significantly affect the expression or relative proportions of βAR subtypes. As β-arrestins are known to modulate β2AR function, our analysis of βAR subtype expression in β-arrestin knockout mice airways sets a reference point for future studies exploiting these knockout mice in various disease models including asthma.

  20. Thermoregulatory responses to beta-adrenergic agonists at low ambient temperatures in the rat.

    PubMed

    Carlisle, H J; Stock, M J

    1993-11-01

    Dose-response effects on heat production (HP) and dry heat loss (DHL) following injection with the non-selective (beta 1/beta 2) adrenergic agonist isoprenaline (ISO) and the atypical B3 agonist BRL 35135 (BRL) were established at an ambient temperature of 25 degrees C in rats. Subsequently, the effects of HP and DHL of a maximal thermogenic dose of ISO (75 micrograms/kg) and a supramaximal dose of BRL (40 micrograms/kg) were tested at ambient temperatures of 5, 10 and 15 degrees C. In terms of heat production, BRL was no different from saline at 5 degrees C, but its thermogenic activity became increasingly evident as ambient temperature increased. For ISO, HP was lower than, or no different from, saline at 5 and 10 degrees C, respectively, but DHL exceeded HP at both temperatures, and colonic temperature fell significantly; ISO and BRL responses were similar at 15 degrees C. ISO was also capable of producing a decrease in HP at 10 degrees C if the rats were shaven. Substitution for endogenous, sympathetically mediated thermogenesis would explain the attenuation of the BRL and ISO effects at cool ambient temperatures, whereas the hypothermic effects of ISO in the cold appeared to be due to an inappropriate increase in DHL, which was exacerbated at 5 degrees C by a reduction in HP below saline values. The increase in DHL was consistent with beta 2-mediated effects of ISO on peripheral blood flow, but the mechanism responsible for the reduction in HP in the cold is unknown, although reduced vascular thermogenesis has been offered as a putative explanation.

  1. Facial vein in the rabbit. Neurogenic vasodilation mediated by beta-adrenergic receptors.

    PubMed

    Pegram, B L; Bevan, R D; Bevan, J A

    1976-12-01

    A segment of the facial vein of the rabbit, that opposite the buccal cavity, responds to norepinephrine (NE) and opposite the buccal cavity, responds to norepinephrine (NE) and transmural nerve stimulation (TNS) by a brisk biphasic dilation. The dilation in response to both procedures is reveresed by prior exposure to propranolol (10(-6)M). Pretreatment with phenoxybenzamine (10(-5)M) increases the size of the neurogenic response and displaces the NE dose-relaxation curve to the left. Histamine causes a constrictor response exclusively. Sympathetic stimulation of a segment of the facial vein proximal to this buccal segment, and also of the external jugular vein, results in constriction. Light microscopy showed no fequtres which can account for the dilation, and fluorescence histochemistry using a modified Flack technique showed a dense adrenergic nerve plexus extending throughout the thickness of the media. We found that frequency-response characteristics and neuronal uptake of 3H-NE were consistent with findings for a blood vessel with a heavy medial innervation. Also, monoamine oxidase and catechol O-methyltransferase activities were similar to those found in other rabbit veins. Furthermore, these results are consistent with an adrenergic neuroeffector organization in which there is a predominance of beta- over alpha-adrenergic receptors. In conclusion, the presence of a dilator response in this buccal segment of the facial vein may be related to its location in the wall of the cheek, where it may be subjected to considerable stretch.

  2. Present state of alpha- and beta-adrenergic drugs I. The adrenergic receptor.

    PubMed

    Ahlquist, R P

    1976-11-01

    The cardiovascular alpha adrenergic receptors evoke vasoconstriction, the cardiovascular beta receptors evoke vasodilation and cardiac stimulation. All blood vessels have both alpha and beta receptors. In some areas, for example skin and kidney, the alpha receptors predominate. In some vascular beds, for example the nutrient vessels in skeletal muscle, beta receptors predominate. In other beds, such as coronary, visceral, and connective tissue both receptors are active. The cardiovascular effects of adrenergic agonists depend on which receptor they act on. Phenylephrine is specific for alpha receptors. Isoproterenol is specific for beta receptors. Epinephrine and norepinephrine act on both. The real value of knowing the receptor specificity of each agonist is that side effects can more easily be predicted. For example, adrenergic cardiac stimulants are antiasthmatics. Therefore, adrenergic antiasthmatics can produce excessive cardiac stimulation. For the future, agonists that are not only receptor-specific but also tissue-specific will be developed. The first of these in the United States is terbutaline. The rest of the world has in addition a similar drug, salbutamol. No one knows if this drug will be approved for use by American physicians.

  3. Effects of long-acting beta adrenergic agonists on vocal fold ion transport.

    PubMed

    Sivasankar, Mahalakshmi; Blazer-Yost, Bonnie

    2009-03-01

    Inhaled medications prescribed for the hypersensitive airway typically combine corticosteroids and long-acting beta2 adrenergic agonists (LABAs). The phonatory side effects of these combination treatments are widely recognized. However, there is limited understanding of the physiological changes induced by these medications that underlie the phonatory side effects. The objective of this study was to investigate the distinct effects of corticosteroids and LABAs on vocal fold mucosal physiology. Understanding the physiological changes to the vocal folds after corticosteroid and LABA treatments is necessary to prevent the prevalent vocal decrement associated with these medications. Experimental in vitro design with treatment and control groups. Native porcine vocal fold mucosae (N = 38) were exposed to corticosteroid or LABA treatments. Ion transport was measured continuously at baseline and after treatment. To quantify the nature of ion transport, vocal folds were also treated with chloride and sodium channel inhibitors. Corticosteroid treatment did not alter ion transport. Conversely, exposure to LABAs significantly increased ion transport. This increase in ion transport was transient, observed immediately after treatment in all tissue and associated with increased chloride secretion. The distinct effects of corticosteroids and LABAs on vocal fold physiology have not been examined to date. This study demonstrates that short-term treatment with LABAs, but not corticosteroids, significantly increases ion transport. These findings suggest that one underlying physiological mechanism for phonatory changes associated with inhaled treatments may be related to acute alterations in vocal fold ion transport and surface hydration.

  4. Homologous desensitization of adenylate cyclase: the role of. beta. -adrenergic receptor phosphorylation and dephosphorylation

    SciTech Connect

    Sibley, D.R.; Strasser, R.H.; Daniel, K.; Lefkowitz, R.J.

    1986-03-05

    The authors utilized the frog erythrocyte (FE) as a ..beta..-adreneric receptor (..beta..AR) model system in which to study homologous desensitization. Preincubation with isoproterenol (ISO) leads to a 50% decline in ISO-stimulated adenylate cyclase (AC) activity without significant changes in basal, PGE/sub 1/-, NaF-, GppNHp-, forskolin-, or MnCl/sub 2/-stimulated AC activities. ISO treatment also induces the sequestration of ..beta..AR from the cell surface as evidenced by a 35% decline in (/sup 3/H)CGP-12177 binding sites on the surface of intact FE. Treatment of intact FE with ISO also promotes ..beta..AR phosphorylation to 2 mol PO/sub 4//mol of ..beta..AR. At 25/sup 0/C, the time courses of ISO-induced AC desensitization, ..beta..AR sequestration and ..beta..AR phosphorylation are identical occurring without a lag and exhibiting a t 1/2 of 30 min and a maximal response at 2.5 hrs. The sequestered ..beta..AR can be partially recovered upon cell lysis in a light membrane fraction (LMF), separable from the plasma membranes using sucrose gradients or differential centrifugation. ..beta..AR phosphorylation is reversed in the sequestered LMF exhibiting a PO/sub 4//..beta..AR stoichiometry of 0.7 mol/mol - similar to that observed under basal conditions. These data suggest that phosphorylation of ..beta..AR in the plasma membrane promotes their translocation away from the cell surface into a sequestered membrane domain where the phosphorylation is reversed, thus, enabling the return of ..beta..AR back to the cell surface and recoupling with AC.

  5. Beta-adrenergic receptor desensitization in man: insight into post-exercise attenuation of cardiac function.

    PubMed

    Hart, Emma; Dawson, Ellen; Rasmussen, Peter; George, Keith; Secher, Niels H; Whyte, Greg; Shave, Rob

    2006-12-01

    Desensitization of the beta-adrenoreceptors (beta-AR) may contribute to a post-exercise reduction in left ventricular (LV) function. However, attenuation of the chronotropic and inotropic responses to a beta-AR agonist may depend upon alterations in parasympathetic tone. Furthermore, changes in cardiac output and LV diastolic function in response to a beta-AR agonist, pre- to post-prolonged exercise, remain unclear. Seven trained males (mean+/-s.d., age 27+/-6 years) performed 4 h of ergometer rowing. Peak heart rate (HR) and LV systolic and diastolic functional responses to incremental isoproterenol (isoprenaline) infusion (2, 4 and 6 microg kg min-1) were assessed after vagal blockade (glycopyrrolate, 1.2 mg). LV systolic function was assessed by the pressure/volume ratio (systolic blood pressure/end systolic volume) and , whilst diastolic function was evaluated as peak early and late transmitral filling velocities. Following exercise, the pressure/volume ratio decreased by 25% (P<0.05), whereas was unchanged (P>0.05). The early/late filling ratio was reduced by 36% after exercise, due to an elevation in late LV filling (P<0.01). The increase in HR response to isoproterenol infusion was blunted post-exercise at both 4 and 6 microg kg min-1 (127+/-7 and 132+/-6 beats min-1) compared with pre-exercise (138+/-8 and 141+/-12 beats min-1, P<0.05). Additionally, the pressure/volume ratio and were blunted post-exercise in response to isoproterenol (P<0.05). In contrast, diastolic function was similar before and after exercise during isoproterenol infusion (P>0.05). Desensitization of the beta-AR contributes to an attenuated left ventricular systolic but not diastolic function following prolonged exercise.

  6. Cardiorespiratory Changes During Microwave-Induced Lethal Heat Stress and Beta-adrenergic Blockade

    DTIC Science & Technology

    1994-01-01

    ceptor blockade on thermoregulatory responses to envi- THz mimfARY AND CIVILAN use of microwave radiation ronmental heat exposure (or to exercise ...labetalol, a combined a- and/t- adrenoreceptor blocking drug. Br. low breathing in guinea pigs (38). Acute administration J. Clin. Pharmacol. 3, Suppl. 3: 681...AppL PhysioL 43: 292-296, 1977. tor antagonism in exercising men. The effects of pro- 5. Cabanac, M. Temperature regulation. Annu. Rev. PhysioL 38: o

  7. beta-Adrenergic receptor polymorphisms: relationship to the beta-agonist controversy and clinical implications.

    PubMed

    Taylor, D Robin

    2007-12-01

    Aspects of the 'beta-agonist controversy' have recently re-emerged with the publication of data implicating the long-acting beta-agonist salmeterol in increased mortality from asthma. The reasons underlying the adverse effects of beta2-agonists as a class are unclear. Polymorphisms of the beta2 adrenoceptor (ADRB2), notably the variant associated with an arginine moiety at position 16 of the ADRB2 protein result in changes in in vitro receptor function. There is now consistent clinical evidence showing that, in vivo, patients with asthma harbouring the Arg-16 genotype may experience reduced lung function and an increased frequency of exacerbations when treated with regular short-acting beta-agonists. This may, in part, explain why beta-agonists have been associated with adverse outcomes in the past. ADRB2 genotyping of patients with severe or difficult-to-control asthma may shed light on a possible contributor to their clinical instability.

  8. [Genetic polymorphism of beta-adrenergic receptors and mortality in ischemic heart disease].

    PubMed

    Jaillon, Patrice; Simon, Tabassome

    2007-01-01

    The genetic polymorphism of beta-2 adrenergic receptors (B2AR) could play a major role in the prognostic of patients with a coronary heart disease. Two recent epidemiological studies could support this hypothesis. In 597 patients treated by a beta-blocker and followed for 3 years after a myocardial infarction or an acute coronary syndrome, the death rate was 5.4 times higher in homozygous Arg 16 and Gln 27 B2AR genotypes than in heterozygous or homozygous Gly 16 and Glu 27 B2AR genotypes. The beta-1 adrenergic receptor (B1AR) genetic polymorphism did not modify mortality. In a second study, in a prospective cohort of 5249 patients aged > or =65 years, the incidence of sudden cardiac death was 1.56 times higher in patients with homozygous Gln 27 B2AR than in heterozygous or homozygous Glu 27 B2AR genotype. This result was confirmed by a case-control study (155 cases of sudden cardiac death versus 144 control subjects). These data suggest that B2AR genetic polymorphism should be systematically studied in clinical trials in myocardial ischemia, with or without congestive heart failure.

  9. Beta-Adrenergic Receptors Regulating Growth and Replication of Breast Cancer Cells: Basic and Therapeutic Implications

    DTIC Science & Technology

    2000-07-01

    following tasks: Task 1 - Dose -response and time-response curves for isoproterenol sensitization or desensitization of 13-receptors and adenylyl cyclase...This was completed in year 1 and described in last year’s progress report. Task 2 - Dose -response and time-response curves for isoproterenol induction...of c-fos protooncogene expression. This is scheduled for year 3. Task 3 - Dose -response and time-response curves for isoproterenol effects on DNA

  10. Real-time monitoring of reduced beta-adrenergic response in fibroblasts from patients with pseudohypoparathyroidism.

    PubMed

    Ong, O C; Dop, C V; Fung, B K

    1996-06-15

    The activation of cell-surface receptors usually produces a transient increase of the extracellular acidification rate in culture cells that can be detected with a biosensor-based instrument. We describe here the application of this method in monitoring hormonal response of Galphas-deficient fibroblasts from patients with pseudohypoparathyroidism type Ia (PHP-Ia). We found that following exposure to isoproterenol, the mean acidification response of fibroblasts from four PHP-Ia patients was only 18% of the response in normal cells. In contrast, these two groups of fibroblasts had similar levels of response to insulin and dibutyryl cAMP. This is the first reported experimental evidence correlating reduced Galphas activity with diminished cellular responsiveness to hormones in cultured living cells. Our results also indicate that this approach will be useful for rapid screening of other metabolic diseases caused by abnormal cellular signaling.

  11. Chagasic IgG modifies the activity of sarcolemmal ATPases through a beta adrenergic mechanism.

    PubMed

    Pascual, J; Borda, E; Sterin-Borda, L

    1987-01-26

    The effect of anti beta adrenoceptor IgG from chagasic sera upon Ca2+-ATPase and Na++K+-ATPase of myocardial membrane was studied. Chagasic IgG stimulated Ca2+-ATPase and inhibited Na++K+-ATPase activities. Both enzymatic effects of the IgG could be prevented after beta adrenoceptor blockade or after the absorption of chagasic IgG with turkey red blood cells. Isoproterenol acted similarly. These results provide information concerning to the biochemical mechanism, by which an antibody, known to activate adenylate cyclase system coupled to cardiac beta adrenoceptor, produces stimulation of myocardial contractility.

  12. Mapping genetic variants associated with beta-adrenergic responses in inbred mice.

    PubMed

    Hersch, Micha; Peter, Bastian; Kang, Hyun Min; Schüpfer, Fanny; Abriel, Hugues; Pedrazzini, Thierry; Eskin, Eleazar; Beckmann, Jacques S; Bergmann, Sven; Maurer, Fabienne

    2012-01-01

    β-blockers and β-agonists are primarily used to treat cardiovascular diseases. Inter-individual variability in response to both drug classes is well recognized, yet the identity and relative contribution of the genetic players involved are poorly understood. This work is the first genome-wide association study (GWAS) addressing the values and susceptibility of cardiovascular-related traits to a selective β(1)-blocker, Atenolol (ate), and a β-agonist, Isoproterenol (iso). The phenotypic dataset consisted of 27 highly heritable traits, each measured across 22 inbred mouse strains and four pharmacological conditions. The genotypic panel comprised 79922 informative SNPs of the mouse HapMap resource. Associations were mapped by Efficient Mixed Model Association (EMMA), a method that corrects for the population structure and genetic relatedness of the various strains. A total of 205 separate genome-wide scans were analyzed. The most significant hits include three candidate loci related to cardiac and body weight, three loci for electrocardiographic (ECG) values, two loci for the susceptibility of atrial weight index to iso, four loci for the susceptibility of systolic blood pressure (SBP) to perturbations of the β-adrenergic system, and one locus for the responsiveness of QTc (p<10(-8)). An additional 60 loci were suggestive for one or the other of the 27 traits, while 46 others were suggestive for one or the other drug effects (p<10(-6)). Most hits tagged unexpected regions, yet at least two loci for the susceptibility of SBP to β-adrenergic drugs pointed at members of the hypothalamic-pituitary-thyroid axis. Loci for cardiac-related traits were preferentially enriched in genes expressed in the heart, while 23% of the testable loci were replicated with datasets of the Mouse Phenome Database (MPD). Altogether these data and validation tests indicate that the mapped loci are relevant to the traits and responses studied.

  13. Betaxolol. A new beta-adrenergic blocking agent for treatment of glaucoma.

    PubMed

    Berrospi, A R; Leibowitz, H M

    1982-06-01

    The intraocular pressure response to topically instilled 0.25% betaxolol hydrochloride was evaluated in 12 patients with chronic open angle glaucoma or ocular hypertension. The drug produced a significant lowering of IOP in all 12 of the patients under study. A 30% to 35% decrease below baseline IOP was observed and was maintained during the one-year observation period. Visual acuity was stable in all subjects throughout the study and corneal anesthesia was not encountered. Tear secretion was not adversely effected by betaxolol, nor did topical administration of the drug produce any systemic cardiovascular response of consequence. Blood pressure and pulse rate remained stable throughout the year. These data suggest that an ophthalmic formulation of betaxolol may have substantial clinical potential for the treatment of glaucoma.

