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Sample records for alpha adrenoceptor antagonists

  1. [Alpha1-adrenoceptor subtypes and alpha1-adrenoceptor antagonists].

    PubMed

    Muramatsu, Ikunobu; Suzuki, Fumiko; Tanaka, Takashi; Yamamoto, Hatsumi; Morishima, Shigeru

    2006-03-01

    Alpha(1)-adrenoceptors are widely distributed in the human body and play important physiologic roles. Three alpha(1)-adrenoceptor subtypes (alpha(1A), alpha(1B) and alpha(1D)) have been cloned and show different pharmacologic profiles. In addition, a putative alpha(1)-adrenoceptor (alpha(1L) subtype) has also been proposed. Recently, three drugs (tamsulosin, naftopidil, and silodosin) have been developed in Japan for the treatment of urinary obstruction in patients with benign prostatic hyperplasia. In this review, we describe recent alpha(1)-adrenoceptor subclassifications and the pharmacologic characteristics (subtype selectivity and clinical relevance) of alpha(1)-adrenoceptor antagonists. PMID:16518082

  2. Preclinical pharmacology of alpha1-adrenoceptor antagonists.

    PubMed

    Martin, D J

    1999-01-01

    The implication of a single adrenoceptor subtype in the contractility of prostatic and urethral smooth muscle cells led to the concept that drugs with selectivity for this subtype may exhibit functional uroselectivity. Comparison of the affinities of the alpha1-adrenoceptor antagonists revealed that few compounds show selectivity for one of the three cloned alpha1-adrenoceptor subtypes (alpha1a/A, alpha1b/B, alpha1d/D) whereas most of them had a similar affinity for the three subtypes. Moreover, data supporting a relationship between selectivity for the alpha1a/A-adrenoceptor subtype and functional uroselectivity are still lacking and recent data challenged the relevance of the selectivity for a given cloned alpha1-adrenoceptor subtype in predicting functional uroselectivity. In vivo data showed that alpha1-adrenoceptor antagonists without adrenoceptor subtype selectivity, like alfuzosin or to a minor extent doxazosin, showed functional uroselectivity whereas prazosin and terazosin were not shown to be uroselective. Compounds considered to be selective for the alpha1a/A-adrenoceptor, like tamsulosin or 5-Me-urapidil, did not show functional uroselectivity since they modified urethral and blood pressures in a manner which was not correlated to their selectivity for the cloned alpha1-adrenoceptor subtypes. Meanwhile, the identification in prostatic tissue, of a new sub-family of alpha1-adrenoceptors with low affinity for prazosin and denominated alpha1L gave rise to numerous studies. However, its functional role as well as the affinity of the known antagonists for this receptor subtype remains to be clarified. In conclusion, the existing alpha1-adrenoceptor antagonists have different pharmacological profiles in vivo which are yet not predictable from their receptor pharmacology based on the actual state of knowledge of the alpha1-adrenoceptor classification. PMID:10393471

  3. The pharmacology of fluparoxan: a selective alpha 2-adrenoceptor antagonist.

    PubMed Central

    Halliday, C. A.; Jones, B. J.; Skingle, M.; Walsh, D. M.; Wise, H.; Tyers, M. B.

    1991-01-01

    1. This paper describes the pharmacology of the novel alpha 2-adrenoceptor antagonist fluparoxan (GR 50360) which is currently being studied clinically as a potential anti-depressant. Idazoxan and yohimbine were included in many studies for comparison. 2. In the rat isolated, field-stimulated vas deferens and the guinea-pig isolated, field-stimulated ileum preparations, fluparoxan was a reversible competitive antagonist of the inhibitory responses to the alpha 2-adrenoceptor agonist UK-14304 with pKB values of 7.87 and 7.89 respectively. In the rat isolated anococcygeus muscle, fluparoxan was a much weaker competitive antagonist of the contractile response to the alpha 1-adrenoceptor agonist phenylephrine with a pKB of 4.45 giving an alpha 2: alpha 1-adrenoceptor selectivity ratio of greater than 2500. 3. In the conscious mouse, fluparoxan (0.2-3.0 mg kg-1) was effective by the oral route and of similar potency to idazoxan in preventing clonidine-induced hypothermia and antinociception. In the rat, UK-14304-induced hypothermia (ED50 = 1.4 mg kg-1, p.o. or 0.5 mg kg-1, i.v.) and rotarod impairment (ED50 = 1.1 mg kg-1 p.o. or 1.3 mg kg-1, i.v.) were antagonized by fluparoxan. Fluparoxan, 0.67-6 mg kg-1, p.o., also prevented UK-14304-induced sedation and bradycardia in the dog. 4. In specificity studies fluparoxan had low or no affinity for a wide range of neurotransmitter receptor sites at concentrations up to at least 1 x 10(-5) M. It displayed weak affinity for 5-HT1A (pIC50 = 5.9) and 5-HT1B (pKi = 5.5) binding sites in rat brain.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1677298

  4. Quinazoline-derived alpha1-adrenoceptor antagonists induce prostate cancer cell apoptosis via an alpha1-adrenoceptor-independent action.

    PubMed

    Benning, Cynthia M; Kyprianou, Natasha

    2002-01-15

    Recent evidence suggests that the quinazoline-based alpha1-adrenoceptor antagonists, doxazosin and terazosin, exhibit a potent apoptotic effect against prostate tumor epithelial cells, whereas tamsulosin, a sulfonamide-based alpha1-adrenoceptor antagonist, was ineffective in inducing a similar apoptotic effect against prostate cells (Cancer Res., 60: 4550-4555, 2000). In this study, to identify the precise molecular mechanism underlying this apoptosis induction, we examined whether doxazosin and terazosin (both piperazinyl quinazolines) affect prostate growth via an alpha1-adrenoceptor-independent action. Transfection-mediated overexpression of alpha1-adrenoceptor in human prostate cancer cells, DU-145 (that lack alpha1-adrenoceptor), did not alter the ability of prostate cancer cells to undergo apoptosis in response to quinazolines. Significantly enough, there was no modification of the apoptotic threshold of the androgen-sensitive prostate cancer cells, LNCaP, to either quinazoline-based alpha1-agonist by androgens. Furthermore, human normal prostate epithelial cells exhibited a very low sensitivity to the apoptotic effects of doxazosin compared with that observed for the malignant prostate cells. These findings provide the first evidence that the apoptotic activity of the quinazoline-based alpha1-adrenoceptor antagonists (doxazosin and terazosin) against prostate cancer cells is independent of: (a) their capacity to antagonize alpha1-adrenoceptors; and (b) the hormone sensitivity status of the cells. This may have potential therapeutic significance in the use of quinazoline-based alpha1-adrenoceptor antagonists (already in clinical use for the treatment of hypertension and benign prostate hyperplasia) for the treatment of androgen-independent human prostate cancer. PMID:11809715

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

    PubMed Central

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

    1996-01-01

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

  6. Synthesis, alpha-adrenoceptors affinity and alpha 1-adrenoceptor antagonistic properties of some 1,4-substituted piperazine derivatives.

    PubMed

    Marona, H; Kubacka, M; Filipek, B; Siwek, A; Dybała, M; Szneler, E; Pociecha, T; Gunia, A; Waszkielewicz, A M

    2011-10-01

    A series of different 1,4-substituted piperazine derivatives (1-11) was synthesized. It comprised 1-(substituted-phenoxyalkyl)-4-(2-methoxyphenyl)piperazine derivatives (1-5); 1,4-bis(substituted-phenoxyethyl)piperazine derivatives (6-8) and 1-(substituted-phenoxy)-3-(substituted-phenoxyalkylpiperazin-1-yl)propan-2-ol derivatives (9-11). All compounds were evaluated for affinity toward alpha 1- and alpha 2-receptors by radioligand binding assays on rat cerebral cortex using [3H]prazosin and [3H]clonidine as specific radioligand, respectively. Furthermore alpha 1-antagonistic properties were checked for most promising compounds (1-5 and 10) by means of inhibition of phenylephrine induced contraction in isolated rat aorta. Antagonistic potency stayed in agreement with radioligand binding results. The most active compounds (1-5) displaced [3H]prazosin from cortical binding sites in low nanomolar range (Ki = 2.1-13.1 nM). Compound 10 showed slightly lower affinity for alpha 1-adrenoceptor (Ki = 781 nM). Compounds 2-5 displayed the strongest antagonistic activity with pA2 values ranging from 8.441 to 8.807. Compound 1 gave a pA2 value of 7.868, while compound 10 showed the weakest antagonistic potency, giving a pA2 value of 6.374. 1-[3-(2-Chloro-6-methylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (5) showed the best alpha 1- affinity properties with a Ki(alpha 1) value of 2.1 nM and it was 61.05 fold more selective toward alpha 1 than alpha 2-receptors. The best properties showed 1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (4) with a Ki(alpha 1) value of 2.4 nM, a 142.13 fold better selectivity to alpha 1 - over alpha 2-adrenoceptors and the best antagonistic potency (pA2 = 8.807). It is worth to emphasized that all most promising compounds possessed an 1-(o-methoxyphenyl)piperazine moiety which probably plays an important role in the affinity to alpha-adrenoceptors. PMID:22026152

  7. Induction of prostate apoptosis by alpha1-adrenoceptor antagonists: mechanistic significance of the quinazoline component.

    PubMed

    Anglin, I E; Glassman, D T; Kyprianou, N

    2002-01-01

    alpha(1)-Adrenoceptor antagonists, have been documented to induce apoptosis and reduce prostate tumor vascularity in benign and malignant prostate cells. The quinazoline based alpha(1)-antagonists, doxazosin and terazosin but not tamsulosin (a sulphonamide derivative) suppress prostate growth without affecting cell proliferation. These quinazoline-mediated apoptotic effects occur via an alpha(1)-adrenoceptor independent mechanism potentially involving activation of the TGF-beta signal transduction pathway. This review discusses the current knowledge of the action of quinazoline-derived alpha(1)-adrenoceptor antagonists in the benign and malignant prostate and their potential therapeutic use in the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. Finally, a molecular pathway is proposed for their observed apoptotic function against prostate cells. Increased understanding of the action of these established and clinically accepted agents would provide a basis for the design of safe, effective therapeutic regimens in the treatment of prostatic diseases. PMID:12496995

  8. The use of alpha1-adrenoceptor antagonists in lower urinary tract symptoms: beyond benign prostatic hyperplasia.

    PubMed

    Nickel, J Curtis

    2003-09-01

    The first empirical use of alpha(1)-adrenoceptor antagonists in urology occurred about 25 years ago in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH), or LUTS/BPH. Today, many randomized, controlled trials have provided evidence for the efficacy and tolerability of alpha(1)-adrenoceptor antagonists in LUTS/BPH, and they are the most frequently used initial treatment option for this cause of LUTS. For many years, alpha(1)-adrenoceptor antagonists have also been used empirically in other types of lower urinary tract dysfunction (LUTD), such as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and neurogenic LUTD (NLUTD). Several investigators have shown that alpha(1)-adrenoceptor antagonists may be useful in patients with CP/CPPS. This was recently confirmed by a 6-week, double-blind, placebo-controlled pilot study evaluating the efficacy and safety of tamsulosin in 58 CP/CPPS patients. Further well-designed and -powered research into the use of alpha(1)-adrenoceptor antagonists in patients with CP/CPPS is currently ongoing. Several small-scale predominantly open-label studies have suggested that alpha(1)-adrenoceptor antagonists may be of benefit in patients with NLUTD. Data from 2 recent large-scale studies with tamsulosin in patients with NLUTD caused by suprasacral spinal cord injury suggest that long-term tamsulosin treatment improves bladder storage and emptying and also reduces symptoms of autonomic dysreflexia. Tamsulosin has also shown promise in ameliorating (early) storage symptoms and urinary retention associated with transurethral microwave thermotherapy, external-beam radiotherapy, and brachytherapy. In BPH patients presenting with the ultimate form of LUTS-acute urinary retention-treatment with tamsulosin before catheter removal results in a higher success rate of catheter-free voiding. Finally, it seems that alpha(1)-adrenoceptor antagonists may reduce the occurrence of urinary retention

  9. RBx 6198: a novel alpha1-adrenoceptor antagonist for the treatment of benign prostatic hyperplasia.

    PubMed

    Nanda, Kamna; Naruganahalli, Krishna S; Gupta, Suman; Malhotra, Shivani; Tiwari, Atul; Hegde, Laxminarayan G; Jain, Sanjay; Sinha, Neelima; Gupta, Jung B; Chugh, Anita; Anand, Nitya; Ray, Abhijit

    2009-04-01

    The present study, investigates the effect of RBx 6198, 2-{3-[4-(2-Isopropoxy-phenyl)-piperazin-1-yl]-propyl}-3a, 4, 7, 7a-tetrahydro-isoindole-1, 3,-dione, a novel alpha(1)-adrenoceptor antagonist, in both in vitro and in vivo test systems. RBx 6198 is a potent (nanomolar affinity) alpha(1A)-adrenoceptor antagonist with demonstrable uroselectivity in anaesthesized dog model. In radioligand binding studies using human recombinant receptors, RBx 6198 exhibited high selectivity (approximately 50 fold) for the alpha(1A)-adrenoceptor subtype as compared to alpha(1B)-adrenoceptor subtype. In order to assess tissue selectivity, the antagonistic effect of RBx 6198 on the phenylephrine induced contractile response of isolated rat prostate, spleen and aorta was characterized. RBx 6198 was 8 fold more potent in inhibiting phenylephrine-evoked contractions of isolated tissues compared to tamsulosin. However, the compound was non-selective for alpha(1A) vs. alpha(1D)-adrenoceptor like tamsulosin. In anaesthetized beagle dogs RBx 6198 suppressed the intraurethral pressure response to phenylephrine to a greater extent than the mean arterial pressure response thereby demonstrating uroselectivity consistent with in vitro binding and functional data. RBx 6198 was 6.4 fold more uroselective as compared to tamsulosin after i.v. route dose administration. Taken together all results from preclinical studies, it is suggested that RBx 6198 is a novel alpha(1)-adrenoceptor antagonist that exhibited improved pharmacological profile over tamsulosin in both in vitro and in vivo. PMID:19239913

  10. Evaluation of the pharmacological selectivity profile of alpha 1 adrenoceptor antagonists at prostatic alpha 1 adrenoceptors: binding, functional and in vivo studies.

    PubMed Central

    Kenny, B. A.; Miller, A. M.; Williamson, I. J.; O'Connell, J.; Chalmers, D. H.; Naylor, A. M.

    1996-01-01

    1. The profile of a range of alpha 1 adrenoceptor antagonists was determined in vitro against cloned human alpha 1A, alpha 1B and alpha 1D adrenoceptors and against noradrenaline-mediated contractions of rat aorta and human prostate. The in vivo profile of compounds was determined in an anaesthetized dog model which allowed the simultaneous assessment of antagonist potency against phenylephrine-mediated increases in blood pressure and prostatic pressure. 2. The quinazoline antagonists, prazosin, doxazosin and alfuzosin displayed high affinity but were non selective for the three cloned human alpha 1 adrenoceptors. Indoramin and SNAP 1069 showed selectivity for alpha 1A and alpha 1B adrenoceptors relative to the alpha 1D subtype. Rec 15/2739, WB 4101, SL 89,0591, (+)- and (-)- tamsulosin showed selectivity for alpha 1A and alpha 1D adrenoceptors relative to the alpha 1B subtype. RS 17053 showed high affinity and selectivity for alpha 1A adrenoceptors (pKi 8.6) relative to alpha 1B (pKi = 7.3) and alpha 1D (pKi = 7.1) subtypes. 3. (+)-Tamsulosin, (-)-tamsulosin, SL 89,0591, Rec 15/2739, SNAP 1069 and RS 17053 appeared to act as competitive antagonists of noradrenaline-mediated contractions of rat aorta yielding pA2 affinity estimates which were similar to binding affinities at cloned human alpha 1D adrenoceptors. The following rank order was obtained: prazosin = (-)-tamsulosin > doxazosin > SL 89,0591 = (+)-tamsulosin > Rec 15/2739 > RS 17053 = SNAP 1069. 4. (-)-Tamsulosin was a very potent, insurmountable antagonist of noradrenaline-mediated contractions of human prostate, yielding an approximate pA2 estimate of 9.8 at 1 nM. The corresponding (+)-enantiomer was 30 fold weaker. SL 89,0591, SNAP 1069 and Rec 15/2739 yielded pA2 estimates which compared well with their alpha 1A binding affinities. The affinity estimate for prazosin on human prostate was lower than the corresponding binding affinity determined at alpha 1A adrenoceptors and RS 17053 was a very weak

  11. Alpha(1) adrenoceptor subtype selectivity. 3D-QSAR models for a new class of alpha(1) adrenoceptor antagonists derived from the novel antipsychotic sertindole.

    PubMed

    Balle, Thomas; Andersen, Kim; Søby, Karina Krøjer; Liljefors, Tommy

    2003-06-01

    Receptor-binding affinities for the alpha(1) adrenoceptor subtypes alpha(1a), alpha(1b) and alpha(1d) for a series of 39 alpha(1) adrenoceptor antagonists derived from the antipsychotic sertindole are reported. The SAR of the compounds with respect to affinity for the alpha(1a), alpha(1b) and alpha(1d) adrenoceptor subtypes as well as affinity obtained by an alpha(1) assay (rat brain membranes) were investigated using a 3D-QSAR approach based on the GRID/GOLPE methodology. Good statistics (r(2)=0.91-0.96; q(2)=0.65-0.73) were obtained with the combination of the water (OH2) and methyl (C3) probes. The combination of steric repulsion and electrostatic attractions explain the affinities of the included molecules. The adrenergic alpha(1a) receptor seems to be more tolerant to large substituents in the area between the indole 5- and 6-positions compared to the adrenergic alpha(1b) and alpha(1d) receptor subtypes. There seems to be minor differences in the position of areas in the alpha(1b) receptor compared to alpha(1a) and alpha(1d) receptors where electrostatic interaction between the molecules and the receptor (OH2 probe) contribute to increased affinity. These observations may be used in the design of new subtype selective compounds. In addition, the model based on biological data from an alpha(1) assay (rat brain membranes) resembles the model for the alpha(1b) adrenoceptor subtype. PMID:12676239

  12. Naftopidil, a novel alpha1-adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human alpha1-adrenoceptors.

    PubMed

    Takei, R; Ikegaki, I; Shibata, K; Tsujimoto, G; Asano, T

    1999-04-01

    The pharmacological profiles of the alpha1-adrenoceptor antagonists naftopidil, tamsulosin and prazosin were studied in an anesthetized dog model that allowed the simultaneous assessment of their antagonist potency against phenylephrine-mediated increases in prostatic pressure and mean blood pressure. The intravenous administration of each of these compounds dose-dependently inhibited phenylephrine-induced increases in prostatic pressure and mean blood pressure. To further assess the ability of the three compounds to inhibit phenylephrine-induced responses, the doses required to produce a 50% inhibition of the phenylephrine-induced increases in prostatic and mean blood pressure and the selectivity index obtained from the ratio of those two doses were determined for each test compound. Forty minutes after the intravenous administration of naftopidil, the selectivity index was 3.76, and those of tamsulosin and prazosin were 1.23 and 0.61, respectively. These findings demonstrated that naftopidil selectively inhibited the phenylephrine-induced increase in prostatic pressure compared with mean blood pressure in the anesthetized dog model. The selectivity of naftopidil for prostatic pressure was the most potent among the test compounds. In addition, using cloned human alpha1-adrenoceptor subtypes, naftopidil was selective for the alpha1d-adrenoceptor with approximately 3- and 17-fold higher affinity than for the alpha1a- and alpha1b-adrenoceptor subtypes, respectively. The selectivity of naftopidil for prostatic pressure may be attributable to its high binding affinity for alpha1a- and alpha1d-adrenoceptor subtypes. PMID:10361884

  13. alpha-Adrenoceptor antagonists in the treatment of benign prostate hyperplasia.

    PubMed

    Thiyagarajan, M

    2002-07-01

    Benign prostate hyperplasia (BPH) is a common malady affecting elderly men throughout the world, and it is the most common cause of voiding dysfunctions in man. The disease becomes prevalent, as the mean age of the population increases. In BPH the glandular cells and myofibroblasts of periurethral and transition zones proliferate excessively. This excessive growth of tissue mass physically compresses the urethra, leading to urinary obstruction and lower urinary tract symptoms (LUTS). Another major factor that contributes to LUTS in BPH is the increase in smooth muscle tone, a dynamic component. Contraction of the prostate gland is mainly under the control of the autonomic system and is mediated through alpha-adrenoceptors. In addition to alpha1-adrenoceptors, there are many other components that influence growth and contraction of the prostate gland, resulting in the development of BPH and LUTS. The prostate gland is contracted on stimulating 5-HT, endothelin, tachykinin, and muscarinic cholinergic receptors. Growth of the prostate gland is under the control of androgens, endothelin growth factor, vasoactive intestinal peptide, nerve growth factor, and growth hormone. The combination of excessive growth and the tone produced by different components results in LUTS and BPH. alpha1-Adrenoceptor antagonists were successfully used in the treatment of BPH to relieve the LUTS. The high selectivity of alpha1A-adrenoceptor antagonists reflects the uroselectivity. The uroselective compounds like terazosin, doxazosin, tamsulosin, and alfuzosin are in clinical use. Other new potent uroselective compounds, which are analogs of nigulidipine, 5-methyl-urapidil, or naftopidil, are in clinical trials. In addition to alpha-antagonists, antiandrogens (5alpha-reductase inhibitors) and polyherbal formulations are used to treat BPH. The success of BPH treatment lies in the development of new chemical entities which are efficacious as well as more uroselective and hence have least side

  14. Subtype selective alpha1-adrenoceptor antagonists for the treatment of benign prostatic hyperplasia.

    PubMed

    Forray; Noble

    1999-12-01

    Benign prostatic hyperplasia (BPH) is highly prevalent in the male population beyond the age of 60. Impairment of urinary flow due to prostate enlargement gives rise to symptoms of 'prostatism' that have a detrimental impact on the quality of life. The current trend in the management of symptomatic BPH favours pharmacotherapy as a first line option, while the number of surgical procedures being performed has experienced a steady decline during the last ten years. Among the pharmacological treatments, the use of alpha1-adrenoceptor blockers has demonstrated to be an effective treatment option for BPH. These agents reduce the adrenergic tone to the prostate and increase urinary flow, with a concomitant reduction of lower urinary tract symptoms. The alpha1-blockers currently approved include compounds such as alfuzosin, terazosin and doxazosin, originally developed for the treatment of hypertension, and more recently tamsulosin, an alpha1-subtype selective drug. The blockade of alpha1-adrenoceptors present in vascular smooth muscle is largely responsible for the most prominent side effects of current drugs, which can be severe and require patients dose titration. The limitation imposed by side effects naturally raises the possibility that complete blockade of prostatic alpha1 receptors is not attained at the maximum tolerated dose. The extensive efforts by the pharmaceutical industry towards the development of uroselective alpha1-blockers, is the subject of this review. Advances in the molecular cloning of genes encoding three alpha1-adrenoceptors led to the identification of the alpha1A-subtype as the predominant receptor responsible for the contraction of prostate smooth muscle. In preclinical animal models, selective alpha1A-antagonists have consistently been found to have minimal cardiovascular effects, thus providing a pharmacological rationale for uroselectivity. It has also become apparent, however, that uroselectivity can emerge in a poorly understood manner

  15. A comparison of the antagonistic activities of tamsulosin and terazosin against human vascular alpha1-adrenoceptors.

    PubMed

    Harada, K; Ohmori, M; Kitoh, Y; Sugimoto, K; Fujimura, A

    1999-07-01

    Tamsulosin, a selective alpha1A-adrenoceptor antagonist, and terazosin, a non-selective one, are effective for the treatment of urinary disturbance due to benign prostatic hypertrophy. In the present study, their alpha1-adrenoceptor-blocking effects on blood vessels, which may cause orthostatic hypotension, were investigated in 10 healthy males. After the subjects took orally 0.2 mg of tamsulosin, 1 mg of terazosin or a lactate capsule as the control in a randomized cross-over fashion, their finger tip vasoconstrictor response to cold stimulation and vasoconstrictor response of the dorsal hand vein to increasing doses of phenylephrine were examined. The finger tip vasoconstrictor response was significantly reduced and the infusion rate of phenylephrine producing a half-maximal constriction was significantly increased by terazosin, but tamsulosin had no significant effect on these parameters. These data suggest that the usual dose of tamsulosin exerts little alpha1-adrenoceptor-blocking activity on blood vessels, and orthostatic episodes might be mild, if any, during the treatment with tamsulosin. PMID:10461765

  16. Analysis of the activity of alpha 1-adrenoceptor antagonists in rat aorta.

    PubMed Central

    Van der Graaf, P. H.; Shankley, N. P.; Black, J. W.

    1996-01-01

    1. In this study, the effect of seven alpha 1-adrenoceptor antagonists (tamsulosin, phentolamine, prazosin, WB-4101, 5-methylurapidil, spiperone and HV723) have been examined on the contractile response to noradrenaline (NA) and phenylephrine (PE) in rat isolated aorta. 2. NA and PE, when administered using a cumulative dosing schedule, both produced concentration-dependent contraction of aortic rings. It was possible to fit the individual concentration-effect (E/[A]) curve data to the Hill equation to provide estimates of the curve midpoint location (p[A]50 = 7.74 +/- 0.10 and 7.14 +/- 0.18), midpoint slope (nH = 0.82 +/- 0.03 and 0.99 +/- 0.10) and upper asymptote (alpha = 3.2 +/- 0.3 and 3.1 +/- 0.2 g) parameters for NA and PE, respectively. However, the Hill equation provided a better fit to the E/[A] curve data obtained with another contractile agent, 5-hydroxytryptamine (5-HT) (p[A50] = 6.09 +/- 0.08, nH = 1.49 +/- 0.09, alpha = 2.6 +/- 0.3 g), as judged by calculation of the mean sum of squares of the differences between the observed and predicted values. 3. All of the antagonists investigated produced concentration-dependent inhibition of the contractile responses of the aorta to NA and PE. Although no significant effects on the upper asymptotes of the E/[A] curves of any of the antagonists tested were detected, only tamsulosin and 5-methylurapidil did not have a significant effect on the slope (nH) of the NA and PE E/[A] curves. The other antagonists produced significant steepening of the curves obtained with NA and/or PE. 4. Notwithstanding the fact that one of the basic criteria for simple competitive antagonism at a single receptor class was not always satisfied, the individual log [A]50 values estimated in the absence and presence of antagonist within each experiment were fitted to the competitive model. The Schild plot slope parameters for the antagonism of NA and PE by phentolamine and HV723 were found to be significantly less than unity. The Schild

  17. Lower urinary tract symptoms suggestive of benign prostatic hyperplasia: latest update on alpha-adrenoceptor antagonists.

    PubMed

    Milani, Shirin; Djavan, Bob

    2005-06-01

    An update of a systematic review of alpha1-adrenoceptor (AR) antagonists in the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) showed that these agents have comparable efficacy. The total symptom score is improved by 30-45% and maximum urinary flow rate by 15-30% vs baseline. alpha1-AR antagonists that can be started at their therapeutic dose have a more rapid onset of action than alpha1-AR antagonists that have to be titrated. alpha1-AR antagonists can be differentiated according to their tolerability. Alfuzosin (especially the 10 mg once daily dose) and tamsulosin (especially the 0.4 mg once daily dose) are better tolerated than doxazosin and terazosin. However, alfuzosin might induce more cardiovascular adverse events (AEs) in the elderly and/or patients with cardiovascular comorbidity and/or comedication. Tamsulosin tends to interfere less with blood pressure regulation and induce less vasodilatory AEs than alfuzosin, especially in the elderly, and is well tolerated in patients with cardiovascular comorbidity and/or comedication. Cardiovascular AEs might lead to potentially serious complications such as falls, fractures and institutionalization. Abnormal ejaculation has mainly been reported in placebo-controlled trials with tamsulosin but in direct comparative trials its rate with tamsulosin 0.4 mg was similar to, or only slightly higher than, the rate with alfuzosin. In addition, abnormal ejaculation is not reported as bothersome by the patient or associated with serious complications. It can be concluded that an alpha1-AR antagonist with a low potential to interfere with blood pressure regulation and to induce cardiovascular AEs, also in patients with cardiovascular comorbidity and/or comedication, can be considered a first-choice treatment option in LUTS/BPH. PMID:15871733

  18. 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.

  19. Antagonistic effects of selective alpha1-adrenoceptor antagonists MDL73005EF and tamsulosin and partial agonists clonidine and tizanidine in rat thoracic aorta and rabbit iliac artery.

    PubMed

    Satoh, M; Enomoto, K; Koike, K

    2001-01-01

    The antagonistic effects of MDL73005EF and tamsulosin and partial agonists clonidine and tizanidine at rat thoracic aorta and rabbit iliac artery alpha1-adrenoceptors were investigated in this study. Selective alpha1-adrenoceptor antagonists MDL73005EF and tamsulosin dose-dependently shifted the concentration-response curves for noradrenaline to the right. Schild plots of the results obtained from the inhibition by MDL73005EF (pA2 8.30 +/- 0.04) and tamsulosin (pA2 10.51 +/- 0.06) of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta. The slopes of Schild plots obtained from the inhibition by MDL73005EF and tamsulosin of noradrenaline were significantly different from unity in rabbit iliac artery. Schild plots of the results obtained from the inhibition by clonidine and tizanidine of noradrenaline yielded a straight line with a slope of unity in rat thoracic aorta (pA2 7.08 +/- 0.04 and 7.32 +/- 0.04, respectively). These results suggest that alpha1D-adrenoceptors play a significant role in the alpha1-adrenoceptor-agonist-induced contraction of rat thoracic aorta and rabbit iliac artery, and that clonidine and tizanidine interact with the alpha1D-adrenoceptor subtype as competitive antagonists in rat thoracic aorta. PMID:11206183

  20. Suppression of human prostate cancer cell growth by alpha1-adrenoceptor antagonists doxazosin and terazosin via induction of apoptosis.

    PubMed

    Kyprianou, N; Benning, C M

    2000-08-15

    Recent evidence from our laboratory has demonstrated that alpha1-adrenoceptor antagonists doxazosin and terazosin induced apoptosis in prostate epithelial and smooth muscle cells in patients with benign prostatic hypertrophy (BPH; J. Urol., 159: 1810-1815, 1998; J. Urol., 161: 2002-2007, 1999). In this study, we investigated the biological action of three alpha1-adrenoceptor antagonists, doxazosin, terazosin, and tamsulosin, against prostate cancer cell growth. The antigrowth effect of the three alpha1-adrenoceptor antagonists was examined in two human prostate cancer cell lines, PC-3 and DU-145, and a prostate smooth muscle cell primary culture, SMC-1, on the basis of: (a) cell viability assay; (b) rate of DNA synthesis; and (c) induction of apoptosis. Our results indicate that treatment of prostate cancer cells with doxazosin or terazosin results in a significant loss of cell viability, via induction of apoptosis in a dose-dependent manner, whereas tamsulosin had no effect on prostate cell growth. Neither doxazosin nor terazosin exerted a significant effect on the rate of cell proliferation in prostate cancer cells. Exposure to phenoxybenzamine, an irreversible inhibitor of alpha1-adrenoceptors, does not abrogate the apoptotic effect of doxazosin or terazosin against human prostate cancer or smooth muscle cells. This suggests that the apoptotic activity of doxazosin and terazosin against prostate cells is independent of their capacity to antagonize alpha1-adrenoceptors. Furthermore, an in vivo efficacy trial demonstrated that doxazosin administration (at tolerated pharmacologically relevant doses) in SCID mice bearing PC-3 prostate cancer xenografts resulted in a significant inhibition of tumor growth. These findings demonstrate the ability of doxazosin and terazosin (but not tamsulosin) to suppress prostate cancer cell growth in vitro and in vivo by inducing apoptosis without affecting cell proliferation. This evidence provides the rationale for targeting both

  1. Effect of YNS-15P, a new alpha-2 adrenoceptor antagonist, on stress-stimulated colonic propulsion in rats.

    PubMed

    Yamamoto, O; Niida, H; Tajima, K; Shirouchi, Y; Kyotani, Y; Ueda, F; Kise, M; Kimura, K

    1998-11-01

    We studied effects of a novel alpha-2 adrenoceptor antagonist, YNS-15P (N-[(2R,11bS)-9-methoxy-1,3,4,6,7, 11b-hexahydro-2H-benzoquinolizin-2-yl]-N-methylmethanesulfonami de hydrochloride), on colonic propulsion stimulated by wrap-restraint stress (WRS) or bethanechol, on normal colonic propulsion and on diarrhea induced by castor oil in rats. Alpha-2 adrenoceptor antagonists, rauwolscine and RX821002, decreased the increase in the number and weight of fecal pellets induced by WRS. YNS-15P also inhibited WRS-stimulated fecal excretion in a dose-dependent manner. A 5-hydroxytryptamine3 receptor antagonist, granisetron, trimebutine and diazepam, but not a 5-hydroxytryptamine4 receptor antagonist, GR113808, significantly inhibited WRS-stimulated fecal excretion. YNS-15P inhibited WRS-stimulated colonic transit in a dose-dependent manner. However, YNS-15P had no significant effect on normal fecal excretion and colonic transit or on bethanechol-stimulated fecal excretion. YNS-15P also failed to inhibit castor-oil-induced diarrhea. These results indicate that YNS-15P selectively inhibits WRS-stimulated colonic propulsion, and that alpha-2 adrenoceptors may be involved in stress-induced colonic motor dysfunction in fed rats. PMID:9808698

  2. In vitro alpha1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel alpha1A-adrenoceptor selective antagonists.

    PubMed

    Williams, T J; Blue, D R; Daniels, D V; Davis, B; Elworthy, T; Gever, J R; Kava, M S; Morgans, D; Padilla, F; Tassa, S; Vimont, R L; Chapple, C R; Chess-Williams, R; Eglen, R M; Clarke, D E; Ford, A P

    1999-05-01

    It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the alpha1A-adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. The present study describes the alpha1-adrenoceptor (alpha1-AR) subtype selectivities of two novel alpha1-AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned alpha1A-, alpha1B- and alpha1D-AR showed nanomolar affinity and significant alpha1A-AR subtype selectivity for both Ro 70-0004 (pKi 8.9: 60 and 50 fold selectivity) and RS-100329 (pKi 9.6: 126 and 50 fold selectivity) over the alpha1B- and alpha1D-AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA2 8.8 and 8.9), RS-100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing alpha1-AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). The alpha1A-AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a 'uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia. PMID:10369480

  3. Induction of apoptosis in the prostate by alpha1-adrenoceptor antagonists: a novel effect of "old" drugs.

    PubMed

    Kyprianou, N; Jacobs, S C

    2000-08-01

    Advances in our understanding of the integrated functions governing prostate cell proliferation and cell death imply that effective therapies for prostate neoplasia should not only be molecularly targeted, but should be customized to take into account the delicate balance of opposing growth influences. Evidence from studies on the dynamics of prostate growth in benign prostatic hyperplasia (BPH) and prostate cancer established that disruption of the molecular mechanisms that regulate apoptosis and cell proliferation among the stroma and epithelial cell populations may underlie the neoplastic development that characterizes the aging gland. Our own efforts have been focused on investigating whether a1-adrenoceptor antagonists clinically used for the relief of the obstructive symptoms associated with BPH affect prostate pathophysiology via mechanisms other than smooth muscle contraction. Such efforts led to the identification of a novel effect of two alpha1-adrenoceptor antagonists, doxazosin and terazosin. More recent in vitro experiments examined the potential anti-tumor action of three clinically used alpha1-adrenoceptor antagonists--doxazosin, terazosin and tamsulosin--against prostate cancer cell growth. These findings demonstrate the ability of doxazosin and terazosin, but not tamsulosin, to suppress prostate growth by inducing apoptosis among the epithelial cells in the benign and malignant prostate. Thus, evidence indicates that rather than just causing pure relaxation of the smooth muscle, certain alpha1-blockers can also affect the dynamics of prostate growth by changing the balance between prostate cell proliferation and apoptosis at the expense of the proliferative process. PMID:12084321

  4. In vivo studies on the effects of alpha1-adrenoceptor antagonists on pupil diameter and urethral tone in rabbits.

    PubMed

    Michel, Martin C; Okutsu, Hiroko; Noguchi, Yukiko; Suzuki, Masanori; Ohtake, Akiyoshi; Yuyama, Hironori; Yanai-Inamura, Hiroko; Ukai, Masashi; Watanabe, Mai; Someya, Akiyoshi; Sasamata, Masao

    2006-02-01

    Alpha1-adrenoceptors mediate contraction of iris dilator smooth muscle and hence pupil dilatation. We compared the ability of i.v. bolus injections of alfuzosin, doxazosin, naftopidil, prazosin, tamsulosin and terazosin to antagonise phenylephrine-induced mydriasis relative to their potency for inhibiting phenylephrine-induced elevations of intraurethral pressure (IUP) in rabbits. Moreover, we compared the ability of these drugs to induce miosis in conscious rabbits in the absence of phenylephrine. All antagonists inhibited the effects of phenylephrine on pupil size and IUP, and the ratio of the respective ED50 values was close to unity in all cases. The doses required to induce statistically significant miosis in the absence of phenylephrine were 30- to 100-fold higher than those inhibiting phenylephrine-induced mydriasis for all antagonists, except for naftopidil. Moreover, the miotic effects of all alpha1-adrenoceptor antagonists were fully reversible within 8 h. We conclude that alfuzosin, doxazosin, naftopidil, prazosin, tamsulosin and terazosin inhibit phenylephrine-induced mydriasis in the same dose range as they inhibit elevations in IUP. Higher doses of all antagonists are required to induce miosis in the absence of an exogenous agonist, and such miosis is always reversible within hours. PMID:16489448

  5. Role of receptor reserve in the inhibition of alpha-1 adrenoceptor-mediated pressor responses by calcium antagonists in the pithed rat.