  14. Opioid antagonists for smoking cessation

    PubMed Central

    David, Sean P; Lancaster, Tim; Stead, Lindsay F; Evins, A. Eden; Prochaska, Judith J

    2014-01-01

    Background The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking. Objectives To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone. Search methods We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using ’Narcotic antagonists’ and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies. Selection criteria We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence. Data collection and analysis We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel

  15. Mineralcorticoid antagonists in heart failure.

    PubMed

    D'Elia, Emilia; Krum, Henry

    2014-10-01

    Mineralocorticoid receptor antagonists (MRAs) have become mandated therapy in patients with reduced ejection fraction (systolic) heart failure (HF) across all symptom classes. These agents should also be prescribed in the early post-myocardial infarction setting in those with reduced ejection fraction and either HF symptoms or diabetes. This article explores the pathophysiological role of aldosterone, an endogenous ligand for the mineralcorticoid receptor (MR), and summarizes the clinical data supporting guideline recommendations for these agents in systolic HF. The use of MRAs in novel areas beyond systolic HF ejection is also explored. Finally, the current status of newer agents will be examined.

  16. NK-1 Antagonists and Itch.

    PubMed

    Ständer, Sonja; Luger, Thomas A

    2015-01-01

    Substance P (SP) is an important mediator of pro-inflammatory mechanisms in the skin. It targets multiple cells such as keratinocytes, mast cells, and fibroblasts which are involved in the cutaneous generation of pruritus. This suggests that SP is an interesting target for therapy. In fact, in recent case reports and case series, SP antagonists demonstrated a significant antipruritic effect in acute and chronic pruritus such as drug-induced pruritus, paraneoplastic pruritus, prurigo nodularis, cutaneous T-cell lymphoma, and brachioradial pruritus.

  17. Synthetic peptide antagonists of glucagon.

    PubMed Central

    Unson, C G; Andreu, D; Gurzenda, E M; Merrifield, R B

    1987-01-01

    Several glucagon analogs were synthesized in an effort to find derivatives that would bind with high affinity to the glucagon receptor of rat liver membranes but would not activate membrane-bound adenylate cyclase and, therefore, would serve as antagonists of the hormone. Measurements on a series of glucagon/secretin hybrids indicated that replacement of Asp9 in glucagon by Glu9, found in secretin, was the important sequence difference in the N terminus of the two hormones. Further deletion of His1 and introduction of a C-terminal amide resulted in des-His1-[Glu9]glucagon amide, which had a 40% binding affinity relative to that of native glucagon but caused no detectable adenylate cyclase activation in the rat liver membrane. This antagonist completely inhibited the effect of a concentration of glucagon that alone gave a full agonist response. It had an inhibition index of 12. The pA2 was 7.2. An attempt was made to relate conformation with receptor binding. The peptides were synthesized by solid-phase methods and purified to homogeneity by reverse-phase high-performance liquid chromatography on C18-silica columns. PMID:3035568

  18. Vitamin K antagonists: beyond bleeding.

    PubMed

    Krüger, Thilo; Floege, Jürgen

    2014-01-01

    Warfarin is the most widely used oral anticoagulant in clinical use today. Indications range from prosthetic valve replacement to recurrent thromboembolic events due to antiphospholipid syndrome. In hemodialysis (HD) patients, warfarin use is even more frequent than in the nonrenal population due to increased cardiovascular comorbidities. The use of warfarin in dialysis patients with atrial fibrillation requires particular caution because side effects may outweigh the assumed benefit of reduced stroke rates. Besides increased bleeding risk, coumarins exert side effects which are not in the focus of clinical routine, yet they deserve special consideration in dialysis patients and should influence the decision of whether or not to prescribe vitamin K antagonists in cases lacking clear guidelines. Issues to be taken into consideration in HD patients are the induction or acceleration of cardiovascular calcifications, a 10-fold increased risk of calciphylaxis and problems related to maintaining a target INR range. New anticoagulants like direct thrombin inhibitors are promising but have not yet been approved for ESRD patients. Here, we summarize the nontraditional side effects of coumarins and give recommendations about the use of vitamin K antagonists in ESRD patients.

  19. Cholinergic antagonists in a solitary wasp venom.

    PubMed

    Piek, T; Mantel, P

    1986-01-01

    The venom of the solitary wasp Philanthus triangulum contains a cholinergic antagonist of the nicotinic receptor of the rectus abdominis muscle of the frog, Xenopus laevis. The venom of African P. triangulum contains two different cholinergic factors, a competitive and a non-competitive antagonist. The venom of the European P. triangulum may not contain a competitive antagonist of the nicotinic receptor of X. laevis, but only a very strong non-competitive antagonist. The possible non-synonymity of both groups of P. triangulum is discussed.

  20. A new alcohol antagonist: Phaclofen

    SciTech Connect

    Allan, A.M. ); Harris, R.A. )

    1989-01-01

    The ability of the GABA{sub B} receptor antagonist, phaclofen to alter behavioral effects of ethanol was evaluated by loss of righting reflex (sleep time), motor incoordination (bar holding), spontaneous locomotion (open field activity) and hypothermia. Pretreatment with phaclofen significantly decreased the effects of ethanol on motor incoordination, locomotor activity and hypothermia. However, phaclofen had no effect on either pentobarbital- or diazepam-induced motor incoordination. Phaclofen slightly increased the ED{sub 50} for loss of the righting reflex but did not alter either the duration of reflex loss produced by ethanol or blood ethanol levels at awakening. Our results suggest phaclofen is rapidly inactivated resulting in difficulty in observing antagonism of long duration ethanol effects. These findings suggest that the GABA{sub B} system may play a role in mediating several important actions of ethanol.

  1. Long-acting muscarinic antagonists.

    PubMed

    Melani, Andrea S

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability worldwide. Inhaled bronchodilators are the mainstay of COPD pharmacological treatment. Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators. Some LAMA/device systems with different characteristics and dosing schedules are currently approved for maintenance therapy of COPD and a range of other products are being developed. They improve lung function and patient-reported outcomes and reduce acute bronchial exacerbations with good safety. LAMAs are used either alone or associated with long-acting β₂-agonists, eventually in fixed dose combinations. Long-acting β₂-agonist/LAMA combinations assure additional benefits over the individual components alone. The reader will obtain a view of the safety and efficacy of the different LAMA/device systems in COPD patients.

  2. Client Perceptions of Two Antagonist Programs.

    ERIC Educational Resources Information Center

    Capone, Thomas A.; And Others

    1980-01-01

    Reports results of a questionnaire administered to participants in an antagonist drug outpatient clinic and an antagonist drug work-release program to obtain awareness of acceptance of the program participants. Naltrexone patients recommended an alternative method of administering the drug and changing the money system to award deserving inmates…

  3. Antagonistic coevolution accelerates molecular evolution

    PubMed Central

    Paterson, Steve; Vogwill, Tom; Buckling, Angus; Benmayor, Rebecca; Spiers, Andrew J.; Thomson, Nicholas R.; Quail, Mike; Smith, Frances; Walker, Danielle; Libberton, Ben; Fenton, Andrew; Hall, Neil; Brockhurst, Michael A.

    2013-01-01

    The Red Queen hypothesis proposes that coevolution of interacting species (such as hosts and parasites) should drive molecular evolution through continual natural selection for adaptation and counter-adaptation1–3. Although the divergence observed at some host-resistance4–6 and parasite-infectivity7–9 genes is consistent with this, the long time periods typically required to study coevolution have so far prevented any direct empirical test. Here we show, using experimental populations of the bacterium Pseudomonas fluorescens SBW25 and its viral parasite, phage Φ2 (refs 10, 11), that the rate of molecular evolution in the phage was far higher when both bacterium and phage coevolved with each other than when phage evolved against a constant host genotype. Coevolution also resulted in far greater genetic divergence between replicate populations, which was correlated with the range of hosts that coevolved phage were able to infect. Consistent with this, the most rapidly evolving phage genes under coevolution were those involved in host infection. These results demonstrate, at both the genomic and phenotypic level, that antagonistic coevolution is a cause of rapid and divergent evolution, and is likely to be a major driver of evolutionary change within species. PMID:20182425

  4. Antianginal Actions of Beta-Adrenoceptor Antagonists

    PubMed Central

    2007-01-01

    Angina pectoris is usually the first clinical sign of underlying myocardial ischemia, which results from an imbalance between oxygen supply and oxygen demand in the heart. This report describes the pharmacology of β-adrenoceptor antagonists as it relates to the treatment of angina. The β-adrenoceptor antagonists are widely used in long-term maintenance therapy to prevent acute ischemic episodes in patients with chronic stable angina. Beta-adrenoceptor antagonists competitively inhibit the binding of endogenous catecholamines to β1-adrenoceptors in the heart. Their anti-ischemic effects are due primarily to a reduction in myocardial oxygen demand. By decreasing heart rate, myocardial contractility and afterload, β-adrenoceptor antagonists reduce myocardial workload and oxygen consumption at rest as well as during periods of exertion or stress. Predictable adverse effects include bradycardia and cardiac depression, both of which are a direct result of the blockade of cardiac β1-adrenoceptors, but adverse effects related to the central nervous system (eg, lethargy, sleep disturbances, and depression) may also be bothersome to some patients. Beta-adrenoceptor antagonists must be used cautiously in patients with diabetes mellitus, peripheral vascular disease, heart failure, and asthma or other obstructive airway diseases. Beta-adrenoceptor antagonists may be used in combination with nitrates or calcium channel blockers, which takes advantage of the diverse mechanisms of action of drugs from each pharmacologic category. Moreover, concurrent use of β-adrenoceptor antagonists may alleviate the reflex tachycardia that sometimes occurs with other antianginal agents. PMID:17998992

  5. Ago-antagonist theory in Darwinian evolution.

    PubMed

    Bazzani, Armando; Freguglia, Paolo

    2013-01-01

    In this paper we discuss a proposal on the essential structural aspects of Darwinian Evolution Theory. Using this point of view we apply a mathematical ago-antagonist theory inspired by Y. Cherruault's (1998) ideas, which we have extended. In the ago-antagonist model, the phenotype characters measure the individual propensity to perform an innovative x(t) (agonist) or conservative y(t) (antagonist) action with respect to mutation and to speciation process. We have mathematically introduced the conflict concept and we present a model that takes into account the environmental effects by means of a stochastic multiplicative process. We shortly discuss the properties of the related stochastic differential equations.

  6. Antagonists of the kappa opioid receptor.

    PubMed

    Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, Edward

    2014-05-01

    The research community has increasingly focused on the development of OPRK antagonists as pharmacotherapies for the treatment of depression, anxiety, addictive disorders and other psychiatric conditions produced or exacerbated by stress. Short-acting OPRK antagonists have been recently developed as a potential improvement over long-acting prototypic ligands including nor-BNI and JDTic. Remarkably the short-acting LY2456302 is undergoing phase II clinical trials for the augmentation of the antidepressant therapy in treatment-resistant depression. This Letter reviews relevant chemical and pharmacological advances in the identification and development of OPRK antagonists.

  7. Plant Evolution: Evolving Antagonistic Gene Regulatory Networks.

    PubMed

    Cooper, Endymion D

    2016-06-20

    Developing a structurally complex phenotype requires a complex regulatory network. A new study shows how gene duplication provides a potential source of antagonistic interactions, an important component of gene regulatory networks.

  8. The Evolution of Sexually Antagonistic Phenotypes

    PubMed Central

    Perry, Jennifer C.; Rowe, Locke

    2015-01-01

    Sexual conflict occurs whenever there is sexually antagonistic selection on shared traits. When shared traits result from interactions (e.g., mating rate) and have a different genetic basis in each sex (i.e., interlocus conflict), then sex-specific traits that shift the value of these interaction traits toward the sex-specific optimum will be favored. Male traits can be favored that increase the fitness of their male bearers, but decrease the fitness of interacting females. Likewise, female traits that reduce the costs of interacting with harmful males may simultaneously impose costs on males. If the evolution of these antagonistic traits changes the nature of selection acting on the opposite sex, interesting coevolutionary dynamics will result. Here we examine three current issues in the study of sexually antagonistic interactions: the female side of sexual conflict, the ecological context of sexual conflict, and the strength of evidence for sexually antagonistic coevolution. PMID:26032715

  9. Emerging cardiovascular indications of mineralocorticoid receptor antagonists.

    PubMed

    Parviz, Yasir; Iqbal, Javaid; Pitt, Bertram; Adlam, David; Al-Mohammad, Abdallah; Zannad, Faiez

    2015-04-01

    Mineralocorticoid receptor (MR) antagonism is a well-established treatment modality for patients with hypertension, heart failure, and left ventricular systolic dysfunction (LVSD) post-myocardial infarction (MI). There are emerging data showing potential benefits of MR antagonists in other cardiovascular conditions. Studies have shown association between MR activation and the development of myocardial fibrosis, coronary artery disease, metabolic syndrome, and cerebrovascular diseases. This review examines the preclinical and clinical data of MR antagonists for novel indications including heart failure with preserved ejection fraction (HFPEF), pulmonary arterial hypertension (PAH), arrhythmia, sudden cardiac death, valvular heart disease, metabolic syndrome, renal disease, and stroke. MR antagonists are not licensed for these conditions yet; however, emerging data suggest that indication for MR antagonists are likely to broaden; further studies are warranted.

  10. Macrophages: micromanagers of antagonistic signaling nanoclusters.

    PubMed

    Eggeling, Christian; Davis, Simon J

    2017-04-03

    How cells integrate antagonistic receptor signaling events is enigmatic. Using superresolution optical microscopy, Lopes et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201608094) demonstrate the nanometer-scale molecular reorganization of antagonistic signaling receptors in macrophages, after engagement by the receptors of activating and inhibitory ligands. They propose that large-scale rearrangements of this type underpin decision-making by these cells.

  11. Caffeine and propranolol block the increase in rat pineal melatonin production produced by stimulation of adenosine receptors.

    PubMed

    Babey, A M; Palmour, R M; Young, S N

    1994-07-18

    The adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) injected i.p. during the light period increased rat pineal melatonin levels and this increase was blocked by simultaneous administration of the non-selective adenosine receptor antagonist caffeine. A single dose of the adenosine A1 agonist cyclopentyladenosine had no effect on nocturnal melatonin production. The NECA-stimulated increase was also blocked by the beta-adrenergic receptor antagonist propranolol. Given alone, neither caffeine nor propranolol had any effect on melatonin levels. The results point to an intermediate role for beta-adrenergic receptors in the adenosine-stimulated increase of melatonin production.

  12. Calcium antagonists and atherosclerosis protection in hypertension.

    PubMed

    Hernández, Rafael Hernández; Armas-Hernández, María José; Velasco, Manuel; Israili, Zafar H; Armas-Padilla, María Cristina

    2003-01-01

    Calcium antagonists are effective in hypertensive patients of all ethnic groups, irrespective of age, dietary salt intake, salt-sensitivity status or plasma renin activity profile. Some prospective studies show that the calcium antagonists, nifedipine GITS and nitrendipine, reduce cardiovascular morbidity and mortality at least to the same extent as the diuretics. Other prospective studies are in progress to evaluate the effect of calcium antagonists on cardiovascular morbidity and mortality, and the progression of atherosclerosis in hypertensive patients. Calcium antagonists, especially the highly lipophilic amlodipine, lacidipine and nisoldipine, are shown to possess antioxidant properties. These drugs reduce the oxidation of LDL and its influx into the arterial wall, and reduce atherosclerotic lesions in animals. Platelet production of malondialdehyde, a marker of oxygen free radical formation, is suppressed by amlodipine, lacidipine or nifedipine in hypertensive patients. New evidence from long-term clinical trials of calcium antagonists indicates that these drugs can reduce the rate of progression of atherosclerosis in hypertensive and coronary heart disease patients. In the Regression Growth Evaluation Statin Study (REGRESS), co-administration of calcium antagonist, amlodipine or nifedipine with pravasatin caused a significant reduction in the appearance of new angiographic lesions. In the Verapamil in Hypertension and Atherosclerosis Study (VHAS), verapamil was more effective than chlorthalidone in promoting regression of thicker carotid lesions in parallel with a reduction in the incidence of cardiovascular events. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), amlodipine slowed the progression of early coronary atherosclerosis in patients with coronary artery disease. In a subprotocol of the Intervention as a Goal in the Hypertension Treatment (INSIGHT) study, nifedipine GITS significantly decreased intima

  13. Embryo implantation and GnRH antagonists: embryo implantation: the Rubicon for GnRH antagonists.

    PubMed

    Hernandez, E R

    2000-06-01

    When gonadotrophin-releasing hormone (GnRH) was discovered, the agonist and antagonist of GnRH were developed to control the release of FSH and LH by the gonadotrophs. More than 10 years of research were needed to develop a GnRH antagonist free of histamine release. Recent studies have shown that these GnRH antagonists are effective in preventing a rise in LH during ovarian stimulation in IVF. However, a decrease in ongoing pregnancies seems to suggest that implantation rates per transferred embryo are reduced in GnRH antagonist-stimulated cycles. In my opinion, these data highlight an area less well known to clinicians: the role of the GnRH antagonist at the cellular level in extrapituitary tissues. There are sufficient data in the literature suggesting that GnRH antagonist is an inhibitor of the cell cycle by decreasing the synthesis of growth factors. Given that, for folliculogenesis, blastomere formation and endometrium development, mitosis is everything; the interaction between the GnRH antagonist and the GnRH receptor (present in all these cells and tissues) may compromise the mitotic programme of these cells. This is the Rubicon for the GnRH antagonist: to demonstrate irrevocably that, at the minimal doses necessary to suppress LH release, it does not affect processes such as implantation, embryo development and folliculogenesis.

  14. [Antagonistic activity of novel green microalgae strain].

    PubMed

    Selivanova, E A; Ignatenko, M E; Nemtseva, N V

    2014-01-01

    Screening of novel microalgae strains for the presence of pronounced antagonistic (antibacterial) activity against opportunistic bacteria. 11 pure cultures of green unicellular algae isolated from fresh and salt basins of Orenburg region were studied for the presence of antagonistic activity against 4 test-strains of opportunistic bacteria by a photometric method. The effect of water extracts of microalgae Astermonas gracilis on the speed of self-purification of brine from Escherichia coli as well as antibacterial activity of peloid were evaluated under co-cultivation conditions. Pure cultures of green unicellular algae Scenedesmus obliquus (Turpin) Kütz, Scenedesmus magnus Meyen var. magnus, Pediastru duplex Meyen var. duplex, Chlorella vulgaris Bory, Monoraphidium arcuatum (Korschikov) Hindak (=Ankistrodesmus arcuatus Korschikov), Dictyosphaerium sp. had the most pronounced antagonistic activit against opportunistic bacteria. Water extract ofA. gracilis microalgae accelerated brine self-purification fro E. coli due to antibacterial effect. Peloid containing extracts of microorganism cells had a pronounced antibacterial effect against opportunistic bacteria. Antagonistic substances localized inside cells of microalgae increased the speed of allochthonic microorganism elimination that is one of the mechanisms of self-purification of a basin and antibacterial effect of peloid. The novel green microalgae strains studied due to the presence of pronounced antagonistic activity may have a wide practical application.

  15. High-affinity neuropeptide Y receptor antagonists.

    PubMed Central

    Daniels, A J; Matthews, J E; Slepetis, R J; Jansen, M; Viveros, O H; Tadepalli, A; Harrington, W; Heyer, D; Landavazo, A; Leban, J J

    1995-01-01

    Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists. Three potent NPY receptor antagonists were synthesized and tested for their biological activity in in vitro, ex vivo, and in vivo functional assays. We describe here the effects of these antagonists inhibiting specific radiolabeled NPY binding at Y1 and Y2 receptors and antagonizing the effects of NPY in human erythroleukemia cell intracellular calcium mobilization perfusion pressure in the isolated rat kidney, and mean arterial blood pressure in anesthetized rats. PMID:7568074

  16. High-affinity neuropeptide Y receptor antagonists.

    PubMed

    Daniels, A J; Matthews, J E; Slepetis, R J; Jansen, M; Viveros, O H; Tadepalli, A; Harrington, W; Heyer, D; Landavazo, A; Leban, J J; Spaltenstein, A

    1995-09-26

    Neuropeptide Y (NPY) is one of the most abundant peptide transmitters in the mammalian brain. In the periphery it is costored and coreleased with norepinephrine from sympathetic nerve terminals. However, the physiological functions of this peptide remain unclear because of the absence of specific high-affinity receptor antagonists. Three potent NPY receptor antagonists were synthesized and tested for their biological activity in in vitro, ex vivo, and in vivo functional assays. We describe here the effects of these antagonists inhibiting specific radiolabeled NPY binding at Y1 and Y2 receptors and antagonizing the effects of NPY in human erythroleukemia cell intracellular calcium mobilization perfusion pressure in the isolated rat kidney, and mean arterial blood pressure in anesthetized rats.

  17. Antagonistic Interactions among Marine Pelagic Bacteria

    PubMed Central

    Long, Richard A.; Azam, Farooq

    2001-01-01

    Recent studies suggest that bacterial abundance and species diversity in the ocean's water column are variable at the millimeter scale, apparently in response to the small-scale heterogeneity in the distribution of organic matter. We hypothesized that bacterium-bacterium antagonistic interactions may contribute to variations in community structure at the microscale. We examined each of the 86 isolates for their inhibition of growth of the remaining 85 isolates by the Burkholder agar diffusion assay. More than one-half of the isolates expressed antagonistic activity, and this trait was more common with particle-associated bacteria than with free-living bacteria. This was exemplified by members of the α subclass of the class Proteobacteria (α-proteobacteria), in which production of antagonistic molecules was dominated by attached bacteria. We found that γ-proteobacteria (members of the orders Alteromonadales and Vibrionales) are the most prolific producers of inhibitory materials and also the most resilient to them, while members of the Bacteriodetes were the organisms that were least productive and most sensitive to antagonistic interactions. Widespread interspecies growth inhibition is consistent with the role of this phenomenon in structuring bacterial communities at the microscale. Furthermore, our results suggest that bacteria from pelagic marine particles may be an underutilized source of novel antibiotics. PMID:11679315

  18. Beta-adrenergic receptor mediated inflammation control by monocytes is associated with blood pressure and risk factors for cardiovascular disease.

    PubMed

    Hong, Suzi; Dimitrov, Stoyan; Cheng, Tiefu; Redwine, Laura; Pruitt, Christopher; Mills, Paul J; Ziegler, Michael G; Green, J Michael; Shaikh, Farah; Wilson, Kathleen

    2015-11-01

    Overwhelming data indicate that individuals with even mildly elevated blood pressure (BP) are at great risk for developing clinical hypertension and future cardiovascular disease (CVD). There remains a lack of consensus regarding treatment strategies for mildly elevated BP, termed prehypertension, and the knowledge of pathophysiology and mechanisms of its clinical outcomes remains limited. Our primary aim was to investigate βAR-mediated inflammation control (BARIC) responses of blood monocytes to isoproterenol (Iso) in relation to BP and CVD risk factors, including obesity, depressive mood, fasting glucose, triglycerides, and cholesterol levels in the 64 prehypertensive compared to 84 individuals with normal BP. BARIC was determined by measuring the degree of inhibition in lipopolysaccharides-stimulated monocytic intracellular TNF production by ex vivo Iso treatment (10(-8)M). Depressive mood was assessed by Beck Depression Inventory (BDI). Fasting metabolic and lipid panels were assessed, and plasma levels of inflammatory cytokines TNF, IL-1β, IL-6 were measured in a subset to confirm proinflammatory state of prehypertensive participants. Prehypertensive participants were older, heavier, included more men, and presented higher levels of fasting glucose, triglycerides, cholesterol, and plasma TNF compared to normotensive participants (p's<.05). BARIC was significantly attenuated in the prehypertensive compared to normotensive group (p<.05). BARIC was negatively associated with systolic BP, diastolic BP, age, BMI, fasting glucose, triglycerides, total and low density cholesterol levels, and somatic depressive symptoms in all participants (p's<.0001 to .05). However, among the prehypertensive individuals BARIC was positively associated with SBP even after controlling for the covariates (age, gender, race, BMI, glucose and lipid panel, somatic BDI scores) (p<.05). This differing nature of the BARIC-SBP relationship between the two BP groups may be attributed to moderating factors such as cardiorespiratory fitness or depressive symptoms that could not be clearly deciphered in this current study. Nonetheless, our findings indicate the associations between inflammation dysregulation mediated by sympathoadrenal activation and BP that is observable even among individuals with normal to mildly elevated BP. BARIC may be a useful and sensitive indicator of elevated risk for vascular inflammatory disease that can be detected even at lower BP levels, especially given its associations with traditional CVD risk factors and the critical role of monocytes in atherogenic processes. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. alpha- and beta-adrenergic receptor mechanisms in spontaneous contractile activity of rat ileal longitudinal smooth muscle.

    PubMed

    Seiler, Roland; Rickenbacher, Andreas; Shaw, Sidney; Balsiger, Bruno M

    2005-02-01

    Gastrointestinal motility is influenced by adrenergic modulation. Our aim was to identify specific subtypes of adrenergic receptors involved in inhibitory mechanisms that modulate gut smooth muscle contractile activity. Muscle strips of rat ileal longitudinal muscle were evaluated for spontaneous contractile activity and for equimolar dose-responses (10(-7) to 3 x 10(-5) M) to the adrenergic agents norepinephrine (nonselective agonist), phenylephrine (alpha(1)-agonist), clonidine (alpha(2)-agonist), prenalterol (beta(1)-agonist), ritodrine (beta(2)-agonist), and ZD7114 (beta(3)-agonist) in the presence and absence of tetrodotoxin (nonselective nerve blocker). Norepinephrine (3 x 10(-5) M) inhibited 65 +/- 6% (mean +/- SEM) of spontaneous contractile activity. The same molar dose of ritodrine, phenylephrine, or ZD7114 resulted in less inhibition (46 +/- 7%, 31 +/- 5%, and 39 +/- 3%, respectively; P < 0.05). The calculated molar concentration of ZD7114 needed to induce 50% inhibition was similar to that of norepinephrine, whereas higher concentrations of phenylephrine or ritodrine were required. Clonidine and prenalterol had no effect on contractile activity. Blockade of intramural neural transmission by tetrodotoxin affected the responses to ritodrine and phenylephrine (but not to norepinephrine or ZD7114), suggesting that these agents exert part of their effects via neurally mediated enteric pathways. Our results suggest that adrenergic modulation of contractile activity in the rat ileum is mediated primarily by muscular beta(3)-, beta(2)-, and alpha(1)-receptor mechanisms; the latter two also involve neural pathways.

  20. "Silent" Priming of Translation-Dependent LTP by [Beta]-Adrenergic Receptors Involves Phosphorylation and Recruitment of AMPA Receptors

    ERIC Educational Resources Information Center

    Tenorio, Gustavo; Connor, Steven A.; Guevremont, Diane; Abraham, Wickliffe C.; Williams, Joanna; O'Dell, Thomas J.; Nguyen, Peter V.

    2010-01-01

    The capacity for long-term changes in synaptic efficacy can be altered by prior synaptic activity, a process known as "metaplasticity." Activation of receptors for modulatory neurotransmitters can trigger downstream signaling cascades that persist beyond initial receptor activation and may thus have metaplastic effects. Because activation of…

  1. Enhanced Noradrenergic Activity Potentiates Fear Memory Consolidation and Reconsolidation by Differentially Recruiting alpha1- and beta-Adrenergic Receptors

    ERIC Educational Resources Information Center

    Gazarini, Lucas; Stern, Cristina A. Jark; Carobrez, Antonio P.; Bertoglio, Leandro J.

    2013-01-01

    Consolidation and reconsolidation are phases of memory stabilization that diverge slightly. Noradrenaline is known to influence both processes, but the relative contribution of alpha1- and beta-adrenoceptors is unclear. The present study sought to investigate this matter by comparing their recruitment to consolidate and/or reconsolidate a…

  2. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment.

    PubMed

    Kim-Fuchs, Corina; Le, Caroline P; Pimentel, Matthew A; Shackleford, David; Ferrari, Davide; Angst, Eliane; Hollande, Frédéric; Sloan, Erica K

    2014-08-01

    Pancreatic cancer cells intimately interact with a complex microenvironment that influences pancreatic cancer progression. The pancreas is innervated by fibers of the sympathetic nervous system (SNS) and pancreatic cancer cells have receptors for SNS neurotransmitters which suggests that pancreatic cancer may be sensitive to neural signaling. In vitro and non-orthotopic in vivo studies showed that neural signaling modulates tumour cell behavior. However the effect of SNS signaling on tumor progression within the pancreatic microenvironment has not previously been investigated. To address this, we used in vivo optical imaging to non-invasively track growth and dissemination of primary pancreatic cancer using an orthotopic mouse model that replicates the complex interaction between pancreatic tumor cells and their microenvironment. Stress-induced neural activation increased primary tumor growth and tumor cell dissemination to normal adjacent pancreas. These effects were associated with increased expression of invasion genes by tumor cells and pancreatic stromal cells. Pharmacological activation of β-adrenergic signaling induced similar effects to chronic stress, and pharmacological β-blockade reversed the effects of chronic stress on pancreatic cancer progression. These findings indicate that neural β-adrenergic signaling regulates pancreatic cancer progression and suggest β-blockade as a novel strategy to complement existing therapies for pancreatic cancer.

  3. Beta-adrenergic stimulation reverses the I Kr-I Ks dominant pattern during cardiac action potential.

    PubMed

    Banyasz, Tamas; Jian, Zhong; Horvath, Balazs; Khabbaz, Shaden; Izu, Leighton T; Chen-Izu, Ye

    2014-11-01

    β-Adrenergic stimulation differentially modulates different K(+) channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of I Ks, I Kr, and I K1 currents in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K(+) current to the total repolarization reserve. In this study, we used an innovative AP-clamp sequential dissection technique to directly record the dynamic I Ks, I Kr, and I K1 currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of I Ks, I Kr, and I K1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca(2+) homeostasis. We found that isoproterenol treatment significantly enhanced I Ks, moderately increased I K1, but slightly decreased I Kr in a dose-dependent manner. The dominance pattern of the K(+) currents was I Kr > I K1 > I Ks at the control condition, but reversed to I Kr < I K1 < I Ks following β-adrenergic stimulation. We systematically determined the changes in the relative contribution of I Ks, I Kr, and I K1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K(+) currents in a dose-dependent manner. This knowledge is important for designing antiarrhythmic drug strategies to treat hearts exposed to various sympathetic tones.

  4. Overexpression Myocardial Inducible Nitric Oxide Synthase Exacerbates Cardiac Dysfunction and Beta-Adrenergic Desensitization in Experimental Hypothyroidism☆,☆☆

    PubMed Central

    Shao, Qun; Cheng, Heng-Jie; Callahan, Michael F.; Kitzman, Dalane W; Li, Wei-Min; Cheng, Che Ping

    2015-01-01

    Background Altered nitric oxide synthase (NOS) has been implicated in the pathophysiology of heart failure (HF). Recent evidence links hypothyroidism to the pathology of HF. However, the precise mechanisms are incompletely understood. The alterations and functional effects of cardiac NOS in hypothyroidism are unknown. We tested the hypothesis that hypothyroidism increases cadiomyocyte inducible NOS (iNOS) expression, which plays an important role in hypothyroidism-induced depression of cardiomyocyte contractile properties, [Ca2+]i transient ([Ca2+]iT), and β-adrenergic hyporesponsiveness. Methods and Results We simultaneously evaluated LV functional performance and compared myocyte three NOS, β-adrenergic receptors (AR) and SERCA2a expressions and assessed cardiomyocyte contractile and [Ca2+]iT responses to β-AR stimulation with and without pretreatment of iNOS inhibitor (1400W, 10−5 mol/L) in 26 controls and 26 rats with hypothyroidism induced by methimazole (~30 mg/kg/day for 8 weeks in the drinking water). Compared with controls, in hypothyroidism, total serum T3 and T4 were significantly reduced followed by significantly decreased LV contractility (EES) with increased LV time constant of relaxation. These LV abnormalities were accompanied by concomitant significant decreases in myocyte contraction (dL/dtmax), relaxation (dR/dtmax), and [Ca2+]iT. In hypothyroidism, isoproterenol (10−8 M) produced significantly smaller increases in dL/dtmax, dR/dtmax and [Ca2+]iT. These changes were associated with decreased β1-AR and SERCA2a, but significantly increased iNOS. Moreover, only in hypothyroidism, pretreatment with iNOS inhibitor significantly improved basal and isoproterenol-stimulated myocyte contraction, relaxation and [Ca2+]iT. Conclusions Hypothyroidism produces intrinsic defects of LV myocyte force-generating capacity and relaxation with β-AR desensitization. Up-regulation of cadiomyocyte iNOS may promote progressive cardiac dysfunction in hypothyroidism. PMID:26681542

  5. The effects of beta-adrenergic stimulation on the length-dependent regulation of myocardial function in coronary surgery patients.

    PubMed

    De Hert, S G; Van der Linden, P J; Broecke, P W; Rodrigus, I E; Sermeus, L A; Moulijn, A C; Gillebert, T C

    1999-10-01

    Increasing cardiac load by leg elevation identifies patients with load-dependent impairment of left ventricular (LV) function. This impairment is related to a deficient length-dependent regulation of LV function. We investigated the effects of dobutamine on length-dependent regulation of LV function in coronary surgery patients (n = 25). High-fidelity LV pressure tracings were obtained at end-expiration, while hearts were paced at a fixed rate of 90 bpm. Effects of leg elevation on contraction and relaxation were compared before and during dobutamine 5 microg x kg(-1) x min(-1). Effects on contraction were evaluated by analysis of changes in dP/dtmax. Effects on relaxation were assessed by analysis of R (slope of the relation between the time constant of isovolumic relaxation and end-systolic pressure). Correlations were calculated with linear regression analysis using Pearson's coefficient r. The effects of leg elevation on variables of contraction and relaxation were coupled. We found a close relationship between changes in dP/dtmax and individual values of R (r = 0.84; P < 0.001). Dobutamine improved myocardial function and accelerated LV pressure decrease. Under dobutamine, the increase in dP/dtmax with leg elevation was larger (P < 0.001) and load dependence of LV relaxation was reduced (P = 0.001). Dobutamine improved the effects of leg elevation on LV function, reflecting improved length-dependent regulation of LV function. This study demonstrated that beta-adrenoreceptor stimulation with dobutamine improved length-dependent regulation of myocardial function assessed during leg elevation in cardiac surgical patients.

  6. Role of the beta-adrenergic receptor-binding agent 'timolol' in the treatment of open-angle glaucoma.

    PubMed

    Strempel, I

    1982-01-01

    A follow-up study was performed on 54 eyes with chronic open-angle glaucoma treated with timolol maleate. It was carried out as an open clinical trial with a selected group of eyes. During 2 years of application the effect of timolol under normal conditions as well as under stress tests (darkness test, water-, coffee- or tea-drinking test, early morning measurements) was observed. Until now 40% of patients were regulated with 0.25% timolol twice daily. Another 50% obtained good pressure values under 0.5% timolol therapy and the rest with 0.5% timolol and 2% pilocarpine twice daily. Early morning measurement was shown to be the most important indicator of intraocular pressure regulation by beta-blocking agents. While timolol is usually very effective in reducing the intraocular pressure during daytime, several patients showed unattended high morning pressure values. Up to now, no severe side-effects of timolol therapy have been observed.

  7. Acupuncture Attenuates Renal Sympathetic Activity and Blood Pressure via Beta-Adrenergic Receptors in Spontaneously Hypertensive Rats

    PubMed Central

    Ye, Yang; Wang, Xue-Rui; Li, Fang; Xiao, Ling-Yong; Shi, Guang-Xia

    2017-01-01

    The sympathetic nervous system, via epinephrine and norepinephrine, regulates β-adrenergic receptor (β-AR) expression, and renal sympathetic activation causes sustained increases in blood pressure by enhanced renin release. In this study, we aim to investigate the effect and underlying mechanism of acupuncture at Taichong (LR3) on renal sympathetic activity in spontaneously hypertensive rats. Unanesthetized rats were subject to daily acupuncture for 2 weeks. Mean blood pressure (MBP) and heart rate variability (HRV) were monitored at days 0, 7, and 14 by radiotelemetry. After euthanasia on the 14th day, blood and the kidneys were collected and subject to the following analyses. Epinephrine and norepinephrine were detected by ELISA. The expression of β-ARs was studied by western blotting and PCR. The renin content was analyzed by radioimmunoassay. 14-day acupuncture significantly attenuates the increase of MBP. The HRV indices, the standard deviation of all normal NN intervals (SDNN), and the ratio of the low-frequency component to the high-frequency component (LF/HF) were improved following acupuncture. Renal sympathetic activation induced upregulation of epinephrine, norepinephrine, and renin content were attenuated by acupuncture. In addition, acupuncture decreased β1-AR expression and improved β2-AR expression. These results indicated that acupuncture relieves the increased MBP via the regulation of renal sympathetic activity and β-ARs. PMID:28270938

  8. Beta-adrenergic or parasympathetic inhibition, heart rate and cardiac output during normoxic and acute hypoxic exercise in humans.