    PubMed

    Jim, K F; Macia, R A; Matthews, W D

    1986-07-01

    The effect of the calcium channel antagonists nifedipine and FR 34235 on the vasopressor response to alpha-1 adrenoceptor stimulation in the pithed normotensive rat was investigated. The maximal pressor response elicited by the full alpha-1 adrenoceptor agonist SK&F l-89748 was slightly but significantly reduced by 1-mg/kg doses of nifedipine (21 +/- 2%) and FR 34235 (34 +/- 4%). In comparison, the maximal pressor response to alpha-1 adrenoceptor stimulation by the partial alpha-1 agonist SK&F 88444 was markedly inhibited by nifedipine (51 +/- 1%) and FR 34235 (65 +/- 3%). Partial inactivation of the postsynaptic alpha-1 adrenoceptors with phenoxybenzamine (0.1 mg/kg) resulted in a maximal increase in diastolic pressure to alpha-1 adrenoceptor activation by SK&F l-89748 less than that induced by SK&F 88444. After phenoxybenzamine treatment, nifedipine and FR 34235 produced even greater reductions in the maximal vasopressor response to alpha-1 adrenoceptor stimulation by SK&F l-89748 (77 +/- 8 and 85 +/- 1%, respectively). Moreover, an inverse linear correlation (r = 1.00) was observed between the sensitivity of the maximal vasopressor response to nifedipine and FR 34235 and the magnitude of the maximal pressor response. The data suggest that the sensitivity of the alpha-1 adrenoceptor-mediated pressor response to inhibition by calcium antagonists in the pithed rat is inversely related to the magnitude of the pressor response, and they are consistent with the notion that the presence of "spare" alpha-1 adrenoceptors may determine the sensitivity of the pressor response to calcium antagonists. PMID:3014124

  6. Alpha1-Adrenoceptor Antagonists Improve Memory by Activating N-methyl-D-Aspartate-Induced Ion Currents in the Rat Hippocampus

    PubMed Central

    Ko, Il Gyu; Kim, Sung Eun; Shin, Mal Soon; Kang, Yeon Ho; Cho, Jung Wan; Shin, Key Moon; Kim, Chang Ju; Lim, Baek Vin

    2015-01-01

    Purpose: Alpha1 (α1)-adrenoceptor antagonists are widely used to treat lower urinary tract symptoms. These drugs not only act on peripheral tissues, but also cross the blood-brain barrier and affect the central nervous system. Therefore, α1-adrenoceptor antagonists may enhance brain functions. In the present study, we investigated the effects of tamsulosin, an α1-adrenoceptor antagonist, on short-term memory, as well as spatial learning and memory, in rats. Methods: The step-down avoidance test was used to evaluate short-term memory, and an eight-arm radial maze test was used to evaluate spatial learning and memory. TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling) staining was performed in order to evaluate the effect of tamsulosin on apoptosis in the hippocampal dentate gyrus. Patch clamp recordings were used to evaluate the effect of tamsulosin on ionotropic glutamate receptors, such as N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate receptors, in hippocampal CA1 neurons. Results: Tamsulosin treatment improved short-term memory, as well as spatial learning and memory, without altering apoptosis. The amplitudes of NMDA-induced ion currents were dose-dependently increased by tamsulosin. However, the amplitudes of AMPA- and kainate-induced ion currents were not affected by tamsulosin. Conclusions: Tamsulosin enhanced memory function by activating NMDA receptor-mediated ion currents in the hippocampus without initiating apoptosis. The present study suggests the possibility of using tamsulosin to enhance memory under normal conditions, in addition to its use in treating overactive bladder. PMID:26739177

  7. Analysis of the effects of alpha 1-adrenoceptor antagonists on noradrenaline-mediated contraction of rat small mesenteric artery.

    PubMed Central

    Van der Graaf, P. H.; Shankley, N. P.; Black, J. W.

    1996-01-01

    1. In this study, we examined the interaction between noradrenaline (NA) and phenylephrine (PE) with seven antagonists (prazosin, tamsulosin, phentolamine, WB-4101, 5-methylurapidil, spiperone and HV 723) in an attempt to characterize the alpha 1-adrenoceptor population of the rat isolated small mesenteric artery (SMA) preparation. 2. Six of the seven antagonists investigated produced concentration-dependent, parallel, rightward shift of the NA concentration-effect (E/[A]) curves. The exception was tamsulosin, which produced significant decrease of the upper asymptote. In the case of 5-methylurapidil and HV723, the Schild plot slope parameters were not significantly different from unity over the range of concentrations used. However, the Schild plot slopes obtained for the other antagonists were all significantly greater than unity, inconsistent with expectations for simple competitive antagonism. 3. HV723, prazosin and tamsulosin were also tested using PE as an agonist. All three antagonists produced concentration-dependent, parallel, rightward shifts of the PE curves and Schild analysis yielded slope parameters not significantly different from unity. The pKB estimates obtained for tamsulosin and prazosin were not significantly different from the pA2 values obtained when NA was used as agonist. In the case of HV723, the 95% confidence intervals for the pKB values yielded with NA and PE did not overlap (pKB = 8.80-9.13 and 8.15-8.77 for NA and PE, respectively). 4. In the absence of evidence to indicate that the steep Schild plots were due to failure to satisfy the basic criteria for quantitative analysis in a one-receptor system, we considered the possibility that the complexity was caused by an action of NA at inhibitory D1 receptors. The selective D1 receptor antagonists, SCH-23390 (10 nM), had no significant effect on the NA E/[A] control curve, but the apparent potency of 100 nM prazosin was reduced by approximately 3.5 fold. 5. This study indicates that the

  8. 5-Methoxy-N,N-dimethyltryptamine-induced analgesia is blocked by alpha-adrenoceptor antagonists in rats.

    PubMed Central

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

    1986-01-01

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

  9. 5-Methoxy-N,N-dimethyltryptamine-induced analgesia is blocked by alpha-adrenoceptor antagonists in rats.

    PubMed

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

    1986-10-01

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

  10. In vivo study on the effects of alpha1-adrenoceptor antagonists on intraurethral pressure in the prostatic urethra and intraluminal pressure in the vas deferens in male dogs.

    PubMed

    Noguchi, Yukiko; Ohtake, Akiyoshi; Suzuki, Masanori; Sasamata, Masao

    2008-02-01

    Alpha-adrenoceptor antagonists are used worldwide for the treatment of voiding dysfunction associated with benign prostatic hyperplasia. Recently, abnormal ejaculation, an adverse effect associated with their use, has attracted attention. Here, we simultaneously investigated the effects of alpha(1)-adrenoceptor antagonists on intraurethral pressure in the prostatic urethra and intraluminal pressure in the vas deferens in anesthetized male dogs, and compared their tissue selectivity. Phenylephrine, an alpha(1)-adrenoceptor agonist, induced simultaneous increases in intraurethral and intraluminal pressure. Alfuzosin, naftopidil, prazosin, silodosin and tamsulosin dose-dependently inhibited both responses. Comparison of ED(50) values in both tissues showed that silodosin had the highest selectivity for the vas deferens (7.5-fold), followed by naftopidil (4.3-fold), alfuzosin (3.8-fold), tamsulosin (2.6-fold) and prazosin (2.5-fold). These results suggest that alpha(1)-adrenoceptor antagonists inhibit contraction of not only the urethra but also the vas deferens in a dose-dependent fashion, and that their high tissue selectivity for the vas deferens over the urethra may contribute to the incidence of abnormal ejaculation. PMID:18078926

  11. Alpha adrenoceptor subtypes involved in the emetic action in dogs.

    PubMed

    Hikasa, Y; Ogasawara, S; Takase, K

    1992-05-01

    In order to assess the involvement of alpha-1 and alpha-2 adrenoceptors in emesis, the emetic effect of eight alpha agonists was studied in dogs. The i.m. administration of each agonist elicited dose-dependent emesis. The order of potency in inducing emesis was: clonidine greater than oxymetazoline greater than tramazoline greater than naphazoline greater than xylazine greater than epinephrine greater than methoxamine = phenylephrine. The clonidine-induced emesis was antagonized by adrenoceptor antagonists showing alpha-2 blocking activity, yohimbine, tolazoline and phentolamine. Among these antagonists, yohimbine was the most effective. The alpha-1 and beta adrenergic, cholinergic, dopaminergic, histaminergic, serotonergic and opioid receptor antagonists did not prevent the clonidine-induced emesis. The emesis induced by oxymetazoline, tramazoline, xylazine, naphazoline and epinephrine was also antagonized by a selective alpha-2 adrenoceptor antagonist, yohimbine, but not by a selective alpha-1 adrenoceptor antagonist, prazosin. In contrast, methoxamine and phenylephrine-induced emesis was antagonized by prazosin, but not by yohimbine. Neither yohimbine nor prazosin prevented the morphine- and histamine-induced emesis. These results indicate that alpha-2 adrenoceptors are involved in the mediation of emetic action, and that the alpha adrenoceptor-mediated emesis does not involve beta adrenergic, cholinergic, dopaminergic, histaminergic, serotonergic and opioid receptors in the emetic pathway. This study further suggests that alpha adrenoceptors involved in the emesis are mainly of the alpha-2 type, although the involvement of alpha-1 adrenoceptors cannot be ruled out. PMID:1349647

  12. Effect of JTH-601, a novel alpha1-adrenoceptor antagonist, on the function of lower urinary tract and blood pressure.

    PubMed

    Suzuki, Y; Kanada, A; Okaya, Y; Aisaka, K; Muramatsu, I

    1999-06-25

    In the present study, we investigated the effect of JTH-601 (3-{N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy)ethyl]-N-methylaminomethyl}-4-methoxy-2,5,6-trimethylphenol hemifumarate), a novel alpha1-adrenoceptor antagonist, in vitro and in vivo. JTH-601 (10(-9)-3 x 10(-8) M) competitively antagonized phenylephrine-induced contraction in lower urinary tract tissues (prostate, urethra and bladder trigon) in a concentration-dependent manner. The mean pA2 values for JTH-601 were 8.59+/-0.14, 8.74+/-0.09 and 8.77+/-0.11 for prostate, urethra and bladder trigon, respectively. In anesthetized rabbits, intraduodenal administration of JTH-601 (0.3-3 mg/kg), prazosin (0.03-0.3 mg/kg) and tamsulosin (0.03-0.3 mg/kg) dose dependently inhibited the phenylephrine-induced increase in urethral pressure for 3 h. Although these drugs also decreased mean blood pressure, JTH-601 was less potent than prazosin or tamsulosin. In conscious rabbits, administered JTH-601 (0.01-1 mg/kg, i.v.) had a tendency to augment orthostatic hypotension, but dose dependency was not evident. Prazosin (0.01-1 mg/kg) and tamsulosin (0.001-1 mg/kg) dose dependently augmented orthostatic hypotension. These results indicate that JTH-601 antagonized alpha1-adrenoceptor-mediated contractile responses more potently than prazosin or tamsulosin in rabbit lower urinary tract both in vitro and in vivo. JTH-601 is therefore expected to be effective in the treatment of urinary outlet obstruction in benign prostatic hypertrophy. PMID:10422795

  13. Effects of alpha1-adrenoceptor antagonists on agonist and tilt-induced changes in blood pressure: relationships to uroselectivity.

    PubMed

    Hieble, J P; Kolpak, D C; McCafferty, G P; Ruffolo, R R; Testa, R; Leonardi, A

    1999-05-28

    We evaluated the uroselectivity of a series of alpha1-adrenoceptor antagonists by comparing their potency against phenylephrine-induced increases in urethral perfusion pressure and diastolic blood pressure in the anesthetized rabbit and pithed rat. In the rabbit, Rec 15/2739 (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl -4H-1-benzopyran-8-carboxamide) as well as analogs with a chlorine substituent on the methoxyphenyl ring (Rec 15/2869) or this substituent combined with the replacement of the phenyl substituent on the pyran ring by cyclohexyl (Rec 15/3011) were 2-6-fold more potent against the urethral vs. vascular response to phenylephrine. Rec 15/2841 (N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-cyc lohexy-4H-1-benzopyran-8-carboxamide) was only 1.5-fold more potent against the urethral response. SL 89.0591 and tamsulosin also showed selectivity for the urethral response (2-2.5-fold), while the quinazolines produced equipotent blockade of urethral and vascular responses (selectivity ratio = 0.9-1.1). The urethral selectivities of Rec 15/2739 and its derivatives were confirmed by evaluation of the response to tilt in sedated, hypovolemic rabbits. Phenylephrine challenge assays did not show any of the antagonists, with the exception of terazosin at 300 microg kg(-1), to be uroselective in the rat (selectivity ratios = 0.2-1.5); potentiation of tilt-induced hypotension in the anesthetized rat showed substantial differences from the rabbit, with Rec 15/2739, but not Rec 15/3011 and Rec 15/2841 showing orthostatic effects equivalent to that observed for prazosin. Hence, Rec 15/2739 was uroselective in the rabbit, but not in the rat, while two of its close structural analogs were highly uroselective in both species. An assay for orthostatic activity in the conscious rat yielded different results, showing prazosin and terazosin, but not Rec 15/2739, to cause a reversal of the pressor response to tilt. Hence, the apparent

  14. The 5-HT and alpha-adrenoceptor antagonist effect of four benzylisoquinoline alkaloids on rat aorta.

    PubMed

    Catret, M; Ivorra, M D; D'Ocón, M P; Anselmi, E

    1998-03-01

    The action of four benzylisoquinoline alkaloids (two aporphines-glaucine and apomorphine, a benzylisoquinoline-papaverine and a bisbenzyltetrahydroisoquinoline-antioquine) on 5-HT-induced contraction in rat thoracic aorta has been examined and compared with that of the control drugs: ketanserin, nifedipine, prazosin and phentolamine. The relaxant action on 5-HT-induced contraction was contrasted with that on the contraction induced by noradrenaline and KCl. The results obtained with control drugs show that ketanserin has clear selectivity for 5-HT receptors, whereas prazosin and phentolamine have high selectivity for the alpha1-adrenoceptor and nifedipine seems to have a more potent effect on KCl-induced contraction than on that induced by 5-HT or noradrenaline. The contraction evoked by 5-HT (10 microM) was inhibited in a concentration-dependent manner by all the alkaloids. The order of potency was: papaverine = glaucine > apomorphine > antioquine. Papaverine had a non-specific relaxant action on 5-HT-, noradrenaline- and KCl-induced contraction, antioquine had a weak relaxant action on the agonist assays, and glaucine and apomorphine inhibited noradrenaline- and 5-HT-induced contraction more potently than they inhibited the K+-depolarized response. These results indicate that the aporphines assayed, S-glaucine and R-aporphine, had selective action against agonist (noradrenaline or 5-HT)-induced contraction rather than against KCl-depolarization of rat aorta. In contrast papaverine, a benzylisoquinoline alkaloid, relaxes all agents used non-selectively as could be expected from the lack of specificity that characterizes this alkaloid. PMID:9600725

  15. New tools for human fat cell alpha-2A adrenoceptor characterization. Identification on membranes and on intact cells using the new antagonist (3H)RX821002

    SciTech Connect

    Galitzky, J.; Larrouy, D.; Berlan, M.; Lafontan, M. )

    1990-01-01

    The pharmacology of the alpha-2 adrenoceptor of the human adipocyte was improved by using some new alpha-2 antagonists from different chemical families (imidazolines, benzazepines and benzofuroquinolizines) in biological and binding assays. Moreover, investigations were also carried out to define the binding properties of a new imidazolinic antagonist, RX821002 (2-(2-methoxy-1,4-benzodioxan-2yl)-2-imidazoline), which could be a potential radioligand. (3H)RX821002 binding was very rapid and reversible. Saturation isotherms indicated that (3H)RX821002 labeled, with high affinity, a homogeneous population of noninteracting binding sites with a mean Kd of 0.98 +/- 0.05 nM (n = 6). The binding of (3H)RX821002 on the human fat cell alpha-2 adrenoceptor displayed a specificity which is strictly similar to that obtained with (3H)rauwolscine and which is classical for an alpha-2 A adrenoceptor. The binding parameters of (3H)RX821002 were compared with those obtained with the classical alpha-2 antagonist (3H)yohimbine. Analysis of the data indicate: (1) that (3H)RX821002 exhibited higher affinity; (2) that the nonspecific binding of (3H)RX821002 was very low; (3) that the total number of sites (maximum binding values) defined with (3H)RX821002 was significantly higher than that defined with (3H)yohimbine. This difference was not due to a specific preferential labeling of one of the two affinity states of the receptor, but suggested that (3H)yohimbine does not label the whole receptor population; (4) that (3H)RX821002 specific binding was less sensitive to magnesium chloride and GTP than (3H)yohimbine binding; and (5) that (3H)RX821002 can be used suitably for identification of alpha-2 adrenoceptors on the intact adipocyte.

  16. Quinazoline-based alpha 1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-beta signalling and I kappa B alpha induction.

    PubMed

    Partin, J V; Anglin, I E; Kyprianou, N

    2003-05-19

    Previous studies documented the ability of quinazoline-based alpha1-adrenoceptor antagonists to induce apoptosis in prostate cancer cells via an alpha 1-adrenoceptor-independent mechanism. In this study we investigated the molecular events initiating this apoptotic effect. Since transforming growth factor-beta 1 (TGF-beta 1) mediates prostate epithelial cell apoptosis, we hypothesised that the activation of the TGF-beta 1 pathway underlies the quinazoline-based apoptotic effect in prostate cancer cells. Treatment of the androgen-independent human prostate cancer cells PC-3 with doxazosin resulted in a strong caspase-3 activation within 24 h, whereas tamsulosin, a sulphonamide-based alpha 1-adrenoceptor antagonist, had no significant apoptotic effect against prostate cancer cells. To identify the molecular components involved in this quinazoline-mediated apoptosis, cDNA microarray analysis of PC-3 prostate cancer cells treated with doxazosin (3 h) was performed. Induced expression of several genes was observed including p21(WAF-1) and I kappa B alpha (inhibitor of NF-kappa B alpha). Relative quantitative reverse transcription-polymerase chain reaction analysis revealed induction of several TGF-beta1 signalling effectors: Induction of mRNA for Smad4 and the TGF-beta1-regulated apoptosis-inducing transcription factor TGF-beta1-inducible early gene (TIEG1) was detected within the first 6 h of doxazosin treatment. Upregulation of I kappa B alpha at both the mRNA and protein level was also detected after 6 h of treatment. Furthermore, doxazosin resulted in a considerable elevation in Smad4 and TIEG protein expression (6 h). A 'latent' increase in TGF-beta mRNA expression was detected after 48 h of treatment. These findings suggest that the quinazoline-based doxazosin mediates prostate cancer apoptosis by initially inducing the expression of TGF-beta1 signalling effectors and subsequently I kappa B alpha. The present study provides an initial insight into the molecular

  17. Pharmacological analysis of the novel, selective alpha1-adrenoceptor antagonist, KMD-3213, and its suitability as a tritiated radioligand.

    PubMed

    Murata, S; Taniguchi, T; Muramatsu, I

    1999-05-01

    Pharmacological profiles of tritiated KMD-3213, a new antagonist of alpha1-adrenoceptor (AR), were examined in recombinant and native alpha1-AR, and compared with those of prazosin (PZ) and tamsulosin (YM-617). In saturation experiments, [3H]-KMD (10-2000 pM) showed high affinity for alpha1a-AR (pK(D) = 10.5). However, no significant binding to alpha1b-AR and insufficient/unsaturated binding to alpha1d-AR were observed at concentrations up to 2000 pM. In contrast, [3H]-PZ and [3H]-YM bound to all subtypes with high affinity (pK(D)>9). In competition experiments, KMD-3213 also had higher affinity for alpha1a-AR than for other two subtypes; pKi = 10.4, 8.1 and 8.6 for alpha1a-, alpha1b- and alpha1d-AR, respectively. [3H]-KMD also bound to the native alpha1A-AR (rat submaxillary gland) with high affinity, but not to alpha1B-AR (rat liver). In rat kidney which expresses alpha1A- and alpha1B-AR, [3H]-KMD and [3H]-PZ bound to a single high-affinity site (pK(D) = 10.8 and 10.1, respectively) with distinct amount of binding sites (Bmax = 159 and 267 fmol mg(-1) protein, respectively). [3H]-PZ binding sites consisted of low- and high-affinity sites for KMD-3213 (pKi = 7.6 and 10.7, respectively), for WB4101 (pK = 8.1 and 10.0) and for YM-617 (pKi = 8.7 and 10.8). The proportion of the high affinity site was approximately 60% in these drugs which was compatible to the ratio between Bmax of [3H]-KMD and [3H]-PZ. [3H]-KMD binding sites consisted of a single site for these drugs with affinities which were similar to those of the high affinity sites in [3H]-PZ binding. In functional experiments, KMD-3213 antagonized the contractile responses to NS-49 or noradrenaline (NA) with higher affinity in functional alpha1A- (rat caudal artery, pA2= 10.0 against NS-49) and alpha1L-AR (dog mesenteric artery, pA2 = 9.9 against NA) than in alpha1B- (dog carotid artery, pA2 = 7.7 against NA) and alpha1D-AR (rat thoracic aorta, pA2 = 8.3 against NA). These results confirm the alpha1A

  18. Effects of alpha1-adrenoceptor antagonist (tamsulosin) on incident of ejaculation and semen quality in the goat.

    PubMed

    Kimsakulvech, S; Suttiyotin, P; Pinyopummin, A

    2015-04-01

    Male temporary contraception is occasionally required in some animals. Alpha1-adrenoceptor antagonist (tamsulosin) can cause ejaculation disorder. Two sets of Latin square were applied to six male goats to received either normal saline, dimethylsulphoxide or tamsulosin (179.8 nmol kg(-1) ) at 1-week interval. Semen collection and libido scoring were undertaken at 3, 6 and 24 h post-injection. For ejaculated semen, its quality was evaluated. Physiological measurements including body temperature, respiration and heart rates were measured before injection and at 30 min before semen collection. The results showed that libido score and physiological changes were not affected by treatments and time periods. Anejaculation was observed in 11 (91.7%), 5 (41.7%) and 1 (8.3%) males at 3, 6 and 24 h post-tamsulosin injection respectively. The incidence returned to normal when compared with control groups at 24 h. The percentages of motile and live spermatozoa at 6 h post-tamsulosin injection were significantly lower (P < 0.05) than that of normal saline group. At 24 h post-injection, there were no significant differences of all semen parameters among treatments. This study demonstrated that tamsulosin had temporary effects on ejaculation and semen quality without reducing sex desire and physiological functions in male goats. PMID:24684217

  19. Impact of physicochemical and structural properties on the pharmacokinetics of a series of alpha1L-adrenoceptor antagonists.

    PubMed

    Betts, Alison; Atkinson, Fidelma; Gardner, Iain; Fox, David; Webster, Rob; Beaumont, Kevin; Morgan, Paul

    2007-08-01

    A rational drug discovery process was initiated to design a potent and prostate-selective alpha1(L)-adrenoceptor antagonist with pharmacokinetic properties suitable for once a day administration after oral dosing, for the treatment of benign prostatic hyperplasia. Two series of compounds based on a quinoline or quinazoline template were identified with appropriate pharmacology. A series of high molecular weight cations with high hydrogen-bonding potential had extensive in vivo clearance, despite demonstrating metabolic stability. Studies in the isolated perfused rat liver and fresh rat hepatocytes indicated that active transport protein-mediated hepatobiliary elimination is an efficient clearance process for these compounds. A reduction in molecular weight and hydrogen-bonding potential resulted in a second series of compounds with in vivo hepatic clearance predictable from in vitro metabolic clearance. Initially, lipophilicity was reduced within this second series to reduce metabolic clearance and increase elimination half-life. However, this strategy also resulted in a concomitant reduction in volume of distribution and a negligible effect on prolonging half-life. An alternative strategy was to increase the intrinsic metabolic stability of the molecule by careful structural modifications while maintaining lipophilicity. Replacement of the metabolically vulnerable morpholine side chain resulted in identification of UK-338,003, (N-[2-(4-amino-6,7-dimethoxy-5-pyridin-2-yl-quinazolin-2-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-methanesulfonamide), which fulfilled the objectives of the discovery program with suitable pharmacology (human prostate alpha1(L) pA(2) of 9.2 with 25-fold selectivity over rat aorta alpha1(D)) and sufficiently long elimination half-life in human volunteers (11-17 h) for once a day administration. PMID:17502340

  20. Effect of Silodosin, an Alpha1A-Adrenoceptor Antagonist, on Ventral Prostatic Hyperplasia in the Spontaneously Hypertensive Rat

    PubMed Central

    Shimizu, Shogo; Shimizu, Takahiro; Tsounapi, Panagiota; Higashi, Youichirou; Martin, Darryl T.; Nakamura, Kumiko; Honda, Masashi; Inoue, Keiji; Saito, Motoaki

    2015-01-01

    Background A decreased prostatic blood flow could be one of the risk factors for benign prostatic hyperplasia/benign prostatic enlargement. The spontaneously hypertensive rat (SHR) shows a chronic prostatic ischemia and hyperplastic morphological abnormalities in the ventral prostate. The effect of silodosin, a selective alpha1A-adrenoceptor antagonist, was investigated in the SHR prostate as a prostatic hyperplasia model focusing on prostatic blood flow. Methods Twelve-week-old male SHRs were administered perorally with silodosin (100 μg/kg/day) or vehicle once daily for 6 weeks. Wistar Kyoto (WKY) rats were used as normotensive controls and were treated with the vehicle. The effect of silodosin on blood pressure and prostatic blood flow were estimated and then the prostates were removed and weighed. The tissue levels of malondialdehyde (MDA), interleukin-6 (IL-6), chemokine (C-X-C motif) ligand 1/cytokine-induced neutrophil chemoattractant 1 (CXCL1/CINC1), tumor necrosis factor-alpha (TNF-α), transforming growth factor beta 1 (TGF-β1), basic fibroblast growth factor (bFGF) and alpha-smooth muscle actin (α-SMA) were measured. The histological evaluation was also performed by hematoxylin and eosin staining. Results There was a significant increase in blood pressure, prostate weight, prostate body weight ratio (PBR), tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA in the SHR compared to the WKY rat. The ventral prostate in the SHR showed the morphological abnormalities compared to the WKY rat. Prostatic blood flow was decreased in the SHR. However, treatment with silodosin significantly restored the decreased prostatic blood flow in the SHR. Moreover, silodosin normalized tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA, and it ameliorated ventral prostatic hyperplasia in the SHR excluding blood pressure. Silodosin decreased PBR but not prostate weight in the SHR. Conclusions Silodosin can inhibit the

  1. Distribution and function of peripheral alpha-adrenoceptors in the cardiovascular system.

    PubMed

    Ruffolo, R R

    1985-05-01

    alpha-Adrenoceptors may be subdivided based on their anatomical distribution within the synapse. Presynaptic alpha-adrenoceptors are generally of the alpha 2-subtype and modulate neurotransmitter liberation via a negative feedback mechanism. Postsynaptic alpha-adrenoceptors are usually of the alpha 1-subtype and mediate the response of the effector organ. Although this "anatomical" subclassification is generally applicable, many exceptions exist. A more useful classification of alpha-adrenoceptor subtypes is based on a pharmacological characterization in which selective agonists and antagonists are used. Peripheral alpha-adrenoceptors are critical in the regulation of the cardiovascular system. Postsynaptic alpha-adrenoceptors in arteries and veins represent a mixed population of alpha 1/alpha 2-adrenoceptors, with both subtypes mediating vasoconstriction. In the peripheral arterial circulation, postsynaptic vascular alpha 1-adrenoceptors are found in the adrenergic neuroeffector junction, whereas postsynaptic vascular alpha 2-adrenoceptors are located extrajunctionally. In the venous circulation, it appears that alpha 2-adrenoceptors may be predominantly junctional, whereas alpha 1-adrenoceptors may be predominantly extrajunctional. It has been proposed that junctional alpha-adrenoceptors will respond predominantly to norepinephrine liberated from sympathetic neurons, whereas extrajunctional alpha-adrenoceptors likely respond to circulating catecholamines. The functional role of extrajunctional alpha-adrenoceptors may be more important in disease states such as hypertension and congestive heart failure where circulating levels of catecholamines may be high and contribute to the maintenance of elevated vascular resistance. alpha 2-Adrenoceptors are also associated with the intima and may play a role in the release of an endogenous relaxing factor from the endothelium.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2989947

  2. The prostatic urethral angle can predict the response to alpha adrenoceptor antagonist monotherapy for treating nocturia in men with lower urinary tract symptom: A multicenter study

    PubMed Central

    Kim, Byung Hoon; Kim, Ki Ho; Ko, Young Hwii; Song, Phil Hyun; Kim, Tae-Hwan; Kim, Bum Soo

    2016-01-01

    Background We evaluated ultrasonography variables associated with the improvement of nocturia after administration of alpha adrenoceptor antagonist (alpha blocker) monotherapy. Methods From February to October 2014, 679 men with lower urinary tract symptoms (LUTS) underwent ultrasonography including prostate volume, transitional zone volume, prostatic urethral length, the ratio between prostatic urethral length and prostate volume (RPUL), intravesical prostatic protrusion (IPP), and prostatic urethral angle (PUA). Among them, 108 men who had pre-treatment nocturia without nocturnal polyuria (nocturnal polyuria index < 33%) and were treated with alpha blocker monotherapy over 3 months were enrolled. Patients were divided into the improved (< 2 times of nocturia) and non-improved group (more than 2 times) after administration of alpha blockers. Along with ultrasonography, international prostate symptom score (IPSS) and uroflowmetry was assessed. Results After alpha blocker treatment, 25.0% of patients (27/108) showed improvement of nocturia. These patients were significantly younger (59.6 vs 68.0 years, P = < 0.001) with lower PUA (31.8 vs. 39.4°, P = 0.009) compared with the non-improved group. In ROC analysis, the area under the curve using the PUA was 0.653 (95% CI = 0.532–0.774, P = 0.018). Using 33.5° as a cut-off level, the sensitivity and specificity for predicting the improvement of nocturia after medication reached 67.9% and 55.6%, respectively. Patients with lower PUA (PUA < 33.5°) had more improvement of nocturia (36.6 vs. 17.9%, P = 0.030), lower IPSS score (14.2 vs. 18.3, P = 0.005), and better quality of life index (3.1 vs 3.8, P = 0.021). Conclusions In the patients with lower PUA (particularly lower than 33.5°), nocturia was improved by administration of alpha blocker monotherapy. PMID:27014662

  3. Role of alpha-1 adrenoceptor subtypes mediating constriction of the rabbit ear thermoregulatory microvasculature.

    PubMed

    Li, Z; Silver, W P; Koman, L A; Strandhoy, J W; Rosencrance, E; Gordon, S; Smith, T L

    2000-01-01

    An acute in vivo preparation of the microvasculature of the rabbit ear was used to evaluate the functional role of alpha1 (alpha1)-adrenoceptor subtypes in thermoregulatory microcirculation. The effect of alpha1-adrenoceptor subtype blockade on phenylephrine-induced vasoconstriction was assessed with the alpha1A, alpha1B, and alpha1D-adrenoceptor-selective antagonists 5-methyl-urapidil (10(-8) M), chloroethylclonidine (10(-5) M), and 8-[2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol[4.5]deca ne-7,9-dione dihydrochloride (BMY7378) (10(-6) M), respectively. The results demonstrated that pretreatment of the ear microvasculature with 5-methyl-urapidil or BMY7378 shifted the phenylephrine concentration-response curve rightward and significantly changed the log of the phenylephrine concentration, causing half-maximum stimulation (EC50) in arterioles (p < 0.05). BMY7378 shifted the phenylephrine concentration-response curve of the arteriovenous anastomoses about 100-fold rightward (p < 0.05). All three alpha1-adrenoceptor antagonists eliminated the vasoconstrictive effects of phenylephrine on venules. The results indicate that the ear microvasculature has a heterogenous distribution of alpha1-adrenoceptor subtypes. The alpha1A and alpha1D-adrenoceptor subtypes appear to have a greater influence on constrictive function in arterioles, whereas the alpha1D-adrenoceptor is the dominant constrictor of arteriovenous anastomoses. In general, the alpha1-adrenoceptor does not play a major vasoconstrictor role in venules. Chloroethylclonidine, an irreversible alpha1B-adrenoceptor antagonist, induced contractile responses in the ear microvasculature, probably due to its alpha2-adrenoceptor agonist effects. This study extended our understanding of the adrenergic receptor control mechanisms of a cutaneous thermoregulatory end organ characterized by two parallel perfusion circuits providing nutritional and thermoregulatory functions. PMID:10716292

  4. Comparison of the effect of alpha1- and alpha2-adrenoceptor agonists and antagonists on muscle contractility of the rabbit abdominal aorta in vitro.

    PubMed

    Gnus, Jan; Rusiecka, Agnieszka; Czerski, Albert; Zawadzki, Wojciech; Witkiewicz, Wojciech; Hauzer, Willy

    2013-01-01

    The aim of the study was to demonstrate the effect of selected agonists and antagonists of alpha-adrenergic receptors on muscle contractility of the rabbit abdominal aorta in vitro with particular emphasis on alpha2-adrenergic receptor subtypes. The study was conducted on 30 New Zealand breed rabbits from which specimens of the abdominal aorta were collected. The sections were set up in an automatic water bath in a Krebs-Henseleit buffer at 37 degrees C. The experiments showed that alpha1-adrenergic receptors played the main role in the contractile response ofthe rabbit abdominal aorta. Stimulation of alpha1-adrenergic receptor by administration ofphenylephrine resulted in an increase in smooth muscle tonus ofthe rabbit abdominal aorta by an average of 4.75 mN. The reaction after stimulation of alpha2-adrenergic receptors by similar doses of their agonists was much weaker. Prolonged tissue response time and time needed to reach maximum tonus for alpha2-adrenergic receptor agonists were observed. The obtained results confirm the thesis that the alpha1-adrenergic receptor is the most important factor controlling the contractility of the rabbit abdominal aorta, but the alpha2-adrenergic receptor is also involved in maintaining muscle tissue tonus. PMID:23767297

  5. Alpha1-adrenoceptors in the guinea pig thoracic aorta.

    PubMed

    Yamamoto, Y; Koike, K

    1999-01-01

    In the present study, we tried to determine which alpha1-adrenoceptor subtypes are involved in the guinea pig thoracic aorta by using in vitro functional analysis. In first, we tried to estimate the pA2 values of some key alpha1-adrenoceptor antagonists (prazosin, 5-methylurapidil, WB4101, BMY7378 and tamsulosin) against responses to norepinephrine in the thoracic aorta of guinea pigs. The concentration-response curves of norepinephrine were rightward shifted by the presence of prazosin, 5 methylurapidil, WB4101, BMY7378 and tamsulosin. The pA2 values for these antagonists against norepinephrine were 7.83, 7.78, 8.20, 5.73 and 9.57, respectively. In second, we tried to compare the estimated pA2 values obtained in the present study with reported pKi and pA2 values for cloned and native alpha1-adrenoceptor subtypes. In rabbit mesenteric artery, trigone, urethra, prostate and human lower urinary tract which were proposed to contain the putative alpha1L-adenoceptor, we obtained the good correlation for the pA2 values reported in these tissues with pA2 values estimated in guinea pig thoracic aorta. Moreover, regression lines were close to the line of identity. These results suggest that the alpha1-adenoceptors mediating contraction of guinea pig thoracic aorta are similar pharmacologically to the putative alpha1L-adenoceptor subtype in rabbit mesenteric artery, trigone, urethra, prostate and human lower urinary tract. As a final point, guinea pig thoracic aorta may be able to use as a tool to develop the new alpha1-adrenoceptor antagonist which is therapeutically advantageous in the treatment of urinary tract obstruction (e. g., in benign prostatic hyperplasia). PMID:10733154

  6. Comparison of relaxation responses of cavernous and trigonal smooth muscles from rabbits by alpha1-adrenoceptor antagonists; prazosin, terazosin, doxazosin, and tamsulosin.

    PubMed

    Seo, K K; Lee, M Y; Lim, S W; Kim, S C

    1999-02-01

    Alpha1a-adrenergic receptor (AR) primarily mediates the contraction of the prostatic and cavernous smooth muscles. Among clinically available alpha1-AR antagonists for the medical management of benign prostatic hyperplasia (BPH), tamsulosin has a modest selectivity for alpha1A- and alpha1D- over alpha1B-ARs. To compare the effects of various alpha1-AR antagonists on relaxation responses of cavernous and trigonal smooth muscles, isometric tension studies with relatively selective (tamsulosin) and non-selective (prazosin, doxazosin, and terazosin) alpha1A-AR antagonists, were conducted in the cavernous and trigonal muscle strips of rabbits (n=10 each). Tamsulosin had the strongest inhibitory effect on contraction of trigonal smooth muscle among the various alpha1-AR antagonists, and the inhibitory activities of prazosin, doxazosin, and terazosin were not statistically different. All alpha1-AR antagonists caused concentration-dependent relaxation of the cavernous muscle strips. Tamsulosin was shown to have greater potency than prazosin (more than 100-fold), doxazosin (more than 1000-fold), and terazosin (more than 1000-fold), in relaxation of cavernous smooth muscle. In conclusion, tamsulosin might be the most effective drug among the four commonly used alpha1-AR antagonists for the medical management of BPH. Tamsulosin might be a potential substitute for phentolamine in combination with vasoactive agents as an intracavernous injection therapy for patients with erectile dysfunction. PMID:10102527

  7. Attenuation of KATP channel-opener induced shortening of repolarization time by alpha 1-adrenoceptor antagonist during ischemia in canine heart.

    PubMed

    Tanabe, T; Aikawa, M; Deguchi, Y; Yoshioka, K; Handa, S

    2000-06-01

    The purpose of the study was to determine whether a new KATP channel opener, Y 26763 (Y), can influence the electrophysiological properties in the ischemic myocardium as well as to determine whether the blunting effect of the alpha 1-adrenoceptor antagonist bunazosin (BN) on an ischemia-induced shortening of repolarization time can be related to the KATP channel activity. The anterior descending branch of the left coronary artery was ligated four times for 5 minutes, separated by 15 minutes of reperfusion (stages 1-4) to test the dose-dependent effect of drugs on repolarization. Dogs received either vehicle (n = 9), Y (0.4, 2.0, and 4.0 micrograms/kg at stages 2, 3, and 4, respectively, with 0.4 microgram/kg/min drip infusion at each of stages 2-4, n = 7), BN (0.1 mg at each of stages 2-4, n = 8), or a combination of these two drugs (BN + Y, the same dose of BN and Y in groups BN and Y, respectively, n = 9). Drugs were administered into the left atrium. The monophasic action potential (MAP) and regional electrograms were recorded. The MAP90 and the duration of the slow deflections (DSD) of the regional electrogram were used as markers of repolarization. The Vmax of the MAP and the rapid deflections (DRD) of the regional electrogram were used as markers of conduction. Y augmented an ischemia-induced shortening of MAP90 and DSD in proportion to an increase in the dose given and the plasma concentration (P < .05-.01), especially at the epicardial site. BN and BN + Y blunted the ischemia-related shortening of MAP90 and DSD, causing a reduction in repolarization time dispersion between the ischemic and normal zones. There were no significant changes in the Vmax or DRD in the ischemic zone between periods before and after an increase in each drug dose in the four groups. None of the seven dogs developed ventricular tachycardia (VT)/ventricular fibrillation (VF) in the Y group, whereas two of the eight dogs in the BN group, three of the nine dogs in the BN + Y group, and

  8. Alpha 1D- and alpha 1A-adrenoceptors mediate contraction in rat renal artery.

    PubMed

    Villalobos-Molina, R; López-Guerrero, J J; Ibarra, M

    1997-03-19

    To investigate the alpha 1-adrenoceptor subtype(s) mediating contraction in rat renal artery, we have compared the effect of the alpha 1-adrenoceptor antagonists, 5-methylurapidil, BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl) ethyl) 8-azaspiro (4.5) decane-7,9-dione 2HCl) and chloroethylclonidine on functional responses to noradrenaline. A clear blockade by chloroethylclonidine (10(-4) M) of noradrenaline-induced contraction was observed and, along with this effect. pKB values of 9.12 and 8.40 for BMY 7378 and 9.75 and 10.06 for 5-methylurapidil were obtained, indicating that the renal artery expresses the alpha 1D-adrenoceptor subtype as the one involved in contraction and not only the alpha 1A subtype as has been reported. PMID:9098691

  9. Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor.