    PubMed

    Hopkins, Susan R; Bogaard, Harm J; Niizeki, Kyuichi; Yamaya, Yoshiki; Ziegler, Michael G; Wagner, Peter D

    2003-07-15

    Acute hypoxia increases heart rate (HR) and cardiac output (Qt) at a given oxygen consumption (VO2) during submaximal exercise. It is widely believed that the underlying mechanism involves increased sympathetic activation and circulating catecholamines acting on cardiac beta receptors. Recent evidence indicating a continued role for parasympathetic modulation of HR during moderate exercise suggests that increased parasympathetic withdrawal plays a part in the increase in HR and Qt during hypoxic exercise. To test this, we separately blocked the beta-sympathetic and parasympathetic arms of the autonomic nervous system (ANS) in six healthy subjects (five male, one female; mean +/- S.E.M. age = 31.7+/-1.6 years, normoxic maximal VO2 (VO2,max)=3.1+/-0.3 l min(-1)) during exercise in conditions of normoxia and acute hypoxia (inspired oxygen fraction=0.125) to VO2,max. Data were collected on different days under the following conditions: (1)control, (2) after 8.0 mg propranolol i.v. and (3) after 0.8 mg glycopyrrolate i.v. Qt was measured using open-circuit acetylene uptake. Hypoxia increased venous [adrenaline] and [noradrenaline] but not [dopamine] at a given VO2 (P<0.05, P<0.01 and P=0.2, respectively). HR/VO2 and Qt/VO2 increased during hypoxia in all three conditions (P<0.05). Unexpectedly, the effects of hypoxia on HR and Qt were not significantly different from control with either beta-sympathetic or parasympathetic inhibition. These data suggest that although acute exposure to hypoxia increases circulating [catecholamines], the effects of hypoxia on HR and Qt do not necessarily require intact cardiac muscarinic and beta receptors. It may be that cardiac alpha receptors play a primary role in elevating HR and Qt during hypoxic exercise, or perhaps offer an alternative mechanism when other ANS pathways are blocked.

  9. Impact of alpha- and beta-adrenergic receptor blockers on fractional flow reserve and index of microvascular resistance.

    PubMed

    Barbato, Emanuele; Sarno, Giovanna; Berza, Catalina Trana; Di Gioia, Giuseppe; Bartunek, Jozef; Vanderheyden, Marc; Di Serafino, Luigi; Wijns, William; Trimarco, Bruno; De Bruyne, Bernard

    2014-12-01

    We investigated the effect of β- and α-adrenergic blockers on fractional flow reserve (FFR) and index of microvascular resistance (IMR). In 43 patients (pts) with intermediate stenoses, we measured FFR and IMR before and after nonselective β-blocker propranolol (30 μg/kg, n = 20) and selective β1-blocker metoprolol (40 μg/kg, n = 23) IC; (b) In additional 21 pts after percutaneous coronary intervention (PCI), FFR and IMR were measured before and after α-blocker phentolamine (3 mg) IC. Neither propranolol nor metoprolol changed values of FFR and IMR. Phentolamine slightly decreased FFR (from 0.88 ± 0.05 to 0.87 ± 0.06, p = 0.025) but did not change IMR. FFR decreased from >0.80 to ≤0.80 in 3 pts (14%), but in none, the value decreased to <0.75. β-blockers do not affect FFR and IMR in intermediate stenoses. After PCI, a mild decrease in FFR occurs after α-blockers, though of limited clinical impact.

  10. Broad-Scale Phosphoprotein Profiling of Beta Adrenergic Receptor (β-AR) Signaling Reveals Novel Phosphorylation and Dephosphorylation Events

    PubMed Central

    Chruscinski, Andrzej J.; Singh, Harvir; Chan, Steven M.; Utz, Paul J.

    2013-01-01

    β-adrenergic receptors (β-ARs) are model G-protein coupled receptors that mediate signal transduction in the sympathetic nervous system. Despite the widespread clinical use of agents that target β-ARs, the signaling pathways that operate downstream of β-AR stimulation have not yet been completely elucidated. Here, we utilized a lysate microarray approach to obtain a broad-scale perspective of phosphoprotein signaling downstream of β-AR. We monitored the time course of phosphorylation states of 54 proteins after β-AR activation mouse embryonic fibroblast (MEF) cells. In response to stimulation with the non-selective β-AR agonist isoproterenol, we observed previously described phosphorylation events such as ERK1/2(T202/Y204) and CREB(S133), but also novel phosphorylation events such as Cdc2(Y15) and Pyk2(Y402). All of these events were mediated through cAMP and PKA as they were reproduced by stimulation with the adenylyl cyclase activator forskolin and were blocked by treatment with H89, a PKA inhibitor. In addition, we also observed a number of novel isoproterenol-induced protein dephosphorylation events in target substrates of the PI3K/AKT pathway: GSK3β(S9), 4E-BP1(S65), and p70s6k(T389). These dephosphorylations were dependent on cAMP, but were independent of PKA and correlated with reduced PI3K/AKT activity. Isoproterenol stimulation also led to a cAMP-dependent dephosphorylation of PP1α(T320), a modification known to correlate with enhanced activity of this phosphatase. Dephosphorylation of PP1α coincided with the secondary decline in phosphorylation of some PKA-phosphorylated substrates, suggesting that PP1α may act in a feedback loop to return these phosphorylations to baseline. In summary, lysate microarrays are a powerful tool to profile phosphoprotein signaling and have provided a broad-scale perspective of how β-AR signaling can regulate key pathways involved in cell growth and metabolism. PMID:24340001

  11. Beta-adrenergic receptor mediated inflammation control by monocytes is associated with blood pressure and risk factors for cardiovascular disease

    PubMed Central

    Hong, Suzi; Dimitrov, Stoyan; Cheng, Tiefu; Redwine, Laura; Pruitt, Christopher; Mills, Paul J.; Ziegler, Michael G.; Green, J. Michael; Shaikh, Farah; Wilson, Kathleen

    2015-01-01

    Overwhelming data indicate that individuals with even mildly elevated blood pressure (BP) are at great risk for developing clinical hypertension and future cardiovascular disease (CVD). There remains a lack of consensus regarding treatment strategies for mildly elevated BP, termed prehypertension, and the knowledge of pathophysiology and mechanisms of its clinical outcomes remains limited. Our primary aim was to investigate βAR-mediated inflammation control (BARIC) responses of blood monocytes to isoproterenol (Iso) in relation to BP and CVD risk factors, including obesity, depressive mood, fasting glucose, triglycerides, and cholesterol levels in the 64 prehypertensive compared to 84 individuals with normal BP. BARIC was determined by measuring the degree of inhibition in lipopolysaccharides-stimulated monocytic intracellular TNF production by ex vivo Iso treatment (10−8 M). Depressive mood was assessed by Beck Depression Inventory (BDI). Fasting metabolic and lipid panels were assessed, and plasma levels of inflammatory cytokines TNF, IL-1β, IL-6 were measured in a subset to confirm proinflammatory state of prehypertensive participants. Prehypertensive participants were older, heavier, included more men, and presented higher levels of fasting glucose, triglycerides, cholesterol, and plasma TNF compared to normotensive participants (p’s< .05). BARIC was significantly attenuated in the prehypertensive compared to normotensive group (p< .05). BARIC was negatively associated with systolic BP, diastolic BP, age, BMI, fasting glucose, triglycerides, total and low density cholesterol levels, and somatic depressive symptoms in all participants (p’s< .0001 to .05). However, among the prehypertensive individuals BARIC was positively associated with SBP even after controlling for the covariates (age, gender, race, BMI, glucose and lipid panel, somatic BDI scores) (p< .05). This differing nature of the BARIC-SBP relationship between the two BP groups may be attributed to moderating factors such as cardiorespiratory fitness or depressive symptoms that could not be clearly deciphered in this current study. Nonetheless, our findings indicate the associations between inflammation dysregulation mediated by sympathoadrenal activation and BP that is observable even among individuals with normal to mildly elevated BP. BARIC may be a useful and sensitive indicator of elevated risk for vascular inflammatory disease that can be detected even at lower BP levels, especially given its associations with traditional CVD risk factors and the critical role of monocytes in atherogenic processes. PMID:26300225

  12. Effects of beta-adrenergic blockers with different ancillary properties on lipid peroxidation in hyperthyroid rat cardiac muscle.

    PubMed

    Asayama, K; Dobashi, K; Hayashibe, H; Kato, K

    1989-10-01

    To determine whether beta-blockade protects rat heart against thyroxine (T4)-induced accelelation of lipid peroxidation, in vivo effects of 3 beta-blockers with different ancillary properties on the mitochondrial oxidative enzyme, antioxidant enzymes and lipid peroxide were investigated. The rats were rendered hyperthyroid by adding T4 to their drinking water for 3 weeks and were treated simultaneously with either carteolol (a blocker with partial agonist activity; 30 mg/kg/day), atenolol (50 mg/kg/day) or arotinolol (a blocker with weak alpha-blocking action; 50 mg/kg/day). The T4-induced tachycardia was alleviated completely by either atenolol or arotinolol, but only partially by carteolol. Cytochrome c oxidase activity in the heart muscle was increased by T4 with a parallel increase in manganese (mitochondrial) superoxide dismutase. Atenolol, but neither carteolol nor arotinolol, suppressed this increase. Similarly, the T4-induced acceleration of lipid peroxidation was suppressed by atenolol alone. Glutathione peroxidase was markedly decreased, and both copper zinc (cytosolic) superoxide dismutase and catalase were also decreased or tended to be decreased by T4. The levels of these 3 enzymes were only minimally affected by the beta-blocker treatments. These results suggest that beta-blockade suppresses mitochondrial hypermetabolism and protects heart muscle against oxidative stress in hyperthyroidism, and that the ancillary properties of beta-blockers such as partial agonist activity and alpha-blocking action negate the protection.

  13. Beta-adrenergic receptor blockade during exercise decreases intestinal lymphocyte apoptosis but not cell loss in mice.

    PubMed

    Marra, S; Hoffman-Goetz, L

    2004-07-01

    Catecholamines induce apoptosis in various lymphoid populations. This process can occur with both alpha- and beta-adrenoreceptors. Heavy exercise increases plasma catecholamine concentrations, and is also a cause of lymphocyte apoptosis, a possible explanation for postexercise lymphocytopenia. The purpose of this study was to examine the effects of adrenoreceptor antagonism on exercise-induced decreases and apoptosis of intestinal lymphocytes. Mice received an intraperitoneal injection of phentolamine (a nonselective alpha-blocker), nadolol (a nonselective beta-blocker), or saline (vehicle) prior to an exhaustive bout of exercise. Total intestinal lymphocyte numbers, percent and number of CD3+ lymphocytes, and cell viability were assessed. Neither alpha- nor beta-antagonism prevented exercise-induced cell loss in the intestine; however, pretreatment with nadolol significantly reduced the number of apoptotic and necrotic cells. Phentolamine administration appeared to increase the incidence of cell death among intestinal lymphocytes. Both drugs decreased the percentage of CD3+ intestinal lymphocytes. Our study suggests that catecholamines are not responsible for postexercise lymphocytopenia, but beta-adrenoceptor blockade may confer protection against exercise-induced apoptosis of intestinal lymphocytes.

  14. Post-Retrieval [beta]-Adrenergic Receptor Blockade: Effects on Extinction and Reconsolidation of Cocaine-Cue Memories

    ERIC Educational Resources Information Center

    Fricks-Gleason, Ashley N.; Marshall, John F.

    2008-01-01

    Contexts and discrete cues associated with drug-taking are often responsible for relapse among addicts. Animal models have shown that interference with the reconsolidation of drug-cue memories can reduce seeking of drugs or drug-paired stimuli. One such model is conditioned place preference (CPP) in which an animal is trained to associate a…

  15. Effect of cardiopulmonary bypass on beta adrenergic receptor-adenylate cyclase system on surfaces of peripheral lymphocytes.

    PubMed

    Luo, A; Tian, Y; Jin, S

    2000-01-01

    The experimental results showed that the level of CAMP, the ratio of cAPM to cGMP, IL-2R expression and IL-2 production in vitro in lymphocytes immediate and 2 weeks after cardiopulmonary bypass (CPB) were significantly lower than those before anesthetics in the patients undergoing cardiac surgery with CPB. These findings suggested that CPB could cause serious damage to adrenergic beta receptor-adenylate cyclase system on circulating lymphocytes surfaces, which might be one of the mechanisms resulting in immunosuppression after open heart surgery with CPB.

  16. "Silent" Priming of Translation-Dependent LTP by [Beta]-Adrenergic Receptors Involves Phosphorylation and Recruitment of AMPA Receptors

    ERIC Educational Resources Information Center

    Tenorio, Gustavo; Connor, Steven A.; Guevremont, Diane; Abraham, Wickliffe C.; Williams, Joanna; O'Dell, Thomas J.; Nguyen, Peter V.

    2010-01-01

    The capacity for long-term changes in synaptic efficacy can be altered by prior synaptic activity, a process known as "metaplasticity." Activation of receptors for modulatory neurotransmitters can trigger downstream signaling cascades that persist beyond initial receptor activation and may thus have metaplastic effects. Because activation of…

  17. Enhanced Noradrenergic Activity Potentiates Fear Memory Consolidation and Reconsolidation by Differentially Recruiting alpha1- and beta-Adrenergic Receptors

    ERIC Educational Resources Information Center

    Gazarini, Lucas; Stern, Cristina A. Jark; Carobrez, Antonio P.; Bertoglio, Leandro J.

    2013-01-01

    Consolidation and reconsolidation are phases of memory stabilization that diverge slightly. Noradrenaline is known to influence both processes, but the relative contribution of alpha1- and beta-adrenoceptors is unclear. The present study sought to investigate this matter by comparing their recruitment to consolidate and/or reconsolidate a…

  18. Beta-adrenergic activation of solute coupled water uptake by toad skin epithelium results in near-isosmotic transport.

    PubMed

    Nielsen, Robert; Larsen, Erik Hviid

    2007-09-01

    Transepithelial potential (V(T)), conductance (G(T)), and water flow (J(V)) were measured simultaneously with good time resolution (min) in isolated toad (Bufo bufo) skin epithelium with Ringer on both sides. Inside application of 5 microM isoproterenol resulted in the fast increase in G(T) from 1.2+/-0.3 to 2.4+/-0.4 mS x cm(-2) and slower increases in equivalent short circuit current, I(SC)(Eqv) = -G(T) x V(T), from 12.7+/-3.2 to 33.1+/-6.8 microA cm(-2), and J(V) from 0.72+/-0.17 to 3.01+/-0.49 nL cm(-2) s(-1). Amiloride in the outside solution abolished I(SC)(Eqv) (-1.6+/-0.1 microA cm(-2)) while J(V) decreased to 0.50+/-0.15 nL cm(-2) x s(-1), which is significantly different from zero. Isoproterenol decreased the osmotic concentration of the transported fluid, C(osm) approximately 2 x I(SC)(Eqv)/J(V), from 351+/-72 to 227+/-28 mOsm (Ringer's solution: 252.8 mOsm). J(V) depicted a saturating function of [Na+]out in agreement with Na+ self-inhibition of ENaC. Ouabain on the inside decreased I(SC)(Eqv) from 60+/-10 to 6.1+/-1.7 microA cm(-2), and J(V) from 3.34+/-0.47 to 1.40+/-0.24 nL cm(-2) x s(-1). Short-circuited preparations exhibited a linear relationship between short-circuit current and J(V) with a [Na+] of the transported fluid of 130+/-24 mM ([Na+]Ringer's solution = 117.4 mM). Addition of bumetanide to the inside solution reduced J(V). Water was transported uphill and J(V) reversed at an excess outside osmotic concentration, deltaC(S,rev) = 28.9+/-3.9 mOsm, amiloride decreased deltaC(S,rev) to 7.5+/-1.5 mOsm. It is concluded that water uptake is accomplished by osmotic coupling in the lateral intercellular space (lis), and hypothesized that a small fraction of the Na+ flux pumped into lis is recirculated via basolateral NKCC transporters.

  19. Post-Retrieval [beta]-Adrenergic Receptor Blockade: Effects on Extinction and Reconsolidation of Cocaine-Cue Memories

    ERIC Educational Resources Information Center

    Fricks-Gleason, Ashley N.; Marshall, John F.

    2008-01-01

    Contexts and discrete cues associated with drug-taking are often responsible for relapse among addicts. Animal models have shown that interference with the reconsolidation of drug-cue memories can reduce seeking of drugs or drug-paired stimuli. One such model is conditioned place preference (CPP) in which an animal is trained to associate a…

  20. Antibodies to beta-adrenergic receptors disclosing agonist-like properties in idiopathic dilated cardiomyopathy and Chagas' heart disease.

    PubMed

    Rosenbaum, M B; Chiale, P A; Schejtman, D; Levin, M; Elizari, M V

    1994-04-01

    Recent studies confirm the existence of antibodies (Abs) to beta-adrenoceptors in patients with idiopathic dilated cardiomyopathy and Chagas' heart disease. These Abs can be shown to exert both stimulatory and inhibitory effects, which may play a role in the development of the cardiac abnormalities known to occur in these diseases, including advanced heart failure. The hypothesis is advanced that Chagas' heart disease and some forms of idiopathic dilated cardiomyopathy may represent, at least partially, a form of "adrenergic cardiomyopathy."