    PubMed

    Newman-Tancredi, Adrian; Cussac, Didier; Audinot, Valérie; Nicolas, Jean-Paul; De Ceuninck, Frédéric; Boutin, Jean-A; Millan, Mark J

    2002-11-01

    The accompanying multivariate analysis of the binding profiles of antiparkinson agents revealed contrasting patterns of affinities at diverse classes of monoaminergic receptor. Herein, we characterized efficacies at human (h)D(2SHORT(S)), hD(2LONG(L)), hD(3), and hD(4.4) receptors and at halpha(2A)-, halpha(2B)-, halpha(2C)-, and halpha(1A)-adrenoceptors (ARs). As determined by guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding, no ligand displayed "full" efficacy relative to dopamine (100%) at all "D(2)-like" sites. However, at hD(2S) receptors quinpirole, pramipexole, ropinirole, quinerolane, pergolide, and cabergoline were as efficacious as dopamine (E(max)100%); TL99, talipexole, and apomorphine were highly efficacious (79-92%); piribedil, lisuride, bromocriptine, and terguride showed intermediate efficacy (40-55%); and roxindole displayed low efficacy (11%). For all drugs, efficacies were lower at hD(2L) receptors, with terguride and roxindole acting as antagonists. At hD(3) receptors, efficacies ranged from 33% (roxindole) to 94% (TL99), whereas, for hD(4) receptors, highest efficacies (approximately 70%) were seen for quinerolane, quinpirole, and TL99, whereas piribedil and terguride behaved as antagonists and bromocriptine was inactive. Although efficacies at hD(2S) versus hD(2L) sites were highly correlated (r = 0.79), they correlated only modestly to hD(3)/hD(4) sites (r = 0.44-0.59). In [(35)S]GTPgammaS studies of halpha(2A)-ARs, TL99 (108%), pramipexole (52%), talipexole (51%), pergolide (31%), apomorphine (16%), and quinerolane (11%) were agonists and ropinirole and roxindole were inactive, whereas piribedil and other agents were antagonists. Similar findings were obtained at halpha(2B)- and halpha(2C)-ARs. Using [(3)H]phosphatidylinositol depletion, roxindole, bromocriptine, lisuride, and terguride displayed potent antagonist properties at halpha(1A)-ARs. In conclusion, antiparkinson agents display diverse agonist and antagonist

  10. Synthesis and α1-adrenoceptor antagonist activity of tamsulosin analogues.

    PubMed

    Sagratini, Gianni; Angeli, Piero; Buccioni, Michela; Gulini, Ugo; Marucci, Gabriella; Melchiorre, Carlo; Poggesi, Elena; Giardinà, Dario

    2010-12-01

    Tamsulosin (-)-1 is the most utilized α(1)-adrenoceptor antagonist in the benign prostatic hyperplasia therapy owing to its uroselective antagonism and capability in relieving both obstructive and irritative lower urinary tract symptoms. Here we report the synthesis and pharmacological study of the homochiral (-)-1 analogues (-)-2-(-)-5, bearing definite modifications in the 2-substituted phenoxyethylamino group in order to evaluate their influence on the affinity profile for α(1)-adrenoceptor subtypes. The benzyl analogue (-)-3, displaying a preferential antagonist profile for α1A-than α1D-and α1B-adrenoceptors, and a 12-fold higher potency at α1A-adrenoceptors with respect to the α1B subtype, may have improved uroselectivity compared to (-)-1. PMID:20934789

  11. Mediation of noradrenaline-induced contractions of rat aorta by the alpha 1B-adrenoceptor subtype.

    PubMed Central

    Testa, R; Guarneri, L; Poggesi, E; Simonazzi, I; Taddei, C; Leonardi, A

    1995-01-01

    1. The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous noradrenaline (NA) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible alpha 1B-adrenoceptor antagonist, chloroethylclonidine (CEC: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to NA after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response. The residual contractions to NA after CEC incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, 5-methylurapidil and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively. 5-Methylurapidil and phentolamine were confirmed as selective for the alpha 1A-adrenoceptors, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the alpha 1-adrenoceptor antagonists tested and their affinity for the alpha 1B-adrenoceptor subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the alpha 1-adrenoceptor population. PMID:7773533

  12. Alpha 1A-adrenoceptor-mediated contractile responses of the human vas deferens.

    PubMed Central

    Furukawa, K.; Rosario, D. J.; Smith, D. J.; Chapple, C. R.; Uchiyama, T.; Chess-Williams, R.

    1995-01-01

    1. The predominant alpha 1-adrenoceptor mediating contractions of the human vas deferens has been characterised in vitro by use of subtype selective antagonists. 2. Responses of human epididymal vas deferens were obtained to phenylephrine in the presence of amine uptake inhibitors and propranolol. The effects of the alpha 1-adrenoceptor antagonists, 5-methylurapidil, oxymetazoline, WB4101, prazosin and chloroethylclonidine were examined and also the L-type calcium channel blocker, nifedipine. 3. 5-Methylurapidil, WB4101, oxymetazoline and prazosin acted as competitive antagonists of the responses to phenylephrine, yielding pA2 values of 8.8, 9.2, 7.7 and 8.8 respectively. All four antagonists produced Schild plots with slopes similar to unity and maximum responses to phenylephrine were not altered in the presence of any of the antagonists. 4. Tamsulosin (1 nM) caused rightward shifts of phenylephrine concentration-response curves yielding an apparent pKB value of 10.0. However, maximum responses were also reduced by 51% with this concentration of antagonist. 5. Incubation of tissues with chloroethylclonidine (100 microM for 40 min) failed to alter responses significantly but the presence of nifedipine (1 microM) reduced maximum responses to phenylephrine by 32%. 6. The high affinity of 5-methylurapidil, oxymetazoline and WB4101, together with the failure of chloroethylclonidine to antagonize responses, indicate that the predominant alpha 1-adrenoceptor mediating contraction of the human vas deferens has the characteristics previously described for the pharmacologically-defined alpha 1A-adrenoceptor. The data are also consistent with those described for the cloned alpha 1c-adrenoceptor subtype thereby supporting the hypothesis that the two receptors are identical. The human vas deferens therefore represents a readily accessible preparation for functional studies of the human alpha 1A-adrenoceptor. PMID:8564226

  13. Stimulation of prostaglandin E2-synthesis by noradrenaline in primary cell cultures from rabbit splenic pulpa is mediated by atypical alpha-adrenoceptors.

    PubMed

    Brückner-Schmidt, R; Jackisch, R; Hertting, G

    1981-02-01

    In primary cell cultures originating from rabbit splenic pulpa the effects of various adrenoceptor agonists on prostaglandin (PG)-synthesis were studied. The cells - microscopically identified as fibroblasts - released PGs into the medium: especially PGE2 besides small amounts of PGF2alpha and PGD2. Noradrenaline increased dose-dependently the amount of PGs released into the medium. Besides noradrenaline, only the catecholamines adrenaline and alpha-methylnoradrenaline strongly activated PG-synthesis. Other alpha-adrenoceptor agonists like the phenylethylamine and imidazoline derivatives were only weak agonists or completely ineffective. All adrenoceptor agonists without intrinsic activity in these cells antagonized the noradrenaline effect on PG-synthesis, the imidazolines being more potent antagonists than the phenylethylamines. The beta-adrenoceptor agonist isoprenaline stimulated PG-synthesis at high concentration only. The effects of both noradrenaline and isoprenaline were inhibited by low concentrations of phentolamine phenoxybenzamine, but not by propranolol. The preferential alpha2-adrenoceptor antagonists yohimbine and rauwolscine were about 50 times more potent in blocking the noradrenaline effect on PG-synthesis than the more alpha1-specific antagonist corynanthine. However, prazosin, another alpha1-adrenoceptor antagonist, was about equipotent with yohimbine. It is concluded that noradrenaline elicits PG-synthesis in rabbit splenic fibroblasts via alpha-adrenoceptor stimulation. The alpha-adrenoceptor involved has properties which are different from those reported so far for alpha1- or alpha2-adrenoceptors. PMID:6268994

  14. Functional studies on alpha 1-adrenoceptor subtypes mediating inotropic effects in rat right ventricle.

    PubMed Central

    Michel, M. C.; Hanft, G.; Gross, G.

    1994-01-01

    1. We have studied the alpha 1-adrenoceptor subtypes mediating inotropic effects of adrenaline in rat right ventricle and the Ca2+ sources used to elicit these effects. alpha 1A-Adrenoceptor-mediated contractile effects in rat vas deferens were studied for comparison in some cases. 2. Treatment with chloroethylclonidine did not affect the maximal beta-adrenoceptor-mediated inotropic effects in rat right ventricle or the maximal alpha 1A-adrenoceptor-mediated contractile effects in rat vas deferens; it did not alter the potency of isoprenaline in the ventricle and reduced the potency of the alpha-adrenoceptor antagonists in vas deferens only slightly. Treatment of right ventricular strips with CdCl2 markedly reduced resting tension and enhanced maximal inotropic effects of isoprenaline but did not affect its potency. 3. Inactivation of cardiac alpha 1B-adrenoceptors by treatment with chloroethylclonidine slightly enhanced the maximal inotropic effects of the full agonist, adrenaline and of several partial agonists. 4. Schild analysis of inhibition experiments with the alpha 1A-adrenoceptor-selective antagonists, 5-methyl-urapidil and (+/-)-tamsulosin, demonstrated that adrenaline causes its inotropic effects mainly via the alpha 1B-adrenoceptor subtype. Schild analysis of 5-methyl-urapidil inhibition experiments in chloroethylclonidine-treated ventricles indicated that only alpha 1A-adrenoceptors mediate the inotropic effects of adrenaline following inactivation of the alpha 1B-adrenoceptors. 5. In control ventricles the organic Ca2+ entry blocker, nitrendipine and treatment with the inorganic Ca2+ entry blocker, CdCl2 did not reduce inotropic effects of adrenaline whereas ryanodine treatment inhibited them. In contrast, nitrendipine and CdCl2 treatment had major inhibitory effects in chloroethylclonidine-treated but lacked inhibitory effects in phenoxybenzamine-treated ventricular strips. 6. We conclude that inotropic effects of adrenaline in rat heart are mediated

  15. Prediction of alpha1-adrenoceptor occupancy in the human prostate from plasma concentrations of silodosin, tamsulosin and terazosin to treat urinary obstruction in benign prostatic hyperplasia.

    PubMed

    Yamada, Shizuo; Kato, Yasuhiro; Okura, Takashi; Kagawa, Yoshiyuki; Kawabe, Kazuki

    2007-07-01

    Alpha1-adrenoceptor antagonists are clinically useful for the improvement of urinary obstruction due to benign prostatic hyperplasia (BPH), and their therapeutic effects are mediated through the blockade of prostatic alpha(1)-adrenoceptors. The present study was undertaken to predict the magnitude and duration of alpha(1)-adrenoceptor occupancy in the human prostate after oral alpha(1)-adrenoceptor antagonists. Prostatic alpha(1)-adrenoceptor-binding parameters of silodosin were estimated by measuring specific [(3)H]prazosin binding in rat prostate after oral administration of this drug. The plasma concentration of silodosin after oral administration in rats and healthy volunteers was measured using a high-performance liquid chromatographic method. The alpha(1)-adrenoceptor-binding affinities (K(i)) of silodosin, tamsulosin, and terazosin in the human prostate and plasma concentrations of tamsulosin and terazosin were obtained from the literature. Using the alpha(1)-adrenoceptor binding parameters of silodosin in rat prostate, alpha(1)-adrenoceptor occupancy in the human prostate was estimated to be around 60-70% at 1-6 h after oral administration of silodosin at doses of 3.0, 8.1, and 16.1 micromol. Thereafter, the receptor occupancy was periodically decreased, to 24% (8.1 micromol) and 54% (16.1 micromol) 24 h later. A similar magnitude and time course of alpha(1)-adrenoceptor occupancy by silodosin in the human prostate were estimated using alpha(1)-adrenoceptor-binding affinities (K(i)) in the human prostate. Despite about two orders of differences in the plasma unbound concentrations after clinically effective oral dosages of silodosin, tamsulosin, and terazosin, there was a comparable magnitude of prostatic alpha(1)-adrenoceptor occupancy by these drugs. In conclusion, the prediction of alpha(1)-adrenoceptor occupancy in the human prostate by alpha(1)-adrenoceptor antagonists may provide the rationale for the optimum dosage regimen of these drugs in the

  16. Correlation between mRNA levels and functional role of alpha1-adrenoceptor subtypes in arteries: evidence of alpha1L as a functional isoform of the alpha1A-adrenoceptor.

    PubMed

    Martí, Daniel; Miquel, Raquel; Ziani, Khalid; Gisbert, Regina; Ivorra, M Dolores; Anselmi, Elsa; Moreno, Lucrecia; Villagrasa, Victoria; Barettino, Domingo; D'Ocon, Pilar

    2005-11-01

    The mRNA levels for the three alpha1-adrenoceptor subtypes, alpha1A, alpha1B, and alpha1D, were quantified by real-time RT-PCR in arteries from Wistar rats. The alpha1D-adrenoceptor was prominent in both aorta (79.0%) and mesenteric artery (68.7%), alpha1A predominated in tail (61.7%) and small mesenteric artery (73.3%), and both alpha1A- and alpha1D-subtypes were expressed at similar levels in iliac artery. The mRNA levels of the alpha1B-subtype were a minority in all vessels (1.7-11.1%). Concentration-response curves of contraction in response to phenylephrine or relaxation in response to alpha1-adrenoceptor antagonists on maximal sustained contraction induced by phenylephrine were constructed from control vessels and vessels pretreated with 100 micromol/l chloroethylclonidine (CEC) for 30 min. The significant decrease in the phenylephrine potency observed after CEC treatment together with the inhibitory potency displayed by 8-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-8-azaspiro (4,5) decane-7-dionedihydrochloride} (BMY-7378, an alpha1D-adrenoceptor antagonist) confirm the relevant role of alpha1D-adrenoceptors in aorta and iliac and proximal mesenteric arteries. The potency of 5-methylurapidil (an alpha1A-adrenoceptor antagonist) and the changes in the potency of both BMY-7378 and 5-methylurapidil after CEC treatment provided evidence of a mixed population of alpha1A- and alpha1D-adrenoceptors in iliac and distal mesenteric arteries. The low potency of prazosin (pIC50 < 9) as well as the high 5-methylurapidil potency in tail and small mesenteric arteries suggest the main role of alpha1A/alpha1L-adrenoceptors with minor participation of the alpha1D-subtype. The mRNA levels and CEC treatment corroborated this pattern and confirmed that the alpha1L-adrenoceptor could be a functional isoform of the alpha1A-subtype. PMID:15951348

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

    NASA Technical Reports Server (NTRS)

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

    1984-01-01

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

  18. Alpha1L-adrenoceptors mediate contractions of the isolated mouse prostate.

    PubMed

    Gray, Katherine T; Ventura, Sabatino

    2006-07-01

    The subtype of alpha1-adrenoceptor mediating noradrenaline-induced contractile responses in isolated mouse prostate glands was investigated. Adrenoceptor agonists were able to produce concentration-dependent contractions with the following rank order of potency: adrenaline > or = noradrenaline > or = clonidine = phenylephrine > dopamine > or = isoprenaline. Concentration-response curves to noradrenaline of the prostatic smooth muscle were antagonised by prazosin, N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha, alpha-dimethyl-1H-indole-3-ethanamine (RS-17053), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), tamsulosin and yohimbine with mean antagonist affinity estimates (pA2 or apparent pKB) of 8.12+/-0.10, 6.56+/-0.11, 8.38+/-0.06, 10.14+/-0.19 and 7.38+/-1.36 respectively. Propranolol (1 microM) had no antagonist activity (P = 0.994, n = 6). Yohimbine (0.01, 0.1, 1 microM) had no antagonist activity in the presence of prazosin (0.1 microM) (P > or = 0.059). The results obtained indicate that alpha1-adrenoceptors mediate the contractile response in isolated preparations of the mouse prostate. Furthermore, the particular subtype of alpha1-adrenoceptor mediating the response to exogenously administered noradrenaline corresponds to the alpha1L-subtype, the same subtype as that which has been shown to mediate noradrenaline-induced contractile activity in the human prostate. PMID:16716294

  19. Ligand-based pharmacophore model of N-Aryl and N-Heteroaryl piperazine alpha 1A-adrenoceptors antagonists using GALAHAD.

    PubMed

    Zhao, Xin; Yuan, Mu; Huang, Biyun; Ji, Hong; Zhu, Liu

    2010-09-01

    Computer aided drug discovery for selective antagonism effects on alpha(1A) subtypes of G-protein coupled receptors are important in the treatment of benign prostatic hyperplasia (BPH). Ligand-based pharmacophore models of N-Aryl and N-Heteroaryl piperazine alpha(1A)-antagonists were developed using two separate training sets. Pharmacophore models were generated using the flexible align method within the GALAHAD module, implemented in SYBYL8.1 software. The most significant pharmacophore hypothesis, characterized by the conflicting demands of maximizing pharmacophore consensus, maximizing steric consensus, and minimizing energy, consisted of one positive nitrogen center, one donor atom center, two acceptor atom centers, and two hydrophobic groups. The most active compound in each class training set showed a good fit with all features of the pharmacophore proposed. The resulting models also had something in common with the hypothesis using the Catalyst software reported in other publications. These alpha(1A) pharmacophore models could predict compounds well, both in the training set and the test set. The pharmacophore models were also validated by an external dataset using a portion of the ZINC database. A 3D-QSAR model using the pharmacophore model to align the compounds was established in this study. The CoMFA model with the cross-validated q(2) value of 0.735 revealed that the model was valid. Our research provides a valuable tool for designing new therapeutic compounds with desired biological activity. PMID:20538497

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

    SciTech Connect

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

    1991-01-01

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

  1. Pharmacological characterization of. cap alpha. /sub 2/-adrenoceptor heterogeneity

    SciTech Connect

    Boyajian, C.L.

    1987-01-01

    Utilizing the techniques of radioligand binding assay and quantitative autoradiography, evidence is provided for the existence of a heterogeneous population of ..cap alpha../sub 2/-adrenoceptors, which is present in central as well as peripheral tissues, and across two species. In rat brain, the autoradiographic distributions of binding sites labeled by two reportedly selective ..cap alpha../sub 2/-adrenoceptor antagonists, (/sup 3/H) rauwolscine and (/sup 3/H) idazoxan, differed markedly throughout the neuraxis. Whereas (/sup 3/H)idazoxan labeling appeared over brain regions receiving noradrenergic innervations, (/sup 3/H)rauwolscine binding sites were localized most densely in several areas corresponding to dopaminergic terminal fields. In areas labeled by (/sup 3/H)rauwolscine, the maximal binding densities for (/sup 3/H)idazoxan labeling were consistently greater than those for (/sup 3/H)rauwolscine sites. The autoradiographic distributions of (/sup 3/H)idazoxan and (/sup 3/H)-rauwolscine binding sites throughout monkey brain were very similar to those observed in rat brain, suggesting that the R/sub I/ and R/sub S/ sites characterized in the rodent central nervous system may also exist in primate brain.

  2. Evidence for an age-dependent functional expression of alpha 1D-adrenoceptors in the rat vasculature.

    PubMed

    Ibarra, M; Terrón, J A; López-Guerrero, J J; Villalobos-Molina, R

    1997-03-19

    The role of the alpha 1-adrenoceptor subtypes, and their possible change with maturation, in alpha 1-adrenoceptor-induced pressor responses in the rat has not been established. Thus, the effects of the alpha 1D-, alpha 1A/1D- and alpha 1B/1D-adrenoceptor antagonists, BMY 7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl) 8-azaspiro (4.5) decane-7,9-dione 2HCl), 5-methyl-urapidil and chloroethylclonidine, respectively, on the pressor responses induced by phenylephrine in 1- and 5-month-old pithed rats were investigated. The pressor responses induced by phenylephrine were competitively antagonized by both BMY 7378 and chloroethylclonidine in 5-month-old, but not in young immature animals; in marked contrast, 5-methylurapidil antagonized with similar potency the phenylephrine-induced pressor responses in animals of both ages. The present pharmacological data suggest that functional expression of alpha 1D-adrenoceptors in the rat resistance vessels increases with age; alpha 1A-, but not alpha 1B- or alpha 1D-adrenoceptors, seem to predominate in immature animals. These findings represent the first evidence that age-related changes in functional alpha 1-adrenoceptor subtypes occur in the systemic vasculature in vivo. PMID:9098690

  3. The alpha 2-adrenoceptors of the human retinoblastoma cell line (Y79) may represent an additional example of the alpha 2C-adrenoceptor.

    PubMed Central

    Gleason, M. M.; Hieble, J. P.

    1992-01-01

    1. In agreement with the literature, correlation of the ability of a series of agonists and antagonists to displace [3H]-rauwolscine binding shows the alpha 2-adrenoceptors of HT29 cells, NG108-15 cells, OK cells and homogenates of rat sublingual gland to represent four distinct subtypes. 2. [3H]-rauwolscine also bound with high affinity (KD = 0.30 +/- 0.10 mM) to a human retinoblastoma cell line (Y79). Specific binding represents 73% of total binding, and a Bmax of 38 +/- 1 fmol mg-1 protein was determined. 3. Correlation of antagonist affinities against [3H]-rauwolscine with corresponding values in the other four tissue sources showed the Y79 cells to resemble most closely the OK cells, the prototype example of an alpha 2C-adrenoceptor, with a correlation coefficient of 0.90 and a regression slope of 1.01 being obtained for 10 antagonists in these two systems. 4. Comparison of KD values for [3H]-rauwolscine also showed a similarity between the OK cells (0.19 +/- 0.07 nM) and Y79 cells. 5. These data suggest that the human retinoblastoma cell line may represent an additional example of the alpha 2C-adrenoceptor subtype. PMID:1358385

  4. Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline.

    PubMed

    Haenisch, Britta; Walstab, Jutta; Herberhold, Stephan; Bootz, Friedrich; Tschaikin, Marion; Ramseger, René; Bönisch, Heinz

    2010-12-01

    Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α-adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α-adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha-adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α-adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α-adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α-adrenoceptor subtypes in human nasal mucosa was: α(2A) > α(1A) ≥ α(2B) > α(1D) ≥ α(2C) > α(1B) . Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α-adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α(1A) - but a lower affinity at α(2B) -adrenoceptors. In functional studies in which adrenoceptor-mediated Ca(2+) signals were measured, both, oxymetazoline and xylometazoline behaved at α(2B) -adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α(1A) -adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α(2B) -adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline. PMID:20030735

  5. Alpha 1-adrenoceptors mediating contraction in arteries of normotensive and spontaneously hypertensive rats are of the alpha 1D or alpha 1A subtypes.

    PubMed

    Villalobos-Molina, R; Ibarra, M

    1996-03-18

    Alpha 1-Adrenoceptor subtypes mediating contraction in carotid, aorta, mesenteric and caudal arteries from both Wistar Kyoto (WKY) normotensive and spontaneously hypertensive (SHR) rats were investigated by using the alpha 1A-adrenoceptor agonist methoxamine and antagonized with selective, competitive antagonists WB-4101, 5-methyl urapidil or BMY 7378 (8-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-8-azaspiro(4,5)decane -7,9-dione dihydrochloride). Isometric tension changes were recorded after methoxamine addition to the arterial rings, and the effects of the antagonists determined. All the antagonists shifted to the right the concentration-response curve to methoxamine. pA2 values indicate that all arteries but caudal express the alpha 1D-adrenoceptor subtype, since BMY 7378 values were high in these arteries. Due to the high pA2 values for 5-methyl urapidil and WB-4101 and the low values for BMY 7378 we conclude that the tail artery expresses the alpha 1A and not the alpha 1B subtype. No differences were found between both strains of rats, suggesting that hypertension does not modify the alpha 1-adrenoceptors in conductance arteries. PMID:8846824

  6. Inhibition of K+ permeability diminishes alpha 2-adrenoceptor mediated effects on norepinephrine release

    SciTech Connect

    Zimanyi, I.; Folly, G.; Vizi, E.S.

    1988-05-01

    The effect of two different potassium channel blockers, 4-aminopyridine (4-AP) and quinine, on the alpha 2-adrenoceptor mediated modulation of norepinephrine (NE) release was investigated. Pairs of mouse vasa deferentia were loaded with /sup 3/H-norepinephrine (/sup 3/H-NE), superfused continuously, and stimulated electrically. 4-AP (5.3 x 10(-4) M), and quinine (10(-5) M) enhanced the stimulation-evoked release of tritium significantly. The electrically induced release of radioactivity was reduced by alpha 2-adrenoceptor agonists (1-NE and xylazine) and enhanced by the alpha 2-adrenoceptor antagonist yohimbine. Both effects were affected markedly by 4-AP or quinine: the depressant action of 1-NA and xylazine was partially antagonized and the facilitatory effect of yohimbine was completely abolished during the blockade of the potassium channels. It is suggested that the blockade of the potassium permeability counteracts negative feedback modulation; therefore, it seems likely that the stimulation of alpha 2-adrenoceptors leads to an enhanced potassium permeability and hyperpolarization of varicose axon terminals.

  7. Meperidine, remifentanil and tramadol but not sufentanil interact with alpha(2)-adrenoceptors in alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptor knock out mice brain.

    PubMed

    Höcker, Jan; Weber, Bernd; Tonner, Peter H; Scholz, Jens; Brand, Philipp-Alexander; Ohnesorge, Henning; Bein, Berthold

    2008-03-17

    alpha(2)-adrenoceptor agonists like clonidine or dexmedetomidine increase the sedative and analgesic actions of opioids. Furthermore opioids like meperidine show potent anti-shivering effects like alpha(2)-adrenoceptor agonists. The underlying molecular mechanisms of these effects are still poorly defined. The authors therefore studied the ability of four different opioids (meperidine, remifentanil, sufentanil and tramadol) to interact with different alpha(2)-adrenoceptor subtypes in mice lacking individual alpha(2A)-, alpha(2B)- or alpha(2C)-adrenoceptors (alpha(2)-adrenoceptor knock out (alpha(2)-AR KO) mice)). The interaction of opioids with alpha(2)-adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of alpha(2A)-, alpha(2B)- or alpha(2C)-adrenoceptor deficient mice. Displacement of the radiolabelled alpha(2)-adrenoceptor agonist [(125)I]-paraiodoclonidine ([(125)I]-PIC) from alpha(2)-adrenoceptors in different brain regions by increasing opioid concentrations was measured, and binding affinity of the analysed opioids to alpha(2)-adrenoceptor subtypes in different brain regions was quantified. Meperidine, remifentanil and tramadol but not sufentanil provoked dose dependent displacement of specifically bound [(125)I]-PIC from all alpha(2)-adrenoceptor subtypes in cortex, cerebellum, medulla oblongata, thalamus, hippocampus and pons. Required concentrations of meperidine and remifentanil for [(125)I]-PIC displacement from alpha(2B)- and alpha(2C)-adrenoceptors were lower than from alpha(2A)-adrenoceptors, indicating higher binding affinity for alpha(2B)- and alpha(2C)-adrenoceptors. In contrast, [(125)I]-PIC displacement by tramadol indicated higher binding affinity to alpha(2A)-adrenoceptors than to alpha(2B)- and alpha(2C)-adrenoceptors. Our results indicate that meperidine, remifentanil and tramadol interact with alpha(2)-adrenoceptors in mouse brain showing different affinity for alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors

  8. The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors.

    PubMed

    Baker, Jillian G

    2005-02-01

    Beta-adrenoceptor antagonists ("beta-blockers") are one of the most widely used classes of drugs in cardiovascular medicine (hypertension, ischaemic heart disease and increasingly in heart failure) as well as in the management of anxiety, migraine and glaucoma. Where known, the mode of action in cardiovascular disease is from antagonism of endogenous catecholamine responses in the heart (mainly at beta1-adrenoceptors), while the worrisome side effects of bronchospasm result from airway beta2-adrenoceptor blockade. The aim of this study was to determine the selectivity of beta-antagonists for the human beta-adrenoceptor subtypes. (3)H-CGP 12177 whole cell-binding studies were undertaken in CHO cell lines stably expressing either the human beta1-, beta2- or the beta3-adrenoceptor in order to determine the affinity of ligands for each receptor subtype in the same cell background. In this study, the selectivity of well-known subtype-selective ligands was clearly demonstrated: thus, the selective beta1 antagonist CGP 20712A was 501-fold selective over beta2 and 4169-fold selective over beta3; the beta2-selective antagonist ICI 118551 was 550- and 661-fold selective over beta1 and beta3, respectively, and the selective beta3 compound CL 316243 was 10-fold selective over beta2 and more than 129-fold selective over beta1. Those beta2-adrenoceptor agonists used clinically for the treatment of asthma and COPD were beta2 selective: 29-, 61- and 2818-fold for salbutamol, terbutaline and salmeterol over beta1, respectively. There was little difference in the affinity of these ligands between beta1 and beta3 adrenoceptors. The clinically used beta-antagonists studied ranged from bisoprolol (14-fold beta1-selective) to timolol (26-fold beta2-selective). However, the majority showed little selectivity for the beta1- over the beta2-adrenoceptor, with many actually being more beta2-selective. This study shows that the beta1/beta2 selectivity of most clinically used beta-blockers is

  9. The stereospecificity of LY253352 for alpha 1-adrenoceptor binding sites in the brain and prostate.

    PubMed Central

    Lepor, H.; Baumann, M.; Shapiro, E.

    1988-01-01

    1. The stereospecificity of the enantiomers of LY253352, a potent and selective alpha 1-adrenoceptor antagonist, were studied in the human prostate and canine brain using radioligand receptor binding methods. 2. The mean equilibrium dissociation constant (KD) in the canine brain and human prostatic adenoma was 84.4 pM and 65.4 pM, respectively. 3. The alpha 1-adrenoceptor density in the canine brain was approximately eight fold greater than in the human prostatic adenoma. 4. The mean Ki values of (-)-LY253352 and (+)-LY253352 in the prostate were 0.19 nM and 5.79 nM, respectively. 5. The mean Ki values of (-)-LY253352 and (+)-LY253352 in the brain were 0.29 nM and 34.7 nM, respectively. 6. This study indicates that the stereochemical specificity of the optical isomers of LY253352 is a manifestation of differential affinities of the enantiomers for alpha 1-adrenoceptor binding sites. 7. The differential affinities of (+)-LY253352 in the brain and prostate are suggestive of subtle unique properties of adrenoceptor binding sites in these tissues. PMID:2851347

  10. (/sup 125/Iodo)BE 2254, a new radioligand for alpha 1-adrenoceptors

    SciTech Connect

    Engel, G.; Hoyer, D.

    1982-01-01

    (/sup 125/cIodo)2-(beta-(14-hydroxyphenyl)-ethyl-aminomethyl)-tetralone((/sup 125/Iodo)BE 2254 or IBE 2254), a new iodinated radioligand of high specific radioactivity (2175 Ci/mmol), was synthesized and used to characterize alpha 1-adrenoceptors in rat lung and cerebral cortex membranes. The binding constants of IBE 2254, using rat lung and cortex membranes, were Kd . 53 +/- 10 pM, Bmax . 53 +/- 8 fmol/mg; and Kd . 78 +/- 14 pM, Bmas . 210 +/- 26 fmol/mg, respectively (Kd . dissociation constant of IBE 2254 determined in saturation experiments). In equilibrium binding experiments with IBE 2254, at concentrations of the free ligand up to 1.2 nM, only one class of binding sites could be detected. In kinetic experiments, the association and dissociation rate constants were 2.3 X 10(9) M-1 min-1 and 0.10 min-1, respectively. In rat cerebral cortex membranes, alpha-adrenoceptor antagonists competed for IBE 2254 binding in the following order: prazosin greater than BE 2254 greater than WB 4101 greater than phentolamine greater than corynanthine greater than yohimbine greater than rauwolscine, indicating strongly that IBE 2254 binds to alpha 1-adrenoceptors. The calculated affinities of different alpha-adrenoceptor blocking agents from inhibition of IBE 2254 binding were nearly identical in rat lung and cerebral cortex. The low dissociation constant of the ligand together with its high specific radioactivity allows binding studies to be carried out with tissue samples where only small densities of alpha 1-adrenoceptors are present.

  11. Evidence that two stereochemically different alpha-2 adrenoceptors modulate norepinephrine release in rat cerebral cortex

    SciTech Connect

    Harsing, L.G. Jr.; Vizi, E.S. )

    1991-01-01

    Cerebral cortex slices from the rat were loaded with (3H)norepinephrine ((3H)NE) and superfused in order to measure the release of radioactivity at rest and in response to electrical stimulation. The (-)-isomer and the (+)-isomer of CH-38083 (7,8-(methylenedioxy)-14- alpha-hydroxyalloberbane HCl), a selective alpha-2-adrenoceptor antagonist with an alloberbane skeleton, increased the electrically induced release of (3H)NE in a concentration-dependent manner, and a similar effect was observed with racemic CH-38083 and idazoxan. The stereoisomers of CH-38083 applied in a concentration range of 10(-8) to 10(-6) mol/l were equipotent in facilitating stimulation-evoked (3H)NE release: concentrations needed to enhance tritium outflow by 50% were 1.3 X 10(-7) mol/l for (-)-CH-38083 and 1.4 X 10(-7) mol/l for (+)-CH-38083. Exogenous NE decreased the electrically stimulated release of (3H)NE, and the stereoisomers of CH-38083 antagonized this inhibition with different potencies: the dissociation constant (KB) values for (-)-isomer and for (+)-isomer of CH-38083 were 14.29 and 97.18 nmol/l. These data indicate that presynaptic alpha-2 adrenoceptors that are available for NE released from axon terminals do not show stereospecificity toward enantiomers of CH-38083, whereas those that are occupied by exogenous NE are much more sensitive toward (-)-CH-38083. The alpha-1 adrenoceptor antagonist prazosin also differentiated between the alpha-2 adrenoceptor subtypes: prazosin (10(-6) mol/l) did not alter the increase of electrically induced (3H)NE release evoked by (-)- and (+)-CH-38083; however, in its presence, the stereoisomers of CH-38083 failed to antagonize the inhibitory effect of exogenous NE on its own release.

  12. Functional evidence of alpha1D-adrenoceptors in the vasculature of young and adult spontaneously hypertensive rats.

    PubMed

    Villalobos-Molina, R; López-Guerrero, J J; Ibarra, M

    1999-04-01

    The role of alpha1D-adrenoceptors in the vasculature of spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY), of different ages was assessed in pithed rats by the use of the selective alpha1D-adrenoceptor antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-8-azaspiro [4.5]decane-7,9-dione dihydrochloride). BMY 7378 displaced the pressor effect of phenylephrine in young pre-hypertensive pithed SHR rats, but produced no effect in young WKY rats (dose ratio of 3.4 and 1.6, respectively), while in adult rats BMY 7378 produced a greater shift in the phenylephrine response curve than in younger animals (dose ratio of 3.2 and 6.2 in WKY and SHR, respectively). The presence of alpha1D-adrenoceptors in the vasculature of pre-hypertensive rats, suggests its role in the pathogenesis/maintenance of increased blood pressure. PMID:10323583

  13. Electroacupuncture-induced analgesia in a rat model of ankle sprain pain is mediated by spinal alpha-adrenoceptors.

    PubMed

    Koo, Sung Tae; Lim, Kyu Sang; Chung, Kyungsoon; Ju, Hyunsu; Chung, Jin Mo

    2008-03-01

    In a previous study, we showed that electroacupuncture (EA) applied to the SI-6 point on the contralateral forelimb produces long-lasting and powerful analgesia in pain caused by ankle sprain in a rat model. To investigate the underlying mechanism of EA analgesia, the present study tested the effects of various antagonists on known endogenous analgesic systems in this model. Ankle sprain was induced in anesthetized rats by overextending their right ankle with repeated forceful plantar flexion and inversion of the foot. When rats developed pain behaviors (a reduction in weight-bearing of the affected hind limb), EA was applied to the SI-6 point on the contralateral forelimb for 30 min under halothane anesthesia. EA significantly improved the weight-bearing capacity of the affected hind limb for 2h, suggesting an analgesic effect. The alpha-adrenoceptor antagonist phentolamine (2mg/kg, i.p. or 30 microg, i.t.) completely blocked the EA-induced analgesia, whereas naloxone (1mg/kg, i.p.) failed to block the effect. These results suggest that EA-induced analgesia is mediated by alpha-adrenoceptor mechanisms. Further experiments showed that intrathecal administration of yohimbine, an alpha(2)-adrenergic antagonist, reduced the EA-induced analgesia in a dose-dependent manner, whereas terazosin, an alpha(1)-adrenergic antagonist, did not produce any effect. These data suggest that the analgesic effect of EA in ankle sprain pain is, at least in part, mediated by spinal alpha(2)-adrenoceptor mechanisms. PMID:17537577

  14. Renal vasodilatation by dopexamine and fenoldopam due to alpha 1-adrenoceptor blockade.

    PubMed Central

    Martin, S. W.; Broadley, K. J.