  1. Corticosterone Time-Dependently Modulates [beta]-Adrenergic Effects on Long-Term Potentiation in the Hippocampal Dentate Gyrus

    ERIC Educational Resources Information Center

    Pu, Zhenwei; Krugers, Harm J.; Joels, Marian

    2007-01-01

    Previous experiments in the hippocampal CA1 area have shown that corticosterone can facilitate long-term potentiation (LTP) in a rapid non-genomic fashion, while the same hormone suppresses LTP that is induced several hours after hormone application. Here, we elaborated on this finding by examining whether corticosterone exerts opposite effects on…

  2. Corticosterone Time-Dependently Modulates [beta]-Adrenergic Effects on Long-Term Potentiation in the Hippocampal Dentate Gyrus

    ERIC Educational Resources Information Center

    Pu, Zhenwei; Krugers, Harm J.; Joels, Marian

    2007-01-01

    Previous experiments in the hippocampal CA1 area have shown that corticosterone can facilitate long-term potentiation (LTP) in a rapid non-genomic fashion, while the same hormone suppresses LTP that is induced several hours after hormone application. Here, we elaborated on this finding by examining whether corticosterone exerts opposite effects on…

  3. Effect of beta-adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial.

    PubMed

    Clark, Andrew L; Coats, Andrew J S; Krum, Henry; Katus, Hugo A; Mohacsi, Paul; Salekin, Damien; Schultz, Melissa K; Packer, Milton; Anker, Stefan D

    2017-08-01

    Cardiac cachexia frequently accompanies the progression of heart failure despite the use of effective therapies for left ventricular dysfunction. Activation of the sympathetic nervous system has been implicated in the pathogenesis of weight loss, but the effects of sympathetic antagonism on cachexia are not well defined. We prospectively evaluated changes in body weight in 2289 patients with heart failure who had dyspnoea at rest or on minimal exertion and a left ventricular ejection fraction <25%. Patients were randomly assigned (double-blind) to receive either placebo (n = 1133) or carvedilol (n = 1156) and were followed for the occurrence of major clinical events for up to 29 months (COPERNICUS trial). Patients were not enrolled if they had signs of clinically significant fluid retention due to heart failure. Patients in the carvedilol group were 33% less likely than patients in the placebo group to experience a further significant loss of weight (>6%) (95% confidence interval: 14-48%, P = 0.002) and were 37% more likely to experience a significant gain in weight (≥5%) (95% confidence interval: 12-66%, P = 0.002). Carvedilol's ability to prevent weight loss was most marked in patients with increased body mass index at baseline, whereas its ability to promote weight gain was most marked in patients with decreased body mass index at baseline. Increases in weight were not accompanied by evidence of fluid retention. Baseline values for body mass index and change in body weight were significant predictors of survival regardless of treatment. Carvedilol attenuated the development and promoted a partial reversal of cachexia in patients with severe chronic heart failure, supporting a role for prolonged sympathetic activation in the genesis of weight loss. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

  4. CRM 1-mediated degradation and agonist-induced down-regulation of beta-adrenergic receptor mRNAs.

    PubMed

    Bai, Ying; Lu, Huafei; Machida, Curtis A

    2006-10-01

    The beta1-adrenergic receptor (beta1-AR) mRNAs are post-transcriptionally regulated at the level of mRNA stability and undergo accelerated agonist-mediated degradation via interaction of its 3' untranslated region (UTR) with RNA binding proteins, including the HuR nuclear protein. In a previous report [Kirigiti et al. (2001). Mol. Pharmacol. 60:1308-1324], we examined the agonist-mediated down-regulation of the rat beta1-AR mRNAs, endogenously expressed in the rat C6 cell line and ectopically expressed in transfectant hamster DDT1MF2 and rat L6 cells. In this report, we determined that isoproterenol treatment of neonatal rat cortical neurons, an important cell type expressing beta1-ARs in the brain, results in significant decreases in beta1-AR mRNA stability, while treatment with leptomycin B, an inhibitor of the nuclear export receptor CRM 1, results in significant increases in beta1-AR mRNA stability and nuclear retention. UV-crosslinking/immunoprecipitation and glycerol gradient fractionation analyses indicate that the beta1-AR 3' UTR recognize complexes composed of HuR and multiple proteins, including CRM 1. Cell-permeable peptides containing the leucine-rich nuclear export signal (NES) were used as inhibitors of CRM 1-mediated nuclear export. When DDT1MF2 transfectants were treated with isoproterenol and peptide inhibitors, only the co-addition of the NES inhibitor reversed the isoproterenol-induced reduction of beta1-AR mRNA levels. Our results suggest that CRM 1-dependent NES-mediated mechanisms influence the degradation and agonist-mediated down-regulation of the beta1-AR mRNAs.

  5. Beta-adrenergic receptor agonist decreases VEGF levels through altered eNOS and PKC signaling in diabetic retina

    PubMed Central

    Jiang, Youde; Zhang, Qiuhua; Steinle, Jena J.

    2015-01-01

    Vascular endothelial cell growth factor (VEGF) is increased in diabetic macular edema. Compound 49b, a novel β-adrenergic receptor agonist, is protective in a type 1 diabetic rat model. We questioned whether Compound 49b could decrease VEGF levels, suggesting that Compound 49b may be effective against edema. Two-month diabetic rats received topical Compound 49b for 7 days only and/or insulin-like growth factor binding protein 3 (IGFBP-3) siRNA. We also measured endothelial nitric oxide synthase (eNOS) and protein kinase C (PKC)ζ and PKCδ phosphorylation. Retinal endothelial cells (RECs) cultured in high glucose were treated with Compound 49b and IGFBP-3 siRNA for evaluation of the same signaling pathways. Compound 49b significantly decreased VEGF through increased IGFBP-3 in the diabetic retina. Compound 49b also reduced eNOS, PKCζ and PKCδ phosphorylation in the diabetic retina and REC. Compound 49b regulated a number of proteins involved in REC barrier properties. PMID:26115368

  6. Acupuncture Attenuates Renal Sympathetic Activity and Blood Pressure via Beta-Adrenergic Receptors in Spontaneously Hypertensive Rats.

    PubMed

    Yang, Jing-Wen; Ye, Yang; Wang, Xue-Rui; Li, Fang; Xiao, Ling-Yong; Shi, Guang-Xia; Liu, Cun-Zhi

    2017-01-01

    The sympathetic nervous system, via epinephrine and norepinephrine, regulates β-adrenergic receptor (β-AR) expression, and renal sympathetic activation causes sustained increases in blood pressure by enhanced renin release. In this study, we aim to investigate the effect and underlying mechanism of acupuncture at Taichong (LR3) on renal sympathetic activity in spontaneously hypertensive rats. Unanesthetized rats were subject to daily acupuncture for 2 weeks. Mean blood pressure (MBP) and heart rate variability (HRV) were monitored at days 0, 7, and 14 by radiotelemetry. After euthanasia on the 14th day, blood and the kidneys were collected and subject to the following analyses. Epinephrine and norepinephrine were detected by ELISA. The expression of β-ARs was studied by western blotting and PCR. The renin content was analyzed by radioimmunoassay. 14-day acupuncture significantly attenuates the increase of MBP. The HRV indices, the standard deviation of all normal NN intervals (SDNN), and the ratio of the low-frequency component to the high-frequency component (LF/HF) were improved following acupuncture. Renal sympathetic activation induced upregulation of epinephrine, norepinephrine, and renin content were attenuated by acupuncture. In addition, acupuncture decreased β1-AR expression and improved β2-AR expression. These results indicated that acupuncture relieves the increased MBP via the regulation of renal sympathetic activity and β-ARs.

  7. Antagonistic and synergistic interactions among predators.

    PubMed

    Huxel, Gary R

    2007-08-01

    The structure and dynamics of food webs are largely dependent upon interactions among consumers and their resources. However, interspecific interactions such as intraguild predation and interference competition can also play a significant role in the stability of communities. The role of antagonistic/synergistic interactions among predators has been largely ignored in food web theory. These mechanisms influence predation rates, which is one of the key factors regulating food web structure and dynamics, thus ignoring them can potentially limit understanding of food webs. Using nonlinear models, it is shown that critical aspects of multiple predator food web dynamics are antagonistic/synergistic interactions among predators. The influence of antagonistic/synergistic interactions on coexistence of predators depended largely upon the parameter set used and the degree of feeding niche differentiation. In all cases when there was no effect of antagonism or synergism (a ( ij )=1.00), the predators coexisted. Using the stable parameter set, coexistence occurred across the range of antagonism/synergism used. However, using the chaotic parameter strong antagonism resulted in the extinction of one or both species, while strong synergism tended to coexistence. Whereas using the limit cycle parameter set, coexistence was strongly dependent on the degree of feeding niche overlap. Additionally increasing the degree of feeding specialization of the predators on the two prey species increased the amount of parameter space in which coexistence of the two predators occurred. Bifurcation analyses supported the general pattern of increased stability when the predator interaction was synergistic and decreased stability when it was antagonistic. Thus, synergistic interactions should be more common than antagonistic interactions in ecological systems.

  8. Antagonist-Elicited Cannabis Withdrawal in Humans

    PubMed Central

    Gorelick, David A.; Goodwin, Robert S.; Schwilke, Eugene; Schwope, David M.; Darwin, William D.; Kelly, Deanna L.; McMahon, Robert P.; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A.

    2013-01-01

    Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ9-tetrahydrocannabinol (THC) dosages (40–120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0–8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses. PMID:21869692

  9. Antagonist-elicited cannabis withdrawal in humans.

    PubMed

    Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; McMahon, Robert P; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A

    2011-10-01

    Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ⁹-tetrahydrocannabinol (THC) dosages (40-120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0-8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses.

  10. Combining Elements from Two Antagonists of Formyl Peptide Receptor 2 Generates More Potent Peptidomimetic Antagonists.

    PubMed

    Skovbakke, Sarah Line; Holdfeldt, André; Nielsen, Christina; Hansen, Anna Mette; Perez-Gassol, Iris; Dahlgren, Claes; Forsman, Huamei; Franzyk, Henrik

    2017-08-24

    Structural optimization of a peptidomimetic antagonist of formyl peptide receptor 2 (FPR2) was explored by an approach involving combination of elements from the two most potent FPR2 antagonists described: a Rhodamine B-conjugated 10-residue gelsonin-derived peptide (i.e., PBP10, RhB-QRLFQVKGRR-OH) and the palmitoylated α-peptide/β-peptoid hybrid Pam-(Lys-βNspe)6-NH2. This generated an array of hybrid compounds from which a new subclass of receptor-selective antagonists was identified. The most potent representatives displayed activity in the low nanomolar range. The resulting stable and potent FPR2-selective antagonists (i.e., RhB-(Lys-βNphe)n-NH2; n = 4-6) are expected to become valuable tools in further elucidation of the physiological role of FPR2 in health and disease.

  11. Progress in corticotropin-releasing factor-1 antagonist development

    PubMed Central

    Zorrilla, Eric P.; Koob, George F.

    2010-01-01

    Corticotropin-releasing factor (CRF) receptor antagonists have been sought since the stress-secreted peptide was isolated in 1981. Although evidence suggests the limited efficacy of CRF1 antagonists as antidepressants, CRF1 antagonists might be novel pharmacotherapies for anxiety and addiction. Progress in understanding the two-domain model of ligand–receptor interactions for CRF family receptors might yield chemically novel CRF1 receptor antagonists, including peptide CRF1 antagonists, antagonists with signal transduction selectivity and nonpeptide CRF1 antagonists that act via the extracellular (rather than transmembrane) domains. Novel ligands that conform to prevalent pharmacophore and exhibit drug-like pharmacokinetic properties have been identified. The therapeutic utility of CRF1 antagonists should soon be clearer: several small molecules are currently in Phase II/III clinical trials for depression, anxiety and irritable bowel syndrome. PMID:20206287

  12. Novel benzimidazole-based MCH R1 antagonists.

    PubMed

    Carpenter, Andrew J; Al-Barazanji, Kamal A; Barvian, Kevin K; Bishop, Michael J; Britt, Christy S; Cooper, Joel P; Goetz, Aaron S; Grizzle, Mary K; Hertzog, Donald L; Ignar, Diane M; Morgan, Ronda O; Peckham, Gregory E; Speake, Jason D; Swain, Will R

    2006-10-01

    The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.

  13. Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

    DTIC Science & Technology

    2010-09-30

    a novel hypocretiniorexin antagonist, almorexant (ALM), to a standard hypnotic , zolpidem (ZOL), and placebo (PBO) on neurocognitive performance at...Placebo-Controlled, Randomized, Parallel- Group Study Comparing the Effect of a Novel HypocretiniOrexin Antagonist (Almorexant) Versus a Standard Hypnotic ...Group Study Comparing the Effect of a Novel HypocretiniOrexin Antagonist (Almorexant) Versus a Standard Hypnotic (Zolpidem) and Placebo on

  14. Altered melatonin production in TGR(mREN2)27 rats: on the regulation by adrenergic agonists, antagonists and angiotensin II in cultured pinealocytes.

    PubMed

    Enzminger, H; Witte, K; Lemmer, B

    2001-10-01

    Transgenic TGR(mREN2)27 rats (TGR), carrying an additional mouse renin gene, are characterized by severe hypertension, an inverse circadian blood pressure profile, a blunted response to photic entrainment signals, and an increased nocturnal production of the pineal hormone melatonin. In order to evaluate the contribution of the over-expressed renin-angiotensin system to the function of the pineal gland in TGR, we studied the adrenergic and angiotensin II (Ang II)-mediated regulation of melatonin synthesis using dispersed pinealocytes from TGR and from Sprague-Dawley control rats (SDR). Isoproterenol was more effective in stimulating melatonin release in pinealocytes from TGR than from SDR, whereas the maximum effect of norepinephrine (NE) stimulation did not differ between the strains. Prazosin reduced the NE-mediated melatonin release only in SDR but not in TGR pinealocytes. Competition experiments with (+/-)-, (+)-, (-)-propranolol and (+/-)-atenolol revealed one homogeneous population of beta1-adrenoceptors. Ang II had no significant effect on basal or isoproterenol-induced melatonin release in either strain. In conclusion, TGR pinealocytes were more sensitive to beta-adrenergic stimulation than SDR pinealocytes, but lacked the alpha1-adrenergic potentiation of beta-adrenergic induced melatonin release. The renin-angiotensin system was not directly involved in the regulation of melatonin synthesis by rat pinealocytes in vitro.

  15. The treatment of hyponatraemia using vasopressin antagonists.

    PubMed

    Gross, P; Palm, C

    2000-03-01

    Hyponatraemia is a frequent electrolyte disorder. It is primarily attributable to vasopressin excess plus sustained fluid intake. Hyponatraemia causes CNS symptoms, especially during the first 2-4 days; these symptoms are related to brain swelling. Hyponatraemia occurs in the setting of liver cirrhosis and congestive cardiac failure, in which it is related to stimulation by low arterial blood pressure acting through baroreceptors. Hyponatraemia also occurs in the syndrome of inappropriate antidiuretic hormone secretion, usually from neoplasms releasing vasopressin. The conventional treatment of hyponatraemia used to be fluid restriction and treatment of the underlying disorder. This kind of treatment has been unreliable, cumbersome and difficult to comply with for the patient. In the future, effective vasopressin V2 antagonists will become available for clinical use in the treatment of hyponatraemia, and are expected to improve the management of hyponatraemia. Pharmacological characteristics and observations of biological effects of three antagonists are reported in the present article.

  16. Development of Kappa Opioid Receptor Antagonists

    PubMed Central

    Carroll, F. Ivy; Carlezon, William A.

    2013-01-01

    Kappa opioid receptors (KORs) belong to the G-protein coupled class of receptors (GPCRs). They are activated by the endogenous opioid peptide dynorphin (DYN) and expressed at particularly high levels within brain areas implicated in modulation of motivation, emotion, and cognitive function. Chronic activation of KORs in animal models has maladaptive effects including increases in behaviors that reflect depression, the propensity to engage in drug-seeking behavior, and drug craving. The fact that KOR activation has such a profound influence on behaviors often triggered by stress has led to interest in selective KOR antagonists as potential therapeutic agents. This perspective provides a description of preclinical research conducted in the development of several different classes of selective KOR antagonists, a summary of the clinical studies conducted thus far, and recommendations for the type of work needed in the future to determine if these agents would be useful as pharmacotherapies for neuropsychiatric illness. PMID:23360448

  17. [PAF antagonistic benzofuran neolignans from Piper kadsura].

    PubMed

    Ma, Y; Han, G Q; Wang, Y Y

    1993-01-01

    In a continuing search for PAF antagonists, five benzofuran neolignans have been isolated from the aerial part of Piper kadsura (Choisy) Ohwi, a Chinese traditional drug used for the treatment of inflammation and rheumatic conditions. The structure determination was based upon spectroscopic analysis. Two of the neolignans were found to have new structures and were named as (-)-denudatin B (the enantiomer of denudatin B, II) and kadsurenin M (7S,8S-3,4,3'-trimethoxy-7'-oxo-nor-8',9'-7.O. 4',8,5'-neolignan, V). The known compounds kadsurenon (I), (-)-acuminatin(III) and (+)-licarin A(IV) were also obtained from the same source. (-)-Denudatin B (II) showed potent PAF antagonistic activity in 3H-PAF receptor binding assay.