    1995-01-01

    1. The renal vascular responses of the rat isolated perfused kidney to the dopamine D1-receptor agonists, dopexamine and fenoldopam, were examined. 2. Both kidneys were perfused in situ at constant flow rate (11 ml min-1) with Krebs-bicarbonate solution at 37 degrees C. The perfusion pressure was monitored and to enable vasodilator responses to be measured, the resting perfusion pressure was raised by infusing noradrenaline (6 x 10(-9) M). 3. Dose-related vasodilator responses to bolus doses of dopexamine and fenoldopam were obtained. However, these were not antagonized by the D1-receptor antagonist, SCH 23390, indicating that D1-receptors were not involved. 4. Bolus doses of the alpha 1-adrenoceptor antagonist, prazosin, caused similar dose-related vasodilator responses indicating the possibility that alpha 1-adrenoceptor blocking properties of dopexamine and fenoldopam were responsible for the vasodilatation. 5. alpha-Adrenoceptor blockade by dopexamine and fenoldopam was confirmed by the parallel displacement of dose-response curves for the vasopressor responses to noradrenaline. pA2 values were determined by Schild analysis for dopexamine, fenoldopam and prazosin antagonism of noradrenaline in the presence of neuronal (cocaine, 10(-5) M) and extraneuronal uptake blockade (metanephrine, 10(-5) M). The values were 6.23, 6.02 and 8.91, respectively. Schild plot slopes of unity were obtained for dopexamine and fenoldopam indicating competitive antagonism. A slope of greater than unity for prazosin may be explained by the lack of equilibrium conditions associated with bolus doses of noradrenaline, the responses of which are affected more by the high affinity antagonist, prazosin, than the two lower affinity antagonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7670737

  15. Role of vascular alpha-2 adrenoceptors in regulating lipid mobilization from human adipose tissue.

    PubMed Central

    Galitzky, J; Lafontan, M; Nordenström, J; Arner, P

    1993-01-01

    The role of alpha-2 adrenoceptors in lipid mobilization and blood flow was investigated in situ using microdialysis of subcutaneous adipose tissue in nonobese healthy subjects. The alpha-2 agonist clonidine caused dose-dependent biphasic response with increased glycerol levels at low clonidine concentrations and decreased glycerol levels at concentrations > 10(-7) mol/liter. Similar results were observed with epinephrine plus propranolol. Clonidine action was unaffected in the presence of labetalol (beta-/alpha-1 antagonist) but completely blunted by the presence of yohimbine (alpha-2 antagonist). The pseudolipolytic effect of clonidine was significantly more pronounced in gluteal as compared with abdominal adipose tissue. When clonidine was added together with the vasodilating agents nitroprusside or hydralazine, the pseudolipolytic effect was abolished and a dose-dependent decrease in dialysate glycerol was observed at all clonidine concentrations (10(-10)-10(-4) mol/liter). When ethanol was added to the perfusate to monitor blood flow, the escape of alcohol from the dialysate was accelerated by 30% with hydralazine or nitroprusside (P < 0.01) and 30% retarded (P < 0.05) by clonidine (10(-10) mol/liter). Thus, the results demonstrate an important role of blood flow for regulating lipid mobilization from adipose tissue in vivo. Alpha-2 adrenoceptor activation causes marked retention of lipids in adipose tissue due to vasoconstriction in combination with antilipoiysis. PMID:8387538

  16. Alpha adrenoceptors in the rabbit ear thermoregulatory microcirculation.

    PubMed

    Li, Z; Koman, L A; Smith, B P; Gordon, E S; Smith, T L

    1998-03-01

    The rabbit ear microcirculation was analyzed in a chronic unanesthetized model to evaluate alpha adrenergic microvascular control in a thermoregulatory end organ. This model allowed direct measurement of microcirculatory responses without the effects of anesthetics or inflammatory responses induced by acute surgical intervention. The ipsilateral facial artery was catheterized for drug injections into the experimental ear. Microvascular diameter changes following stimulation or blockade of adrenoceptor (AR) subtypes were observed directly through a chronic microvascular chamber implanted in the rabbit ear. Vascular alpha1- and alpha2-ARs appear to be distributed differently across the arterioles and AVAs of the rabbit ear. Both alpha1- and alpha2-ARs appear to contribute to vasoconstriction of AVAs in the conscious rabbit ear. In contrast, alpha1-AR's (vs alpha2-ARs) appear to predominate in adrenergically mediated sympathetic vasoconstriction of arterioles. PMID:9521886

  17. The relationship between density of alpha-adrenoceptor binding sites and contractile responses in several porcine isolated blood vessels.

    PubMed Central

    Wright, I K; Blaylock, N A; Kendall, D A; Wilson, V G

    1995-01-01

    1. The aim of this study was to investigate constrictor alpha-adrenoceptors in three isolated blood vessels of the pig, the thoracic aorta (TA), the splenic artery (SA) and marginal ear vein (MEV) and then compare the functional response with the densities of alpha 1- and alpha 2-adrenoceptor binding sites in these and several other porcine vascular tissues, palmar common digital artery (PCDA), palmar lateral vein (PLV) and ear artery (EA). 2. Noradrenaline (NA), phenylephrine (PE) and UK14304 (all at 0.03-10 microM) elicited concentration-dependent contractions in the TA and MEV, with a rank order of potency of UK14304 > NA > PE. UK14304 produced maximal responses which were 58% (TA) and 65% (MEV) of that of NA. In the SA, UK14304 and PE produced maximal responses which were less than 10% and 50% of the NA-induced maximal response respectively, with an order of potency of NA > PE. In the SA, NA-induced contractions were competitively antagonized by prazosin (pA2 = 8.60 +/- 0.15). Further, rauwolscine (1-10 microM) antagonized NA-induced contractions with an apparent pKB of 6.09 +/- 0.11 (n = 6), indicating an action at alpha 1-adrenoceptors. The combination of the two antagonists at concentrations selective for alpha 1- (0.1 microM) and alpha 2-adrenoceptors (1 microM) had no greater effect than either antagonist alone. This suggests that the SA expresses only post-junctional alpha 1-adrenoceptors. 3. In the TA, prazosin produced non-parallel shifts in the NA-induced CRC and this was also observed with rauwolscine, where reductions in the maximal responses were also observed. In the MEV, prazosin was largely inactive in antagonizing NA-induced contractions. In both these vessels a combination of these two antagonists had a greater effect than either alone, indicating the presence of functional alpha 1- and alpha 2-adrenoceptors. The post-junctional alpha 2-adrenoceptors in all of these vessels were resistant to prazosin, suggesting the alpha 2-adrenoceptor to be

  18. [Alpha1-adrenoceptor subtype selectivity and organ specificity of silodosin (KMD-3213)].

    PubMed

    Tatemichi, Satoshi; Kobayashi, Kumi; Maezawa, Ayaka; Kobayashi, Mamoru; Yamazaki, Yoshinobu; Shibata, Nobuo

    2006-03-01

    The selectivity of silodosin (KMD-3213), an antagonist of alpha(1)-adrenoceptor (AR), to the subtypes (alpha(1A)-, alpha(1B)- and alpha(1D)-ARs) was examined by a receptor-binding study and a functional pharmacological study, and we compared its subtype-selectivity with those of other alpha(1)-AR antagonists. In the receptor-binding study, a replacement experiment using [(3)H]-prazosin was conducted using the membrane fraction of mouse-derived LM (tk-) cells in which each of three human alpha(1)-AR subtypes was expressed. In the functional pharmacological study, the following isolated tissues were used as representative organs with high distribution densities of alpha(1)-AR subtypes (alpha(1A)-AR: rabbit prostate, urethra and bladder trigone; alpha(1B)-AR: rat spleen; alpha(1D)-AR: rat thoracic aorta). Using the Magnus method, we studied the inhibitory effect of silodosin on noradrenaline-induced contraction, and compared it with those of tamsulosin hydrochloride, naftopidil and prazosin hydrochloride. Silodosin showed higher selectivity for the alpha(1A)-AR subtype than tamsulosin hydrochloride, naftopidil or prazosin hydrochloride (affinity was highest for tamsulosin hydrochloride, followed by silodosin, prazosin hydrochloride and naftopidil in that order). Silodosin strongly antagonized noradrenaline-induced contractions in rabbit lower urinary tract tissues (including prostate, urethra and bladder trigone, with pA(2) or pKb values of 9.60, 8.71 and 9.35, respectively). On the other hand, the pA(2) values for antagonism of noradrenaline-induced contractions in rat isolated spleen and rat isolated thoracic aorta were 7.15 and 7.88, respectively. Selectivity for lower urinary tract was higher for silodosin than for the other alpha(1)-AR antagonists. Our data suggest that silodosin has a high selectivity for the alpha(1A)-AR subtype and for the lower urinary tract. PMID:16518085

  19. Effects of metoclopramide and isoprenaline in the rat vas deferens; interactions with alpha-adrenoceptors.

    PubMed Central

    Spedding, M.

    1980-01-01

    1 Metoclopramide (2.8 to 280 microM) augmented contractions of rat vas deferens preparations induced by field stimulation (6 Hz for 1 s). This effect was antagonized by phentolamine (0.1 microM). Metoclopramide (2.8 to 280 microM) did not affect phenylephrine-induced contractions. 2 Metoclopramide (2.8 to 280 microM) antagonized the inhibitory effects of clonidine on the contractions induced by field stimulation, but not the inhibitory effects of purine nucleosides. 3 From these results it is concluded that metoclopramide (2.8 to 280 microM) is a presynaptic alpha-adrenoceptor antagonist in the rat vas deferens. 4 Following beta-adrenoceptor blockade with (+/-)-propranolol (3.3 microM), (-)-isoprenaline (0.47 to 14 microM) inhibited responses to field stimulation but not to phenylephrine. These propranolol-resistant effects of isoprenaline were antagonized by metoclopramide (2.8 to 280 microM) and by phentolamine (0.1 to 10 microM), indicating that isoprenaline may stimulate presynaptic alpha-adrenoceptors in this preparation. PMID:6258684

  20. Influences of the endothelium and hypoxia on alpha 1- and alpha 2-adrenoceptor-mediated responses in the rabbit isolated pulmonary artery.

    PubMed Central

    MacLean, M. R.; McCulloch, K. M.; McGrath, J. C.

    1993-01-01

    1. The effects of the inhibitor of nitric oxide synthase, N omega-nitro-L-arginine methylester (L-NAME, 10(-4) M), mechanical disruption of the endothelium and hypoxia on contraction to noradrenaline (alpha 1- and alpha 2-adrenoceptor agonist), phenylephrine (alpha 1-adrenoceptor agonist) and UK 14304 (alpha 2-adrenoceptor agonist) were compared in the rabbit isolated pulmonary artery. The effects of the selective antagonists rauwolscine (10(-6) M, alpha 2-adrenoceptors) and prazosin (10(-7) M, alpha 1-adrenoceptors) on the contractions to noradrenaline before and after exposure to L-NAME were also assessed. 2. Noradrenaline, phenylephrine and UK 14304 all produced concentration-dependent increases in vascular tone. The responses to noradrenaline were sensitive to both rauwolscine and prazosin (effect of prazosin >> rauwolscine). L-NAME increased the potency of both noradrenaline and UK 14304, and also the maximum tension achieved. It had no effect on the responses to phenylephrine. After L-NAME, contractions to noradrenaline, although still sensitive to both rauwolscine and prazosin, were now more sensitive to inhibition by rauwolscine. 3. Endothelium removal augmented the potency and maximum contractions to noradrenaline, phenylephrine and UK 14304. 4. Hypoxia decreased both the potency of phenylephrine and its maximum contractile response, but increased the maximum response to noradrenaline without effecting responses to UK 14304. 5. In conclusion, in the rabbit pulmonary artery, augmentation of contractile responses to noradrenaline by L-NAME involves a potentiation of alpha 2-adrenoceptor-mediated contraction probably through an effect on the synthesis of endothelium-derived nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8094023

  1. Insights into cardio-oncology: Polypharmacology of quinazoline-based α1-adrenoceptor antagonists

    PubMed Central

    Patanè, Salvatore

    2015-01-01

    New uses of cardiovascular drugs with proven experience are emerging, including for treating cancer. Quinazoline is a compound made up of two fused six member simple aromatic rings, benzene and pyrimidine rings, with several biological effects. Cardiologists first used quinazoline-based α1-adrenoceptor antagonists prazosin, doxazosin, and terazosin; currently available data support their use as safe, well tolerated, and effective add-on therapy in uncontrolled hypertension with additional favourable metabolic effects. Recent findings highlight the anticancer effects of quinazoline-based α1-adrenoceptor antagonists, indicating that they may have a significant role in uncontrolled hypertensive cancer patients without signs of ischemia. PMID:26015856

  2. Alpha-adrenoceptor mediated responses of the cauda epididymis of the guinea-pig.

    PubMed Central

    Haynes, J. M.; Hill, S. J.

    1996-01-01

    1. The subtypes of alpha-adrenoceptor mediating the contractile responses of the cauda epididymis of the guinea-pig were investigated. The alpha 1-adrenoceptor agonist phenylephrine, but not the alpha 2-adrenoceptor agonist, xylazine (up to 10 microM), elicited concentration-dependent contractions from preparations of cauda epididymis (EC50 3.4 microM). The L-type Ca2+ channel antagonist, nifedipine (10 microM), reduced the maximal response to phenylephrine (by 77%). Preincubation of tissues with the alpha 1B-adrenoceptor-alkylating agent, chloroethylclonidine (50 microM, 30 min), shifted phenylephrine concentration-response curves to the right (4 fold) only when the alpha 2-adrenoceptor antagonist idazoxan (100 nM) was included during the pre-incubation with chloroethylclonidine. 2. Xylazine (1 microM) significantly shifted phenylephrine concentration-response curves to the left (3 fold); this effect was attenuated by idazoxan (100 nM). Both the incubation of preparations with nifedipine (10 microM) and the pre-incubation of preparations with chloroethylclonidine (50 microM, 30 min) attenuated the potentiating effects of xylazine (1 microM). Protection of alpha 2-adrenoceptors with idazoxan (100 nM) during the chloroethylclonidine (50 microM, 30 min) incubation restored the xylazine-mediated enhancement of phenylephrine concentration-response curves. Pertussis toxin (200 ng ml-1, 24 h) attenuated the xylazine (1 microM)-mediated potentiation of phenylephrine concentration-response curves. 3. Following the pre-incubation of preparations with chloroethylclonidine (50 microM, 30 min) 5-methylurapidil (10 nM to 3 microM) shifted phenylephrine concentration-response curves, in parallel, to the right with mean pKB values in the range of 8.27 (at 10 nM 5-methylurapidil) to 7.76 (at 3 microM 5-methylurapidil), the addition of idazoxan (100 nM) to the incubation medium did not significantly affect the 5-methylurapidil (10 to 300 nM) pKB values (8.41 to 7.64, respectively

  3. A study of presynaptic alpha2-autoreceptors in alpha2A/D-, alpha2B- and alpha2C-adrenoceptor-deficient mice.

    PubMed

    Trendelenburg, A U; Klebroff, W; Hein, L; Starke, K

    2001-08-01

    The function of presynaptic alpha2-autoreceptors was studied in the hippocampus, occipito-parietal cortex, atria and vas deferens of NMRI mice, mice in which the alpha2A/D-, the alpha2B- or alpha2c-adrenoceptor gene had been disrupted (alpha2A/DKO, alpha2BKO and alpha2CKO, respectively), and the wildtype mice from which the knockout animals had been generated. Tissue pieces were preincubated with 3H-noradrenaline and then superfused and stimulated electrically. The alpha2-adrenoceptor agonist medetomidine reduced the electrically evoked overflow of tritium in all tissues from all mouse strains (stimulation with single pulses or single high-frequency pulse trains, called POPs, i.e. pulse patterns leading to minimal autoinhibition). The effects of medetomidine did not differ in NMRI, wildtype, alpha2BKO and alpha2CKO mice but were greatly reduced in alpha2A/DKO brain preparations and to a lesser extent in alpha2A/DKO atria and vasa deferentia. Six drugs were tested as antagonists against medetomidine. Their pKd values indicated that the hippocampal and occipito-parietal alpha2-autoreceptors in NMRI and wildtype mice were alpha2D (the rodent variant of the alpha2A/D-adrenoceptor) whereas the atrial and vas deferens alpha2-autoreceptors in NMRI and wildtype mice could not be identified with a single alpha2 subtype. Deletion of the alpha2A/D gene changed the pKd values in all tissues so that they now reflected alpha2C properties, whereas deletion of the alpha2C gene changed the pKd values in atria and vasa deferentia so that they now had alpha2D properties (as they had in NMRI and wildtype brain preparations). Autoinhibition by released noradrenaline was created using trains of up to 64 pulses or up to 4 POPs, and the overflow-enhancing effect of the alpha2 antagonist rauwolscine was determined. Results did not differ, irrespective of whether preparations were obtained from NMRI, wildtype, alpha2BKO or alpha2CKO mice: the overflow of tritium elicited by p pulses or POPs

  4. (3H)bunazosin, a novel selective radioligand of alpha 1 adrenoceptors in human prostates

    SciTech Connect

    Yamada, S.; Suzuki, M.; Matsuoka, Y.; Kato, Y.; Kimura, R.; Maruyama, M.; Kawabe, K. )

    1991-09-01

    The binding properties of a new radioligand, (3H)bunazosin, were studied in membranes of human prostates with benign prostatic hypertrophy (BPH). Specific binding of (3H)bunazosin was saturable, reversible, and of high affinity (Kd = 0.55 {plus minus} 0.04 nM). The density of (3H)bunazosin binding sites (Bmax) was 676 {plus minus} 33 fmol/mg. protein. (3H)Bunazosin rapidly associated with its binding sites in membranes of human prostates and reached steady state by 20 min. at 25C. The rate constants for association and dissociation of (3H)bunazosin binding were calculated to be 0.11 {plus minus} 0.01/nM/min. and 0.05 {plus minus} 0.02/min. (n = 4), respectively. Seven alpha 1 adrenoceptor antagonists competed with (3H)bunazosin for the binding sites in the rank order: R-(-)-YM-12617 greater than prazosin greater than SGB-1534 greater than bunazosin greater than terazosin greater than naftopidil greater than urapidil. In parallel studies with (3H)bunazosin, the Kd and Bmax values for (3H)prazosin binding in human prostates were slightly lower. There was a similarity in the potency and rank order of seven alpha 1, adrenoceptor antagonists for the inhibition of (3H) bunazosin and (3H)prazosin binding in human prostates. The new (3H)bunazosin binding assay in human prostates is remarkable for its low degree of nonspecific binding as compared to (3H)prazosin, especially at high ligand concentrations. Thus, (3H)bunazosin may become a useful radioligand for the further analysis of the alph 1 adrenoceptor binding sites in human prostates.

  5. [beta]1-Adrenoceptor or [alpha]1-Adrenoceptor Activation Initiates Early Odor Preference Learning in Rat Pups: Support for the Mitral Cell/cAMP Model of Odor Preference Learning

    ERIC Educational Resources Information Center

    Harley, Carolyn W.; Darby-King, Andrea; McCann, Jennifer; McLean, John H.

    2006-01-01

    We proposed that mitral cell [beta]1-adrenoceptor activation mediates rat pup odor preference learning. Here we evaluate [beta]1-, [beta]2-, [alpha]1-, and [alpha]2-adrenoceptor agonists in such learning. The [beta]1-adrenoceptor agonist, dobutamine, and the [alpha]1-adrenoceptor agonist, phenylephrine, induced learning, and both exhibited an…

  6. The effect of urapidil, an alpha-1 adrenoceptor antagonist and a 5-HT1A agonist, on the vascular tone of the porcine coronary and pulmonary arteries, the rat aorta and the human pulmonary artery.

    PubMed

    Bopp, Claire; Auger, Cyril; Diemunsch, Pierre; Schini-Kerth, Valérie

    2016-05-15

    Urapidil (Eupressyl(®)) an antihypertensive drug acting as an α1 antagonist and a 5-HT1A agonist, may be of special interest in the treatment of hypertension associated with preeclamptic toxaemia and hypoxia-induced pulmonary arterial vasoconstriction. However, the effect of urapidil on vascular tone has been poorly investigated. Vascular reactivity was evaluated using pulmonary and coronary arteries from 36 pigs, aortae from 22 rats and 9 human pulmonary artery samples suspended in organ chambers. Concentration-relaxation curves either to urapidil, 5-HT, or the 5-HT1A receptor agonist 8-OH-DPAT were constructed after pre-contraction of rings. Pig pulmonary and coronary artery rings were contracted with U46619, a thromboxane mimetic, rat aortic rings with either endothelin-1 or phenylephrine, and human pulmonary artery rings with U46619 or phenylephrine. Urapidil markedly inhibited phenylephrine-induced contractions in rat aortic rings with and without endothelium with a more pronounced effect observed in rings without endothelium. Both 5-HT and 8-OH-DPAT failed to induce relaxation in rat aortic rings with an intact endothelium. 5-HT, but not urapidil and 8-OH-DPAT, induced a concentration-dependent relaxation in the porcine coronary and pulmonary artery rings with an intact endothelium (P<0.05). 5-HT and phenylephrine but not urapidil caused concentration-dependent contractions in human pulmonary artery rings. The present findings, while confirming that urapidil is a potent inhibitor of α1-adrenoceptor-induced contraction, do not support the role of 5-HT1A receptor activation in the control of the vascular tone of the different types of arteries tested in response to urapidil. In addition, they indicate that urapidil seems to preferentially target arteries with endothelial dysfunction. PMID:26957055

  7. Modulatory role of a constitutively active population of alpha(1D)-adrenoceptors in conductance arteries.

    PubMed

    Ziani, Khalid; Gisbert, Regina; Noguera, Maria Antonia; Ivorra, Maria Dolores; D'Ocon, Pilar

    2002-02-01

    A constitutively active population of alpha(1D)-adrenoceptors in iliac and proximal, distal, and small mesenteric rat arteries was studied. The increase in resting tone (IRT) that evidences it was observed only in iliac and proximal mesenteric and was inhibited by prazosin (pIC(50) = 9.57), 5-methylurapidil (pIC(50) = 7.61), and BMY 7378 (pIC(50) = 8.77). Chloroethylchlonidine (100 micromol/l) did not affect IRT, but when added before the other antagonists it blocked their effect. The potency shown by BMY 7378 confirms the alpha(1D)-subtype as responsible for IRT. BMY 7378 displayed greater inhibition of adrenergic responses in iliac (pIC(50) = 7.57 +/- 0.11) and proximal mesenteric arteries (pIC(50) = 8.05 +/- 0.2) than in distal (pIC(50) = 6.94 +/- 0.13) or small mesenteric arteries (pIC(50) = 6.30 +/- 0.14), which confirms the functional role of the alpha(1D)-adrenoceptor in iliac and proximal mesenteric arteries. This subtype prevents abrupt changes in iliac and proximal mesenteric artery caliber when the agonist disappears, and this modulatory role is evidenced by the slower decay in the response to norepinephrine after removal. PMID:11788394

  8. Cross-talk between receptors with intrinsic tyrosine kinase activity and alpha1b-adrenoceptors.

    PubMed Central

    del Carmen Medina, L; Vázquez-Prado, J; García-Sáinz, J A

    2000-01-01

    The effect of epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) on the phosphorylation and function of alpha(1b)-adrenoceptors transfected into Rat-1 fibroblasts was studied. EGF and PDGF increased the phosphorylation of these adrenoceptors. The effect of EGF was blocked by tyrphostin AG1478 and that of PDGF was blocked by tyrphostin AG1296, inhibitors of the intrinsic tyrosine kinase activities of the receptors for these growth factors. Wortmannin, an inhibitor of phosphoinositide 3-kinase, blocked the alpha(1b)-adrenoceptor phosphorylation induced by EGF but not that induced by PDGF. Inhibition of protein kinase C blocked the adrenoceptor phosphorylation induced by EGF and PDGF. The ability of noradrenaline to increase [(35)S]guanosine 5'-[gamma-thio]triphosphate ([(35)S]GTP[S]) binding in membrane preparations was used as an index of the functional coupling of the alpha(1b)-adrenoceptors and G-proteins. Noradrenaline-stimulated [(35)S]GTP[S] binding was markedly decreased in membranes from cells pretreated with EGF or PDGF. Our data indicate that: (i) activation of EGF and PDGF receptors induces phosphorylation of alpha(1b)-adrenoceptors, (ii) phosphatidylinositol 3-kinase is involved in the EGF response, but does not seem to play a major role in the action of PDGF, (iii) protein kinase C mediates this action of both growth factors and (iv) the phosphorylation of alpha(1b)-adrenoceptors induced by EGF and PDGF is associated with adrenoceptor desensitization. PMID:10947955

  9. Comparison of guinea-pig, bovine and rat alpha 1-adrenoceptor subtypes.

    PubMed Central

    Büscher, R.; Heeks, C.; Taguchi, K.; Michel, M. C.

    1996-01-01

    1. To elucidate a possible role of species differences in the classification of alpha 1-adrenoceptor subtypes, we have characterized the alpha 1-adrenoceptors in guinea-pig spleen, kidney and cerebral cortex and in bovine cerebral cortex using concentration-dependent alkylation by chloroethylclonidine and competitive binding with 5-methlurapidil, methoxamine, (+)-niguldipine, noradrenaline, oxymetazoline, phentolamine, SDZ NVI-085, tamsulosin and (+)-tamsulosin. Rat liver alpha 1B-adrenoceptors were studied for comparison. Chloroethylclonidine-sensitivity and (+)-niguldipine affinity were also compared at cloned rat and bovine alpha 1a-adrenoceptors. 2. Chloroethylclonidine concentration-dependently inactivated alpha 1-adrenoceptors in all five tissues. While chloroethylclonidine inactivated almost all alpha 1-adrenoceptors in rat liver and guinea-pig kidney and brain, 20-30% of alpha 1-adrenoceptors in guinea-pig spleen and bovine brain were resistant to alkylation by 10 microM chloroethylclonidine. With regard to concentration-dependency guinea-pig kidney and brain were approximately 10 fold less sensitive than guinea-pig spleen or rat liver. 3. In rat liver, all drugs tested competed for [3H]-prazosin binding with steep and monophasic curves. Drug affinities were relatively low and resembled most closely those of cloned rat alpha 1b-adrenoceptors. 4. In guinea-pig spleen, all drugs tested competed for [3H]-prazosin binding with steep and monophasic curves. Drug affinities were relatively low and resembled most closely those of cloned rat alpha 1b-adrenoceptors. 5. In guinea-pig kidney most drugs tested competed for [3H]-prazosin binding with steep and monophasic curves and had relatively low drug affinities close to those of cloned rat alpha 1b- and alpha 1d-adrenoceptors. However, noradrenaline and tamsulosin had consistently biphasic competition curves recognizing 36-39% high and 61-64% low affinity sites. 6. In guinea-pig cerebral cortex, all drugs tested

  10. Radioligand binding studies of alpha 1-adrenoceptor subtypes in rat heart.

    PubMed Central

    Michel, M. C.; Hanft, G.; Gross, G.

    1994-01-01

    1. In order to characterize the alpha 1-adrenoceptor subtypes mediating positive inotropic effects of adrenaline (in the presence of propranolol) in rat right ventricular strips and the Ca2+ sources used to elicit them, we have used radioligand binding to identify the alpha 1-adrenoceptor subtypes present in rat heart and the alpha 1-adrenoceptor affinity and subtype-selectivity of various pharmacological tools. 2. Amitryptiline, mianserin, trimipramine, oxaprotiline, clonidine, chloroethylclonidine, phenoxybenzamine, BE 2254 and 8-OH-DPAT competed for [3H]-prazosin binding in rat heart, vas deferens, liver, spleen, cerebral cortex and hippocampus but none of them displayed detectable alpha 1-adrenoceptor subtype-selectivity; nitrendipine did not compete for [3H]-prazosin binding in concentrations up to 5 mumol 1(-1). 3. The alpha 1 A-adrenoceptor-selective, 5-methyl-urapidil, (+)-niguldipine, and to a lesser extent (-)-niguldipine competed for [3H]-prazosin binding in rat heart, vas deferens, cerebral cortex and hippocampus with shallow and biphasic curves; analysis of these curves demonstrated that rat heart contains alpha 1A-and alpha 1B-adrenoceptors in a 20:80 ratio. 4. Treatment of rat right ventricular strips with 100 mumol l-1 chloroethylclonidine for 30 min at 30 degrees C followed by 60 min washout reduced the number of alpha 1-adrenoceptors, as assessed by [3H]-prazosin saturation experiments, by 74%. Treatment with 100 mumol l(-1) CdCl2 did not affect number or affinity of cardiac alpha 1-adrenoceptors and combined treatment with chlorethylclonidine and CdCl2 reduced alpha 1-adrenoceptor number by 90%.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7911718

  11. Characterization of central alpha-adrenoceptors using /sup 3/H-clonidine and its derivatives

    SciTech Connect

    Jarrott, B.; Louis, W.J.; Summers, R.J.

    1983-02-01

    alpha-Adrenoceptors in brain can be studied readily by radioligand binding techniques. This provides valuable information not only on the distribution of receptors in brain regions, but also on the regulation of receptors. The usefulness of this technique is dependent in part on a radioligand with high specificity for the receptor under study. Researchers' studies have shown that /sup 3/H-clonidine does not bind exclusively to alpha 2-adrenoceptor subtypes, but also interacts with alpha 1-adrenoceptors. In contrast, /sup 3/H-guanfacine labels a high affinity alpha 2 subtype with good selectivity, but /sup 3/H-lofexidine probably labels with both alpha 2 and alpha 1-adrenoceptor binding sites.

  12. Clebopride enhances contractility of the guinea pig stomach by blocking peripheral D2 dopamine receptor and alpha-2 adrenoceptor

    SciTech Connect

    Takeda, K.; Taniyama, K.; Kuno, T.; Sano, I.; Ishikawa, T.; Ohmura, I.; Tanaka, C. )

    1991-05-01

    The mechanism of action of clebopride on the motility of guinea pig stomach was examined by the receptor binding assay for bovine brain membrane and by measuring gastric contractility and the release of acetylcholine from the stomach. The receptor binding assay revealed that clebopride bound to the D2 dopamine receptor with a high affinity and to the alpha-2 adrenoceptor and 5-HT2 serotonin receptor with relatively lower affinity, and not to D1 dopamine, alpha-1 adrenergic, muscarinic acetylcholine, H1 histamine, or opioid receptor. In strips of the stomach, clebopride at 10{sup {minus} 8} M to 10{sup {minus} 5} M enhanced the electrical transmural stimulation-evoked contraction and the release of acetylcholine. This enhancement was attributed to the blockade of the D2 dopamine receptor and alpha-2 adrenoceptor because: (1) Maximum responses obtained with specific D2 dopamine receptor antagonist, domperidone, and with specific alpha-2 adrenoceptor antagonist, yohimbine, were smaller than that with clebopride, and the sum of the effects of these two specific receptor antagonists is approximately equal to the effect of clebopride. (2) The facilitatory effect of clebopride was partially eliminated by pretreatment of the sample with domperidone or yohimbine, and the facilitatory effect of clebopride was not observed in preparations treated with the combination of domperidone and yohimbine. Clebopride also antagonized the inhibitory effects of dopamine and clonidine on the electrical transmural stimulation-evoked responses. These results indicate that clebopride acts on post ganglionic cholinergic neurons at D2 and alpha-2 receptors in this preparation to enhance enteric nervous system stimulated motility.

  13. How intrinsic sympathomimetic activity modulates the haemodynamic responses to β-adrenoceptor antagonists

    PubMed Central

    Veld, A. J. Man in 'T; Schalekamp, M. A. D. H.

    1982-01-01

    1 A survey has been made of the literature on acute and long-term haemodynamic effects of ten different β-adrenoceptor antagonists. The β-adrenoceptor blockers are: pindolol, practolol, alprenolol, oxprenolol, acebutolol, penbutolol, metoprolol, atenolol, propranolol and timolol. The total numbers of patients included in this review are 396 patients in 41 acute studies and 410 patients in 36 long-term studies. 2 The effects of β-adrenoceptor blockers on the concentrations of plasma noradrenaline have also been reviewed. Ten studies including 110 patients on non-ISA-β-adrenoceptor blockers and eight studies including 116 patients on pindolol are presented. 3 In the acute studies (i.e. 15-90 min) arterial pressure was lowered by 1-7% and in the long-term studies (i.e. 3 days-5 years) by 6-17%. 4 The degree of cardio-depression induced by the various β-adrenoceptor blockers was inversely correlated with their pharmacologically defined quantity of intrinsic sympathomimetic activity (ISA) both in acute and in long-term studies. 5 In the acute studies the increments in peripheral vascular resistance were directly correlated with the degree of cardio-depression. This suggests that a fall in arterial pressure immediately after administration of a β-adrenoceptor blocker is prevented by increased vasoconstrictor nerve activity mediated through the arterial baroreflex. 6 The compensatory response of vascular resistance to cardio-depression was similar for β1-selective and non-selective blockers, thereby indicating that extra-junctional vascular β-receptors are relatively unimportant for maintaining basal vascular tone. 7 In the long-term studies the correlation between changes in cardiac output and changes in vascular resistance was shifted to a lower level of vascular resistance. This means that the onset of blood pressure reduction during β-adrenoceptor blockade was associated with a fall in vascular resistance at any level of cardiac output. Thus vascular

  14. Delineation of three pharmacological subtypes of alpha 2-adrenoceptor in the rat kidney.

    PubMed Central

    Uhlén, S.; Wikberg, J. E.

    1991-01-01

    1. Simultaneous computer modelling of plain and ARC 239- and guanoxabenz-masked [3H]-RX821002 saturation curves, plain ARC 239 and guanoxabenz competition curves as well as ARC 239-masked guanoxabenz competition curves revealed that the drugs bound to three alpha 2-adrenoceptor subtypes in the rat kidney with grossly differing selectivities. These alpha 2-adrenoceptor subtypes were termed alpha 2 A, alpha 2B1 and alpha 2B2. The order of affinities for [3H]-RX821002 for the adrenoceptor sites was alpha 2A greater than alpha 2B1 greater than alpha 2B2, the KdS being 0.62 +/- 0.05, 2.52 +/- 0.11 and 6.74 +/- 1.21 nM, respectively. The order of affinities for ARC 239 was alpha 2B1 greater than alpha 2B2 much greater than alpha 2A with KdS 4.78 +/- 1.04, 28.8 +/- 4.1 and 1460 +/- 270 nM, respectively. For guanoxabenz the order of affinities was alpha 2A greater than alpha 2B1 much greater than alpha 2B2 with KdS 99.7 +/- 15.1, 508 +/- 135 and 25,400 +/- 2400 nM, respectively. 2. Binding constants for 14 compounds for the three rat kidney alpha 2-adrenoceptor subtypes were determined by the simultaneous computer modelling of plain and ARC 239- and guanoxabenz-masked drug competition curves, plain ARC 239 and guanoxabenz competition curves as well as ARC 239-masked guanoxabenz competition curves. Of the 14 compounds tested, oxymetazoline and guanfacine were found to bind with low affinities to both of the alpha 2B1- and alpha 2B2-adrenoceptor but with high affinity to the alpha 2A-adrenoceptor.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1665747

  15. The inhibitory effects of alpha(2)-adrenoceptor agonists on gastrointestinal transit during croton oil-induced intestinal inflammation.

    PubMed Central

    Pol, O.; Valle, L.; Ferrer, I.; Puig, M. M.

    1996-01-01

    1. The peripheral effects of alpha(2)-adrenoceptor agonists were investigated in a model of intestinal inflammation induced by intragastric administration of croton oil (CO). Our hypothesis was that inflammation would 'sensitize' adrenoceptors in peripheral and/or central terminals of myenteric and submucous plexus neurones, and enhance systemic effects of alpha(2)-adrenoceptor agonists. 2. Male swiss CD-1 mice, received intragastrically CO (0.05 ml), castor oil (CA, 0.1 ml) or saline (SS) 3 h before the study: gastrointestinal transit (GIT) was evaluated 20 min afterwards with a charcoal meal. The presence of inflammation was assessed by electron microscopy. 3. The intragastric administration of CA or CO caused an increase in GIT and weight loss, but only CO induced an inflammatory response. Both clonidine (imidazoline1/alpha(2)-agonist) and UK-14304 (alpha(2)-agonist) produced dose-related inhibitions of GIT in all groups. During inflammatory diarrhoea (CO), potencies of systemic (s.c.) clonidine and UK-14304 were significantly increased 3.5 and 2.1 times, respectively, while potencies remained unaltered in the presence of diarrhoea without inflammation (CA). The effects were reversed by administration (s.c.) of receptor-specific adrenoceptor antagonists, but not by naloxone. 4. Clonidine was 8.3 (SS) and 2.8 (CO) times more potent when administered intracerebroventricularly (i.c.v.), than when administered s.c. Inflammation of the gut did not alter the potency of i.c.v. clonidine, demonstrating that enhanced effects of s.c. clonidine are mediated by peripheral receptors. During inflammation, i.c.v. efaroxan did not antagonize low doses of s.c. clonidine (ED20 and ED50S), but partially reversed ED80S, further supporting the peripheral effects of the agonists in CO treated animals. 5. The results demonstrate that inflammation of the gut enhances the potency of alpha(2)-adrenoceptor agonists by a peripheral mechanism. The results also suggest that the inflammatory

  16. Inhibitory effects of amiloride on alpha adrenoceptors in canine vascular smooth muscle

    SciTech Connect

    Shi, A.G.; Wang, Z.L.; Kwan, C.Y.; Daniel, E.E. )

    1990-05-01

    Amiloride inhibits vascular smooth muscle contractions from canine aorta and saphenous vein. The mechanisms were studied using radioligand binding and functional techniques. Amiloride inhibited ({sup 3}H)prazosin and ({sup 3}H)rauwolscine binding to alpha-1 and alpha-2 adrenoceptors in a concentration-dependent manner. Amiloride increased Kd values for ({sup 3}H)rauwolscine without affecting the maximum binding of ({sup 3}H)prazosin. These results suggest that the drug interacts with the alpha-1 adrenoceptor binding sites in a competitive manner and with the alpha-2 adrenoceptor binding sites in a noncompetitive manner. Amiloride reduced maximal contractile responses to agonists selective for both alpha adrenoceptors and to elevated K+, the EC50 values were increased by about 10-fold in the presence of amiloride. In Ca+(+)-free Krebs' solution, contractions induced in saphenous vein after addition of Ca++ in saphenous vein in the presence of adrenoceptor agonists were inhibited by amiloride. Our results suggest that amiloride reduced alpha-1 and alpha-2 adrenoceptor-mediated responses and inhibited Ca++ influx.

  17. Pharmacologically distinct phenotypes of α1B-adrenoceptors: variation in binding and functional affinities for antagonists

    PubMed Central

    Yoshiki, Hatsumi; Uwada, Junsuke; Anisuzzaman, Abu Syed Md; Umada, Hidenori; Hayashi, Ryoji; Kainoh, Mie; Masuoka, Takayoshi; Nishio, Matomo; Muramatsu, Ikunobu

    2014-01-01

    Background and Purpose The pharmacological properties of particular receptors have recently been suggested to vary under different conditions. We compared the pharmacological properties of the α1B-adrenoceptor subtype in various tissue preparations and under various conditions. Experimental Approach [3H]-prazosin binding to α1B-adrenoceptors in rat liver (segments, dispersed hepatocytes and homogenates) was assessed and the pharmacological profiles were compared with the functional and binding profiles in rat carotid artery and recombinant α1B-adrenoceptors. Key Results In association and saturation-binding experiments with rat liver, binding affinity for [3H]-prazosin varied significantly between preparations (KD value approximately ten times higher in segments than in homogenates). The binding profile for various drugs in liver segments also deviated from the representative α1B-adrenoceptor profile observed in liver homogenates and recombinant receptors. L-765,314 and ALS-77, selective antagonists of α1B-adrenoceptors, showed high binding and antagonist affinities in liver homogenates and recombinant α1B-adrenoceptors. However, binding affinities for both ligands in the segments of rat liver and carotid artery were 10 times lower, and the antagonist potencies in α1B-adrenoceptor-mediated contractions of carotid artery were more than 100 times lower than the representative α1B-adrenoceptor profile. Conclusions and Implications In contrast to the consistent profile of recombinant α1B-adrenoceptors, the pharmacological profile of native α1B-adrenoceptors of rat liver and carotid artery varied markedly under various receptor environments, showing significantly different binding properties between intact tissues and homogenates, and dissociation between functional and binding affinities. In addition to conventional ‘subtype’ characterization, ‘phenotype’ pharmacology must be considered in native receptor evaluations in vivo and in future

  18. Electroacupuncture-induced analgesia in a rat model of ankle sprain pain is mediated by spinal alpha-adrenoceptors

    PubMed Central

    Koo, Sung Tae; Lim, Kyu Sang; Chung, Kyungsoon; Ju, Hyunsu; Chung, Jin Mo

    2008-01-01

    In a previous study, we showed that electroacupuncture (EA) applied to the SI-6 point on the contralateral forelimb produces long-lasting and powerful analgesia in pain caused by ankle sprain in a rat model. To investigate the underlying mechanism of EA analgesia, the present study tested the effects of various antagonists to known endogenous analgesic systems in this model. Ankle sprain was induced in anesthetized rats by overextending their right ankle with repeated forceful plantar flexion and inversion of the foot. When rats developed pain behaviors (a reduction in weight bearing of the affected hind limb), EA was applied to the SI-6 point on the contralateral forelimb for 30 minutes under halothane anesthesia. EA significantly improved the weight-bearing capacity of the affected hind limb for 2 hours, suggesting an analgesic effect. The alpha-adrenoceptor antagonist phentolamine (2 mg/kg, i.p. or 30 μg, i.t.) completely blocked the EA-induced analgesia, whereas naloxone (1 mg/kg, i.p.) and failed to block the effect. These results suggest that EA-induced analgesia is mediated by alpha-adrenoceptor mechanisms. Further experiments showed that intrathecal administration of yohimbine (10 μg), an α2-adrenergic antagonist, reduced the EA-induced analgesia in a dose-dependent manner, whereas terazosin (10 μg), an α1-adrenergic antagonist, did not produce any effect. These data suggest that the analgesic effect of EA in ankle sprain pain is, at least in part, mediated by spinal α2-adrenoceptor mechanisms. PMID:17537577

  19. A quantitative analysis of antagonism and inverse agonism at wild-type and constitutively active hamster alpha1B-adrenoceptors.

    PubMed

    Hein, P; Goepel, M; Cotecchia, S; Michel, M C

    2001-01-01

    In order to characterize inverse agonism at alpha1B-adrenoceptors, we have compared the concentration-response relationships of several quinazoline and non-quinazoline alpha1-adrenoceptor antagonists at cloned hamster wild-type (WT) alpha1B-adrenoceptors and a constitutively active mutant (CAM) thereof upon stable expression in Rat-1 fibroblasts. Receptor activation or inhibition thereof was assessed as [3H]inositol phosphate (IP) accumulation. Quinazoline (alfuzosin, doxazosin, prazosin, terazosin) and non-quinazoline alpha1-adrenoceptor antagonists (BE 2254, SB 216,469, tamsulosin) concentration-dependently inhibited phenylephrine-stimulated IP formation at both WT and CAM with Ki values similar to those previously found in radioligand binding studies. At CAM in the absence of phenylephrine, the quinazolines produced concentration-dependent inhibition of basal IP formation; the maximum inhibition was approximately 55%, and the corresponding EC50 values were slightly smaller than the Ki values. In contrast, BE 2254 produced much less inhibition of basal IP formation, SB 216,469 was close to being a neutral antagonist, and tamsulosin even weakly stimulated IP formation. The inhibitory effects of the quinazolines and BE 2254 as well as the stimulatory effect of tamsulosin were equally blocked by SB 216,469 at CAM. At WT in the absence of phenylephrine, tamsulosin did not cause significant stimulation and none of the other compounds caused significant inhibition of basal IP formation. We conclude that alpha1-adrenoceptor antagonsits with a quinazoline structure exhibit greater efficacy as inverse agonists than those without. PMID:11191834

  20. ( sup 3 H)rauwolscine binding to myometrial. alpha. sub 2 -adrenoceptors in pregnant guinea pig

    SciTech Connect

    Arkinstall, S.J.; Jones, C.T. )

    1988-09-01

    Uterine sympathetic nerves can exert an excitatory influence in late pregnancy and during parturition. Neuronal norepinephrine release is increased at these times and a diminished {alpha}{sub 2}-adrenoceptor-mediated prejunctional inhibition could account for this. To assess whether an altered receptor population may contribute, ({sup 3}H)rauwolscine was used to measure {alpha}{sub 2}-adrenoceptors in myometrial membranes at time intervals throughout pregnancy. High affinity ({sup 3}H)rauwolscine binding yielded linear Scatchard plots that in nonpregnant myometrium indicated a maximum binding density B{sub max} of 217 {plus minus} 42.4 fmol/mg protein. {alpha}{sub 2}-Adrenoceptor density was increased twofold at midpregnancy (31 days) and thereafter fell sharply by up to 90% toward term (67 {plus minus} 2 days). When uterine growth is accounted for and data are expressed in terms of total myometrial population, {alpha}{sub 2}-adrenoceptor number was eightfold (midpregnancy) and fourfold (term) greater than the nonpregnant value of 804 {plus minus} 322.4 fmol/uterus. {alpha}{sub 2}-Adrenoceptors were also found to bind dopamine with high affinity. These observations could indicate a pregnancy-related change in uterine sympathetic autoinhibitory capacity and, since {alpha}{sub 2}-adrenoceptors appear also to be located postjunctionally, explain in part reports of altered myometrial responsiveness to norepinephrine infusion and also the uterotonic actions of dopamine.

  1. Identification of alpha 2-adrenoceptors and of non-adrenergic idazoxan binding sites in pancreatic islets from young and adult hamsters.

    PubMed

    Lacombe, C; Viallard, V; Paris, H

    1993-07-01

    1. The current study was undertaken to investigate the characteristics of alpha 2-adrenoceptors and to search for the presence of NAIBS in hamster pancreatic islets. 2. Pancreatic islets were isolated from young (6-7 weeks) and adult (14-15 weeks) animals. 3. The identification of alpha 2-adrenoceptors using [3H]RX821002 indicated that adults exhibited higher number of alpha 2-adrenoceptors than the young animals (194 +/- 20 vs 105 +/- 16 fmol/mg protein) while the Kd value was unchanged. 4. Glucose-evoked insulin release was completely inhibited by the alpha 2-agonist clonidine (0.1 microM) whatever the age of the animals. Agonist inhibition curves showed the following rank order of potency: clonidine > UK14304 > adrenaline. 5. Blockade of UK14304-elicited inhibition by various antagonists indicated that yohimbine has a low affinity for the receptor supporting the conclusion that the receptor is of the alpha 2-D subtype. 6. Binding experiments with [3H]idazoxan under conditions allowing to discriminate between alpha 2-adrenoceptors and NAIBS showed that hamster pancreatic islets express a high number of NAIBS. The density of NAIBS was similar in young and adult hamsters (1550 +/- 245 and 1342 +/- 332 fmol/mg protein). PMID:8103467

  2. A possible structural determinant of selectivity of boldine and derivatives for the alpha 1A-adrenoceptor subtype.

    PubMed Central

    Madrero, Y.; Elorriaga, M.; Martinez, S.; Noguera, M. A.; Cassels, B. K.; D'Ocon, P.; Ivorra, M. D.

    1996-01-01

    1. The selectivity of action of boldine and the related aporphine alkaloids, predicentrine (9-O-methylboldine) and glaucine (2,9-O-dimethylboldine) and alpha 1-adrenoceptor subtypes was studied by examining [3H]-prazosin competition binding in rat cerebral cortex. WB 4101 and benoxathian were used as selective alpha 1A-adrenoceptor antagonists. 2. In the competition experiments [3H]-prazosin (0.2 nM) binding was inhibited by WB 4101 and benoxathian. The inhibition curves displayed shallow slopes which could be subdivided into high and low affinity components (pKi = 9.92 and 8.29 for WB 4101, 9.35 and 7.94 for benoxathian). The two antagonists recognized approximately 37% of the sites with high affinity from among the total [3H]-prazosin specific binding sites. 3. Boldine, predicentrine and glaucine also competed for [3H]-prazosin (0.2 nM) binding with shallow and biphasic curves recognizing 30-40% of the sites with high affinity. Drug affinities (pKi) at the high and low affinity sites were, 8.31 and 6.50, respectively, for boldine, 8.13 and 6.39 for predicentrine, and 7.12 and 5.92 for glaucine. The relative order of selectivity for alpha 1A-adrenoceptors was boldine (70 fold alpha 1A-selective) = predicentrine (60 fold, alpha 1A-selective) > glaucine (15 fold, alpha 1A-selective). 4. Pretreatment of rat cerebral cortex membranes with chloroethylclonidine (CEC, 10 microM) for 30 min at 37 degrees C followed by thorough washing out reduced specific [3H]-prazosin binding by approximately 70%. The CEC-insensitive [3H]-prazosin binding was inhibited by boldine monophasically (Hill slope = 0.93) with a single pKi value (7.76). 5. These results suggest that whereas the aporphine structure shared by these alkaloids is responsible for their selectively of action for the alpha 1A-adrenoceptor subtype in rat cerebral cortex, defined functional groups, namely the 2-hydroxy function, induces a significant increase in alpha 1A-subtype selectivity and affinity. PMID:8982502

  3. A possible structural determinant of selectivity of boldine and derivatives for the alpha 1A-adrenoceptor subtype.

    PubMed

    Madrero, Y; Elorriaga, M; Martinez, S; Noguera, M A; Cassels, B K; D'Ocon, P; Ivorra, M D

    1996-12-01

    1. The selectivity of action of boldine and the related aporphine alkaloids, predicentrine (9-O-methylboldine) and glaucine (2,9-O-dimethylboldine) and alpha 1-adrenoceptor subtypes was studied by examining [3H]-prazosin competition binding in rat cerebral cortex. WB 4101 and benoxathian were used as selective alpha 1A-adrenoceptor antagonists. 2. In the competition experiments [3H]-prazosin (0.2 nM) binding was inhibited by WB 4101 and benoxathian. The inhibition curves displayed shallow slopes which could be subdivided into high and low affinity components (pKi = 9.92 and 8.29 for WB 4101, 9.35 and 7.94 for benoxathian). The two antagonists recognized approximately 37% of the sites with high affinity from among the total [3H]-prazosin specific binding sites. 3. Boldine, predicentrine and glaucine also competed for [3H]-prazosin (0.2 nM) binding with shallow and biphasic curves recognizing 30-40% of the sites with high affinity. Drug affinities (pKi) at the high and low affinity sites were, 8.31 and 6.50, respectively, for boldine, 8.13 and 6.39 for predicentrine, and 7.12 and 5.92 for glaucine. The relative order of selectivity for alpha 1A-adrenoceptors was boldine (70 fold alpha 1A-selective) = predicentrine (60 fold, alpha 1A-selective) > glaucine (15 fold, alpha 1A-selective). 4. Pretreatment of rat cerebral cortex membranes with chloroethylclonidine (CEC, 10 microM) for 30 min at 37 degrees C followed by thorough washing out reduced specific [3H]-prazosin binding by approximately 70%. The CEC-insensitive [3H]-prazosin binding was inhibited by boldine monophasically (Hill slope = 0.93) with a single pKi value (7.76). 5. These results suggest that whereas the aporphine structure shared by these alkaloids is responsible for their selectively of action for the alpha 1A-adrenoceptor subtype in rat cerebral cortex, defined functional groups, namely the 2-hydroxy function, induces a significant increase in alpha 1A-subtype selectivity and affinity. PMID:8982502

  4. Possible dopaminergic stimulation of locus coeruleus alpha1-adrenoceptors involved in behavioral activation.

    PubMed

    Lin, Yan; Quartermain, David; Dunn, Adrian J; Weinshenker, David; Stone, Eric A

    2008-07-01

    alpha(1)-Adrenoceptors of the locus coeruleus (LC) have been implicated in behavioral activation in novel surroundings, but the endogenous agonist that activates these receptors has not been established. In addition to the canonical activation of alpha(1)-receptors by norepinephrine (NE), there is evidence that dopamine (DA) may also activate certain brain alpha(1)-receptors. This study examined the contribution of DA to exploratory activity in a novel cage by determining the effect of infusion of various dopaminergic and adrenergic drugs into the mouse LC. It was found that the D2/D3 agonist, quinpirole, which selectively blocks the release of CNS DA, produced a dose-dependent and virtually complete abolition of exploration and all movement in the novel cage test. The quinpirole-induced inactivity was significantly attenuated by coinfusion of DA but not by the D1 agonist, SKF38390. Furthermore, the DA attenuation of quinpirole inactivity was blocked by coinfusion of the alpha(1)-adrenergic receptor antagonist, terazosin, but not by the D1 receptor antagonist, SCH23390. LC infusions of either quinpirole or terazosin also produced profound inactivity in DA-beta-hydroxylase knockout (Dbh -/-) mice that lack NE, indicating that their behavioral effects were not due to an alteration of the release or action of LC NE. Measurement of endogenous DA, NE, and 5HT and their metabolites in the LC during exposure to the novel cage indicated an increase in the turnover of DA and NE but not 5HT. These results indicate that DA is a candidate as an endogenous agonist for behaviorally activating LC alpha(1)-receptors and may play a role in the activation of this nucleus by novel surroundings. PMID:18435418

  5. Cardioprotective and β-adrenoceptor antagonistic activity of a newly synthesized aryloxypropanolamine derivative PP-36

    PubMed Central

    Bhatt, Lokesh K; Bansal, Jyotika; Piplani, Poonam; Bodhankar, SL; Veeranjaneyulu, A

    2010-01-01

    The present study was performed to evaluate the cardioprotective effects and pharmacological characterization of newly synthesized β-adrenoreceptor antagonists 3-(3-tert-butylamino-2-hydroxypropoxy)-4-methoxybenzaldehyde (PP-36) in the rat model of coronary artery occlusion and reperfusion. Pre-ischemic administration (20 minutes before coronary occlusion) of PP-36 showed cardioprotective effects against ischemia/reperfusion injury in rats. PP-36 (6 mg kg−1) significantly reduced arrhythmia score (6.33 ± 0.55, P < 0.05), infarct size/left ventricle size (38.9 ± 3.2, P < 0.05) and no mortality compared to vehicle-treated control group (14.17 ± 1.83, 44.9 ± 4.6 and 17% respectively). In-vitro studies in rat isolated right atria, guinea-pig trachea and rat distal colon preparations, were carried out to investigate the potency of PP-36 towards different β-adrenoceptor subtypes. pA2/pKB values of PP-36 for β1-β2-and β3-adrenoceptors were 6.904 ± 0.190, 6.44 ± 0.129 and 5.773 ± 0.129, respectively. In conclusion, PP-36 is a β-adrenoceptor antagonist possessing potent anti-arrhythmic and cardioprotective effects against ischemia/reperfusion injury in rats.

  6. EFFECT OF α1-ADRENOCEPTOR ANTAGONIST EXPOSURE ON PROSTATE CANCER INCIDENCE: AN OBSERVATIONAL COHORT STUDY

    PubMed Central

    Harris, Andrew M.; Warner, Bradley W.; Wilson, John M.; Becker, Aaron; Rowland, Randall G.; Conner, William; Lane, Matthew; Kimbler, Kimberly; Durbin, Eric B.; Baronand, Andre T.; Kyprianou, Natasha

    2007-01-01

    PURPOPSE Quinazoline-based α1-adrenoceptor antagonists (α1-blockers), doxazosin and terazosin, suppress prostate tumor growth via induction of apoptosis and reduction of tissue vascularity. We hypothesize that by inducing apoptosis and targeting angiogenesis these drugs serve as chemopreventive agents of human prostate cancer. We therefore performed an exploratory observational cohort study to assess whether α1-blocker exposure affects the incidence prostate cancer and overall survival experience. MATERIALS AND METHODS The medical records of all male patients enrolled at the Lexington Veterans Administration (VA) Medical Center were searched to identify men treated with quinazoline-based α1-adrenoreceptor antagonists between Jan 1, 1998 and Dec 31, 2002 for either hypertension and/or benign prostate enlargement. Medical records were subsequently linked to the Markey Cancer Center’s Kentucky Cancer Registry (KCR), a statewide population-based central cancer registry that is part of the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program to identify all incident prostate cancer cases diagnosed. All newly diagnosed, prostate cancer cases unexposed to α1-adrenoreceptor antagonists in the total male VA population during this time period also were identified from the KCR’s database. Measures of disease incidence, relative risk, and attributable risk were calculated to compare the risk of developing prostate cancer for α1-blocker-exposed versus unexposed men. Kaplan Meier curves and Cox regression models were used to compare the overall survival between α1-blocker-exposed and unexposed prostate cancer cases. RESULTS Our analysis revealed a cumulative incidence of 1.65% among the α1-blocker-exposed men compared to 2.41% in the unexposed group. These data yield an unadjusted risk ratio of 0.683 (95% CI: 0.532, 0.876) and risk difference of −0.0076, which indicates that 7.6 fewer prostate cancer cases developed per 1000 exposed men. Exposure to

  7. Adrenoceptor mechanisms in the regulation of contractile activity in the human cervix.

    PubMed

    Bryman, I; Lindblom, B; Norström, A; Sahni, S

    1984-09-01

    The effects of adrenoceptor agonists and antagonists on the contractile activity of cervical strips from early pregnant and nonpregnant women were studied. Noradrenaline and the alpha-adrenoceptor agonist, phenylephrine, had a stimulatory effect on smooth muscle activity. This response could be blocked totally by the alpha-adrenoceptor antagonist, phenoxybenzamine. Isoprenaline, known to be a beta-adrenoceptor agonist with some alpha-adrenoceptor activity, had stimulatory and inhibitory effects, whereas the beta 2-adrenoceptor agonist, terbutaline, exhibited a pure inhibitory action. The inhibitory effects of isoprenaline and terbutaline were totally blocked by the beta-adrenoceptor antagonist propranolol. In pregnant patients, the sensitivity to noradrenaline was significantly higher, and the inhibitory action of terbutaline was less pronounced, which indicated the predominance of alpha-receptor activity in the uterine cervix during pregnancy. PMID:6146956

  8. Effects of α1-adrenoceptor antagonists on phenylephrine-induced salivary secretion and intraurethral pressure elevation in anesthetized rats.

    PubMed

    Yanai-Inamura, Hiroko; Ohtake, Akiyoshi; Noguchi, Yukiko; Hatanaka, Toshiki; Suzuki, Masanori; Ueshima, Koji; Sato, Shuichi; Sasamata, Masao

    2012-03-15

    α(1)-Adrenoceptor antagonists are widely used for the treatment of voiding dysfunction associated with benign prostatic hyperplasia. Activation of α(1)-adrenoceptors is reported to induce salivary secretion in rats and humans. However, the effects of α(1)-adrenoceptor antagonists on salivary secretion remain unknown. Here, we investigated the effects of the α(1)-adrenoceptor antagonists prazosin, silodosin, tamsulosin and urapidil on phenylephrine-induced salivary secretion and compared the results with the effects on phenylephrine-induced intraurethral pressure (IUP) elevation in anesthetized rats. All antagonists inhibited phenylephrine-induced salivary secretion and IUP elevation in a dose-dependent fashion. Comparison of DR(10) values (the dose required to shift the dose-response curve 10-fold to the right) in both tissues showed that the inhibitory effect of silodosin was significantly more potent in the salivary gland than in the urethra (18-fold), but tamsulosin (2.3-fold), prazosin (1.7-fold) and urapidil (1.1-fold) did not show comparable tissue selectivity. These results suggest that α(1)-adrenoceptor antagonists inhibit not only urethral contraction but also salivary secretion, and that high tissue selectivity for the salivary gland over the urethra as shown by silodosin may contribute to the incidence of dry mouth. PMID:22314219

  9. Effect of endothelium on basal and alpha-adrenoceptor stimulated calcium fluxes in rat aorta.

    PubMed

    Malta, E; Schini, V; Miller, R C

    1986-09-01

    The rate of unstimulated influx of Ca2+ into rat aorta smooth muscle, measured as uptake of 45Ca, was inhibited in the presence of endothelium as compared to influx in the absence of endothelium. Efflux of 45Ca from unstimulated prelabelled tissues was also reduced in the presence of endothelium. In normal physiological solution the rate of influx and efflux of Ca2+ stimulated by B-HT 920 (1 and 10 microM), but not that stimulated by phenylephrine (30 nM and 1 microM), was also reduced in the presence of endothelium. In the presence of the calcium entry blocker flunarizine (3 microM), phenylephrine (1 microM) stimulated efflux of Ca2+ was inhibited by the presence of endothelium. A correlation between inhibition of Ca2+ influx and modulation of alpha-adrenoceptor agonist-induced contractions by endothelium could not be demonstrated, and methylene blue, an antagonist of endothelium mediated inhibition of B-HT 920 contractions, did not affect Ca2+ influx stimulated by the agonist. The effects of endothelium on Ca2+ influx and efflux are unlikely to be due to alterations by endothelium of diffusion of 45Ca or the agonists in the vessel. The results demonstrate that an endothelial derived factor or factors can reduce calcium influx into smooth muscle cells and also modulate the release of calcium from cells, perhaps by affecting intracellular calcium pumping mechanisms. A reduction of calcium influx cannot be the sole explanation for the modulatory effect of endothelium on alpha-adrenoceptor agonist-induced contractions but an effect on intracellular calcium metabolism may be important. PMID:3024024

  10. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers.

    PubMed

    Batty, Mallory; Pugh, Rachel; Rathinam, Ilampirai; Simmonds, Joshua; Walker, Edwin; Forbes, Amanda; Anoopkumar-Dukie, Shailendra; McDermott, Catherine M; Spencer, Briohny; Christie, David; Chess-Williams, Russ

    2016-01-01

    This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. PMID:27537875

  11. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

    PubMed Central

    Batty, Mallory; Pugh, Rachel; Rathinam, Ilampirai; Simmonds, Joshua; Walker, Edwin; Forbes, Amanda; Anoopkumar-Dukie, Shailendra; McDermott, Catherine M.; Spencer, Briohny; Christie, David; Chess-Williams, Russ

    2016-01-01

    This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. PMID:27537875

  12. The effect of S-(+)-boldine on the alpha 1-adrenoceptor of the guinea-pig aorta.

    PubMed Central

    Chuliá, S.; Moreau, J.; Naline, E.; Noguera, M. A.; Ivorra, M. D.; D'Ocón, M. P.; Advenier, C.

    1996-01-01

    1. The cardiovascular activity of S-(+)-boldine, an aporphine alkaloid structurally related to papaverine, was determined. The work includes functional studies on guinea-pig isolated aorta contracted with noradrenaline, caffeine, KCl or Ca2+, and on guinea-pig trachea contracted with acetylcholine or histamine. 2. S-(+)-boldine inhibited in a concentration-dependent manner the contractile response evoked by noradrenaline (10 microM) in guinea-pig aorta (IC50 = 1.4 +/- 0.2 microM) while the KCl depolarizing solution (60 mM)- or the Ca2+ (1 mM)-induced contractions were only partially affected by boldine up to 300 microM. In contrast, papaverine relaxed noradrenaline (NA), KCl or Ca2+ induced contractions showing similar IC50 values in all cases. S-(+)-boldine had a greater potency on the contraction elicited by NA whereas papaverine acted in a non-selective manner. 3. S-(+)-boldine was found to be an alpha 1-adrenoceptor blocking agent in guinea-pig aorta as revealed by its competitive antagonism of noradrenaline-induced vasoconstriction (pA2 = 5.64 +/- 0.08), and its potency was compared with that of prazosin (pA2 = 8.56 +/- 0.24), a known potent alpha 1-adrenoceptor antagonist. In contrast, papaverine caused rightward shifts of the NA concentration-response curves with depression of maximal response indicating that it acts as a non-competitive antagonist. 4. Contraction of guinea-pig aorta induced by caffeine (60 mM) in a Ca(2+)-containing Krebs solution was not affected by a 60 min incubation period with different doses of S-(+)-boldine (1-300 microM). Papaverine inhibited partially this caffeine-induced contraction at the maximal dose used (100 microM). 5. Inositol phosphates formation induced by noradrenaline (10 microM) in guinea-pig thoracic aorta was inhibited by S-(+)-boldine (30 microM) but not by papaverine (10 microM). 6. Contractions of guinea-pig trachea caused by acetylcholine (100 microM) or histamine (10 microM) were not modified by S-(+)-boldine (0

  13. Restricted alpha- and beta-adrenoceptor affinity of sulfoconjugated catecholamines in human mononuclear leukocytes, platelets, and fat cells and reduction of the postreceptor mechanisms.

    PubMed

    Werle, E; Michel, G; Lenz, T; Kather, H; Schneider, B; Weicker, H

    1988-08-01

    The physiologic significance of the racemic 3-O-sulfate esters of epinephrine (EPI-3-O-S) and norepinephrine (NE-3-O-S) as well as 4-O-sulfoconjugated dopamine (DA-4-O-S) was evaluated. For this purpose these conjugated catecholamines (CA) were synthesized and investigated with respect to their alpha 2- and beta 2-adrenoceptor affinities and their biological activity in three different human cell systems: in mononuclear leukocytes (MNL), platelets, and fat cells. The unequivocal identification and the minimal degree of contamination of the synthesized sulfoconjugates with free CA was proved by 1H-NMR and by high-performance liquid chromatography with amperometric detection (HPLCA) respectively. In isolated human MNL, beta-adrenoceptor affinities of these conjugated CA were determined in competition experiments with the lipophilic nonspecific radioligand (-) 125I-cyanopindolol (ICYP) and, in addition, with the hydrophilic ligand 3H-CGP12177. With both ligands the affinity constants (KD) of the sulfoconjugated CA under investigation were about 100- to 1000-fold higher when compared with the respective free amines. Moreover, these sulfoconjugated CA per se induced no intracellular production of cyclic adenosine monophosphate (cAMP) in MNL. In comparison with the free amines, metanephrine (MN) and normetanephrine (NMN) showed a highly reduced competitive potency on the MNL beta-adrenoceptors labelled with 3H-CGP or ICYP. The KD values for MN and NMN in competition studies with ICYP were 10- and 5-fold higher than in those with 3H-CGP respectively, indicating a restricted access of MN and NMN to intracellular receptors. The adenylate cyclase system was not stimulated at all by MN or by NMN. In human platelets EPI-3-O-S and NE-3-O-S neither competed with the specific alpha 2-adrenoceptor antagonist 3H-yohimbine nor elicited any aggregation response at all. MN and NMN exhibited an about 40-fold reduced affinity for alpha 2-adrenoceptors in platelets when compared with the

  14. Age-related change of the role of alpha1L-adrenoceptor in canine urethral smooth muscle.

    PubMed

    Suzuki, Y; Moriyama, N; Okaya, Y; Nishimatsu, H; Kawabe, K; Aisaka, K

    1999-10-01

    To examine age-related alteration of the role of alpha1L-adrenoceptor in the urethra, young non-parous and aged parous female dogs were used. In a functional study, we evaluated phenylephrine-induced contraction and antagonistic effects of JTH-601, a newly synthesized alpha1-adrenoceptor antagonist, and prazosin; in a localization survey using autoradiographic technique, we investigated specific [3H]JTH-601 and [3H]tamsulosin binding. Concentration-response curves were obtained for phenylephrine (pD2 = 5.0-5.3). JTH-601 and prazosin antagonized this contraction with pA2 values of 8.2-8.3 and 8.0-8.1, respectively. Specific binding of both [3H]JTH-601 and [3H]tamsulosin were observed in the bladder neck and proximal section of urethra. There were no significant differences of the pD2, pA2, and radio ligand binding between young non-parous and aged parous dogs. PMID:10523074

  15. Adrenalectomy abolishes antagonism of alpha-adrenoceptor-mediated hypotension by a beta-blocker in conscious rats.

    PubMed Central

    Tabrizchi, R.; Pang, C. C.

    1990-01-01

    1. The effects of a single bolus injection of propranolol, atenolol or ICI 118,551, non-selective beta-, selective beta 1- and selective beta 2-adrenoceptor antagonists, respectively, on mean arterial pressure (MAP) and plasma catecholamine concentrations were examined in seven groups of conscious and unrestrained adrenalectomized rats receiving a continuous infusion of the alpha-adrenoceptor antagonist phentolamine. In all rats adrenaline was undetectable in the plasma four days after adrenalectomy. 2. In the first three groups, phentolamine significantly decreased MAP and increased the plasma concentrations of noradrenaline. The injection of propranolol, atenolol or ICI 118,551 in Groups I, II and III, respectively, caused a small increase in MAP and a small, but not significant, decrease in plasma noradrenaline concentrations. 3. Groups IV, V and VI were given a continuous infusion of adrenaline for 1 h prior to the infusion of phentolamine, followed by a bolus injection of propranolol, atenolol or ICI 118,551, respectively. Group VII was treated similarly to IV, but was also given daily cortisone replacement after adrenalectomy. Adrenaline slightly, but not significantly, decreased MAP while phentolamine significantly decreased MAP and increased plasma noradrenaline concentrations in all groups. A subsequent injection of a beta-blocker caused a significant increase in MAP in each group and a slight decrease in the plasma level of noradrenaline which reached statistical significance in group VII. The pressor effect of propranolol was significantly greater in the cortisone-treated rats (Group VII) than in Group IV. 5. The results suggest that adrenaline and adrenocortical steroids are both involved in the antagonism of alpha-adrenoceptor-induced hypotension by a beta-blocker. PMID:1979508

  16. Binding and functional characterization of alpha1-adrenoceptor subtypes in the rat prostate.

    PubMed

    Hiraoka, Y; Ohmura, T; Oshita, M; Watanabe, Y; Morikawa, K; Nagata, O; Kato, H; Taniguchi, T; Muramatsu, I

    1999-01-29

    The alpha1-adrenoceptor subtypes of rat prostate were characterized in binding and functional experiments. In binding experiments, [3H]tamsulosin bound to a single class of binding sites with an affinity (pKD) of 10.79+/-0.04 and Bmax of 87+/-2 fmol mg(-1) protein. This binding was inhibited by prazosin, 2-(2,6-dimethoxy-phenoxyethyl)-aminomethyl-1,4-benzodioxane hydrochloride (WB4101), 5-methylurapidil, alpha-ethyl-3,4,5,-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy)ethyl)-amin o)-propyl)benzeneacetonitrile fumarate (HV723) and oxymetazoline with high efficacy, resulting in a good correlation with the binding characteristics of cloned alpha1a but not alpha1b and alpha1d-adrenoceptor subtypes. In functional studies, noradrenaline and oxymetazoline produced concentration-dependent contractions. These contractions were antagonized by tamsulosin, prazosin, WB4101 and 5-methylurapidil with an efficacy lower than that exhibited by these agents for inhibition of [3H]tamsulosin binding. The relationship between receptor occupancy and contractile amplitude revealed the presence of receptor reserve for noradrenaline, but the contraction induced by oxymetazoline was not in parallel with receptor occupation and developed after predicted receptor saturation. From these results, it is suggested that alpha1A-adrenoceptors are the dominant subtype in the rat prostate which can be detected with [3H]tamsulosin, but that the functional subtype mediating adrenergic contractions has the characteristics of the alpha1L-adrenoceptor subtype, having a lower affinity for prazosin and some other drugs than the alpha1A-adrenoceptor subtype. PMID:10064160

  17. Selective deficit in no-go performance induced by blockade of prefrontal cortical alpha 2-adrenoceptors in monkeys.

    PubMed

    Ma, Chao-Lin; Qi, Xue-Lian; Peng, Ji-Yun; Li, Bao-Ming

    2003-05-23

    Two monkeys (Macaca mulatta) were trained to make a go response (go to touch a computer screen) when a red signal (go signal) was presented or a no-go response (inhibit the screen-touching action) when a green signal (no-go signal) was given. The alpha2-adrenergic antagonist yohimbine was infused locally, bilaterally and continuously for 8 days into the prefrontal cortex (PFC) by using mini-osmotic pump. The no-go but not go performance was selectively impaired during the 8-day administration of yohimbine: the monkeys showed an inability to inhibit the touching response to the no-go signal, indicating that there was a deficit in the inhibitory ability of the animals. Similar infusion of saline into the same cortical area was without effect. The present study provides behavioral pharmacological evidence that alpha2-adrenoceptors in the PFC are involved in the neural mechanisms underlying response inhibition. PMID:12802193

  18. Identification and characterization of (/sup 3/H)-rauwolscine binding to alpha2-adrenoceptors in the canine saphenous vein

    SciTech Connect

    Gout, B.

    1988-01-01

    The biochemical exploration of the alpha2-adrenergic receptors was investigated in the canine saphenous vein using the highly selective alpha2-adrenergic antagonist rauwolscine as a tritiated ligand. Following an enzymatic digestive pretreatment, the authors isolated a purified smooth muscle cell membranes fraction from saphenous veins in quantity sufficient to permit them to study the venous alpha2-adrenoreceptor content. The binding of tritiated rauwolscine was rapid, specific, saturable and reversible. The presence of high affinity sites with a density of binding Bmax of 125.2 /+ -/ 43.1 fmol/mg protein was demonstrated on a unique class of non interacting sites. The kinetically derived Kd was 1.28 nM, in good agreement with the value obtained from saturation isotherms. The pharmacological profile of these sites was assessed by the comparison of the potency of alpha-adrenergic agonists and antagonists to inhibit 1 nM (/sup 3/H)-rauwolscine. Their efficacy was respectively: rauwolscine > phentolamine > RX 781094 > clonidine >> prazosin > (-)-phenylephrine > (-)-noradrenaline. The results showed that (/sup 3/H)-rauwolscine bound specifically to sites in their membranal preparation, which had the pharmacological characteristics of the alpha2-adrenoceptors. The correlation between biochemical and pharmacological data revealed the usefulness of binding methods in the further study of adrenergic mechanisms in the canine saphenous vein.

  19. In vitro studies of release of adenine nucleotides and adenosine from rat vascular endothelium in response to alpha 1-adrenoceptor stimulation.

    PubMed Central

    Shinozuka, K; Hashimoto, M; Masumura, S; Bjur, R A; Westfall, D P; Hattori, K

    1994-01-01

    1. Noradrenaline-induced release of endogenous adenine nucleotides (ATP, ADP, AMP) and adenosine from both rat caudal artery and thoracic aorta was characterized, using high-performance liquid chromatography with fluorescence detection. 2. Noradrenaline, in a concentration-dependent manner, increased the overflow of ATP and its metabolites from the caudal artery. The noradrenaline-induced release of adenine nucleotides and adenosine from the caudal artery was abolished by bunazosin, an alpha 1-adrenoceptor antagonist, but not by idazoxan, an alpha 2-adrenoceptor antagonist. Clonidine, an alpha 2-adrenoceptor agonist, contracted caudal artery smooth muscle but did not induce release of adenine nucleotides or adenosine. 3. Noradrenaline also significantly increased the overflow of ATP and its metabolites from the thoracic aorta in the rat; however, the amount of adenine nucleotides and adenosine released from the aorta was considerably less than that released from the caudal artery. 4. Noradrenaline significantly increased the overflow of ATP and its metabolites from cultured endothelial cells from the thoracic aorta and caudal artery. The amount released from the cultured endothelial cells from the thoracic aorta and caudal artery. The amount released from the cultured endothelial cells from the aorta was also much less than that from cultured endothelial cells from the caudal artery. In cultured smooth muscle cells from the caudal artery, a significant release of ATP or its metabolites was not observed. 5. These results suggest that there are vascular endothelial cells that are able to release ATP by an alpha 1-adrenoceptor-mediated mechanism, but that these cells are not homogeneously distributed in the vasculature. PMID:7889273

  20. Pharmacological characterization and CNS effects of a novel highly selective α2C-adrenoceptor antagonist JP-1302

    PubMed Central

    Sallinen, J; Höglund, I; Engström, M; Lehtimäki, J; Virtanen, R; Sirviö, J; Wurster, S; Savola, J-M; Haapalinna, A

    2007-01-01

    Background and purpose: Pharmacological validation of novel functions for the α2A-, α2B-, and α2C-adrenoceptor (AR) subtypes has been hampered by the limited specificity and subtype-selectivity of available ligands. The current study describes a novel highly selective α2C-adrenoceptor antagonist, JP-1302 (acridin-9-yl-[4-(4-methylpiperazin-1-yl)-phenyl]amine). Experimental approach: Standard in vitro binding and antagonism assays were employed to demonstrate the α2C-AR specificity of JP-1302. In addition, JP-1302 was tested in the forced swimming test (FST) and the prepulse-inhibition of startle reflex (PPI) model because mice with genetically altered α2C-adrenoceptors have previously been shown to exhibit different reactivity in these tests when compared to wild-type controls. Key results: JP-1302 displayed antagonism potencies (K B values) of 1,500, 2,200 and 16 nM at the human α2A-, α2B-, and α2C-adrenoceptor subtypes, respectively. JP-1302 produced antidepressant and antipsychotic-like effects, i.e. it effectively reduced immobility in the FST and reversed the phencyclidine-induced PPI deficit. Unlike the α2-subtype non-selective antagonist atipamezole, JP-1302 was not able to antagonize α2-agonist–induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, α2-agonist-induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the α2A-adrenoceptor subtype. In contrast to JP-1302, atipamezole did not antagonize the PCP-induced prepulse-inhibition deficit. Conclusions and implications: The results provide further support for the hypothesis that specific antagonism of the α2C-adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders. PMID:17220913

  1. Alpha2 adrenoceptors regulate proliferation of human intestinal epithelial cells

    PubMed Central

    Schaak, S; Cussac, D; Cayla, C; Devedjian, J; Guyot, R; Paris, H; Denis, C

    2000-01-01

    BACKGROUND AND AIMS—Previous studies on rodents have suggested that catecholamines stimulate proliferation of the intestinal epithelium through activation of α2 adrenoceptors located on crypt cells. The occurrence of this effect awaits demonstration in humans and the molecular mechanisms involved have not yet been elucidated. Here, we examined the effect of α2 agonists on a clone of Caco2 cells expressing the human α2A adrenoceptor.
METHODS—Cells were transfected with a bicistronic plasmid containing the α2C10 and neomycin phosphotransferase genes. G418 resistant clones were assayed for receptor expression using radioligand binding. Receptor functionality was assessed by testing its ability to couple Gi proteins and to inhibit cAMP production. Mitogen activated protein kinase (MAPK) phosphorylation was followed by western blot, and cell proliferation was estimated by measuring protein and DNA content.
RESULTS—Permanent transfection of Caco2 cells allowed us to obtain a clone (Caco2-3B) expressing α2A adrenoceptors at a density similar to that found in normal human intestinal epithelium. Caco2-3B retained morphological features and brush border enzyme expression characteristic of enterocytic differentiation. The receptor was coupled to Gi2/Gi3 proteins and its stimulation caused marked diminution of forskolin induced cAMP production. Treatment of Caco2-3B with UK14304 (α2 agonist) induced a rapid increase in the phosphorylation state of MAPK, extracellular regulated protein kinase 1 (Erk1), and 2 (Erk2). This event was totally abolished in pertussis toxin treated cells and in the presence of kinase inhibitors (genistein or PD98059). It was unaffected by protein kinase C downregulation but correlated with a transient increase in Shc tyrosine phosphorylation. Finally, sustained exposure of Caco2-3B to UK14304 resulted in modest but significant acceleration of cell proliferation. None of these effects was observed in the parental cell line Caco2.

  2. Evidence that locus coeruleus is the site where clonidine and drugs acting at alpha 1- and alpha 2-adrenoceptors affect sleep and arousal mechanisms.