  18. Interactions of Freshwater Cyanobacteria with Bacterial Antagonists

    PubMed Central

    Beier, Sara; Grabherr, Manfred

    2017-01-01

    ABSTRACT Cyanobacterial and algal mass development, or blooms, have severe effects on freshwater and marine systems around the world. Many of these phototrophs produce a variety of potent toxins, contribute to oxygen depletion, and affect water quality in several ways. Coexisting antagonists, such as cyanolytic bacteria, hold the potential to suppress, or even terminate, such blooms, yet the nature of this interaction is not well studied. We isolated 31 cyanolytic bacteria affiliated with the genera Pseudomonas, Stenotrophomonas, Acinetobacter, and Delftia from three eutrophic freshwater lakes in Sweden and selected four phylogenetically diverse bacterial strains with strong-to-moderate lytic activity. To characterize their functional responses to the presence of cyanobacteria, we performed RNA sequencing (RNA-Seq) experiments on coculture incubations, with an initial predator-prey ratio of 1:1. Genes involved in central cellular pathways, stress-related heat or cold shock proteins, and antitoxin genes were highly expressed in both heterotrophs and cyanobacteria. Heterotrophs in coculture expressed genes involved in cell motility, signal transduction, and putative lytic activity. l,d-Transpeptidase was the only significantly upregulated lytic gene in Stenotrophomonas rhizophila EK20. Heterotrophs also shifted their central metabolism from the tricarboxylic acid cycle to the glyoxylate shunt. Concurrently, cyanobacteria clearly show contrasting antagonistic interactions with the four tested heterotrophic strains, which is also reflected in the physical attachment to their cells. In conclusion, antagonistic interactions with cyanobacteria were initiated within 24 h, and expression profiles suggest varied responses for the different cyanobacteria and studied cyanolytes. IMPORTANCE Here, we present how gene expression profiles can be used to reveal interactions between bloom-forming freshwater cyanobacteria and antagonistic heterotrophic bacteria. Species

  19. TRPV1 antagonists as potential antitussive agents.

    PubMed

    McLeod, Robbie L; Correll, Craig C; Jia, Yanlin; Anthes, John C

    2008-01-01

    Cough is an important defensive pulmonary reflex that removes irritants, fluids, or foreign materials from the airways. However, when cough is exceptionally intense or when it is chronic and/or nonproductive it may require pharmacologic suppression. For many patients, antitussive therapies consist of OTC products with inconsequential efficacies. On the other hand, the prescription antitussive market is dominated by older opioid drugs such as codeine. Unfortunately, "codeine-like" drugs suppress cough at equivalent doses that also often produce significant ancillary liabilities such as GI constipation, sedation, and respiratory depression. Thus, the discovery of a novel and effective antitussive drug with an improved side effect profile relative to codeine would fulfill an unmet clinical need in the treatment of cough. Afferent pulmonary nerves are endowed with a multitude of potential receptor targets, including TRPV1, that could act to attenuate cough. The evidence linking TRPV1 to cough is convincing. TRPV1 receptors are found on sensory respiratory nerves that are important in the generation of the cough reflex. Isolated pulmonary vagal afferent nerves are responsive to TRPV1 stimulation. In vivo, TRPV1 agonists such as capsaicin elicit cough when aerosolized and delivered to the lungs. Pertinent to the debate on the potential use of TRPV1 antagonist as antitussive agents are the observations that airway afferent nerves become hypersensitive in diseased and inflamed lungs. For example, the sensitivity of capsaicin-induced cough responses following upper respiratory tract infection and in airway inflammatory diseases such as asthma and COPD is increased relative to that of control responses. Indeed, we have demonstrated that TRPV1 antagonism can attenuate antigen-induced cough in the allergic guinea pig. However, it remains to be determined if the emerging pharmacologic profile of TRPV1 antagonists will translate into a novel human antitussive drug. Current

  20. Interactions of Freshwater Cyanobacteria with Bacterial Antagonists.

    PubMed

    Osman, Omneya Ahmed; Beier, Sara; Grabherr, Manfred; Bertilsson, Stefan

    2017-04-01

    Cyanobacterial and algal mass development, or blooms, have severe effects on freshwater and marine systems around the world. Many of these phototrophs produce a variety of potent toxins, contribute to oxygen depletion, and affect water quality in several ways. Coexisting antagonists, such as cyanolytic bacteria, hold the potential to suppress, or even terminate, such blooms, yet the nature of this interaction is not well studied. We isolated 31 cyanolytic bacteria affiliated with the genera Pseudomonas, Stenotrophomonas, Acinetobacter, and Delftia from three eutrophic freshwater lakes in Sweden and selected four phylogenetically diverse bacterial strains with strong-to-moderate lytic activity. To characterize their functional responses to the presence of cyanobacteria, we performed RNA sequencing (RNA-Seq) experiments on coculture incubations, with an initial predator-prey ratio of 1:1. Genes involved in central cellular pathways, stress-related heat or cold shock proteins, and antitoxin genes were highly expressed in both heterotrophs and cyanobacteria. Heterotrophs in coculture expressed genes involved in cell motility, signal transduction, and putative lytic activity. l,d-Transpeptidase was the only significantly upregulated lytic gene in Stenotrophomonas rhizophila EK20. Heterotrophs also shifted their central metabolism from the tricarboxylic acid cycle to the glyoxylate shunt. Concurrently, cyanobacteria clearly show contrasting antagonistic interactions with the four tested heterotrophic strains, which is also reflected in the physical attachment to their cells. In conclusion, antagonistic interactions with cyanobacteria were initiated within 24 h, and expression profiles suggest varied responses for the different cyanobacteria and studied cyanolytes.IMPORTANCE Here, we present how gene expression profiles can be used to reveal interactions between bloom-forming freshwater cyanobacteria and antagonistic heterotrophic bacteria. Species-specific responses in

  1. NMDA Receptor Antagonists for Treatment of Depression

    PubMed Central

    Ates-Alagoz, Zeynep; Adejare, Adeboye

    2013-01-01

    Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA) receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker), and CGP 37849 (an NMDA receptor antagonist) have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery. PMID:24276119

  2. Medicinal Chemistry of Competitive Kainate Receptor Antagonists

    PubMed Central

    2010-01-01

    Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1−5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure−activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field. PMID:22778857

  3. Medicinal chemistry of competitive kainate receptor antagonists.

    PubMed

    Larsen, Ann M; Bunch, Lennart

    2011-02-16

    Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1-5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure-activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field.

  4. Pharmacological analysis of calcium antagonist receptors

    SciTech Connect

    Reynolds, I.J.

    1987-01-01

    This work focuses on two aspects of the action of calcium antagonist drugs, namely, the interaction of drugs with receptors for verapamil-like calcium antagonists, and the interactions of drugs with voltage-sensitive calcium fluxes in rat brain synaptosomes. From binding studies I have found that the ligand of choice for labeling the verapamil receptor is (-)(/sup 3/H)desmethoxy-verapamil. This drug labels potently, reversibly and stereoselectively two receptors in membranes prepared from rat brain and rabbit skeletal muscle tissues. In equilibrium studies dihydropyridine calcium antagonists interact in a non-competitive fashion, while many non-DHPs are apparently competitive. In-depth kinetic studies in skeletal muscle membranes indicate that the two receptors are linked in a negative heterotropic fashion, and that low-affinity binding of (-) (/sup 3/H)desmethoxy-verapamil may be to the diltiazem receptor. However, these studies were not able to distinguish between the hypothesis that diltiazem binds to spatially separate, allosterically coupled receptors, and the hypothesis that diltiazem binds to a subsite of the verapamil receptor.

  5. Effect of age on upregulation of the cardiac adrenergic beta receptors

    SciTech Connect

    Tumer, N.; Houck, W.T.; Roberts, J.

    1990-03-01

    Radioligand binding studies were performed to determine whether upregulation of postjunctional beta receptors occurs in sympathectomized hearts of aged animals. Fischer 344 rats 6, 12, and 24 months of age (n = 10) were used in these experiments. To produce sympathectomy, rats were injected with 6-hydroxydopamine hydrobromide (6-OHDA; 2 x 50 mg/kg iv) on days 1 and 8; the animals were decapitated on day 15. The depletion of norepinephrine in the heart was about 86% in each age group. 125I-Iodopindolol (IPIN), a beta adrenergic receptor antagonist, was employed to determine the affinity and total number of beta adrenergic receptors in the ventricles of the rat heart. The maximal number of binding sites (Bmax) was significantly elevated by 37%, 48%, and 50% in hearts from sympathectomized 6-, 12-, and 24-month-old rats, respectively. These results indicate that beta receptor mechanisms in older hearts can respond to procedures that cause upregulation of the beta adrenergic receptors.

  6. Leptin regulates bone formation via the sympathetic nervous system

    NASA Technical Reports Server (NTRS)

    Takeda, Shu; Elefteriou, Florent; Levasseur, Regis; Liu, Xiuyun; Zhao, Liping; Parker, Keith L.; Armstrong, Dawna; Ducy, Patricia; Karsenty, Gerard

    2002-01-01

    We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.

  7. Leptin regulates bone formation via the sympathetic nervous system

    NASA Technical Reports Server (NTRS)

    Takeda, Shu; Elefteriou, Florent; Levasseur, Regis; Liu, Xiuyun; Zhao, Liping; Parker, Keith L.; Armstrong, Dawna; Ducy, Patricia; Karsenty, Gerard

    2002-01-01

    We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.

  8. From the Cover: Glutamate antagonists limit tumor growth

    NASA Astrophysics Data System (ADS)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  9. Limited Efficacy of Propranolol on the Reconsolidation of Fear Memories

    ERIC Educational Resources Information Center

    Muravieva, Elizaveta V.; Alberini, Cristina M.

    2010-01-01

    Previous studies suggested that the beta-adrenergic receptor antagonist propranolol might be a novel, potential treatment for post-traumatic stress disorder (PTSD). This hypothesis stemmed mainly from rodent studies showing that propranolol interferes with the reconsolidation of Pavlovian fear conditioning (FC). However, subsequent investigations…

  10. Betaxolol and levobunolol: new beta-blocking antiglaucoma agents.

    PubMed

    Tierney, D W

    1987-09-01

    The Food and Drug Administration has recently approved the use of two new ophthalmic beta-adrenergic antagonistic agents: betaxolol hydrochloride (Betoptic) and levobunolol hydrochloride (Betagan). This paper reviews the history, pharmacologic properties, clinical efficacy and potential side effects of this expanding class of antiglaucoma medication.

  11. Intrahippocampal Infusions of Anisomycin Produce Amnesia: Contribution of Increased Release of Norepinephrine, Dopamine, and Acetylcholine

    ERIC Educational Resources Information Center

    Qi, Zhenghan; Gold, Paul E.

    2009-01-01

    Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the beta-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and…

  12. Intrahippocampal Infusions of Anisomycin Produce Amnesia: Contribution of Increased Release of Norepinephrine, Dopamine, and Acetylcholine

    ERIC Educational Resources Information Center

    Qi, Zhenghan; Gold, Paul E.

    2009-01-01

    Intra-amygdala injections of anisomycin produce large increases in the release of norepinephrine (NE), dopamine (DA), and serotonin in the amygdala. Pretreatment with intra-amygdala injections of the beta-adrenergic receptor antagonist propranolol attenuates anisomycin-induced amnesia without reversing the inhibition of protein synthesis, and…

  13. Limited Efficacy of Propranolol on the Reconsolidation of Fear Memories

    ERIC Educational Resources Information Center

    Muravieva, Elizaveta V.; Alberini, Cristina M.

    2010-01-01

    Previous studies suggested that the beta-adrenergic receptor antagonist propranolol might be a novel, potential treatment for post-traumatic stress disorder (PTSD). This hypothesis stemmed mainly from rodent studies showing that propranolol interferes with the reconsolidation of Pavlovian fear conditioning (FC). However, subsequent investigations…

  14. Pharmacotherapy in the Developmental Disabilities: New Developments.

    ERIC Educational Resources Information Center

    Aman, Michael G.

    1991-01-01

    This paper identifies and evaluates emerging developments in the behavioral pharmacotherapy of people with developmental disabilities, including such medications as the opiate antagonists, fenfluramine, beta adrenergic blockers, buspirone, antipsychotics, amantadine hydrochloride, and antilibidinal drugs. The need for more well-designed drug…

  15. Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

    DTIC Science & Technology

    2010-06-01

    has produced the original finding that the anti-progesterone and glucocorticoid receptor antagonist mifepristone , when administered systemically...further original discovery that the beta-adrenergic blocker propranolol blocks this mifepristone effect. We have produced the further original...as powerful as mifepristone . We have produced the further original discovery that post- reactivation rapamycin reduces synaptic strength underlying

  16. Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists.

    PubMed

    Skudlarek, Jason W; DiMarco, Christina N; Babaoglu, Kerim; Roecker, Anthony J; Bruno, Joseph G; Pausch, Mark A; O'Brien, Julie A; Cabalu, Tamara D; Stevens, Joanne; Brunner, Joseph; Tannenbaum, Pamela L; Wuelfing, W Peter; Garson, Susan L; Fox, Steven V; Savitz, Alan T; Harrell, Charles M; Gotter, Anthony L; Winrow, Christopher J; Renger, John J; Kuduk, Scott D; Coleman, Paul J

    2017-03-15

    In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX2R subtype and culminating in the discovery of 23, a highly potent, OX2R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX1R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.

  17. Combination decongestion therapy in hospitalized heart failure: loop diuretics, mineralocorticoid receptor antagonists and vasopressin antagonists.

    PubMed

    Vaduganathan, Muthiah; Mentz, Robert J; Greene, Stephen J; Senni, Michele; Sato, Naoki; Nodari, Savina; Butler, Javed; Gheorghiade, Mihai

    2015-01-01

    Congestion is the most common reason for admissions and readmissions for heart failure (HF). The vast majority of hospitalized HF patients appear to respond readily to loop diuretics, but available data suggest that a significant proportion are being discharged with persistent evidence of congestion. Although novel therapies targeting congestion should continue to be developed, currently available agents may be utilized more optimally to facilitate complete decongestion. The combination of loop diuretics, natriuretic doses of mineralocorticoid receptor antagonists and vasopressin antagonists represents a regimen of currently available therapies that affects early and persistent decongestion, while limiting the associated risks of electrolyte disturbances, hemodynamic fluctuations, renal dysfunction and mortality.

  18. Antagonistic functional duality of cancer genes.

    PubMed

    Stepanenko, A A; Vassetzky, Y S; Kavsan, V M

    2013-10-25

    Cancer evolution is a stochastic process both at the genome and gene levels. Most of tumors contain multiple genetic subclones, evolving in either succession or in parallel, either in a linear or branching manner, with heterogeneous genome and gene alterations, extensively rewired signaling networks, and addicted to multiple oncogenes easily switching with each other during cancer progression and medical intervention. Hundreds of discovered cancer genes are classified according to whether they function in a dominant (oncogenes) or recessive (tumor suppressor genes) manner in a cancer cell. However, there are many cancer "gene-chameleons", which behave distinctly in opposite way in the different experimental settings showing antagonistic duality. In contrast to the widely accepted view that mutant NADP(+)-dependent isocitrate dehydrogenases 1/2 (IDH1/2) and associated metabolite 2-hydroxyglutarate (R)-enantiomer are intrinsically "the drivers" of tumourigenesis, mutant IDH1/2 inhibited, promoted or had no effect on cell proliferation, growth and tumorigenicity in diverse experiments. Similar behavior was evidenced for dozens of cancer genes. Gene function is dependent on genetic network, which is defined by the genome context. The overall changes in karyotype can result in alterations of the role and function of the same genes and pathways. The diverse cell lines and tumor samples have been used in experiments for proving gene tumor promoting/suppressive activity. They all display heterogeneous individual karyotypes and disturbed signaling networks. Consequently, the effect and function of gene under investigation can be opposite and versatile in cells with different genomes that may explain antagonistic duality of cancer genes and the cell type- or the cellular genetic/context-dependent response to the same protein. Antagonistic duality of cancer genes might contribute to failure of chemotherapy. Instructive examples of unexpected activity of cancer genes and

  19. Neuromuscular adaptations following antagonist resisted training.

    PubMed

    MacKenzie, Sasho J; Rannelli, Luke A; Yurchevich, Jordan J

    2010-01-01

    The purpose was to assess a novel form of strength training, antagonist resisted training (ART), with potential use in microgravity and athletic rehabilitation settings. ART uses the force from antagonist muscles, during cocontractions, as the source of resistance for the agonists. Strength and electromyography (EMG) measurements were recorded before and after a 6-week training program during which participants trained the left arm while the right arm served as a control. Training was designed so that the elbow extensors (antagonists) served as resistance for the elbow flexors (agonists). Elbow flexor and extensor strengths were measured during maximal isometric contractions with the elbow fixed at 90 degrees. EMG was recorded from the biceps brachii and lateral head of the triceps brachii during all strength tests. EMG was also recorded from both muscles during a maximal isometric cocontraction of the elbow flexors and extensors. Elbow flexion strength increased significantly for the trained arm (5.8%) relative to the control (0.5%) (p = 0.003). Elbow extension strength of the trained limb also increased significantly (8.5%) relative to the control (4.5%) (p = 0.029). Biceps and triceps EMG, during maximum strength tests, increased significantly for the trained arm (18.5 and 18.6%) relative to the control (0.5 and -5.2%) (p = 0.035 and p = 0.01). Biceps and triceps EMG, during maximum cocontraction tests, increased significantly for the trained arm (30.1 and 61.1%) relative to the control (9.2 and 1.1%) (p = 0.042 and p = 0.0005). ART was found to increase strength and therefore could be an effective form of resistance training. Because it requires no equipment, ART may be especially applicable in microgravity environments, which have space and weight constraints.

  20. Agonists and antagonists for P2 receptors

    PubMed Central

    Jacobson, Kenneth A.; Costanzi, Stefano; Joshi, Bhalchandra V.; Besada, Pedro; Shin, Dae Hong; Ko, Hyojin; Ivanov, Andrei A.; Mamedova, Liaman

    2015-01-01

    Recent work has identified nucleotide agonists selective for P2Y1, P2Y2 and P2Y6 receptors and nucleotide antagonists selective for P2Y1, P2Y12 and P2X1 receptors. Selective non-nucleotide antagonists have been reported for P2Y1, P2Y2, P2Y6, P2Y12, P2Y13, P2X2/3/P2X3 and P2X7 receptors. For example, the dinucleotide INS 37217 (Up4dC) potently activates the P2Y2 receptor, and the non-nucleotide antagonist A-317491 is selective for P2X2/3/P2X3 receptors. Nucleotide analogues in which the ribose moiety is substituted by a variety of novel ring systems, including conformation-ally locked moieties, have been synthesized as ligands for P2Y receptors. The focus on conformational factors of the ribose-like moiety allows the inclusion of general modifications that lead to enhanced potency and selectivity. At P2Y1,2,4,11 receptors, there is a preference for the North conformation as indicated with (N)-methanocarba analogues. The P2Y1 antagonist MRS2500 inhibited ADP-induced human platelet aggregation with an IC50 of 0.95 nM. MRS2365, an (N)-methanocarba analogue of 2-MeSADP, displayed potency (EC50) of 0.4 nM at the P2Y1 receptor, with >10 000-fold selectivity in comparison to P2Y12 and P2Y13 receptors. At P2Y6 receptors there is a dramatic preference for the South conformation. Three-dimensional structures of P2Y receptors have been deduced from structure activity relationships (SAR), mutagenesis and modelling studies. Detailed three-dimensional structures of P2X receptors have not yet been proposed. PMID:16805423

  1. Muscarinic Receptor Antagonists: Effects on Pulmonary Function

    PubMed Central

    Buels, Kalmia S.