    PubMed Central

    De Sarro, G. B.; Ascioti, C.; Froio, F.; Libri, V.; Nisticò, G.

    1987-01-01

    The behavioural and electrocortical (ECoG) effects of clonidine were studied after microinjection into the third cerebral ventricle, or microinfusion into some specific areas of the rat brain rich in noradrenaline-containing cell bodies (locus coeruleus) or into areas receiving noradrenergic terminals (dorsal hippocampus, amygdaloid complex, thalamus, frontal and sensimotor cortex). The ECoG effects were continuously analysed and quantified by means of a Berg-Fourier analyser as total power and as power in preselected bands of frequency. Clonidine (9.4 to 75 nmol) given into the third cerebral ventricle produced behavioural sedation and sleep and a dose-dependent increase in ECoG total voltage power as well as in the lower frequency bands. Much lower doses were required to produce similar behavioural and ECoG spectrum power effects after either unilateral or bilateral microinfusion of clonidine into the locus coeruleus. Doses of clonidine equimolar to those given into the third cerebral ventricle, were almost ineffective in inducing behavioural and ECoG sleep after their microinfusion into the dorsal hippocampus. In addition, a dose (0.56 nmol) of clonidine which, given into the locus coeruleus, produced marked behavioural sleep and ECoG synchronization, lacked effects when given into the ventral or anterior thalamus, into the amygdaloid complex or onto the frontal and sensimotor cortex. The behavioural and ECoG spectrum power effects of clonidine given into the third cerebral ventricle or into the locus coeruleus were prevented by antagonists of alpha 2-adrenoceptors but not by alpha 1-adrenoceptor antagonists. Intraventricular microinjection, or microinfusion into the locus coeruleus, of yohimbine, a selective alpha 2-adrenoceptor antagonist, produced behavioural arousal, increase in locomotor and exploratory activity, tachypnoea and ECoG desynchronization with a significant reduction in total voltage power. Similar stimulatory effects were also observed after

  3. Lack of effect of chronic calcium antagonist treatment on beta 1- and beta 2-adrenoceptors in right atria from patients with or without heart failure.

    PubMed Central

    Brodde, O E; Hundhausen, H J; Zerkowski, H R; Michel, M C

    1992-01-01

    1. We studied the effects of chronic calcium antagonist (calcium entry blocker, CEB; nifedipine, verapamil, diltiazem) treatment on beta-adrenoceptor density (assessed by (-)-[125I]-iodocyanopindolol [ICYP] binding) and subtype distribution in right atria from 65 patients without apparent heart failure undergoing elective coronary artery bypass grafting (CAD-patients) and from 13 patients with moderate heart failure (NYHA class III to class III-IV) undergoing mitral valve replacement (MVD-patients). 2. In CAD-patients atrial beta-adrenoceptor density was 79.3 +/- 7.9 fmol ICYP bound mg-1 protein (n = 18), the beta 1:beta 2-adrenoceptor ratio 69:31%. Chronic CEB-treatment did not affect either atrial beta-adrenoceptor density or beta 1:beta 2-adrenoceptor ratio. 3. In contrast, in CAD-patients chronically treated with beta 1-adrenoceptor antagonists (atenolol, bisoprolol, metoprolol) and CEB, atrial beta-adrenoceptor density was significantly increased (108.6 +/- 10.5 fmol ICYP bound mg-1 protein, n = 21); this increase was due to a selective increase in beta 1-adrenoceptors. 4. In MVD-patients atrial beta-adrenoceptor density (55.5 +/- 8.7 fmol ICYP bound mg-1 protein, n = 7) was significantly lower (P less than 0.05) than in CAD-patients; beta 1:beta 2-adrenoceptor ratio, however, was not changed (67:33%). Chronic CEB-treatment of MVD-patients did not prevent the decrease in atrial beta-adrenoceptors. 5. We conclude that chronic CEB-treatment does not affect human right atrial beta-adrenoceptor density, either in patients without apparent heart failure or in patients with moderate heart failure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1315561

  4. Effects of beta-adrenoceptor antagonists on Ca(2+)-overload induced by lysophosphatidylcholine in rat isolated cardiomyocytes.

    PubMed Central

    Chen, M.; Hashizume, H.; Abiko, Y.

    1996-01-01

    1. The effects of beta-adrenoceptor antagonists including (-)- and (+)-propranolol, (-)- and (+)-penbutolol, timolol, pindolol, atenolol, acebutolol and practolol on the Ca(2+)-overload induced by lysophosphatidylcholine (LPC) were examined in isolated cardiomyocytes of the rat. 2. Fura-2 was used for measurement of the intracellular calcium concentration ([Ca2+]i). LPC (15 microM) produced a rapid increase in [Ca2+]i from 72 +/- 5 to 3042 +/- 431 nM which coincided with a decrease in the percentage of rod-shaped cells from 69 +/- 2 to 5 +/- 2%. 3. Preincubation with (-)-propranolol (20 microM), (+)-propranolol (50 microM), or (-)- or (+)-penbutolol (20 microM), the lipophilicity of which is higher than other beta-adrenoceptor antagonists, significantly inhibited both the increase in [Ca2+]i and the cell-shape change induced by 15 microM LPC. The inhibitory effects of the four drugs on the LPC-induced increase in [Ca2+]i and cell-shape change were concentration-dependent. The IC50S of (-)-propranolol, (+)-propranolol, (-)- and (+)-penbutolol for the increase in [Ca2+]i were 1.28, 10.50, 0.67 and 0.76 microM, respectively. 4. Pretreatment with pindolol, timolol, acebutolol, practolol, atenolol or lignocaine did not inhibit the increase in [Ca2+]i and the morphological change induced by LPC. 5. LPC markedly increased the release of creatine phosphokinase from 9 +/- 1 to 45 +/- 2% which could be significantly reduced by (-)- or (+)-propranolol but not by acebutolol or timolol. 6. The protective effects of (-)- and (+)-propranolol, (-)- and (+)-penbutolol against the Ca(2+)-overload induced by LPC were not associated with the beta-adrenoceptor antagonistic action, but probably with an unknown action which is related to the preservation of membrane integrity. Further studies are necessary to clarify the exact mechanisms of the protective action of these beta-adrenoceptor antagonists against the Ca(2+)-overload induced by LPC. PMID:8799555

  5. Identification of a novel snake peptide toxin displaying high affinity and antagonist behaviour for the α2-adrenoceptors

    PubMed Central

    Rouget, Céline; Quinton, Loïc; Maïga, Arhamatoulaye; Gales, Céline; Masuyer, Geoffrey; Malosse, Christian; Chamot-Rooke, Julia; Thai, Robert; Mourier, Gilles; de Pauw, Edwin; Gilles, Nicolas; Servent, Denis

    2010-01-01

    BACKGROUND AND PURPOSE Muscarinic and adrenergic G protein-coupled receptors (GPCRs) are the targets of rare peptide toxins isolated from snake or cone snail venoms. We used a screen to identify novel toxins from Dendroaspis angusticeps targeting aminergic GPCRs. These toxins may offer new candidates for the development of new tools and drugs. EXPERIMENTAL APPROACH In binding experiments with 3H-rauwolscine, we studied the interactions of green mamba venom fractions with α2-adrenoceptors from rat brain synaptosomes. We isolated, sequenced and chemically synthesized a novel peptide, ρ-Da1b. This peptide was pharmacologically characterized using binding experiments and functional tests on human α2-adrenoceptors expressed in mammalian cells. KEY RESULTS ρ-Da1b, a 66-amino acid peptide stabilized by four disulphide bridges, belongs to the three-finger-fold peptide family. Its synthetic homologue inhibited 80% of 3H-rauwolscine binding to the three α2-adrenoceptor subtypes, with an affinity between 14 and 73 nM and Hill slopes close to unity. Functional experiments on α2A-adrenoceptor demonstrated that ρ-Da1b is an antagonist, shifting adrenaline activation curves to the right. Schild regression revealed slopes of 0.97 and 0.67 and pA2 values of 5.93 and 5.32 for yohimbine and ρ-Da1b, respectively. CONCLUSIONS AND IMPLICATIONS ρ-Da1b is the first toxin identified to specifically interact with α2-adrenoceptors, extending the list of class A GPCRs sensitive to toxins. Additionally, its affinity and atypical mode of interaction open up the possibility of its use as a new pharmacological tool, in the study of the physiological roles of α2-adrenoceptor subtypes. PMID:20659106

  6. In vivo binding in rat brain and radiopharmaceutical preparation of radioiodinated HEAT, an alpha-1 adrenoceptor ligand

    SciTech Connect

    Couch, M.W.; Greer, D.M.; Thonoor, C.M.; Williams, C.M.

    1988-03-01

    In vivo binding of (/sup 125/I)-2-(beta-(3-iodo-4-hydroxyphenyl)ethylaminomethyl tetralone) ((/sup 125/I)HEAT) to alpha-1 adrenoceptors in the rat brain was determined over 4 hr. Uptake in the thalamus and frontal cortex was approximately 0.1% injected dose per gram tissue. Thalamus/cerebellum ratios of 10:1 and frontal cortex/cerebellum ratios of 5:1 were found at 4 hr. Pretreatment with prazosin, an alpha-1 antagonist, completely inhibited the accumulation of (/sup 125/I)HEAT in thalamus and frontal cortex; yet uptake of radioactivity was not significantly affected by antagonists and agonists for other receptors classes (propranolol, beta-1; apomorphine, D-1; spiperone, D-2). Binding of (/sup 125/I)HEAT is saturable. At 4 hr, (/sup 125/I)HEAT or (/sup 123/I)HEAT was shown to be the only radioactive material in rat thalamus and frontal cortex. Iodine-123 HEAT and (/sup 125/I)HEAT were synthesized as radiopharmaceuticals within 3 hr in 99% radiochemical purity.

  7. Identification of an alpha sub 2 -adrenoceptor in human coronary arteries by radioligand binding assay

    SciTech Connect

    Ishikawa, Y.; Umemura, S.; Uchino, K.; Shindou, T.; Yasuda, G.; Minamisawa, K.; Hayashi, S.; Hirawa, N.; Ishii, M. )

    1991-01-01

    A single high affinity binding site for an alpha{sub 2}-adrenoceptor in human coronary arteries was identified by radioligand binding assay. Human coronary arteries were obtained at autopsy within 6 hours of death. A crude membrane solution was incubated with ({sup 3}H)-rauwolscine at 25C for 30 min. The binding of ({sup 3}H)-rauwolscine was rapidly saturable and reversible. Kd was 1.2 {plus minus} 0.2 (SE) nM and Bmax 22 {plus minus} 3 fmol/mg protein. This is the first study which has shown the presence of an alpha{sub 2}-adrenoceptor in human coronary arteries using a radioligand binding assay method.

  8. The properties of imidazoline derivatives to stimulate insulin release by hamster pancreatic islets are probably due to alpha 2-adrenoceptor blockade but not to interaction with non-adrenergic idazoxan binding sites.

    PubMed

    Lacombe, C R; Viallard, V P; Paris, H J

    1993-01-01

    The present study attempts to define the roles of alpha 2-adrenoceptors and of non-adrenergic idazoxan binding sites on insulin release using various alpha 2-adrenoceptor blocking agents belonging to the imidazoline family or not. Experiments were performed either on freshly isolated or on 24 h-cultured pancreatic islets from adult male hamsters. Neither the densities of alpha 2-adrenoceptors and non adrenergic idazoxan binding sites nor the response to the alpha 2-agonist, clonidine, were changed after the survival period. The effect of various alpha 2-antagonists: idazoxan, RX821002, phentolamine and yohimbine on the rate of insulin release was investigated. On freshly isolated islets, the imidazoline compounds stimulated insulin release while yohimbine did not. Nevertheless, this stimulation was no more observed with any of these compounds when tested on islets maintained in survival for 24 h. The measurement of catecholamines indicated that the level of noradrenaline was high in freshly isolated islets while it was undetectable after 24 h-culture. Taken together these results suggest that alpha 2-antagonists stimulate insulin release by relieving the beta-cell from the inhibitory effect of prebound endogenous catecholamines. PMID:7904946

  9. Determination of molecular size of alpha-1 and alpha-2 adrenoceptors in rat mesenteric artery by radiation inactivation

    SciTech Connect

    Agrawal, D.K.; Grover, A.K.; Daniel, E.E.; Jung, C.Y.

    1986-03-01

    Radiation inactivation of alpha-1 and alpha-2 adrenoceptors in the purified plasma membranes of rat mesenteric artery has been performed with high energy electrons at -45 to -55 degrees C. Alpha-1 and alpha-2 adrenoceptor inactivation was monitored with (3H) prazosin and (3H)yohimbine binding, respectively. Internal endogenous and external standards of known molecular weight were used in these studies to determine the molecular size. The average value of D37 for the (3H)prazosin binding site was 6.75 +/- 0.62 Mrad (n = 4) with an estimated molecular size of 122,921 +/- 11,329 Daltons. However, the average value of D37 for the (3H) yohimbine binding site was higher (D37 = 10.05 +/- 0.91 Mrad) and accordingly the molecular size of this binding site was less than the (3H)prazosin binding sites (molecular weight = 82,540 +/- 7478 Daltons; n = 4). Irradiation did not change the dissociation constant of either radioligand, suggesting that the loss of the radioligand binding sites after radiation is due to receptor protein inactivation. These results confirm our earlier finding that (3H)prazosin and (3H)yohimbine bind to two distinct sites in the plasma membranes of rat mesenteric artery. Whether both of these sites are the subunits of a common macromolecule of alpha adrenoceptor on vascular smooth muscle in rat mesenteric artery cannot be concluded from these results. This report is the first one in the literature on the molecular size of alpha-1 and alpha-2 binding sites in vascular smooth muscle.

  10. Centaurin-alpha 1, an ADP-ribosylation factor 6 GTPase activating protein, inhibits beta 2-adrenoceptor internalization.

    PubMed

    Lawrence, Joanna; Mundell, Stuart J; Yun, Hongruo; Kelly, Eamonn; Venkateswarlu, Kanamarlapudi

    2005-06-01

    The small GTP-binding protein ADP ribosylation factor 6 (ARF6) has recently been implicated in the internalization of G protein-coupled receptors (GPCRs), although its precise molecular mechanism in this process remains unclear. We have recently identified centaurin alpha(1) as a GTPase activating protein (GAP) for ARF6. In the current study, we characterized the effects of centaurin alpha(1) on the agonist-induced internalization of the beta(2)-adrenoceptor transiently expressed in human embryonic kidney (HEK) 293 cells. Using an enzyme-linked immunosorbent assay as well as confocal imaging of cells, we found that expression of centaurin alpha(1) strongly inhibited the isoproterenol-induced internalization of beta(2)-adrenoceptor. On the other hand, expression of functionally inactive versions of centaurin alpha(1), including an R49C mutant, which has no catalytic activity, and a double pleckstrin homology (PH) mutant (DM; R148C/R273C), which has mutations in both the PH domains of centaurin alpha(1), rendering it unable to translocate to the cell membrane, were unable to inhibit beta(2)-adrenoceptor internalization. In addition, a constitutively active version of ARF6, ARF6Q67L, reversed the ability of centaurin alpha(1) to inhibit beta(2)-adrenoceptor internalization. Finally, expression of centaurin alpha(1) also inhibited the agonist-induced internalization of beta(2)-adrenoceptor endogenously expressed in HEK 293 cells, whereas the R49C and DM mutant versions of centaurin alpha(1) had no effect. Together, these data indicate that by acting as an ARF6 GAP, centaurin alpha(1) is able to switch off ARF6 and so inhibit its ability to mediate beta(2)-adrenoceptor internalization. Thus, ARF6 GAPs, such as centaurin alpha(1), are likely to play a crucial role in GPCR trafficking by modulating the activity of ARF6. PMID:15778454

  11. Alpha 1-Adrenoceptor Blocker May Improve Not Only Voiding But Also Storage Lower Urinary Tract Symptoms Caused by 125I Brachytherapy for Prostate Cancer

    PubMed Central

    Aoki, Yoshitaka; Ito, Hideaki; Miwa, Yoshiji; Akino, Hironobu; Shioura, Hiroki; Kimura, Hirohiko; Yokoyama, Osamu

    2014-01-01

    Purpose. To assess changes in lower urinary tract symptoms (LUTS) within 1 year after brachytherapy in patients receiving alpha 1-adrenoceptor antagonists. Methods. We retrospectively evaluated 116 patients who underwent 125I prostate brachytherapy in our institute. Seventy-one patients were treated with a combination of external beam radiation therapy and brachytherapy. Alpha 1-adrenoceptor antagonists were prescribed to all patients after brachytherapy. International Prostate Symptom Score (IPSS) forms and postvoid residual urine volume were recorded at all follow-up visits. Results. Forty-nine patients were given tamsulosin hydrochloride, 32 were given silodosin hydrochloride, and 35 were given naftopidil for up to 6 months after seed implantation. Patients given tamsulosin or naftopidil tended to show a higher peak IPSS and slower recovery to baseline values than those given silodosin. The patients given naftopidil showed an insufficient recovery in storage symptoms in naftopidil group in comparison with tamsulosin group at 3 months and with silodosin group at 6 and 9 months. Conclusions. In the management of LUT after brachytherapy, silodosin may provide a more favorable improvement. Silodosin and tamsulosin may have an advantage in improving not only voiding but also storage lower urinary tract symptoms after brachytherapy. PMID:25006516

  12. Rayleigh light scattering detection of three α1-adrenoceptor antagonists coupled with high performance liquid chromatograph

    NASA Astrophysics Data System (ADS)

    Li, Ai Ping; Peng, Huanjun; Peng, Jing Dong; Zhou, Ming Qiong; Zhang, Jing

    2015-08-01

    Herein, a Rayleigh light-scattering (RLS) detection method combined with high performance liquid chromatograph (HPLC) without any post-column probe was developed for the separation and determination of three α1-adrenoceptor antagonists. The quantitative analysis is benefiting from RLS signal enhancement upon addition of methanol which induced molecular aggregation to form an hydrophobic interface between aggregates and water that produce a sort of superficial enhanced scattering effect. A good chromatographic separation among the compounds was achieved using a Gemini 5u C18 reversed phase column (250 mm × 4.6 mm; 4 μm) with a mobile phase consisting of methanol and ammonium acetate-formic acid buffer solution (25 mM; pH = 3.0) at the flow rate of 0.7 mL min-1. The RLS signal was monitored at λex = λem = 354 nm. A limit of detection (LOD) of 0.065-0.70 μg L-1 was reached and a linear range was found between peak height and concentration in the range of 0.75-15 μg L-1 for doxazosin mesylate (DOX), 0.075-3.0 μg L-1 for prazosin hydrochloride (PRH), and 0.25-5 μg L-1 for terazosin hydrochloride (TEH), with linear regression coefficients all above 0.999. Recoveries from spiked urine samples were 88.4-99.0% which is within acceptable limits. The proposed method is convenient, reliable and sensitive which has been used successfully in human urine samples.

  13. [alpha]2A-Adrenoceptor Stimulation Improves Prefrontal Cortical Regulation of Behavior through Inhibition of cAMP Signaling in Aging Animals

    ERIC Educational Resources Information Center

    Verduzco, Luis; van Dyck, Christopher H.; Arnsten, Amy F. T.; Ramos, Brian P.; Stark, David

    2006-01-01

    The working-memory functions of the prefrontal cortex (PFC) are improved by stimulation of postsynaptic, [alpha]2A-adrenoceptors, especially in aged animals with PFC cognitive deficits. Thus, the [alpha]2A-adrenoceptor agonist, guanfacine, greatly improves working-memory performance in monkeys and rats following systemic administration or…

  14. Selective action of two aporphines at alpha 1-adrenoceptors and potential-operated Ca2+ channels.

    PubMed

    Ivorra, M D; Chuliá, S; Lugnier, C; D'Ocon, M P

    1993-02-01

    Contractions evoked by noradrenaline (1 microM) or a depolarizing solution of 60 mM KCl were concentration dependently depressed by the aporphine alkaloids (S)-boldine and (R)-apomorphine in rat aorta. Both drugs had a greater inhibitory potency on the contraction elicited by noradrenaline. Dose-response curves for noradrenaline were shifted to the right in presence of (S)-boldine. (R)-Apomorphine acted by a complex mechanism at alpha 1-adrenoceptors and its inhibitory effect was irreversible. The conformational features of these alkaloids may explain their different behaviour at alpha 1-adrenoceptors. In Ca(2+)-free solution, the alkaloids inhibited the contraction evoked by noradrenaline but did not modify (apomorphine) or increase (boldine) the contractile response induced by caffeine. Both alkaloids interacted with [3H]prazosin binding and with the benzothiazepine binding site of the Ca2+ entry receptor complex but had no effect at the dihydropyridine binding site in the rat cerebral cortex. Both drugs showed some selectivity as inhibitors of [3H]prazosin binding as opposed to [3H]d-cis diltiazem binding. (R)-Apomorphine slightly inhibited one of the two forms of the Ca(2+)-independent, low Km cyclic AMP-phosphodiesterase (type IV), whereas it did not have a significant effect on the other phosphodiesterase forms. (S)-Boldine had negligible inhibitory effects on all phosphodiesterase forms. The present study provides evidence that (S)-boldine and (R)-apomorphine have interesting properties as Ca2+ entry blockers (through the benzothiazepine receptor site in the Ca2+ channel) and at alpha 1-adrenoceptors. PMID:8384112

  15. Heterogeneous /sup 3/H-rauwolscine binding sites in rat complex: two alpha/sub 2/-adrenoceptor subtypes or and additional non-adrenergic interaction

    SciTech Connect

    Broadhurst, A.M.; Alexander, B.S.; Wood, M.D.

    1988-01-01

    Ligand binding and isolated tissue data have provided evidence for the existence of two, tissue-specific, alpha/sub 2/-adrenoceptor in various rodent and non-rodent species. Thus, it has been proposed that the complex binding of alpha/sub 2/-antagonists to rat cortical membranes is due to the presence of both subtypes in this tissue. The authors have previously shown that the alpha/sub 2/-antagonist /sup 3/H-rauwolscine binds to two sites on rat cortical membranes: a high affinity component characterized pharmacologically as an alpha/sub 2/-binding site, and a low affinity, spiperone-sensitive, serotonergic-like component. By the use of computerized non-linear curve fitting, and the inclusion of a concentration of spiperone previously shown to selectively occlude the low affinity component of the /sup 3/H-rauwolscine saturation isotherm, they have determined the rank order of affinity at each of the two sites. Whereas the rank order of affinity at the high affinity site retains the pharmacological profile of a single, monophaisc alpha/sub 2/-binding-site, that at the low affinity component is markedly different and is similar to that at the putative 5HT subtype.

  16. Does prostate volume affect the efficacy of α1D/A: Adrenoceptor antagonist naftopidil?

    PubMed Central

    Tanuma, Yasushi; Tanaka, Yoshinori; Takeyama, Ko; Okamoto, Tomoshi

    2016-01-01

    Introduction: There have been reports that one of the factors affecting the efficacy of α1-adrenoceptor antagonists (α1-blocker; α1-B) was prostate volume (PV). However, there are few reports of short-term prospective trials comparing the efficacy of α1-B by PV. We examined the influence of PV on the short-term efficacy of naftopidil dose increase therapy to administration of 75 mg/day after an initial dose of 50 mg/day. Materials and Methods: A total of 85 patients with lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) received 50 mg/day of naftopidil for 4 weeks. After 4 weeks, the dosage of naftopidil was increased to 75 mg/day for a further 4 weeks. We divided the patients into two groups of PV ≥40 mL at baseline (Group L) and PV <40 mL at baseline (Group S). Results: International Prostate Symptom Score (IPSS), IPSS storage symptoms, and IPSS quality-of-life score were significantly improved at 4 and 8 weeks compared with baseline in both Groups. IPSS voiding symptoms (IPSS-VS) were significantly improved at 4 and 8 weeks compared with baseline in Group S. IPSS and IPSS-VS were significantly improved at 8 weeks compared with 4 weeks only in Group L. IPSS-VS and intermittency at 4 weeks were significantly decreased in Group S compared with Group L. Maximum flow rate was significantly improved at 8 weeks compared with baseline in Group L. Conclusions: PV is a predictive factor affecting the efficacy of naftopidil 50 mg/day for IPSS-VS, and the dose increase to 75 mg/day effective for IPSS-VS. A total of 50 mg/day of naftopidil is the maintenance dose for LUTS/BPH patients with a small PV, and 75 mg/day of dose increase therapy should be chosen for patients with a large PV. PMID:26834396

  17. Structural determinants of the alpha2 adrenoceptor subtype selectivity

    PubMed Central

    Ostopovici-Halip, Liliana; Curpăn, Ramona; Mracec, Maria; Bologa, Cristian G.

    2012-01-01

    Alpha2-adrenergic receptor (α2-AR) subtypes, acting mainly on the central nervous and cardiovascular systems, represent important targets for drug design, confirmed by the high number of studies published so far. Presently, only few α2-AR subtype selective compounds are known. Using homology modeling and ligand docking, the present study analyzes the similarities and differences between binding sites, and between extracellular loops of the three subtypes of α2-AR. Several α2-AR subtype selective ligands were docked in the active sites of the three α2-AR subtypes, key interactions between ligands and receptors were mapped, and the predicted results were compared to experimental results. Binding site analysis reveals a strong identity between important amino acid residues in each receptor, the very few differences being the key towards modulating selectivity of α2-AR ligands. The observed differences between binding site residues provide an excellent starting point for virtual screening of chemical databases in order to identify potentially selective ligands for α2-ARs. PMID:21602069

  18. Modulation of intracellular Ca2+ via L-type calcium channels in heart cells by the autoantibody directed against the second extracellular loop of the alpha1-adrenoceptors.

    PubMed

    Bkaily, Ghassan; El-Bizri, Nesrine; Bui, Michel; Sukarieh, Rami; Jacques, Danielle; Fu, Michael L X

    2003-03-01

    The effects of methoxamine, a selective alpha1-adrenergic receptor agonist, and the autoantibody directed against the second extracellular loop of alpha1-adrenoceptors were studied on intracellular free Ca2+ levels using confocal microscopy and ionic currents using the whole-cell patch clamp technique in single cells of 10-day-old embryonic chick and 20-week-old fetal human hearts. We observed that like methoxamine, the autoantibody directed against the second extracellular loop of alpha1-adrenoreceptors significantly increased the L-type calcium current (I(Ca(L))) but had no effect on the T-type calcium current (I(Ca(T))), the delayed outward potassium current, or the fast sodium current. This effect of the autoantibody was prevented by a prestimulation of the receptors with methoxamine and vice versa. Moreover, treating the cells with prazosin, a selective alpha1-adrenergic receptor antagonist blocked the methoxamine and the autoantibody-induced increase in I(Ca(L)), respectively. In absence of prazosin, both methoxamine and the autoantibody showed a substantial enhancement in the frequency of cell contraction and that of the concomitant cytosolic and nuclear free Ca2+ variations. The subsequent addition of nifedipine, a specific L-type Ca2+ channel blocker, reversed not only the methoxamine or the autoantibody-induced effect but also completely abolished cell contraction. These results demonstrated that functional alpha1-adrenoceptors exist in both 10-day-old embryonic chick and 20-week-old human fetal hearts and that the autoantibody directed against the second extracellular loop of this type of receptors plays an important role in stimulating their activity via activation of L-type calcium channels. This loop seems to have a functional significance by being the target of alpha1-receptor agonists like methoxamine. PMID:12733822

  19. Measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in mouse brain by h.p.l.c. with electrochemical detection, as an index of noradrenaline utilisation and presynaptic alpha 2-adrenoceptor function.

    PubMed Central

    Heal, D. J.; Prow, M. R.; Buckett, W. R.

    1989-01-01

    1. A novel method for measurement of 3-methoxy-4-hydroxyphenylglycol (MHPG) in mouse brain by use of high performance liquid chromatography (h.p.l.c.) with electrochemical detection is described. This technique incorporates an ethyl acetate purification procedure and uses 3-hydroxy-4-methoxyphenylglycol (iso-MHPG) as the internal standard. 2. Inhibition of monoamine oxidase by injection of tranylcypromine (5 and 10 mg kg-1) or pargyline (50 and 100 mg kg-1) markedly decreased brain MHPG concentrations. After injection of the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine (200 mg kg-1), there were time-dependent linear decreases in the concentrations of noradrenaline and MHPG in mouse brain. In addition, a very good correlation (r = 0.95, n = 30; P less than 0.001) was found between the concentrations of noradrenaline and MHPG present in the brains of the same mice after alpha-methyl-p-tyrosine treatment. 3. Mouse brain MHPG concentrations were dose-dependently reduced after administration of the alpha 2-adrenoceptor agonist, clonidine (1-3000 micrograms kg-1), and elevated by the antagonists, idazoxan (1 and 5 mg kg-1), and yohimbine (1 and 5 mg kg-1). Intracerebroventricular injection of the alpha 1-adrenoceptor agonist, phenylephrine (5-50 micrograms) dose-dependently increased MHPG levels. The alpha 1-adrenoceptor antagonist, prazosin, had no effect at the moderate dose of 1 mg kg-1, but increased MHPG concentrations at 5 mg kg-1. The beta-adrenoceptor agonist, clenbuterol (10-1000 micrograms kg-1) and the antagonist, pindolol (1 and 5 mg kg-1), were both without effect. 4. The decrease in brain MHPG concentrations induced by clonidine (100 micrograms kg-1) was prevented by prior injection of 1 mg kg-1 of idazoxan or yohimbine, but not by prazosin or pindolol. 5. MHPG levels were decreased after administration of the noradrenaline reuptake inhibitor desipramine (5 and 10 mg kg-1) and the non-selective monoamine reuptake inhibitors, sibutramine HCl (BTS

  20. Pathological role of a constitutively active population of alpha(1D)-adrenoceptors in arteries of spontaneously hypertensive rats.

    PubMed

    Gisbert, Regina; Ziani, Khalid; Miquel, Raquel; Noguera, M Antonia; Ivorra, M Dolores; Anselmi, Elsa; D'Ocon, Pilar

    2002-01-01

    1. The role of a constitutively active population of alpha(1D)-adrenoceptors was analysed in arteries obtained from spontaneously hypertensive rats (SHR) and controls (WKY) divided into three groups: young prehypertensive, adult hypertensive, and adult animals chronically treated with captopril (50 mg kg(-1) per day orally) in order to prevent the hypertensive state. 2. In adult SHR, a significant increase in BMY 7378 potency (not in prazosin potency) was observed in aorta, mesenteric artery, and the first and second branches of the small mesenteric arteries with respect to WKY rats. This difference was not observed in iliac and tail arteries, which suggests an increased functional role of alpha(1D)-adrenoceptors only in some vessels of SHR. 3. The increase in the resting tone (IRT) observed in absence of agonist, inhibited by BMY 7378, that represents the constitutively active population of alpha(1D)-adrenoceptors, was also significantly greater in aorta and mesenteric artery from adult SHR. 4. In young and captopril treated adult animals, no differences between strains with respect to BMY 7378 potency, or IRT were observed. 5. The increase in the functional role of alpha(1D)-adrenoceptors and their constitutive activity observed in hypertension is prevented by captopril treatment. The pathological consequence of this change is the slower rate of recovery of the basal tone after removal of an adrenergic stimulus, observed in vessels from hypertensive animals that had shown an increase in the functionality of constitutively active alpha(1D)-adrenoceptors. This change was not observed in prehypertensive or captopril treated animals. PMID:11786496

  1. In vitro α1-adrenoceptor pharmacology of Ro 70-0004 and RS-100329, novel α1A-adrenoceptor selective antagonists

    PubMed Central

    Williams, T J; Blue, D R; Daniels, D V; Davis, B; Elworthy, T; Gever, J R; Kava, M S; Morgans, D; Padilla, F; Tassa, S; Vimont, R L; Chapple, C R; Chess-Williams, R; Eglen, R M; Clarke, D E; Ford, A P D W

    1999-01-01

    It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the α1A-adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms.The present study describes the α1-adrenoceptor (α1-AR) subtype selectivities of two novel α1-AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned α1A-, α1B- and α1D-AR showed nanomolar affinity and significant α1A-AR subtype selectivity for both Ro 70-0004 (pKi 8.9: 60 and 50 fold selectivity) and RS-100329 (pKi 9.6: 126 and 50 fold selectivity) over the α1B- and α1D-AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity.Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA2 8.8 and 8.9), RS-100329 (pA2 9.2 and 9.2), tamsulosin (pA2 10.4 and 9.8) and prazosin (pA2 8.7 and 8.3 respectively). Affinity estimates for tamsulosin and prazosin in antagonizing α1-AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively).The α1A-AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a ‘uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia. PMID:10369480

  2. Influence of prostaglandins and adrenoceptor agonists on contractile activity in the human cervix at term.

    PubMed

    Bryman, I; Norström, A; Lindblom, B

    1986-04-01

    The influence of prostaglandins as well as adrenoceptor agonists and antagonists on contractile activity of isolated cervical smooth muscle from term pregnant women was studied. Prostaglandin E2 had an inhibitory effect at extremely low concentrations. Inhibition also was induced by prostaglandin F2 alpha, prostaglandin I2, and 6-keto-prostaglandin F1 alpha, but at considerably higher concentrations. Contractions evoked by noradrenaline or phenylephrine were blocked by the alpha-adrenoceptor antagonist phenoxybenzamine. The beta-adrenoceptor agonist terbutaline acted as an inhibitor, whereas isoprenaline in most cases stimulated contractile activity. The inhibitory action of prostaglandins and especially the high sensitivity to prostaglandin E2 point to a physiologic role of these compounds for cervical dilatation and retraction. A predominance of alpha-adrenoceptors might be of importance for the maintenance of cervical competence during pregnancy. PMID:2870450

  3. 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.

  4. Involvement of medial prefrontal cortex alpha-2 adrenoceptors on memory acquisition deficit induced by arachidonylcyclopropylamide, a cannabinoid CB1 receptor agonist, in rats; possible involvement of Ca2+ channels.

    PubMed

    Beiranvand, Afsaneh; Nasehi, Mohammad; Zarrindast, Mohammad-Reza; Moghaddasi, Mehrnoush

    2016-09-01

    Functional interactions between cannabinoid and alpha-2 adrenergic systems in cognitive control in the medial prefrontal cortex (mPFC) seem possible. The present study evaluated the possible role of alpha-2 adrenoceptors of the prefrontal cortex on effect of arachidonylcyclopropylamide (ACPA), a cannabinoid CB1 receptor (CB1R) agonist, in adult male Wistar rats. The animals were bilaterally implanted with chronic cannulae in the mPFC, trained in a step-through task, and tested 24 h after training to measure step-through latency. Results indicate that pre-training microinjection of ACPA (0.05 and 0.5 μg/rat) and clonidine (alpha-2 adrenoceptor agonist; 1 and 2 μg/rat) reduce memory acquisition. Pre-training subthreshold dose of clonidine (0.5 µg/rat) restored memory-impairing effect of ACPA (0.05 and 0.5 µg/rat). On the other hand, pre-training administration of the alpha-2 adrenoceptor antagonist yohimbine in all doses used (0.5, 1, and 2 μg/rat) did not affect memory acquisition by itself, while a subthreshold dose of yohimbine (2 µg/rat) potentiated memory impairment induced by ACPA (0.005 µg/rat). Finally, a subthreshold dose of SKF96365 (a Ca(2+) channel blocker) blocked clonidine and yohimbine effect of memory responses induced by ACPA. In conclusion, these data indicate that mPFC alpha-2 adrenoceptors play an important role in ACPA-induced amnesia and Ca(2+) channels have a critical role this phenomenon. PMID:27317021

  5. Alpha-adrenoceptors in dog mesenteric vessels--subcellular distribution and number of ( sup 3 H)prazosin and ( sup 3 H)rauwolscine binding sites

    SciTech Connect

    Shi, A.G.; Ahmad, S.; Kwan, C.Y.; Daniel, E.E. )

    1990-04-01

    Binding of the alpha-adrenergic antagonists ({sup 3}H)prazosin and ({sup 3}H)rauwolscine to well-characterized subcellular membrane fractions isolated from dog mesenteric arteries and veins was studied. Binding of both ligands was saturable with Kd values of 0.5 +/- 0.1 nM for ({sup 3}H)prazosin and 5.85 +/- 0.85 nM for ({sup 3}H)rauwolscine in arteries, and 0.87 +/- 0.4 nM for ({sup 3}H)prazosin and 6.6 +/- 1.5 nM for ({sup 3}H)rauwolscine in veins. In veins, the maximum number of binding sites for ({sup 3}H)rauwolscine was higher than that for ({sup 3}H)prazosin, whereas in arteries the maximum number of binding sites for each ligand was similar. In microsomes from dog aorta, the maximum number of bindings sites for ({sup 3}H)prazosin was higher than that for ({sup 3}H)rauwolscine. Neuronal membrane contamination in these studies was minimized by dissection procedures and evaluated by the comparison of ({sup 3}H)saxitoxin binding in various preparations. Only mesenteric veins responded functionally to agonists acting on alpha 2 adrenoceptors. This study thus identified two distinct populations of ({sup 3}H)prazosin and ({sup 3}H)rauwolscine binding sites in the plasma membranes of dog mesenteric vessels and suggests that a much higher density of alpha 2-compared to alpha 1-adrenoceptor binding sites is required for a contractile response.

  6. [3H]RS79948-197 binding to human, rat, guinea pig and pig alpha2A-, alpha2B- and alpha2C-adrenoceptors. Comparison with MK912, RX821002, rauwolscine and yohimbine.

    PubMed

    Uhlén, S; Dambrova, M; Näsman, J; Schiöth, H B; Gu, Y; Wikberg-Matsson, A; Wikberg, J E

    1998-02-01

    The Kd values of the recently introduced radioligand [3H]RS79948-197 ((8a R,12aS,13a-S)-5,8,8a,9,10,11,12,12a,13,13a-decahydro-3-metho xy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]naphthyridine) were determined for the recombinant human and rat alpha2A-, alpha2B- and alpha2C- as well as guinea pig alpha2B- and alpha2c-adrenoceptors expressed in COS (CV-1 Origin, SV40) cells. In addition, the Kd values were also determined for [3H]RS79948-197 for the guinea pig spleen alpha2A-adrenoceptor and for pig alpha2A-, alpha2B- and alpha2C-adrenoceptors in membranes obtained from kidney and striatum. Available radioligands for alpha2-adrenoceptors, besides [3H]RS79948-197 are the tritiated forms of MK912 ((2S,12bS)1',3'-dimethylspiro(1,3,4,5',6,6',7,12b-octa hydro-2H-benzo[b]furo[2,3-a]quinazoline)-2,4'-pyrimidin-2'-one), RX821002 (2-methoxy-idazoxan), rauwolscine and yohimbine. In the present article the binding constants of all these substances for the alpha2A-, alpha2B- and alpha2C-adrenoceptor subtypes in human, pig, rat and guinea pig are reviewed. In all species tested MK912 was alpha2C-selective, RX821002 showed a minor alpha2A-selectivity, whereas [3H]RS79948-197 was non-selective among the alpha2-adrenoceptor subtypes, showing high affinity for all three subtypes. Rauwolscine and yohimbine showed relatively low affinities for nmost of the alpha2-adrenoceptor subtypes investigated, the exception being rauwolscine having high affinity for the human and porcine alpha2C-adrenoceptors. PMID:9551719

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

    PubMed

    Arora, Shivani; Vohora, Divya

    2016-08-01

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

  8. Alpha2C-adrenoceptors play a prominent role in sympathetic constriction of porcine pulmonary arteries.

    PubMed

    Jantschak, Florian; Pertz, Heinz H

    2012-06-01

    Enhanced pulmonary vasoconstriction in response to injuries of the central nervous system and hypoxia result in pulmonary edema due to increased sympathetic activation. This study aimed to characterize α(2)-adrenoceptor (AR)-mediated responses in porcine pulmonary arteries. α(2)-AR-mediated vasoconstriction was studied using a tissue bath protocol. α(2)-AR protein was determined by Western blotting. UK14304 (α(2)-AR agonist) elicited only a slight contraction in pulmonary arteries compared to veins. Verapamil (voltage-operated Ca(2+) channel blocker), 2-APB (store-operated Ca(2+) channel inhibitor), and P1075 (K(ATP) channel opener) induced a marked decrease of the basal tone in veins, but not in arteries. The UK14304-induced contraction in arteries was enhanced by (S)-(-)-Bay K 8644 (L-type Ca(2+) channel activator), N (ω)-nitro-L: -arginine methyl ester hydrochloride (L-NAME, eNOS inhibitor), and (S)-(-)-Bay K 8644 plus L-NAME to the same extent. Endothelium denudation failed to affect the UK14304 response. (S)-(-)-Bay K 8644 did not increase the maximal noradrenaline (non-selective α-AR agonist) or phenylephrine (α(1)-AR agonist) response. The rightward shift of the concentration-response curve to noradrenaline by prazosin (α(1)-AR antagonist) plus (S)-(-)-Bay K 8644 was smaller and non-parallel compared to that in the presence of prazosin alone. UK14304 responses were inhibited by MK912 (α(2C)-AR antagonist). Affinity of MK912 (pA(2) 9.76) and Western blotting analysis argue for an involvement of α(2C)-ARs in noradrenaline-induced contraction of pulmonary arteries. It is concluded that postjunctional α(2C)-ARs predominantly mediate contraction in porcine pulmonary arteries when the cytosolic Ca(2+) concentration is elevated. α(2C)-AR antagonists may be beneficial in the treatment of pulmonary edema. PMID:22371269

  9. Agonist binding and function at the human alpha(2A)-adrenoceptor: allosteric modulation by amilorides.

    PubMed

    Leppik, R A; Birdsall, N J

    2000-11-01

    It has been found previously that amilorides act via an allosteric site on the alpha(2A)-adrenergic receptor to strongly inhibit antagonist binding. In this study, allosteric modulation of agonist binding and function at the alpha(2A)-adrenergic receptor was explored. The dissociation rate of the agonist [(3)H]UK14304 from alpha(2A)-receptors was decreased by the amilorides in a concentration-dependent manner. This contrasts with the increases in (3)H-antagonist dissociation rate found previously. The agonist-amiloride analog interaction data could be fitted to equations derived from the ternary complex allosteric model. The calculated log affinities of the amilorides at the [(3)H]UK14304-occupied receptor increased with the size of the 5-N-alkyl side chain and ranged from 2.4 for amiloride to 4.2 for 5-(N,N-hexamethylene)-amiloride. The calculated negative cooperativities cover a narrow range, in sharp contrast to the broad range found for antagonist-amiloride analog interactions. The effects of the amilorides on the agonist actions of UK14304, epinephrine, and norepinephrine were explored using a [(35)S]GTPgammaS functional assay, and the parameters calculated for the cooperativities and affinities of the UK14304-amiloride analog interactions, using the equation derived from the ternary complex allosteric model, were in good agreement with those derived from the kinetic studies. Therefore both the binding and functional data provide further support for the existence of a well defined allosteric site on the human alpha(2A)-adrenergic receptor. The binding mode of the amilorides at the agonist-occupied and antagonist-occupied receptor differs markedly but, within each group, the structure of either the agonist or the antagonist examined has only a slight effect on the allosteric interactions. PMID:11040058

  10. Tumor necrosis factor-alpha antagonists and neuropathy.

    PubMed

    Stübgen, Joerg-Patrick

    2008-03-01

    Tumor necrosis factor (TNF)-alpha plays an important role in many aspects of immune system development, immune-response regulation, and T-cell-mediated tissue injury. The evidence that TNF-alpha, released by autoreactive T cells and macrophages, may contribute to the pathogenesis of immune-mediated demyelinating neuropathies is reviewed. TNF-alpha antagonists (infliximab, etanercept, adalimumab) are indicated for the treatment of advanced inflammatory rheumatic and bowel disease, but these drugs can induce a range of autoimmune diseases that also attack the central and peripheral nervous systems. Case histories and series report on the association between anti-TNF-alpha treatment and various disorders of peripheral nerve such as Guillain-Barré syndrome, Miller Fisher syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy with conduction block, mononeuropathy multiplex, and axonal sensorimotor polyneuropathies. The proposed pathogeneses of TNF-alpha-associated neuropathies include both a T-cell and humoral immune attack against peripheral nerve myelin, vasculitis-induced nerve ischemia, and inhibition of signaling support for axons. Most neuropathies improve over a period of months by withdrawal of the TNF-alpha antagonist, with or without additional immune-modulating treatment. Preliminary observations suggest that TNF-alpha antagonists may be useful as an antigen-nonspecific treatment approach to immune-mediated neuropathies in patients with a poor response to, or intolerance of, standard therapies, but further studies are required. PMID:18041052

  11. Down-regulation of. alpha. sub 2 adrenoceptors in ventrolateral medulla of spontaneously hypertensive rats

    SciTech Connect

    Gulati, A. )

    1991-01-01

    The binding of ({sup 3}H)idaxazon to imidazole sites and ({sup 3}H)rauwolscine to {alpha}{sub 2} adrenoceptors of neuronal membranes prepared from cerebral cortex and ventrolateral medulla of 10 week old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats was determined. ({sup 3}H)idaxazon bound to the membranes of cerebral cortex and ventrolateral medulla at a single high affinity site. The binding of ({sup 3}H)idaxazon in ventrolateral medulla and cerebral cortex was found to be similar in SHR and WKY rats. ({sup 3}H)Rauwolscine bound to the membranes of cerebral cortex and ventrolateral medulla at a single high affinity site. The binding of ({sup 3}H)rauwolscine in the cerebral cortex was found to be similar in SHR and WKY rats. However, in the ventrolateral medulla ({sup 3}H)rauwolscine binding was found to be significantly lower in SHR as compared to WKY rats. The decreased binding was due a decrease (32%) in the B{sub max} value in SHR rats as compared to WKY rats. The K{sub d} values were similar in SHR and WKY rats. It is concluded that imidazole binding sites are not affected while, {alpha}{sub 2} adrenergic binding sites are decreased in the ventrolateral medulla of SHR rats and may be contributing to the regulation of blood pressure.

  12. Changes in [3H]-UK 14304 binding to alpha 2-adrenoceptors in morphine-dependent guinea-pigs.

    PubMed Central

    Varani, K.; Beani, L.; Bianchi, C.; Borea, P. A.; Simonato, M.

    1995-01-01

    1. The aim of this study was to investigate the effect of a noradrenergic input in the cortex of morphine-dependent animals. Binding of the alpha 1-adrenoceptor ligand [3H]-prazosin did not change in cortical membranes taken from morphine-dependent as compared to control guinea-pigs. However, binding of the alpha 2-adrenoceptor ligand [3H]-UK 14304 showed decreased KD (-30%) in the absence of significant changes in Bmax, either in cortical membranes or in synaptosomes. 2. Several characteristics of this phenomenon were identified. First, it occurs in a time-dependent fashion, in that it takes 5 days of chronic morphine treatment to start developing. Second, it can be observed after acute administration of high doses of morphine (100 mg kg-1). Third, it does not require a connection with the locus coeruleus or with other subcortical structures, in that it can be reproduced in vitro in isolated cortical slices. Fourth, it requires the integrity of cortical structures, since it cannot be reproduced in vitro in cortical synaptosomes. 3. Release studies were run to attempt identification of a functional correlate of the above observations. No changes were observed in the ability of the alpha 2-adrenoceptor agonist UK 14304 to inhibit 35 mM K(+)-evoked [3H]-noradrenaline outflow from cortical synaptosomes taken from morphine-dependent as compared to control guinea-pigs. However, a large decrease in the IC50 of UK 14304 for the inhibition of 35 mM K(+)-evoked [3H]-gamma-aminobutyric acid ([3H]-GABA) outflow (41 vs. 501 nM) was observed in morphine-dependent as compared to control animals. 4. These data suggest that, in the guinea-pig, chronic morphine treatment is associated with a shift from a low to high affinity agonist state in alpha 2-adrenoceptors on cortical GABA terminals. PMID:8719786

  13. Neuroprotective effects of selective β-1 adrenoceptor antagonists, landiolol and esmolol, on transient forebrain ischemia in rats; a dose-response study.

    PubMed

    Goyagi, Toru; Horiguchi, Takashi; Nishikawa, Toshiaki; Tobe, Yoshitsugu; Masaki, Yoko

    2012-06-21

    Although selective beta-1 adrenoceptor antagonists are known to provide neuroprotective effects after brain ischemia, dose-response relationships of their neuroprotective effects have not been examined. The present study was conducted to evaluate whether the degree of brain protection against transient forebrain ischemia would be influenced by different doses of selective beta-1 adrenoceptor antagonists, esmolol and landiolol, in rats. Adult male S.D. rats received intravenous infusion of saline 0.5 ml/h, esmolol 20, 200, 2,000 μg/kg/min, or landiolol 5, 50, 500 μg/kg/min. Infusion was initiated 30 min prior to ischemia and continued for 24h. Ten-minute forebrain ischemia was induced by hemorrhagic hypotension and occlusion of the bilateral carotid arteries. Neurological and histological examinations were performed. Neurological deficit scores at 1, 4 and 7 days were lower, and the number of intact neurons in CA1 hippocampal region was larger in the rats treated with esmolol and landiolol after ischemia, compared with saline-treated rats (P<0.05), whereas no difference was found among different doses of esmolol and landiolol. These results suggested that selective beta-1 adrenoceptor antagonists improved neurological and histological outcomes following forebrain ischemia in rats, irrespective of their doses. PMID:22583856

  14. alpha-Adrenergic inhibition of the beta-adrenoceptor-dependent chloride current in guinea-pig ventricular myocytes.

    PubMed Central

    Iyadomi, I; Hirahara, K; Ehara, T

    1995-01-01

    1. alpha 1-Adrenoceptor-mediated inhibition of the beta-adrenoceptor-dependent Cl- current was investigated in guinea-pig ventricular myocytes using the patch clamp technique. The Cl- conductance activated by noradrenaline (0.1-10 microM) with an alpha 1-blocker (prazosin, 5 microM) was significantly greater than that activated by noradrenaline alone. Phenylephrine and methoxamine, alpha 1-agonists, exerted an inhibitory effect on the Cl- conductance activated by isoprenaline. The dose-response relationship for isoprenaline and the Cl- current activation was shifted to higher doses in the presence of phenylephrine (30 microM). 2. The interaction of alpha 1- and beta-agonists on Cl- current was also observed on the single channel level; in some of the outside-out membrane patches, phenylephrine (50 microM) depressed the activity of the single Cl- channel which was induced by 5 microM adrenaline. 3. Phenylephrine had no effect on the Cl- conductance induced by forskolin (0.5-5 microM), an activator of adenylate cyclase. The Cl- conductance activated persistently by isoprenaline in GTP gamma S-loaded cells was also insensitive to phenylephrine. The results suggest that the observed alpha 1-adrenergic attenuation of the beta-adrenergic response is not primarily due to inhibition of adenylate cyclase activity. The alpha 1-adrenergic action may interfere with the processes leading to enzyme activation in the beta-adrenergic pathway. PMID:8583419

  15. Rapid Eye Movement Sleep Deprivation Induces Neuronal Apoptosis by Noradrenaline Acting on Alpha1 Adrenoceptor and by Triggering Mitochondrial Intrinsic Pathway

    PubMed Central

    Somarajan, Bindu I.; Khanday, Mudasir A.; Mallick, Birendra N.

    2016-01-01

    Many neurodegenerative disorders are associated with rapid eye movement sleep (REMS) loss; however, the mechanism was unknown. As REMS loss elevates noradrenaline (NA) level in the brain as well as induces neuronal apoptosis and degeneration, in this study, we have delineated the intracellular molecular pathway involved in REMS deprivation (REMSD)-associated NA-induced neuronal apoptosis. Rats were REMS deprived for 6 days by the classical flower pot method; suitable controls were conducted and the effects on apoptosis markers evaluated. Further, the role of NA was studied by one, intraperitoneal (i.p.) injection of NA-ergic alpha1 adrenoceptor antagonist prazosin (PRZ) and two, by downregulation of NA synthesis in locus coeruleus (LC) neurons by local microinjection of tyrosine hydroxylase siRNA (TH-siRNA). Immunoblot estimates showed that the expressions of proapoptotic proteins viz. Bcl2-associated death promoter protein, apoptotic protease activating factor-1 (Apaf-1), cytochrome c, caspase9, caspase3 were elevated in the REMS-deprived rat brains, while caspase8 level remained unaffected; PRZ treatment did not allow elevation of these proapoptotic factors. Further, REMSD increased cytochrome c expression, which was prevented if the NA synthesis from the LC neurons was blocked by microinjection of TH-siRNA in vivo into the LC during REMSD in freely moving normal rats. Mitochondrial damage was re-confirmed by transmission electron microscopy, which showed distinctly swollen mitochondria with disintegrated cristae, chromosomal condensation, and clumping along the nuclear membrane, and all these changes were prevented in PRZ-treated rats. Combining findings of this study along with earlier reports, we propose that upon REMSD NA level increases in the brain as the LC, NA-ergic REM-OFF neurons do not cease firing and TH is upregulated in those neurons. This elevated NA acting on alpha1 adrenoceptors damages mitochondria causing release of cytochrome c to activate

  16. Rapid Eye Movement Sleep Deprivation Induces Neuronal Apoptosis by Noradrenaline Acting on Alpha1 Adrenoceptor and by Triggering Mitochondrial Intrinsic Pathway.

    PubMed

    Somarajan, Bindu I; Khanday, Mudasir A; Mallick, Birendra N

    2016-01-01

    Many neurodegenerative disorders are associated with rapid eye movement sleep (REMS) loss; however, the mechanism was unknown. As REMS loss elevates noradrenaline (NA) level in the brain as well as induces neuronal apoptosis and degeneration, in this study, we have delineated the intracellular molecular pathway involved in REMS deprivation (REMSD)-associated NA-induced neuronal apoptosis. Rats were REMS deprived for 6 days by the classical flower pot method; suitable controls were conducted and the effects on apoptosis markers evaluated. Further, the role of NA was studied by one, intraperitoneal (i.p.) injection of NA-ergic alpha1 adrenoceptor antagonist prazosin (PRZ) and two, by downregulation of NA synthesis in locus coeruleus (LC) neurons by local microinjection of tyrosine hydroxylase siRNA (TH-siRNA). Immunoblot estimates showed that the expressions of proapoptotic proteins viz. Bcl2-associated death promoter protein, apoptotic protease activating factor-1 (Apaf-1), cytochrome c, caspase9, caspase3 were elevated in the REMS-deprived rat brains, while caspase8 level remained unaffected; PRZ treatment did not allow elevation of these proapoptotic factors. Further, REMSD increased cytochrome c expression, which was prevented if the NA synthesis from the LC neurons was blocked by microinjection of TH-siRNA in vivo into the LC during REMSD in freely moving normal rats. Mitochondrial damage was re-confirmed by transmission electron microscopy, which showed distinctly swollen mitochondria with disintegrated cristae, chromosomal condensation, and clumping along the nuclear membrane, and all these changes were prevented in PRZ-treated rats. Combining findings of this study along with earlier reports, we propose that upon REMSD NA level increases in the brain as the LC, NA-ergic REM-OFF neurons do not cease firing and TH is upregulated in those neurons. This elevated NA acting on alpha1 adrenoceptors damages mitochondria causing release of cytochrome c to activate

  17. Ingestive and locomotor behaviours induced by pharmacological manipulation of <Alpha>-adrenoceptors into the median raphe nucleus.

    PubMed

    Levone, Brunno Rocha; Cella, Elisa Caroline; Kochenborger, Larissa; da Silva, Eduardo Simão; Taschetto, Ana Paula Dambros; Mansur, Samira Schultz; Terenzi, Mariana Graciela; Faria, Moacir Serralvo; Paschoalini, Marta Aparecida

    2015-02-01

    The present study evaluated the involvement of α-adrenoceptors of the median raphe nucleus (MRN) in satiated rats, in food and water intake and motor behaviour. Control groups were treated with saline (SAL) or adrenaline (ADR), injected into the MRN seven minutes after injection of the vehicle used to solubilize the antagonists, propylene glycol (PLG) or SAL. Experimental groups were treated with an α-adrenoceptor antagonist, prazosin (α1, 20 or 40 nmol) or yohimbine (α2, 20 or 40 nmol) or phentolamine (non-selective α, 20 or 40 nmol), followed (later) by injection of ADR or SAL. Behaviour was recorded for 30 min. The injection of ADR and the blockade of α1 receptors resulted in hyperphagia whereas blocking α2 or α1 and α2 simultaneously did not change feeding behaviour. Pre-treatment with prazosin, followed by injection of ADR was not able to cause an increase in the amount of food ingested, while the higher dose of the α1 antagonist reduced the latency to start feeding. Pre-treatment with prazosin also caused hyperactivity. However, pre-treatment with phentolamine or yohimbine was able to block ADR-induced feeding. The present study supports the hypothesis that there is a tonic activation of α1-adrenoceptors in the MRN in satiated rats, which activates an inhibitory influence in areas that control food intake. Injection of ADR seems to activate α2 receptors, resulting in a decrease in the availability of endogenous catecholamines, which reduces the release of the signal that inhibits food intake, leading to hyperphagia. PMID:25261784

  18. Multiple actions of glaucine on cyclic nucleotide phosphodiesterases, alpha 1-adrenoceptor and benzothiazepine binding site at the calcium channel.

    PubMed

    Ivorra, M D; Lugnier, C; Schott, C; Catret, M; Noguera, M A; Anselmi, E; D'Ocon, P

    1992-06-01

    respect.5. This study confirms the presence of four phosphodiesterase (PDE) activities in bovine aorta: a calmodulin-activated PDE (CaM-PDE type I) which hydrolyzed preferentially guanosine 3':5'-cyclic monophosphate (cyclic GMP); a cyclic GMP selective form (cGMP-PDE type V); and two low Km adenosine 3':5'-cyclic monophosphate (cyclic AMP) PDEs that are insensitive to the stimulatory effect of CaM, one of which was inhibited by cyclic GMP (CGI-PDE, type III) and the other by rolipram (cAMP-PDE, type IV). Glaucine selectively inhibits one of the two forms of Ca2+-independent low Km cAMP-PDE, the type IV. In contrast, papaverine exerts a non-selective inhibitory effect upon all PDE forms.6. The present work provides evidence that glaucine, a benzyltetrahydroisoquinoline alkaloid, has interesting properties as an alpha l-adrenoceptor antagonist, calcium entry blocker (through the benzothiazepine recognition site in the calcium channel) and as a selective inhibitor of the rolipram-sensitive cAMP-PDE, type IV PDE. PMID:1327380

  19. alpha2-Adrenoceptors control the release of noradrenaline but not neuropeptide Y from perivascular nerve terminals.

    PubMed

    Donoso, M Veronica; Carvajal, Andrés; Paredes, Alfonso; Tomic, Alexander; Koenig, Cecilia S; Huidobro-Toro, J Pablo

    2002-09-01

    Neuropeptide Y (NPY) and noradrenaline (NA) are co-transmitters at many sympathetic synapses, but it is not yet clear if their release is independently regulated. To address this question, we quantified the electrically evoked release of these co-transmitters from perivascular nerve terminals to the mesenteric circulation in control and drug-treated rats. 6-Hydroxydopamine reduced the tissue content and the electrically evoked release of ir-NPY and NA as well as the rise in perfusion pressure. A 0.001 mg/kg reserpine reduced the content of ir-NPY and NA, but did not modify their release nor altered the rise in perfusion pressure elicited by the electrical stimuli. However, 0.1mg/kg reserpine reduced both the content and release of NA but decreased only the content but not the release of ir-NPY; the rise in perfusion pressure was halved. Clonidine did not affect the release of ir-NPY while it lowered the outflow of NA, not altering the rise in perfusion pressure elicited by the electrical stimuli. Yohimbine, did not modify the release of ir-NPY but increased the NA outflow, it antagonized the clonidine effect. Therefore, presynaptic alpha2-adrenoceptors modulate the release of NA but not NPY, implying separate regulatory mechanisms. PMID:12217427

  20. Effects of ethanol ingestion on alpha-adrenoceptor-mediated circulatory responses in man.

    PubMed Central

    Eisenhofer, G; Lambie, D G; Johnson, R H

    1984-01-01

    The acute effects of ethanol on pressor responses to graded intravenous infusions of noradrenaline (24, 48, 90 ng kg-1 min-1) and methoxamine (0.2, 0.4, 0.8, 1.6, 2.0 mg/min, 1 min each) were each investigated in eight normal male subjects. The effects of ethanol on blood pressure, heart rate and plasma catecholamine responses to lower body negative pressure were also examined in six normal male subjects. Each subject acted as his own control by participating twice, once after consumption of ethanol (1.0 ml/kg, 20% v/v, in orange juice) and once after an equivalent volume of orange juice. Ethanol consumption significantly reduced the diastolic blood pressure response to infusion of noradrenaline. This occurred despite a significantly greater increase in plasma noradrenaline concentrations during infusion after ethanol. The systolic and diastolic blood pressure responses to infusion of methoxamine were both significantly reduced after ethanol. During lower body negative pressure, prior consumption of ethanol resulted in a greater fall in systolic blood pressure and a smaller rise in diastolic blood pressure. Plasma noradrenaline responses to lower body negative pressure were significantly increased after ethanol. It is concluded that acute ethanol ingestion depresses alpha-adrenoceptor-mediated vasoconstriction, with resulting impairment of blood pressure control. PMID:6091712

  1. Alpha-1 adrenoceptors in brown adipose tissue of lean and ob/ob mice

    SciTech Connect

    Behrens-Zaror, G.; Himms-Hagen, J.

    1986-03-01

    Obese (ob/ob) mice have a low capacity to increase thyroxine 5'-deiodinase (T4 5'-D) in brown adipose tissue (BAT) when exposed to cold. This effect is mediated by alpha-1 (A-1) adrenoceptors. The authors objective was to find out whether BAT of the ob/ob mouse has normal A-1 receptors. Saturation analysis of binding of (3H)-WB4101 at 0.05 nM to 10 ..mu..M to crude membrane preparations (100,000 g pellets from Polytron homogenates) using the LIGAND program of Munson and Rodbard, showed two populations of binding sites in BAT of lean (+/+, 11-15 wk old) mice. Acute exposure (12 h, 14/sup 0/C) or acclimation to cold (3 wk, 14/sup 0/C) did not alter affinity or concentration of sites. Displacement with yohimbine and prazosin indicated binding of WB4101 to A-1 receptors. Very young (5 wk) lean (+/.) and obese mice had similar affinity constants (lean 0.13 +/- 0.043 and 34.2 +/- 14.9; obese, 0.12 +/- 0.028 and 20.9 +/- 5.48 nM) and concentrations (lean 22.4 +/- 3.8 and 647 +/- 137; obese, 28.6 +/- 4.6 and 547 +/- 105 fmol/mg protein) of sites. Old (1 yr) mice had high affinity sites similar to those in younger animals (KD lean 0.19 +/- 0.028, obese, 0.25 +/- 0.075; Bmax lean, 60.2 +/- 12.1; obese, 63.1 +/- 13.5 fmol/mg protein). The authors conclude that the ob/ob mouse has normal high affinity A-1 receptors in BAT. Anomalous properties of low affinity binding in old ob/ob mice could not be characterized because of high nonspecific binding. BAT of the ob/ob mouse does not lack A-1 receptors but may have a post-receptor alteration in the A-1 adrenoceptor-mediated response.

  2. Ontogeny of rat hepatic adrenoceptors

    SciTech Connect

    McMillian, M.K.; Schanberg, S.M.; Kuhn, C.M.

    1983-10-01

    Hepatic alpha-1, alpha-2 and beta-2 adrenoceptors were characterized during development of the rat through Scatchard analysis of (3H)prazosin, (3H)rauwolscine and (125I)pindolol binding to liver membrane preparations. Major changes in adrenoceptor numbers occur shortly before birth at weaning. The fetal rat liver is characterized by a large number of alpha-2 adrenoceptors, which falls 10-fold by birth. The number of hepatic beta-2 adrenoceptors decreases gradually during development, and is lower at all times than the number of alpha-1 and alpha-2 adrenoceptors. The developmental profile of the hepatic alpha-1 adrenoceptor is biphasic: there is a 2 to 3-fold fall in alpha-1 adrenoceptor number at birth and a 3- to 5-fold rise at weaning. While absolute numbers of alpha-1 and beta-2 adrenoceptors do not correlate precisely with reported actions of epinephrine and norepinephrine on hepatic metabolism during ontogeny, the increasing ratio of alpha-1/beta-2 hepatic adrenoceptors may contribute to the conversion from predominantly beta effects of catecholamines reported in fetal and suckling rat liver to the predominantly alpha-1 effects that are well documented in the adult male rat.

  3. Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats.

    PubMed

    Pytka, Karolina; Lustyk, Klaudia; Żmudzka, Elżbieta; Kotańska, Magdalena; Siwek, Agata; Zygmunt, Małgorzata; Dziedziczak, Agnieszka; Śniecikowska, Joanna; Olczyk, Adrian; Gałuszka, Adam; Śmieja, Jarosław; Waszkielewicz, Anna M; Marona, Henryk; Filipek, Barbara; Sapa, Jacek; Mogilski, Szczepan

    2016-01-01

    Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e., α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 μg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity toward α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A-stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values-it blocked α1A-adrenoceptors around seven-fold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18, and HBK-19 (ED50 = 0.18-0.21) was comparable to that of carvedilol (ED50 = 0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18, and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18, and HBK-19 decreased heart

  4. Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats

    PubMed Central

    Pytka, Karolina; Lustyk, Klaudia; Żmudzka, Elżbieta; Kotańska, Magdalena; Siwek, Agata; Zygmunt, Małgorzata; Dziedziczak, Agnieszka; Śniecikowska, Joanna; Olczyk, Adrian; Gałuszka, Adam; Śmieja, Jarosław; Waszkielewicz, Anna M.; Marona, Henryk; Filipek, Barbara; Sapa, Jacek; Mogilski, Szczepan

    2016-01-01

    Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e., α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 μg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity toward α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A-stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values—it blocked α1A-adrenoceptors around seven-fold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18, and HBK-19 (ED50 = 0.18–0.21) was comparable to that of carvedilol (ED50 = 0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18, and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18, and HBK-19 decreased heart

  5. Alpha 1-adrenoceptors and calcium sources in adrenergic neurogenic contractions of rat vas deferens.

    PubMed Central

    Bültmann, R.; Kurz, A. K.; Starke, K.

    1994-01-01

    1. The involvement of alpha 1-adrenoceptor subtypes in adrenergic neurogenic contractions of different type was studied in epididymal and prostatic portions of the rat vas deferens. 2. The adrenergic component of neurogenic contractions was isolated by suramin (300 microM). Twitch-like and tonic contractions were elicited by appropriate pulse patterns of electrical field stimulation, and contractions relying on intracellular calcium mobilization and calcium entry were isolated by means of nifedipine (10 microM) and ryanodine (20 microM), respectively. Increasing concentrations of 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), alpha-ethyl-3,4,5-trimethoxy-alpha-(3-((2-(2-methoxyphenoxy)ethyl)- amino)-propyl)benzeneacetonitrile (HV 723), prazosin and 5-methylurapidil progressively, monophasically and with potency decreasing in that order reduced and finally abolished all types of contraction, with one exception: concentration-effect curves of 5-methylurapidil in epididymal segments in the presence of ryanodine levelled off at about 75% inhibition. In the presence of both nifedipine (10 microM) and ryanodine (20 microM), contractions were abolished. 3. Contractions elicited by exogenous noradrenaline were also studied in the presence of either nifedipine 10 microM (prostatic segments) or ryanodine 20 microM (epididymal segments). Increasing concentrations of tamsulosin, WB 4101, benoxathian, HV 723, prazosin, 5-methylurapidil and urapidil progressively, monophasically and with potency decreasing in that order reduced and eventually abolished both kinds of contraction, with two exceptions: in epididymal segments in the presence of ryanodine, the concentration-effect curve of 5-methylurapidil was biphasic and the curve of urapidil levelled off at only partial inhibition. 4. In slices prepared from the prostatic end and preincubated with [3H]-noradrenaline, WB 4101, HV 723, prazosin and 5-methylurapidil, at the highest concentrations tested against

  6. Determination of the role of noradrenergic and 5-hydroxytryptaminergic neurones in postsynaptic alpha 2-adrenoceptor desensitization by desipramine and ECS.

    PubMed Central

    Heal, D. J.; Prow, M. R.; Buckett, W. R.

    1991-01-01

    1. Experiments were conducted to determine the respective roles which noradrenergic and 5-hydroxytryptaminergic neurones play in the down-regulation of postsynaptic alpha 2-adrenoceptors by desipramine and electroconvulsive shock (ECS). The functional status of these receptors was monitored by use of clonidine-induced mydriasis in conscious mice. 2. Mydriasis to clonidine (0.1 mg kg-1, i.p.) was markedly attenuated by administration of either desipramine (10 mg kg-1, i.p.) for 14 days or ECS (200 V, 2s) given five times over ten days confirming our previous observations. 3. The neurotoxin, DSP-4 (100 mg kg-1, i.p. X 2), reduced brain noradrenaline levels by 64% and abolished the mydriasis induced by the noradrenaline releasing agent and reuptake inhibitor, methamphetamine, without significantly altering the response to clonidine, confirming our earlier results. This lesion prevented the attenuation of clonidine mydriasis by repeated administration of desipramine, but not ECS. 4. Lesioning of central 5-hydroxytryptaminergic neurones with 5,7-dihydroxytryptamine (75 micrograms, i.c.v.) had no influence on the reduction in clonidine mydriasis produced by repeated administration of either desipramine or ECS. 5. Since noradrenergic neurones are essential for the desensitization of postsynaptic alpha 2-adrenoceptors by desipramine, it indicates that this effect is probably the result of increased synaptic noradrenaline levels. This mechanism is not responsible for the change induced by ECS because this adaptation is independent of an intact noradrenergic input. 5-HT-containing neurones do not play a permissive role in the down-regulation of postsynaptic alpha 2-adrenoceptors by either antidepressant treatment. PMID:1655144

  7. The α1 adrenoceptor antagonist prazosin enhances sleep continuity in fear-conditioned Wistar-Kyoto rats

    PubMed Central

    Laitman, Benjamin M.; Gajewski, Nicholas D.; Mann, Graziella L.; Kubin, Leszek; Morrison, Adrian R.; Ross, Richard J.

    2014-01-01

    Fragmentation of rapid eye movement sleep (REMS) is well described in individuals with posttraumatic stress disorder (PTSD) and likely has significant functional consequences. Fear-conditioned rodents may offer an attractive model of the changes in sleep that characterize PTSD. Following fear conditioning (FC), Wistar-Kyoto (WKY) rats, a strain known to be particularly stress-sensitive, have increased REMS fragmentation that can be quantified as a shift in the distribution of REMS episodes towards the more frequent occurrence of sequential REMS (inter-REMS episode interval ≤ 3 min) vs. single REMS (interval > 3 min). The α1 adrenoceptor antagonist prazosin has demonstrated efficacy in normalizing sleep in PTSD. To determine the utility of fear-conditioned WKY rats as a model of sleep disturbances typical of PTSD and as a platform for the development of new treatments, we tested the hypothesis that prazosin would reduce REMS fragmentation in fear-conditioned WKY rats. Sleep parameters and freezing (a standard measure of anxiety in rodents) were quantified at baseline and on days 1, 7, and 14 following FC, with either prazosin (0.01 mg/kg, i.p.) or vehicle injections administered prior to testing in a between-group design. Fear conditioning was achieved by pairing tones with a mild electric foot shock (1.0 mA, 0.5 s). One, 7, and 14 days following FC, prazosin or vehicle was injected, the tone was presented, freezing was measured, and then sleep was recorded from 11 AM to 3 PM. WKY rats given prazosin, compared to those given vehicle, had a lower amount of seq-REMS relative to total REMS time 14 days after FC. They also had a shorter non-REMS latency and fewer non-REMS arousals at baseline and on days 1 and 7 after FC. Thus, in FC rats, prazosin reduced both REMS fragmentation and non-REMS discontinuity. PMID:24246572

  8. Contrasting effects of the imidazol(in)e alpha 2-adrenoceptor agonists, medetomidine, clonidine and UK 14,304 on extraneuronal levels of noradrenaline in the rat frontal cortex: evaluation using in vivo microdialysis and synaptosomal uptake studies.

    PubMed Central

    Dalley, J W; Stanford, S C

    1995-01-01

    1. In vivo microdialysis in halothane-anaesthetized rats and synaptosomal [3H]-noradrenaline uptake studies in vitro were used to evaluate the effects of imidazole (medetomidine) and imidazoline (clonidine and UK 14,304) alpha 2-adrenoceptor agonists on extraneuronal levels of noradrenaline in the frontal cortex. 2. Levels of noradrenaline in the dialysate were increased by a depolarizing concentration of K+ (60 mM for 20 min) and substantially attenuated by reducing Ca2+ supply in the perfusate. These results suggest that spontaneous efflux of noradrenaline in the cortex is regulated predominantly by cation-dependent exocytotic mechanisms. 3. At a low perfusion concentration (0.5 microM), medetomidine, clonidine and UK 14,304 all reduced the level of noradrenaline in cortical dialysates. Continuous perfusion of the selective alpha 2-adrenoceptor antagonist, atipamezole (0.5 microM) caused a sustained increase in noradrenaline efflux and reversed the inhibitory effects of medetomidine. All these changes are consistent with drug actions at presynaptic alpha 2-adrenoceptors. 4. Higher concentrations of medetomidine (5-50 microM), but not clonidine or UK 14,304, evoked a non-desensitizing increase in noradrenaline efflux. This effect was not antagonized by 0.5 microM atipamezole. 5. The tricyclic noradrenaline reuptake inhibitor, desmethylimipramine (0.5-50 microM), increased noradrenaline efflux in a concentration-dependent manner. 6. The specific uptake of [3H]-noradrenaline into cortical synaptosomes was inhibited by medetomidine and desmethylimipramine with IC50 values of approximately 7 microM and 8 microM respectively. Neither clonidine nor UK 14,304 inhibited [3H]-noradrenaline uptake.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7599940

  9. Influence of β-adrenoceptor antagonists on the pharmacokinetics of rizatriptan, a 5-HT1B/1D agonist: differential effects of propranolol, nadolol and metoprolol

    PubMed Central

    Goldberg, Michael R; Sciberras, David; De Smet, Marina; Lowry, Richard; Tomasko, Lisa; Lee, Yih; Olah, Timothy V; Zhao, Jamie; Vyas, Kamlesh P; Halpin, Rita; Kari, Prasad H; James (deceased), Ian

    2001-01-01

    Aims Patients with migraine may receive the 5-HT1B/1D agonist, rizatriptan (5 or 10 mg), to control acute attacks. Patients with frequent attacks may also receive propranolol or other β-adrenoceptor antagonists for migraine prophylaxis. The present studies investigated the potential for pharmacokinetic or pharmacodynamic interaction between β-adrenoceptor blockers and rizatriptan. Methods Four double-blind, placebo-controlled, randomized crossover investigations were performed in a total of 51 healthy subjects. A single 10 mg dose of rizatriptan was administered after 7 days' administration of propranolol (60 and 120 mg twice daily), nadolol (80 mg twice daily), metoprolol (100 mg twice daily) or placebo. Rizatriptan pharmacokinetics were assessed. In vitro incubations of rizatriptan and sumatriptan with various β-adrenoceptor blockers were performed in human S9 fraction. Production of the indole-acetic acid-MAO-A metabolite of each triptan was measured. Results Administration of rizatriptan during propranolol treatment (120 mg twice daily for 7.5 days) increased the AUC(0,∞) for rizatriptan by approximately 67% and the Cmax by approximately 75%. A reduction in the dose of propranolol (60 mg twice daily) and/or the incorporation of a delay (1 or 2 h) between propranolol and rizatriptan administration did not produce a statistically significant change in the effect of propranolol on rizatriptan pharmacokinetics. Administration of rizatriptan together with nadolol (80 mg twice daily) or metoprolol (100 mg twice daily) for 7 days did not significantly alter the pharmacokinetics of rizatriptan. No untoward adverse experiences attributable to the pharmacokinetic interaction between propranolol and rizatriptan were observed, and no subjects developed serious clinical, laboratory, or other significant adverse experiences during coadministration of rizatriptan with any of the β-adrenoceptor blockers. In vitro incubations showed that propranolol, but not other β-adrenoceptor

  10. "Ejaculatory disorders and α1-adrenoceptor antagonists therapy: clinical and experimental researches"

    PubMed Central

    Grasso, Marco; Fortuna, Flavio; Lania, Caterina; Blanco, Salvatore

    2006-01-01

    Background It is well known that the use of the α-adrenergic receptor antagonists in the BPH therapy may induce ejaculatory disorder. A review of clinical literature shows a greater incidence of ejaculatory disorder during the use of tamsulosin compared with alfuzosin. Anejaculation has been until now referred to retrograde ejaculation due to relaxation of prostatic and bladder neck smooth muscle tone. In a recent researches was evaluated the effect of tamsulosin and alfuzosin on rat vas deferent "in vitro", concluding that tamsulosin may "cause ejaculatory dysfunction by altering the progression and emission of sperm". An abnormal increase of contraction would be the cause of ejaculatory disorder. The aim of our paper is to compare human and rat vas deferens contractile activity and to evaluate with a clinical study if tamsulosin causes retrograde ejaculation disorder. Methods We have revaluated the human and rat vas deferens contractile activity in vitro according to our experience and literature. We have also performed a clinical study on 10 patients (48–72 y) affected by anejaculation. Post-coital urine was examined to search spermatozoa. Results Human and rat vas deferens activity is not comparable. Contractile activity induced by norepinephrin after tamsulosin incubation in rat prostatic vas deferens strips is similar to the contractile activity evoked by norepinephrin in human strips. Spermatozoa were found in post coital urine of 6 patients. Conclusion In our opinion the treatment with tamsulosin may induce retrograde ejaculation but not other ejaculatory disorder due to abnormal sperm progression. PMID:16842616

  11. Effect of silodosin, a selective α(1A)-adrenoceptor antagonist, on voiding behavior and bladder blood flow in a rat model of bladder outlet obstruction.