    2014-01-01

    In healthy lungs, muscarinic receptors control smooth muscle tone, mucus secretion, vasodilation, and inflammation. In chronic obstructive pulmonary disease (COPD) and asthma, cholinergic mechanisms contribute to increased bronchoconstriction and mucus secretion that limit airflow. This chapter reviews neuronal and nonneuronal sources of acetylcholine in the lung and the expression and role of M1, M2, and M3 muscarinic receptor subtypes in lung physiology. It also discusses the evidence for and against the role of parasympathetic nerves in asthma, and the current use and therapeutic potential of muscarinic receptor antagonists in COPD and asthma. PMID:22222705

  2. Azetidinones as Vasopressin V1a Antagonists

    PubMed Central

    Guillon, Christophe D.; Koppel, Gary A.; Brownstein, Michael J.; Chaney, Michael O.; Ferris, Craig F.; Lu, Shi-fang; Fabio, Karine M.; Miller, Marvin J.; Heindel, Ned D.; Hunden, David C.; Cooper, Robin D. G.; Kaldor, Stephen W.; Skelton, Jeffrey J.; Dressman, Bruce A.; Clay, Michael P.; Steinberg, Mitchell I.; Bruns, Robert F.; Simon, Neal G.

    2007-01-01

    The azetidinone LY307174 (1) was identified as a screening lead for the vasopressin V1a receptor (IC50 45 nM at the human V1a receptor) based on molecular similarity to ketoconazole (2), a known antagonist of the luteinizing hormone releasing hormone receptor. Structure-activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with Ki values < 1 nM and brain levels after oral dosing ~100-fold higher than receptor affinities. PMID:17234419

  3. Endothelin antagonists: new bullets against lung injury?

    PubMed

    Leeman, Marc

    2005-06-01

    Acute lung injury is a syndrome of inflammation and of increased permeability of the blood-gas barrier. Endothelins are thought to exert proinflammatory effects. Kuklin and colleagues show that the endothelin receptor antagonist tezosentan reduces pulmonary edema in endotoxemic sheep, in parallel with a prevention of protein kinase C-alpha activation. In turn, the level of some cytokines increased after tezosentan treatment. Whether these contrasting effects of endothelin blockade on inflammatory mechanisms have clinical relevance and whether these agents might benefit patients with acute lung injury is unknown.

  4. Mineralocorticoid receptor antagonists and endothelial function

    PubMed Central

    Maron, Bradley A.; Leopold, Jane A.

    2010-01-01

    Hyperaldosteronism has been associated with endothelial dysfunction and impaired vascular reactivity in patients with hypertension or congestive heart failure. The mineralocorticoid receptor (MR) antagonists spironolactone and eplerenone have been shown to reduce morbidity and mortality, in part, by ameliorating the adverse effects of aldosterone on vascular function. Although spironolactone and eplerenone are increasingly utilized in patients with cardiovascular disease, widespread clinical use is limited by the development of gynecomastia with spironolactone and hyperkalemia with both agents. This suggests that the development of newer agents with favorable side effect profiles is warranted. PMID:18729003

  5. Locomotor activity and one-way active avoidance after intrahippocampal injection of neurotransmitter antagonists.

    PubMed

    Brito, L S; Brito, G N

    1990-01-01

    Sixty-three rats with previous training in a T-maze, bilaterally implanted with cannulae directed toward the dorsal hippocampus, were used in this study. All rats received bilateral 1-microliter injections 20 min before testing for locomotor activity (day 1) and one-way active avoidance (day 3). The following drugs were injected into groups of 4 to 8 animals: scopolamine (9 or 18 micrograms/microliters), propranolol (5 or 10 micrograms/microliters), cimetidine (0.75 or 1.5 micrograms/microliters), sulpiride (5 or 10 micrograms/microliters), or vehicle (Krebs-Ringer). Locomotor activity was not changed by injection of any drug. However, intrahippocampal injections of scopolamine (9 micrograms/microliters) and sulpiride (10 micrograms/microliters) impaired avoidance behavior, particularly during the last five trials of the task. We conclude that muscarinic-cholinergic and D2-dopaminergic, but not beta-adrenergic or H2-histaminergic, mechanisms in the hippocampus are involved in the performance of one-way active avoidance behavior.

  6. Bromoacetylated analogue of cyanopindolol: an irreversible antagonist at rat beta-adrenoceptors

    SciTech Connect

    Kusiak, J.W.; Pitha, J.

    1987-07-06

    A high affinity, chemically reactive cyanopindolol derivative N/sup 8/-bromoacetyl-N/sup 1/-3'-(2-cyano-4-indolyloxy)-2'-hydroxypropyl-(Z)-1,8-diamino-p-menthane (Br-CYP) was synthesized and its interaction with ..beta..-adrenoceptors characterized. Studies with rat heart, lung, brain and red blood cell membranes indicated that the compound displaced /sup 3/H-dihydroalprenolol (/sup 3/H-DHA) from ..beta..-adrenoceptors with IC/sub 50/ values in the nanomolar range. The concentration of functional ..beta..-adrenoceptors in membranes was markedly reduced when membranes were preincubated with Br-CYP and then extensively washed prior to assay. (+/-)Alprenolol and (-)isoproterenol, but not (+)isoproterenol, when included in the preincubation prevented this reduction in binding sites by Br-CYP. Br-CYP was active in vivo when injected intraperitoneally into rats. A dose of 10 ..mu..g/kg reduced the concentration of binding sites in membranes from heart by 30%, lung by 36%, and RBC by 70%, but did not affect sites on brain membranes 16 hours after injection. Higher doses blocked virtually all the /sup 3/H-DHA binding sites in the peripheral organs studied. These results suggest that Br-CYP may be a useful compound for in vivo studies of the biochemistry and pharmacology of ..beta..-adrenergic systems. 27 references, 4 figures, 3 tables.

  7. Elucidating the `Jekyll and Hyde' Nature of PXR: The Case for Discovering Antagonists or Allosteric Antagonists

    PubMed Central

    Biswas, Arunima; Mani, Sridhar; Redinbo, Matthew R.; Krasowski, Matthew D.; Li, Hao; Ekins, Sean

    2010-01-01

    The pregnane X receptor belongs to the nuclear hormone receptor superfamily and is involved in the transcriptional control of numerous genes. It was originally thought that it was a xenobiotic sensor controlling detoxification pathways. Recent studies have shown an increasingly important role in inflammation and cancer, supporting its function in abrogating tissue damage. PXR orthologs and PXR-like pathways have been identified in several non-mammalian species which corroborate a conserved role for PXR in cellular detoxification. In summary, PXR has a multiplicity of roles in vivo and is being revealed as behaving like a “Jekyll and Hyde” nuclear hormone receptor. The importance of this review is to elucidate the need for discovery of antagonists of PXR to further probe its biology and therapeutic applications. Although several PXR agonists are already reported, virtually nothing is known about PXR antagonists. Here, we propose the development of PXR antagonists through chemical, genetic and molecular modeling approaches. Based on this review it will be clear that antagonists of PXR and PXR-like pathways will have widespread utility in PXR biology and therapeutics. PMID:19415465

  8. Sexually Antagonistic Selection in Human Male Homosexuality

    PubMed Central

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-01-01

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling ‘Darwinian paradox’. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait. PMID:18560521

  9. Sexually antagonistic selection in human male homosexuality.

    PubMed

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-06-18

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait.

  10. Antagonistic coevolution between quantitative and Mendelian traits.

    PubMed

    Yamamichi, Masato; Ellner, Stephen P

    2016-03-30

    Coevolution is relentlessly creating and maintaining biodiversity and therefore has been a central topic in evolutionary biology. Previous theoretical studies have mostly considered coevolution between genetically symmetric traits (i.e. coevolution between two continuous quantitative traits or two discrete Mendelian traits). However, recent empirical evidence indicates that coevolution can occur between genetically asymmetric traits (e.g. between quantitative and Mendelian traits). We examine consequences of antagonistic coevolution mediated by a quantitative predator trait and a Mendelian prey trait, such that predation is more intense with decreased phenotypic distance between their traits (phenotype matching). This antagonistic coevolution produces a complex pattern of bifurcations with bistability (initial state dependence) in a two-dimensional model for trait coevolution. Furthermore, with eco-evolutionary dynamics (so that the trait evolution affects predator-prey population dynamics), we find that coevolution can cause rich dynamics including anti-phase cycles, in-phase cycles, chaotic dynamics and deterministic predator extinction. Predator extinction is more likely to occur when the prey trait exhibits complete dominance rather than semidominance and when the predator trait evolves very rapidly. Our study illustrates how recognizing the genetic architectures of interacting ecological traits can be essential for understanding the population and evolutionary dynamics of coevolving species. © 2016 The Author(s).

  11. Antagonistic coevolution between quantitative and Mendelian traits

    PubMed Central

    Ellner, Stephen P.

    2016-01-01

    Coevolution is relentlessly creating and maintaining biodiversity and therefore has been a central topic in evolutionary biology. Previous theoretical studies have mostly considered coevolution between genetically symmetric traits (i.e. coevolution between two continuous quantitative traits or two discrete Mendelian traits). However, recent empirical evidence indicates that coevolution can occur between genetically asymmetric traits (e.g. between quantitative and Mendelian traits). We examine consequences of antagonistic coevolution mediated by a quantitative predator trait and a Mendelian prey trait, such that predation is more intense with decreased phenotypic distance between their traits (phenotype matching). This antagonistic coevolution produces a complex pattern of bifurcations with bistability (initial state dependence) in a two-dimensional model for trait coevolution. Furthermore, with eco-evolutionary dynamics (so that the trait evolution affects predator–prey population dynamics), we find that coevolution can cause rich dynamics including anti-phase cycles, in-phase cycles, chaotic dynamics and deterministic predator extinction. Predator extinction is more likely to occur when the prey trait exhibits complete dominance rather than semidominance and when the predator trait evolves very rapidly. Our study illustrates how recognizing the genetic architectures of interacting ecological traits can be essential for understanding the population and evolutionary dynamics of coevolving species. PMID:27009218

  12. D-Cycloserine: Agonist turned antagonist.

    PubMed

    Lanthorn, T H

    1994-10-01

    D-Cycloserine can enhance activation of the NMDA receptor complex and could enhance the induction of long-term potentiation (LTP). In animals and humans, D-cycloserine can enhance performance in learning and memory tasks. This enhancing effect can disappear during repeated administration. The enhancing effects are also lost when higher doses are used, and replaced by behavioral and biochemical effects like those produced by NMDA antagonists. It has been reported that NMDA agonists, applied before or after tetanic stimulation, can block the induction of LTP. This may be the result of feedback inhibition of second messenger pathways stimulated by receptor activation. This may explain the antagonist-like effects of glycine partial agonists like D-cycloserine. In clinical trials of D-cycloserine in age-associated memory impairment (AAMI) and Alzheimer's disease, chronic treatment provided few positive effects on learning and memory. This may be due to inhibition of second messenger pathways following chronic stimulation of the receptor complex.

  13. Hypocretin antagonists in insomnia treatment and beyond.

    PubMed

    Ruoff, Chad; Cao, Michelle; Guilleminault, Christian

    2011-01-01

    Hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep through stabilization of sleep promoting GABAergic and wake promoting cholinergic/monoaminergic neural pathways. Hypocretin also influences other physiologic processes such as metabolism, appetite, learning and memory, reward and addiction, and ventilatory drive. The discovery of hypocretin and its effect upon the sleep-wake cycle has led to the development of a new class of pharmacologic agents that antagonize the physiologic effects of hypocretin (i.e. hypocretin antagonists). Further investigation of these agents may lead to novel therapies for insomnia without the side-effect profile of currently available hypnotics (e.g. impaired cognition, confusional arousals, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle while also influencing non-sleep physiologic processes may create an entirely different but equally concerning side-effect profile such as transient loss of muscle tone (i.e. cataplexy) and a dampened respiratory drive. In this review, we will discuss the discovery of hypocretin and its receptors, hypocretin and the sleep-wake cycle, hypocretin antagonists in the treatment of insomnia, and other implicated functions of the hypocretin system.

  14. The antiatherogenic potential of calcium antagonists.

    PubMed

    Weinstein, D B

    1988-01-01

    Atherosclerosis is an arterial disease characterized by focal accumulation of collagen, elastin, lipids, and calcium at sites associated with macrophage infiltration and altered smooth muscle metabolic function. Studies in several types of animal models, especially cholesterol-fed rabbits, have shown that calcium competitors, calcium chelators, anticalcifying agents, and calcium channel blockers can reduce the accumulation of atherogenic lesion components and thus apparently decrease the progression of lesions. Although there are some conflicting data in the animal model studies using calcium channel antagonists, as a result of differences in experimental designs, it is now apparent that several classes of calcium channel blockers inhibit the progression of early arterial lesions induced by cholesterol feeding. The dihydropyridine calcium channel blockers appear to be more potent antiatherosclerotic agents than other classes of calcium channel antagonists. Several mechanisms involving regulation of endothelial cell, smooth muscle cell, and macrophage metabolic functions may be responsible for the calcium channel blocker effects on early lesion progression. For example, recent studies in cell culture model systems suggest that calcium channel blockers may significantly alter activities that regulate lipoprotein-derived cholesterol accumulation by cells. Some of these activities are independent of calcium flux across voltage-operated calcium channels. Thus, calcium channel blockers may reduce the progression of atherogenic lesions by a combination of decreasing calcium accumulation within arterial wall cells and by altering calcium-independent metabolic activities.

  15. Zebrafish phenotypic screen identifies novel Notch antagonists.

    PubMed

    Velaithan, Vithya; Okuda, Kazuhide Shaun; Ng, Mei Fong; Samat, Norazwana; Leong, Sze Wei; Faudzi, Siti Munirah Mohd; Abas, Faridah; Shaari, Khozirah; Cheong, Sok Ching; Tan, Pei Jean; Patel, Vyomesh

    2017-04-01

    Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27(KIP1). Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

  16. Rational discovery of novel nuclear hormone receptor antagonists

    NASA Astrophysics Data System (ADS)

    Schapira, Matthieu; Raaka, Bruce M.; Samuels, Herbert H.; Abagyan, Ruben

    2000-02-01

    Nuclear hormone receptors (NRs) are potential targets for therapeutic approaches to many clinical conditions, including cancer, diabetes, and neurological diseases. The crystal structure of the ligand binding domain of agonist-bound NRs enables the design of compounds with agonist activity. However, with the exception of the human estrogen receptor-, the lack of antagonist-bound "inactive" receptor structures hinders the rational design of receptor antagonists. In this study, we present a strategy for designing such antagonists. We constructed a model of the inactive conformation of human retinoic acid receptor- by using information derived from antagonist-bound estrogen receptor-α and applied a computer-based virtual screening algorithm to identify retinoic acid receptor antagonists. Thus, the currently available crystal structures of NRs may be used for the rational design of antagonists, which could lead to the development of novel drugs for a variety of diseases.

  17. Antioxidant effects of calcium antagonists in rat brain homogenates.

    PubMed

    Yao, K; Ina, Y; Nagashima, K; Ohmori, K; Ohno, T

    2000-06-01

    We studied the antioxidant activities of calcium antagonists against autoxidation in rat brain homogenates. The homogenates were incubated for 30 min at 37 degrees C with or without a calcium antagonist and subsequently assayed for lipid peroxide content. Percent inhibition of the lipid peroxidation was used as an index of the antioxidant effect. Dihydropyridine calcium antagonists exhibited concentration-dependent (3-300 micromol/l) inhibitory effects against lipid peroxidation. The relative order of antioxidant potency and associated IC50 values (micromol/l) of the calcium antagonists for inhibition of the lipid peroxidation were as follows: nifedipine (51.5)>barnidipine (58.6)>benidipine (71.2)>nicardipine (129.3)>amlodipine (135.5)>nilvadipine (167.3)>nitrendipine (252.1)> diltiazem (>300)=verapamil (>300). These results suggest that some dihydropyridine calcium antagonists show antioxidant properties. The antioxidant effects of the calcium antagonists may contribute to their pharmacological actions.

  18. Phenylacetamides as selective alpha-1A adrenergic receptor antagonists.

    PubMed

    Patane, M A; DiPardo, R M; Newton, R C; Price, R P; Broten, T P; Chang, R S; Ransom, R W; Di Salvo, J; Nagarathnam, D; Forray, C; Gluchowski, C; Bock, M G

    2000-08-07

    A novel class of potent and selective alpha-1a receptor antagonists has been identified. The structures of these antagonists were derived from truncating the 4-aryl dihydropyridine subunit present in known alpha-1a antagonists. The design principles which led to the discovery of substituted phenylacetamides, the synthesis and SAR of key analogues, and the results of select in vitro and in vivo studies are described.

  19. Synthesis of actively adjustable springs by antagonistic redundant actuation

    NASA Technical Reports Server (NTRS)

    Yi, Byung-Ju; Freeman, Robert A.

    1992-01-01

    A methodology for active spring generation is presented based on antagonistic redundant actuation. Antagonistic properties are characterized using an effective system stiffness. 'Antagonistic stiffness' is generated by preloading a closed-chain (parallel) linkage system. Internal load distribution is investigated along with the necessary conditions for spring synthesis. The performance and stability of a proposed active spring are shown by simulation, and applications are discussed.

  20. Mechanisms of immune regulation by norepinephrine and cholera toxin

    SciTech Connect

    Campbell, K.S.

    1988-01-01

    Norepinephrine has previously been demonstrated by this laboratory to potentiate the in vitro T-dependent antibody response through the stimulation of {beta}-adrenergic receptors. The role of {beta}-adrenergic receptor subtypes in norepinephrine-induced potentiation of the antibody responses was examined with selective {beta}-adrenergic antagonists. The antagonists were metoprolol ({beta}{sub 1}-selective), ICI 118-551 ({beta}{sub 2}-selective), and propranolol ({beta}-non-selective). Both propranolol and ICI 118-551 blocked norepinephrine-induced potentiation of the antibody response, but metoprolol was ineffective. Receptor binding competition of antagonists with the radioligant, ({sup 3}H)CGP-12177 was examined and results were analyzed with the computer program, LIGAND. Competition by ICI 118-551 identified 75% {beta}{sub 2}- and 25% {beta}{sub 1}-adrenergic receptors on splenic mononuclear cells. Enriched T lymphocytes exhibited 75% {beta}{sub 2}-adrenergic receptors, while enriched B lymphocytes contained 90% {beta}{sub 2}-adrenergic receptors as identified by ICI 118-551. Greater than twice as many total receptors were identified on B lymphocytes than T lymphocytes. A T cell lymphoma contained about 60% {beta}{sub 2}-receptors, while 100% were {beta}{sub 2} receptors on a B cell lymphoma, as assessed by ICI 118-551. Results support a heterogeneous {beta}-adrenergic receptor population on T lymphocytes and a more homogeneous {beta}{sub 2}-population on B lymphocytes.

  1. Mutually-antagonistic interactions in baseball networks

    NASA Astrophysics Data System (ADS)

    Saavedra, Serguei; Powers, Scott; McCotter, Trent; Porter, Mason A.; Mucha, Peter J.

    2010-03-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit structural changes over time. We find interesting structure in the networks and examine their sensitivity to baseball’s rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to (1) compare the performance of players who competed under different conditions and (2) include information about which particular players a given player has faced. We find that a player’s position in the network does not correlate with his placement in the random walker ranking. However, network position does have a substantial effect on the robustness of ranking placement to changes in head-to-head matchups.

  2. Drug effects: agonistic and antagonistic processes.

    PubMed

    Flaten, Magne Arve

    2009-12-01

    The research presented here has shown that tolerance to drugs can be accelerated by conditioning processes. Placebo effects may be considered the opposite of tolerance, and we have shown that placebo effects may be objectively recorded by physiological measures (electromyography, skin conductance responses, and event-related potentials), as well as by behavioral and subjective methods. The placebo response, or more precisely, the expectation of drug effects, can add to the effect of the drug. Drug antagonistic expectations can also reverse the effect of the drug. There is some evidence that placebo effects are strongest when expectations are reinforced by administration of an active drug. Expectations have graded effects and may affect symptoms to a smaller or larger degree. Although drug effects can be considered stimuli, the investigation of the role of classical conditioning in drug use and drug effects involves special issues that must be carefully considered.

  3. Antagonists of IAP proteins as cancer therapeutics.

    PubMed

    Dynek, Jasmin N; Vucic, Domagoj

    2013-05-28

    Inhibitor of apoptosis (IAP) proteins play pivotal roles in cellular survival by blocking apoptosis, modulating signal transduction, and affecting cellular proliferation. Through their interactions with inducers and effectors of apoptosis IAP proteins can effectively suppress apoptosis triggered by diverse stimuli including death receptor signaling, irradiation, chemotherapeutic agents, or growth factor withdrawal. Evasion of apoptosis, in part due to the action of IAP proteins, enhances resistance of cancer cells to treatment with chemotherapeutic agents and contributes to tumor progression. Additionally, IAP genes are known to be subject to amplification, mutation, and chromosomal translocation in human malignancies and autoimmune diseases. In this review we will discuss the role of IAP proteins in cancer and the development of antagonists targeting IAP proteins for cancer treatment.

  4. Pervasive antagonistic interactions among hybrid incompatibility loci.

    PubMed

    Guerrero, Rafael F; Muir, Christopher D; Josway, Sarah; Moyle, Leonie C

    2017-06-01

    Species barriers, expressed as hybrid inviability and sterility, are often due to epistatic interactions between divergent loci from two lineages. Theoretical models indicate that the strength, direction, and complexity of these genetic interactions can strongly affect the expression of interspecific reproductive isolation and the rates at which new species evolve. Nonetheless, empirical analyses have not quantified the frequency with which loci are involved in interactions affecting hybrid fitness, and whether these loci predominantly interact synergistically or antagonistically, or preferentially involve loci that have strong individual effects on hybrid fitness. We systematically examined the prevalence of interactions between pairs of short chromosomal regions from one species (Solanum habrochaites) co-introgressed into a heterospecific genetic background (Solanum lycopersicum), using lines containing pairwise combinations of 15 chromosomal segments from S. habrochaites in the background of S. lycopersicum (i.e., 95 double introgression lines). We compared the strength of hybrid incompatibility (either pollen sterility or seed sterility) expressed in each double introgression line to the expected additive effect of its two component single introgressions. We found that epistasis was common among co-introgressed regions. Interactions for hybrid dysfunction were substantially more prevalent in pollen fertility compared to seed fertility phenotypes, and were overwhelmingly antagonistic (i.e., double hybrids were less unfit than expected from additive single introgression effects). This pervasive antagonism is expected to attenuate the rate at which hybrid infertility accumulates among lineages over time (i.e., giving diminishing returns as more reproductive isolation loci accumulate), as well as decouple patterns of accumulation of sterility loci and hybrid incompatibility phenotypes. This decoupling effect might explain observed differences between pollen and

  5. Pharmacological and clinical importance of narcotic antagonists and mixed antagonists — use in cardiology

    PubMed Central

    Coltart, D. John; Malcolm, Alasdair D.

    1979-01-01

    1 The treatment of pain of cardiac origin requires a knowledge of the haemodynamic action of the analgesic agents used. 2 The haemodynamic effects of morphine, diamorphine, pavaveretum, pethidine and pentazocine are reviewed. 3 Clinical experience with the new antagonist analgesic buprenorphine is reported. 4 These studies indicate that buprenorphine may be the agent of choice for the relief of severe pain in patients with unstable circulation. PMID:465292

  6. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    ERIC Educational Resources Information Center

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  7. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    ERIC Educational Resources Information Center

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  8. [Effects of PAF antagonists in experimental models. Therapeutical perspectives].

    PubMed

    Desquand, S

    1993-01-01

    The discovery, during the last ten years, of Platelet Activating Factor (PAF) antagonists with different frameworks, but efficient on platelets tests, led the authors to study their activity in vivo against PAF-induced effects. These antagonists inhibit, with various potencies, the effects of PAF administration such as hypotension and bronchoconstriction in different animal species. Since PAF is assumed to play a central role in many diseases, effects of its antagonists have been studied in experimentally induced pathologies and in few clinical studies. We have been particularly interested in their effects on the first manifestation of asthma which is hypersensitivity. This manifestation is experimentally reproduced by anaphylactic bronchoconstriction, usually in the guinea-pig. Our results showed that different sensitization procedures may determine the relative efficiency of a PAF antagonist on subsequent antigen challenge. Indeed, the booster injection of antigen to a pre-sensitized animal could account for the refractoriness of anaphylactic bronchoconstriction to PAF antagonists. This booster injection mimics the clinical situation of atopic patients repeatedly exposed to allergen. Thus, it seems that immediate hypersensitivity could not be treated by the unique administration of a PAF antagonist. However, those antagonists may have more benefit in the clinical management of the late phase of asthma and of hyperreactivity and could thus provide anti-asthmatic drugs. PAF antagonists may have also therapeutical effects in septic shock, in myocardial ischemia and cardiac rhythm disturbances, in brain damage following cerebral ischemia and neurological trauma, in gastric and intestinal damages or in some inflammatory reactions.

  9. Microbial antagonists of Verticillium dahliae colonize cotton root system

    USDA-ARS?s Scientific Manuscript database

    Verticillium wilt remains one of the most severe diseases affecting cotton production in Uzbekistan. We are investigating microbial antagonist to control this pathogen. To this end, we have identified several antagonists of Verticillium dahliae (Bacillus sp. 234, Bacillus sp. 3, Streptomyces roseofl...

  10. Identification of a sulfonamide series of CCR2 antagonists.

    PubMed

    Peace, Simon; Philp, Joanne; Brooks, Carl; Piercy, Val; Moores, Kitty; Smethurst, Chris; Watson, Steve; Gaines, Simon; Zippoli, Mara; Mookherjee, Claudette; Ife, Robert

    2010-07-01

    A series of sulfonamide CCR2 antagonists was identified by high-throughput screening. Management of molecular weight and physical properties, in particular moderation of lipophilicity and study of pK(a), yielded highly potent CCR2 antagonists exhibiting good pharmacokinetic properties and improved potency in the presence of human plasma.

  11. Third Generation Mineralocorticoid Receptor Antagonists; Why We Need a Fourth

    PubMed Central

    Gomez-Sanchez, Elise

    2015-01-01

    The first mineralocorticoid receptor (MR) antagonist, spironolactone, was developed almost 60 years ago to treat primary aldosteronism and pathological edema. Its use waned in part due to its lack of selectivity. Subsequently knowledge of the scope of MR function was expanded along with clinical evidence of the therapeutic importance of MR antagonists to prevent the ravages of inappropriate MR activation. Forty-two years elapsed between the first and MR-selective second generation of MR antagonists. Fifteen years later, despite serious shortcomings of the existing antagonists, a third generation antagonist has yet to be marketed. Progress has been slowed by the lack of appreciation of the large variety of cell types that express the MR and its diverse cell-type-specific actions, as well as its uniquely complex interactions actions at the molecular level. New MR antagonists should preferentially target the inflammatory and fibrotic effects of MR and perhaps its excitatory effects on sympathetic nervous system, but not the renal tubular epithelium or neurons of the cortex and hippocampus. This review briefly describes efforts to develop a third generation MR antagonist and why fourth generation antagonists and selective agonists based on structural determinants of tissue and ligand-specific MR activation should be contemplated. PMID:26466326

  12. Early gonadotropin-releasing hormone antagonist start improves follicular synchronization and pregnancy outcome as compared to the conventional antagonist protocol.

    PubMed

    Park, Chan Woo; Hwang, Yu Im; Koo, Hwa Seon; Kang, Inn Soo; Yang, Kwang Moon; Song, In Ok

    2014-12-01

    To assess whether an early GnRH antagonist start leads to better follicular synchronization and an improved clinical pregnancy rate (CPR). A retrospective cohort study. A total of 218 infertile women who underwent IVF between January 2011 and February 2013. The initial cohort (Cohort I) that underwent IVF between January 2011 and March 2012 included a total of 68 attempted IVF cycles. Thirty-four cycles were treated with the conventional GnRH antagonist protocol, and 34 cycles with an early GnRH antagonist start protocol. The second cohort (Cohort II) that underwent IVF between June 2012 and February 2013 included a total of 150 embryo-transfer (ET) cycles. Forty-three cycles were treated with the conventional GnRH antagonist protocol, 34 cycles with the modified early GnRH antagonist start protocol using highly purified human menopause gonadotropin and an addition of GnRH agonist to the luteal phase support, and 73 cycles with the GnRH agonist long protocol. The analysis of Cohort I showed that the number of mature oocytes retrieved was significantly higher in the early GnRH antagonist start cycles than in the conventional antagonist cycles (11.9 vs. 8.2, p=0.04). The analysis of Cohort II revealed higher but non-significant CPR/ET in the modified early GnRH antagonist start cycles (41.2%) than in the conventional antagonist cycles (30.2%), which was comparable to that of the GnRH agonist long protocol cycles (39.7%). The modified early antagonist start protocol may improve the mature oocyte yield, possibly via enhanced follicular synchronization, while resulting in superior CPR as compared to the conventional antagonist protocol, which needs to be studied further in prospective randomized controlled trials.

  13. Prostanoid receptor antagonists: development strategies and therapeutic applications

    PubMed Central

    Jones, RL; Giembycz, MA; Woodward, DF

    2009-01-01

    Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 …) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are ‘non-prostanoid’ (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage. PMID:19624532

  14. Propranolol-induced elevation of pulmonary collagen

    SciTech Connect

    Lindenschmidt, R.C.; Witschi, H.P.

    1985-01-01

    Current concepts of collagen metabolism suggest that fibroblasts tightly control collagen production. One of the possible mechanisms of control is via the cyclic nucleotides, cyclic AMP (cAMP) and cyclic GMP (cGMP). Beta adrenergic agonists, by elevating intracellular cAMP levels, have been shown in vitro to suppress fibroblast collagen production; whereas beta adrenergic antagonists were effective in removing this suppression by blocking the rise in cAMP. In the present study with mice, the authors showed that administration of the beta adrenergic antagonists, propranolol, at a dose demonstrated to decrease the ratio of cAMP to cGMP, resulted in an elevation in total lung collagen in vivo. The increase in collagen was evident only when propranolol was administered before and during acute lung damage induced by either butylated hydroxytoluene, bleomycin or high concentrations of oxygen. There was no increase in lung collagen when propranolol administration was delayed after injury or when given to an undamaged lung. The authors propose that via beta adrenergic blockage by propranolol, fibroblasts involved in the normal reparative process may have lost a mechanism for regulatory control, resulting in excessive deposition of collagen. 38 references, 3 figures, 2 tables.

  15. Antagonistic neural networks underlying differentiated leadership roles

    PubMed Central

    Boyatzis, Richard E.; Rochford, Kylie; Jack, Anthony I.

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks – the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success. PMID:24624074

  16. Autoimmune encephalomyelitis ameliorated by AMPA antagonists.

    PubMed

    Smith, T; Groom, A; Zhu, B; Turski, L

    2000-01-01

    Multiple sclerosis is an immune-mediated disorder of the central nervous system leading to progressive decline of motor and sensory functions and permanent disability. The therapy of multiple sclerosis is only partially effective, despite anti-inflammatory, immunosuppresive and immunomodulatory measures. White matter inflammation and loss of myelin, the pathological hallmarks of multiple sclerosis, are thought to determine disease severity. Experimental autoimmune encephalomyelitis reproduces the features of multiple sclerosis in rodents and in nonhuman primates. The dominant early clinical symptom of acute autoimmune encephalomyelitis is progressive ascending muscle weakness. However, demyelination may not be profound and its extent may not correlate with severity of neurological decline, indicating that targets unrelated to myelin or oligodendrocytes may contribute to the pathogenesis of acute autoimmune encephalomyelitis. Here we report that within the spinal cord in the course of autoimmune encephalomyelitis not only myelin but also neurons are subject to lymphocyte attack and may degenerate. Blockade of glutamate AMPA receptors ameliorated the neurological sequelae of autoimmune encephalomyelitis, indicating the potential for AMPA antagonists in the therapy of multiple sclerosis.

  17. Antagonists of alcohol inhibition of cell adhesion

    PubMed Central

    Wilkemeyer, Michael F.; Sebastian, Anita B.; Smith, Sherri A.; Charness, Michael E.

    2000-01-01

    Increasing evidence suggests that alcohols act within specific binding pockets of selective neural proteins; however, antagonists at these sites have not been identified. 1-Alcohols from methanol through 1-butanol inhibit with increasing potency the cell–cell adhesion mediated by the immunoglobulin cell adhesion molecule L1. An abrupt cutoff exists after 1-butanol, with 1-pentanol and higher 1-alcohols showing no effect. Here, we demonstrate surprisingly strict structural requirements for alcohol inhibition of cell–cell adhesion in L1-transfected NIH 3T3 fibroblasts and in NG108–15 neuroblastoma × glioma hybrid cells treated with BMP-7, an inducer of L1 and neural cell adhesion molecule. The target site discriminates the tertiary structure of straight-chain and branched-chain alcohols and appears to comprise both a hydrophobic binding site and an adjacent hydrophilic allosteric site. Modifications to the 2- and 3-carbon positions of 1-butanol increased potency, whereas modifications that restrict movement about the 4-carbon abolished activity. The effects of ethanol and 1-butanol on cell–cell adhesion were antagonized by 1-pentanol (IC50 = 715 μM) and 1-octanol (IC50 = 3.6 μM). Antagonism by 1-octanol was complete, reversible, and noncompetitive. 1-Octanol also antagonized ethanol inhibition of BMP-7 morphogenesis in NG108–15 cells. 1-Octanol and related compounds may prove useful in dissecting the role of altered cell adhesion in ethanol-induced injury of the nervous system. PMID:10725368

  18. Noradrenergic antagonists mitigate amphetamine-induced recovery.

    PubMed

    Hylin, M J; Brenneman, M M; Corwin, J V

    2017-09-15

    Brain injury, including that due to stroke, leaves individuals with cognitive deficits that can disrupt daily aspect of living. As of now there are few treatments that shown limited amounts of success in improving functional outcome. The use of stimulants such as amphetamine have shown some success in improving outcome following brain injury. While the pharmacological mechanisms for amphetamine are known; the specific processes responsible for improving behavioral outcome following injury remain unknown. Understanding these mechanisms can help to refine the use of amphetamine as a potential treatment or lead to the use of other methods that share the same pharmacological properties. One proposed mechanism is amphetamine's impact upon noradrenaline (NA). In the current, study noradrenergic antagonists were administered prior to amphetamine to pharmacologically block α- and β-adrenergic receptors. The results demonstrated that the blockade of these receptors disrupted amphetamines ability to induce recovery from hemispatial neglect using an established aspiration lesion model. This suggests that amphetamine's ability to ameliorate neglect deficits may be due in part to noradrenaline. These results further support the role of noradrenaline in functional recovery. Finally, the development of polytherapies and combined therapeutics, while promising, may need to consider the possibility that drug interactions can negate the effectiveness of treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. HIGH AFFINITY ACYLATING ANTAGONISTS FOR MUSCARINIC RECEPTORS

    PubMed Central

    Baumgold, Jesse; Karton, Yishai; Malka, Naftali; Jacobson, Kenneth A.

    2012-01-01

    Summary The muscarinic antagonists pirenzepine and telenzepine were derivitized as alkylamino derivatives at a site