    PubMed

    Goi, Yoshiaki; Tomiyama, Yoshitaka; Yokoyama, Ayaka; Tatemichi, Satoshi; Maruyama, Kazuyasu; Kobayashi, Mamoru; Yamaguchi, Osamu

    2015-10-01

    This study was performed to investigate the effects of silodosin (selective α1A-adrenoceptor antagonist) on bladder blood flow (BBF) and bladder function in a rat model of bladder outlet obstruction (BOO) and to determine the expression of α1-adrenoceptor subtype mRNA in human and rat bladder microvessels. BOO was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. The BOO rats received either silodosin at a rate of 0.3mg/kg/day or vehicle subcutaneously via an osmotic pump for 2 weeks after BOO surgery. A metabolic cage study was performed in conscious animals. BBF was measured using a Laser Speckle Blood Flow Imager. Urinary levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nerve growth factor (NGF) were measured. Immunohistological examinations of nerve distribution and NGF expression in the rat bladder were conducted. The expression of each α1-adrenoceptor subtype mRNA in human and rat bladder microvessels was determined by in situ hybridization. Silodosin ameliorated the increase in voiding frequency and decrease in mean voided volume in BOO rats in the metabolic cage study. Silodosin also abrogated the decrease in BBF in BOO rats. The levels of 8-OHdG and NGF in BOO rats were significantly decreased by administration of silodosin. Silodosin prevented the decrease in nerve distribution and increase in NGF expression. Human and rat bladder microvessels showed expression of all α1-adrenoceptor subtype mRNAs. The results presented here suggest that silodosin improves voiding behavior in rat models with BOO by inducing recovery of BBF. PMID:26189024

  12. The role of spinal serotonin receptor and alpha adrenoceptor on the antiallodynic effects induced by intrathecal milnacipran in chronic constriction injury rats.

    PubMed

    Nakamura, Takehiro; Ikeda, Tetsuya; Takeda, Ryuichiro; Igawa, Kaori; Naono-Nakayama, Rumi; Sakoda, Sumio; Nishimori, Toshikazu; Ishida, Yasushi

    2014-09-01

    Milnacipran, a reuptake inhibitor of noradrenaline (NA) and serotonin (5-HT), elicits an antiallodynic effect in rats with neuropathic pain; however, the role of NA and 5-HT receptors in the induction of the antiallodynic effect of milnacipran remains unclear. Thus, we examined the effects of prazosin as an α1 adrenoceptor antagonist, yohimbine as an α2 adrenoceptor antagonist, metergoline as a 5-HT1, 5-HT2 and 5-HT7 receptor antagonist, cyanopindolol as a 5-HT1A/1B receptor antagonist, ketanserin as a 5-HT2 receptor antagonist, and ondansetoron as a 5-HT3 receptor antagonist on the antiallodynic effect of milnacipran in neuropathic rats with chronic constriction injury (CCI). The CCI rats expressed mechanical and thermal allodynia, which was attenuated by intrathecal injection of milnacipran. Yohimbine, but not prazosin, reversed the milnacipran-induced antiallodynic effect. The antiallodynic effect of milnacipran was also reversed by metergoline, ketanserin and ondansetron, while cyanopindolol reversed the antiallodynic effect on mechanical, but not thermal stimulation. Furthermore, c-Fos expression in lamina I/II of the spinal dorsal horn was enhanced by thermal stimulation and the enhanced expression of c-Fos was suppressed by milnacipran. This effect of milnacipran was reversed by yohimbine, metergoline, katanserin and ondansetron, but not prazosin. These results indicate that the effect of milnacipran on mechanical and thermal allodynia and c-Fos expression is elicited through the α2 adrenoceptor, but not α1 adrenoceptor, and 5-HT2 and 5-HT3 receptors; furthermore, the 5-HT1A/1B receptor is involved in mechanical allodynia, but not thermal allodynia. PMID:24876059

  13. X-ray Crystallography, DFT Calculations and Molecular Docking of Indole-Arylpiperazine Derivatives as α1A-Adrenoceptor Antagonists.

    PubMed

    Xu, Wei; Huang, Jun-Jun; Shao, Bin-Hao; Xu, Xing-Jie; Jiang, Ren-Wang; Yuan, Mu

    2015-01-01

    Indole-arylpiperazine derivatives have exhibited good selectivity for the α1A-adrenoceptor, but the structure-activity-binding mechanism relationship remains unclear. In the current study, three compounds (1, 2 and 3) were investigated through single-crystal X-ray diffraction analysis, density functional theory (DFT) calculations and molecular docking using a homology model of the α1A receptor. Compounds 1 and 3 form H-bonds networks to stabilize their three-dimensional structures, while C-H···π interactions play a significant role in the packing of 2. Based on DFT-optimized conformations, the HOMO-LUMO energy gaps and molecular electrostatic potential (MEP) were theoretically calculated at the B3LYP/6-311G (d, p) level of theory. Chemical reactivity increases in the order of 3 < 2 < 1, and the maximum positive region of the MEP maps is mainly localized over the NH group. The binding mechanisms of ligand-α1A-adrenoceptor complexes were illustrated by molecular docking. Binding to Gln177 of the second extracellular loop region via hydrogen bonds is likely to be essential for α1A-selective antagonists. The present work sheds light on the studies of structure-activity-binding mechanism and aids in the design of α1A antagonists with high selectivity. PMID:26528963

  14. Effects of glutamate and {alpha}2-noradrenergic receptor antagonists on the development of neurotoxicity produced by chronic rotenone in rats

    SciTech Connect

    Alam, Mesbah Danysz, Wojciech; Schmidt, Werner Juergen; Dekundy, Andrzej

    2009-10-15

    Systemic inhibition of complex I by rotenone in rats represents a model of Parkinson's disease (PD). The aim of this study was to elucidate whether neramexane (NMDA, nicotinic {alpha}9/{alpha}10 and 5-HT{sub 3} receptor antagonist), idazoxan ({alpha}{sub 2}-adrenoceptor antagonist) or 2-methyl-6-(phenyl-ethyl)-pyrimidine (MPEP, metabotropic glutamate receptor 5 antagonist) prevents rotenone-induced parkinsonian-like behaviours and neurochemical changes in rats. Rotenone (2.5 mg/kg i.p. daily) was administered over 60 days together with saline, neramexane (5 mg/kg i.p., b.i.d.), idazoxan (2.5 mg/kg i.p., b.i.d.) or MPEP (2.5 mg/kg i.p., b.i.d.). The same doses of neramexane, idazoxan and MPEP were administered to rats treated with vehicle instead of rotenone. Treatment-related effects on parkinsonian-like behaviours, such as hypokinesia/rigidity and locomotor activity, were evaluated. Moreover, concentrations of dopamine, serotonin and their metabolites were measured in rats from each experimental group. Over the 60-day treatment period, the rotenone + saline treated animals developed hypokinesia, expressed as an increase in the bar and grid descent latencies in the catalepsy test, and a decrease in locomotor activity. Neramexane and idazoxan partially prevented the development of catalepsy in rotenone-treated rats. Co-administration of MPEP with rotenone resulted only in a decrease in descent latency in the grid test on day 60. Chronic rotenone treatment reduced concentrations of dopamine and serotonin in the anterior striatum, which was blocked by co-treatment with neramexane or idazoxan but not with MPEP. Only neramexane treatment blocked the rotenone-induced decrease in dopamine levels in the substantia nigra pars compacta. In conclusion, neramexane and idazoxan counteracted to some extent the development of parkinsonian symptoms and neurochemical alterations in the rotenone model of Parkinson's disease.

  15. Constitutive precoupling to G(i) and increased agonist potency in the alpha(2B)-adrenoceptor.

    PubMed

    Ge, Huifang; Scheinin, Mika; Kallio, Jaana

    2003-07-11

    The human alpha(2B)-adrenoceptor (alpha(2B)-AR) was mutated by substituting the D(3.49) aspartate in position 109 with an alanine (alpha(2B)-D109A) in the conserved DRY sequence at the cytoplasmic face of TM3. We studied the effects of the mutation on agonist binding and on receptor activation in CHO cells, including possible inverse agonism monitored by measuring intracellular Ca(2+) concentrations ([Ca(2+)](i)). The mutated receptor had increased binding affinity for agonists, especially dexmedetomidine (3.8-fold). The increased affinity was abolished by pretreatment of the cells with pertussis toxin. The mutation produced constitutive receptor activity evidenced as increased basal [Ca(2+)](i) and increased potency and efficacy of agonists to elicit Ca(2+) responses. The imidazoline derivative RX821002 functioned as an inverse agonist only through the alpha(2B)-D109A, reducing [Ca(2+)](i). The results thus indicate that this mutation causes constitutive receptor-G(i)-protein precoupling, and that the D(3.49) aspartate residue of the DRY motif is involved in controlling coupled and uncoupled conformations of alpha(2B)-AR. PMID:12821136

  16. Pharmacologic characterization of GSK-961081 (TD-5959), a first-in-class inhaled bifunctional bronchodilator possessing muscarinic receptor antagonist and β2-adrenoceptor agonist properties.

    PubMed

    Hegde, Sharath S; Hughes, Adam D; Chen, Yan; Steinfeld, Tod; Jasper, Jeffrey R; Lee, Tae-Weon; McNamara, Alexander; Martin, William J; Pulido-Rios, M Teresa; Mammen, Mathai

    2014-10-01

    The objective of the present studies was to characterize the pharmacologic properties of GSK-961081 [TD-5959; (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl) piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate], a novel first-in-class inhaled bifunctional compound possessing both muscarinic antagonist (MA) and β2-adrenoceptor agonist (BA) properties (MABA). In competition radioligand binding studies at human recombinant receptors, GSK-961081 displayed high affinity for hM2 (Ki = 1.4 nM), hM3 muscarinic receptors (Ki = 1.3 nM) and hβ2-adrenoceptors (Ki = 3.7 nM). GSK-961081 behaved as a potent hβ2-adrenoceptor agonist (EC50 = 0.29 nM for stimulation of cAMP levels) with 440- and 320-fold functional selectivity over hβ1- and hβ3-adrenoceptors, respectively. In guinea pig isolated tracheal tissues, GSK-961081 produced smooth muscle relaxation through MA (EC50 = 50.2 nM), BA (EC50=24.6 nM), and MABA (EC50 = 11 nM) mechanisms. In the guinea pig bronchoprotection assay, inhaled GSK-961081 produced potent, dose-dependent inhibition of bronchoconstrictor responses via MA (ED50 = 33.9 µg/ml), BA (ED50 = 14.1 µg/ml), and MABA (ED50 = 6.4 µg/ml) mechanisms. Significant bronchoprotective effects of GSK-961081 were evident in guinea pigs via MA, BA, and MABA mechanisms for up to 7 days after dosing. The lung selectivity index of GSK-961081 in guinea pigs was 55- to 110-fold greater than that of tiotropium with respect to systemic antimuscarinic antisialagogue effects and was 10-fold greater than that of salmeterol with respect to systemic β2-adrenoceptor hypotensive effects. These preclinical findings studies suggest that GSK-961081 has the potential to be a promising next-generation inhaled lung-selective bronchodilator for the treatment of airway diseases, including chronic obstructive pulmonary disease. PMID:25100753

  17. A Comparison of the Anorectic Effect and Safety of the Alpha2-Adrenoceptor Ligands Guanfacine and Yohimbine in Rats with Diet-Induced Obesity.

    PubMed

    Dudek, Magdalena; Knutelska, Joanna; Bednarski, Marek; Nowiński, Leszek; Zygmunt, Małgorzata; Mordyl, Barbara; Głuch-Lutwin, Monika; Kazek, Grzegorz; Sapa, Jacek; Pytka, Karolina

    2015-01-01

    The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial α2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of α2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of α2-adrenoceptor--yohimbine and guanfacine--act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of α2A-adrenoceptors and partial stimulation of α2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of α1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. α1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA) to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity. PMID:26506439

  18. Pharmacological analysis of the novel, selective α1-adrenoceptor antagonist, KMD-3213, and its suitability as a tritiated radioligand

    PubMed Central

    Murata, Satoshi; Taniguchi, Takanobu; Muramatsu, Ikunobu

    1999-01-01

    Pharmacological profiles of tritiated KMD-3213, a new antagonist of α1-adrenoceptor (AR), were examined in recombinant and native α1-AR, and compared with those of prazosin (PZ) and tamsulosin (YM-617). In saturation experiments, [3H]-KMD (10–2000 pM) showed high affinity for α1a-AR (pKD=10.5). However, no significant binding to α1b-AR and insufficient/unsaturated binding to α1d-AR were observed at concentrations up to 2000 pM. In contrast, [3H]-PZ and [3H]-YM bound to all subtypes with high affinity (pKD>9). In competition experiments, KMD-3213 also had higher affinity for α1a-AR than for other two subtypes; pKi=10.4, 8.1 and 8.6 for α1a-, α1b- and α1d-AR, respectively. [3H]-KMD also bound to the native α1A-AR (rat submaxillary gland) with high affinity, but not to α1B-AR (rat liver). In rat kidney which expresses α1A- and α1B-AR, [3H]-KMD and [3H]-PZ bound to a single high-affinity site (pKD=10.8 and 10.1, respectively) with distinct amount of binding sites (Bmax=159 and 267 fmol mg−1 protein, respectively). [3H]-PZ binding sites consisted of low- and high-affinity sites for KMD-3213 (pKi=7.6 and 10.7, respectively), for WB4101 (pKi=8.1 and 10.0) and for YM-617 (pKi=8.7 and 10.8). The proportion of the high affinity site was approximately 60% in these drugs which was compatible to the ratio between Bmax of [3H]-KMD and [3H]-PZ. [3H]-KMD binding sites consisted of a single site for these drugs with affinities which were similar to those of the high affinity sites in [3H]-PZ binding. In functional experiments, KMD-3213 antagonized the contractile responses to NS-49 or noradrenaline (NA) with higher affinity in functional α1A- (rat caudal artery, pA2=10.0 against NS-49) and α1L-AR (dog mesenteric artery, pA2=9.9 against NA) than in α1B- (dog carotid artery, pA2=7.7 against NA) and α1D-AR (rat thoracic aorta, pA2=8.3 against NA). These results confirm the α1A-AR selectivity and high affinity of KMD-3213, and indicate that [3H]-KMD can

  19. Prazosin, an alpha 1-adrenergic receptor antagonist, suppresses experimental autoimmune encephalomyelitis in the Lewis rat.

    PubMed Central

    Brosnan, C F; Goldmuntz, E A; Cammer, W; Factor, S M; Bloom, B R; Norton, W T

    1985-01-01

    Prazosin, an antagonist of alpha 1-adrenergic receptors, has been found to suppress the clinical and histological expression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Suppression was more significant in females than in males and was a dose-dependent phenomenon. Analysis of the effect of other adrenergic receptor antagonists supports the conclusion that the suppressive effect of prazosin is a consequence of blockade of the alpha 1-receptor since treatment with either the alpha 2-antagonist yohimbine or the beta-antagonist propranolol exacerbated the disease, whereas treatment with the long-acting mixed alpha 1/alpha 2-antagonist phenoxybenzamine had some suppressive activity. Treatment with prazosin was also able to suppress clinical and histological signs of EAE in animals sensitized by adoptive transfer with activated spleen or lymph node cells. Whether prazosin acts through altering vascular permeability or the immune response, or both, remains to be determined. Images PMID:2994053

  20. Modeling the interactions between alpha(1)-adrenergic receptors and their antagonists.

    PubMed

    Du, Lupei; Li, Minyong

    2010-09-01

    As crucial members of the G-protein coupled receptor (GPCR) superfamily, alpha (1)-adrenergic receptors (alpha(1)-ARs) are recognized to intervene the actions of endogenous catecholamines such as norepinephrine and epinephrine. So far three distinct alpha(1)-AR subtypes, alpha(1A), alpha(1B) and alpha(1D), have been characterized by functional analysis, radio-ligand binding and molecular biology studies. The alpha(1)-ARs are of therapeutic interest because of their distinct and critical roles in many physiological processes, containing hypertension, benign prostatic hyperplasia, smooth muscle contraction, myocardial inotropy and chronotropy, and hepatic glucose metabolism. Accordingly, designing subtype-selective antagonists for each of the three alpha(1)-AR subtypes has been an enthusiastic region of medicinal research. Even though a large number of studies on GPCRs have been conducted, understanding of how known antagonists bind to alpha(1)-ARs still remains sketchy and has been a serious impediment to search for potent and subtype-selective alpha(1)-AR antagonists because of the lack of detailed experimental structural knowledge. This review deliberates the simulation of alpha(1)-ARs and their interactions with antagonists by using ligand-based (pharmacophore identification and QSAR modeling) and structure-based (comparative modeling and molecular docking) approaches. Combined with experimental data, these computational attempts could improve our understanding of the structural basis of antagonist binding and the molecular basis of receptor activation, thus offering a more reasonable approach in the design of drugs targeting alpha(1)-ARs. PMID:20412040

  1. Effects of ρ-Da1a a peptidic α1A-adrenoceptor antagonist in human isolated prostatic adenoma and anaesthetized rats

    PubMed Central

    Palea, S; Maiga, A; Guilloteau, V; Rekik, M; Guérard, M; Rouget, C; Rischmann, P; Botto, H; Camparo, P; Lluel, P; Gilles, N

    2013-01-01

    Background and Purpose ρ-Da1a, a 65 amino-acid peptide, has subnanomolar affinity and high selectivity for the human α1A-adrenoceptor subtype. The purpose of this study was to characterize the pharmacological effects of ρ-Da1a on prostatic function, both in vivo and in vitro. Experimental Approach ρ-Da1a was tested as an antagonist of adrenaline-induced effects on COS cells transfected with the human α1A-adrenoceptor as well as on human isolated prostatic adenoma obtained from patients suffering from benign prostatic hyperplasia. Moreover, we compared the effects of ρ-Da1a and tamsulosin on phenylephrine (PHE)-induced increases in intra-urethral (IUP) and arterial pressures (AP) in anaesthetized rats, following i.v. or p.o. administration. Key Results On COS cells expressing human α1A-adrenoceptors and on human prostatic strips, ρ-Da1a inhibited adrenaline- and noradrenaline-induced effects. In anaesthetized rats, ρ-Da1a and tamsulosin administered i.v. 30 min before PHE significantly antagonized the effects of PHE on IUP. The pKB values for tamsulosin and ρ-Da1a for this effect were similar. With regards to AP, ρ-Da1a only reduced the effect of PHE on AP at the lowest dose tested (10 μg·kg−1), whereas tamsulosin significantly reduced PHE effects at doses between 10 and 150 μg·kg−1. Conclusions and Implications ρ-Da1a exhibited a relevant effect on IUP and a small effect on AP. In contrast, tamsulosin antagonized the effects of PHE on both IUP and AP. We conclude that ρ-Da1a is more uroselective than tamsulosin. ρ-Da1a is the most selective peptidic antagonist for α1A-adenoceptors identified to date and could be a new treatment for various urological diseases. PMID:23005263

  2. A Comparison of the Anorectic Effect and Safety of the Alpha2-Adrenoceptor Ligands Guanfacine and Yohimbine in Rats with Diet-Induced Obesity

    PubMed Central

    Dudek, Magdalena; Knutelska, Joanna; Bednarski, Marek; Nowiński, Leszek; Zygmunt, Małgorzata; Mordyl, Barbara; Głuch-Lutwin, Monika; Kazek, Grzegorz; Sapa, Jacek; Pytka, Karolina

    2015-01-01

    The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial α2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of α2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of α2-adrenoceptor––yohimbine and guanfacine––act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of α2A-adrenoceptors and partial stimulation of α2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of α1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. α1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA) to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity. PMID:26506439

  3. Comparison of 7 α(1)-adrenoceptor antagonists in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia:a short-term crossover study.

    PubMed

    Araki, Tohru; Monden, Koichi; Araki, Motoo

    2013-01-01

    A crossover study was conducted to identify the best α1-adrenoceptor (α1AR) antagonist for individual patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH). One hundred thirteen patients (mean age 70.8 years) were enrolled. All patients met BPH clinical study guidelines. Seven agents were utilized:tamsulosin 0.2mg, silodosin 8mg, urapidil 60mg, naftopidil 50mg, prazosin 1mg, terazosin 2mg, and doxazosin 1mg. Patients were initially prescribed tamsulosin or silodosin for a week and then urapidil for a week. Two weeks later, they were prescribed the better of the 2 agents for a week and a new agent for the next week. This cycle was repeated until all 7 agents were tested. Efficacy was evaluated with the International Prostate Symptom Score. The agent rankings were doxazosin (25 [22%]), silodosin (22 [19%]), urapidil (19 [17%]), naftopidil (17 [15%]), terazosin (12 [11%]), tamsulosin (11 [10%]), prazosin (7 [6%]). Only 12 patients (11%) changed agents after the crossover study was completed. The major reason was adverse events (83%). We found that each of the 7 α1AR antagonists has its own supporters. Further, the one-week crossover study was useful in identifying the best agent for the treatment of each individual with LUTS. PMID:23970323

  4. New Multi-target Antagonists of α1A-, α1D-Adrenoceptors and 5-HT1A Receptors Reduce Human Hyperplastic Prostate Cell Growth and the Increase of Intraurethral Pressure.

    PubMed

    Nascimento-Viana, Jéssica B; Carvalho, Aline R; Nasciutti, Luiz Eurico; Alcántara-Hernández, Rocío; Chagas-Silva, Fernanda; Souza, Pedro A R; Romeiro, Luiz Antonio S; García-Sáinz, J Adolfo; Noël, François; Silva, Claudia Lucia Martins

    2016-01-01

    Benign prostatic hyperplasia (BPH) is characterized by stromal cell proliferation and contraction of the periurethral smooth muscle, causing lower urinary tract symptoms. Current BPH treatment, based on monotherapy with α1A-adrenoceptor antagonists, is helpful for many patients, but insufficient for others, and recent reports suggest that stimulation of α1D-adrenoceptors and 5-hydroxytryptamine (serotonin) (5-HT)1A receptors contributes to cell proliferation. In this study, we investigated the potential of three N-phenylpiperazine derivatives (LDT3, LDT5, and LDT8) as multi-target antagonists of BPH-associated receptors. The affinity and efficacy of LDTs were estimated in isometric contraction and competition-binding assays using tissues (prostate and aorta) and brain membrane samples enriched in specific on- or off-target receptors. LDTs' potency was estimated in intracellular Ca(2+) elevation assays using cells overexpressing human α1-adrenoceptor subtypes. The antiproliferative effect of LDTs on prostate cells from BPH patients was evaluated by viable cell counting and 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays. We also determined LDTs' effects on rat intraurethral and arterial pressure. LDT3 and LDT5 are potent antagonists of α1A-, α1D-adrenoceptors, and 5-HT1A receptors (Ki values in the nanomolar range), and fully inhibited phenylephrine- and 5-HT-induced proliferation of BPH cells. In vivo, LDT3 and LDT5 fully blocked the increase of intraurethral pressure (IUP) induced by phenylephrine at doses (ED50 of 0.15 and 0.09 μg.kg(-1), respectively) without effect on basal mean blood pressure. LDT3 and LDT5 are multi-target antagonists of key receptors in BPH, and are capable of triggering both prostate muscle relaxation and human hyperplastic prostate cell growth inhibition in vitro. Thus, LDT3 and LDT5 represent potential new lead compounds for BPH treatment. PMID:26493747

  5. Role of calcium in the interaction of alpha and beta adrenoceptor-mediated renin release in isolated, constant pressure perfused rabbit kidneys.

    PubMed

    Opgenorth, T J; Zehr, J E

    1983-10-01

    These experiments were designed to study the role of calcium in the modulation of renin secretion by alpha and beta adrenoceptors. Rabbit kidneys were isolated and single-pass perfused with a modified Ringer's solution. Renal perfusion pressure was precisely controlled by an electronic servocontrol system. Tubular events were minimized by ligation of the ureter before initiating the studies. Under these conditions the predominant factor modifying renin secretion was assumed to originate directly on the juxtaglomerular cells. Isoproterenol infused at 0.1, 0.5, 1.0 and 5.0 nM/min/g of kidney weight increased renin secretion in a dose-dependent manner whereas phenylephrine infused at identical molar doses did not. In addition, phenylephrine (5.0 nM/min/g of kidney weight) blocked the usual response to isoproterenol. Removal of calcium from the perfusing medium had no effect on either the response to isoproterenol or the lack of a response to phenylephrine. On the other hand, when calcium is removed from the perfusate or when D-600, a calcium channel blocker, is added to calcium-containing medium, phenylephrine failed to block the usual response to isoproterenol. We conclude that the suppression of beta adrenoceptor stimulation of renin release by alpha adrenoceptor agonists is calcium dependent by a final mechanism as yet undefined, but probably involving movement of calcium into the juxtaglomerular cells. PMID:6312014

  6. Olfactory Bulb [alpha][subscript 2]-Adrenoceptor Activation Promotes Rat Pup Odor-Preference Learning via a cAMP-Independent Mechanism

    ERIC Educational Resources Information Center

    Shakhawat, Amin MD.; Harley, Carolyn W.; Yuan, Qi

    2012-01-01

    In this study, three lines of evidence suggest a role for [alpha][subscript 2]-adrenoreceptors in rat pup odor-preference learning: olfactory bulb infusions of the [alpha][subscript 2]-antagonist, yohimbine, prevents learning; the [alpha][subscript 2]-agonist, clonidine, paired with odor, induces learning; and subthreshold clonidine paired with…

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

    PubMed Central

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

    2016-01-01

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

  8. Solution structure of {alpha}-conotoxin PIA, a novel antagonist of {alpha}6 subunit containing nicotinic acetylcholine receptors

    SciTech Connect

    Chi, Seung-Wook; Lee, Si-Hyung; Kim, Do-Hyoung; Kim, Jae-Sung; Olivera, Baldomero M.; McIntosh, J. Michael; Han, Kyou-Hoon . E-mail: khhan600@kribb.re.kr

    2005-12-30

    {alpha}-Conotoxin PIA is a novel nicotinic acetylcholine receptor (nAChR) antagonist isolated from Conus purpurascens that targets nAChR subtypes containing {alpha}6 and {alpha}3 subunits. {alpha}-conotoxin PIA displays 75-fold higher affinity for rat {alpha}6/{alpha}3{beta}2{beta}3 nAChRs than for rat {alpha}3{beta}2 nAChRs. We have determined the three-dimensional structure of {alpha}-conotoxin PIA by nuclear magnetic resonance spectroscopy. The {alpha}-conotoxin PIA has an '{omega}-shaped' overall topology as other {alpha}4/7 subfamily conotoxins. Yet, unlike other neuronally targeted {alpha}4/7-conotoxins, its N-terminal tail Arg{sup 1}-Asp{sup 2}-Pro{sup 3} protrudes out of its main molecular body because Asp{sup 2}-Pro{sup 3}-Cys{sup 4}-Cys{sup 5} forms a stable type I {beta}-turn. In addition, a kink introduced by Pro{sup 15} in the second loop of this toxin provides a distinct steric and electrostatic environment from those in {alpha}-conotoxins MII and GIC. By comparing the structure of {alpha}-conotoxin PIA with other functionally related {alpha}-conotoxins we suggest structural features in {alpha}-conotoxin PIA that may be associated with its unique receptor recognition profile.

  9. Functional and radioligand binding characterization of the α1L-adrenoceptor subtype of the human vas deferens.

    PubMed

    Davis, B J; Wiener, M; Chapple, C R; Sellers, D J; Chess-Williams, R

    2015-04-01

    Alpha1 -adrenoceptor antagonists can cause ejaculatory dysfunction as an adverse effect. Contractions of the human vas deferens are mediated via α1A -adrenoceptors, and this study investigated whether the low affinity state of this receptor (α1L -adrenoceptor) is involved in mediating contractions of this tissue. The potency of agonists and the affinity of receptor subtype selective antagonists were determined in functional experiments and in [(3) H]tamsulosin binding experiments to identify the α1 -adrenoceptor subtype population present in the human vas deferens. The α1A -adrenoceptor selective agonist A61603 was a full agonist and was 250-fold more potent than noradrenaline. Prazosin antagonized contractile responses to phenylephrine with a low affinity (pKd = 8.6). Only high concentrations of RS17053 antagonized responses to phenylephrine and yielded a relatively low affinity estimate of 7.0. BMY7378 (α1D -adrenoceptor selective) gave a low affinity estimate (pKd = 6.7), whilst tamsulosin (α1A - and α1D -adrenoceptor selective) had a high affinity (pKd = 9.9). [(3) H]Tamsulosin bound to human vas deferens membranes with a high affinity (pKd = 10.0). Prazosin, RS17053 and BMY7378 competed with [(3) H]tamsulosin with low affinities for a single population of binding sites (pKd values of 8.5, 7.2 and 6.3, respectively). These functional and radioligand binding data indicate that the human vas deferens possesses a homogeneous population of α1 -adrenoceptors which have the pharmacological properties of the putative α1L -adrenoceptor, the same functional receptor previously identified in the human prostate. PMID:25790239

  10. The antidepressant drugs fluoxetine and duloxetine produce anxiolytic-like effects in a schedule-induced polydipsia paradigm in rats: enhancement of fluoxetine's effects by the α2 adrenoceptor antagonist yohimbine.

    PubMed

    Prus, Adam J; Mooney-Leber, Sean M; Berquist, Michael D; Pehrson, Alan L; Porter, Nicholas P; Porter, Joseph H

    2015-08-01

    Similar to the time-course for treating depression, several weeks of administration are required for serotonin (5-HT) reuptake inhibitors to produce anxiolytic effects. Previous studies with the schedule-induced polydipsia paradigm (a putative preclinical anxiety model) have shown that repeated administration of antidepressant drugs is necessary to produce a suppression of polydipsia, which is interpreted as an anxiolytic-like effect. The present study sought to expand past findings by evaluating the selective 5-HT reuptake inhibitor (SSRI) fluoxetine and the 5-HT-norepinephrine reuptake inhibitor duloxetine in the schedule-induced polydipsia paradigm with rats. Dose combinations of the α2 adrenoceptor antagonist yohimbine with fluoxetine were also explored to determine whether α2 adrenoceptor antagonism could enhance the anxiolytic-like effects produced by an SSRI. Fluoxetine and duloxetine significantly reduced water intake over the course of daily administrations. Daily treatment with the combination of fluoxetine and yohimbine produced a significantly greater reduction in water intake than fluoxetine alone. The present results confirmed previous findings that inhibition of 5-HT reuptake reduces water consumption in this paradigm. The results for the α2 antagonist yohimbine (in combination with fluoxetine) also indicate that α2 adrenoceptor antagonism may significantly enhance anxiolytic-like effects of SSRIs. PMID:26154437

  11. A novel D2-dopaminergic and alpha2-adrenoceptor receptor agonist induces substantial and prolonged IOP decrease in normotensive rabbits.

    PubMed

    Savolainen, Jouko; Rautio, Jarkko; Razzetti, Roberta; Järvinen, Tomi

    2003-06-01

    The effects of a novel and selective D2-dopaminergic/alpha2-adrenoceptor agonist, CHF1035, and its metabolite CHF1024 on intraocular pressure (IOP) were determined in rabbits. Because CHF1035 is a mixture of two enantiomers, CHF1800 (+) and CHF1810 (-), pure enantiomers were also studied to determine possible differences in IOP-decreasing ability depending on the stereochemistry of the molecule. CHF1035, CHF1800 (+), CHF1810 (-), CHF1024, brimonidine and 0.9% NaCl were administered topically to rabbits and IOP was then measured at fixed time intervals. The dose-response profile (0.01-1.0% w/v) was determined for CHF1035. CHF1035 and its metabolite CHF1024 significantly lowered IOP in the treated eyes. CHF1035 showed a maximum IOP decrease (7.6 +/- 1.5 mmHg) 5 h post-dosing, whereas the metabolite CHF1024 showed a maximum decrease in IOP (7.0 +/- 0.8 mmHg) 3 h post-dosing. The maximum IOP decrease produced by CHF1035 in the treated eye was comparable with that produced by brimonidine (7.8 +/- 0.9 mmHg), but CHF1035 had a significantly longer duration of action. Unlike brimonidine, CHF1035 and CHF1024 did not decrease IOP in the untreated eye. CHF1810 (-) lowered the IOP more than CHF1800 (+). No irritation, evaluated as eyelid closure, was observed after topical administration of any of the compounds. Only in the case of CHF1035 1% solution, two rabbits out of six closed the eye for 30-45 s. In conclusion, CHF1035 and its metabolite CHF1024 significantly decreased the IOP in rabbits, and are potential novel IOP lowering agents. Especially, CHF1035 produced a substantial decrease in IOP for a prolonged period of time, and thus may prove useful in glaucoma therapy. PMID:12841939

  12. Evidence for two mechanisms of depolarization associated with alpha 1-adrenoceptor activation in the rat anococcygeus muscle.

    PubMed

    Byrne, N G; Large, W A

    1985-11-01

    Membrane potential responses in the rat isolated anococcygeus to bath-applied noradrenaline and field stimulation have been investigated by use of intracellular microelectrode and combined extracellular electrical and mechanical (sucrose gap) recording techniques. Intracellular recordings were made usually from tissues immobilized with hypertonic Krebs solution. Bath-application of noradrenaline produced depolarizations which consisted of two components; an initial 'fast' phase which peaked within 1-2 s and which was followed by a 'slow' sustained depolarization. Both components were concentration-dependent. Noradrenaline could also evoke oscillations in membrane potential which, unlike the 'fast' component of depolarization, were prevented by conditioning hyperpolarization of the membrane and were evoked by direct membrane depolarization with externally applied current pulses. Thus, the oscillations are voltage-dependent phenomena. Replacement of the external NaCl of the Krebs solution with an equimolar amount of Na benzenesulphonate abolished the noradrenaline-evoked 'fast' depolarization while the 'slow' phase was unaffected. This suggests that two mechanisms of depolarization are activated in this muscle by the bath-application of noradrenaline. The adrenergic excitatory junction potential was also abolished in Na benzenesulphonate. Prazosin reduced both the 'fast' and 'slow' components of depolarization produced by noradrenaline indicating their mediation by alpha 1-adrenoceptors. The membrane potential (-29 mV) at the maximum amplitude of the 'fast' depolarization was similar to the equilibrium potential (-27 mV) for the depolarization evoked by ionophoretically applied noradrenaline and which was obtained by extrapolation from the relationship between amplitude of the ionophoretic response and membrane potential displacement in the partition chamber. These results suggest that the 'fast' depolarization and the ionophoretic response are due to an increased

  13. Ranolazine enhances nicardipine-induced relaxation of alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta.

    PubMed

    Malavaki, Christina; Hatziefthimiou, Apostolia; Daskalopoulou, Stella S; Stefanidis, Ioannis; Karatzaferi, Christina; Aidonidis, Isaac

    2015-04-01

    Ranolazine (RAN) and nicardipine (NIC) have been studied for their vasorelaxing effects but the combination of these agents against adrenergic vasoconstriction has not been tested. The present study aimed at investigating the vasorelaxing effect by the combination of the two agents on alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta. Aortic rings were mounted for isometric tension recording in organ baths containing Krebs-Henseleit solution. Concentration-response curves of RAN (10(-9) to 10(-4) M), NIC (10(-1) to 10(-5) M), and RAN + NIC (3 x 10(-6) M) were obtained in a cumulative manner using phenylephrine (PE, 2 x 10(-6) M) as constrictor agent. The effective concentration (EC)50 values for RAN and NIC were 6.5 x 10(-6) M and 1.4 x 10(-5) M, respectively. The treatment of PE-precontracted aortic rings with either RAN or NIC up to 65 min revealed that both agents displayed a biphasic pattern of initial rising and late sustained phases of relaxation. At 35 min of incubation, RAN and NIC induced relaxation by 23 +/- 3% and 14 +/- 4%, respectively (N = 7, P=NS, RAN vs. NIC); their combination resulted in a 34 +/- 4% relaxation (N=7; P < 0.01, RAN + NIC vs. NIC). At 65 min the effect of NIC prevailed and tended to be closer to the values of the combination treatment (P < 0.01, RAN + NIC vs. RAN). The results indicate that RAN at therapeutic concentrations exerts a significant additive vasorelaxing effect when combined with NIC in rabbit aorta. PMID:26148375

  14. Multiple actions of glaucine on cyclic nucleotide phosphodiesterases, alpha 1-adrenoceptor and benzothiazepine binding site at the calcium channel.

    PubMed Central

    Ivorra, M. D.; Lugnier, C.; Schott, C.; Catret, M.; Noguera, M. A.; Anselmi, E.; D'Ocon, P.

    1992-01-01

    1. In the present study, the properties of glaucine (an aporphine structurally related to papaverine) were compared with those of papaverine, diltiazem, nifedipine and prazosin. The work includes functional studies on rat isolated aorta contracted with noradrenaline, caffeine or KCl, and a determination of the affinity of glaucine at calcium channel binding sites of alpha-adrenoceptors, by use of [3H]-(+)-cis-diltiazem, [3H]-nitrendipine and [3H]-prazosin binding to cerebral cortical membranes. The effects of glaucine on the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta were also determined. 2. Contraction evoked by noradrenaline (1 microM) or depolarizing solution (60 mM KCl) were inhibited in a concentration-dependent manner by all the compounds tested. As expected, prazosin showed a greater selectivity of action on NA-induced contraction, whereas nifedipine and diltiazem appeared more potent on KCl-induced contraction. Glaucine had a greater potency on the contraction elicited by noradrenaline whereas papaverine acted non specifically. 3. In Ca(2+)-free solution, prazosin (0.1 microM) and glaucine (0.1 mM) inhibited the contraction evoked by NA; diltiazem (0.1 mM) diminished this contraction whereas nifedipine (1 microM) had no effect. Preincubation of tissues with glaucine, diltiazem, nifedipine and prazosin did not modify the contractile response induced by caffeine. In contrast, papaverine (0.1 mM) significantly inhibited the contractions evoked by NA or caffeine in Ca(2+)-free medium. 4. Glaucine and papaverine show affinity at the [3H]-prazosin binding site and at the benzothiazepine binding site of the Ca(2+)-channel receptor complex, but have no effect at the dihydropyridine binding site in rat cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1327380

  15. Stimulatory effect of isoferulic acid on alpha1A-adrenoceptor to increase glucose uptake into cultured myoblast C2C12 cell of mice.

    PubMed

    Liu, I M; Tsai, C C; Lai, T Y; Cheng, J T

    2001-05-14

    In an attempt to elucidate the effect of isoferulic acid on alpha1-adrenoceptor (AR), the myoblast C2C12 cells of mice were employed to investigate the change of glucose uptake in the present study. Isoferulic acid enhanced the uptake of radioactive glucose into C2C12 cells in a concentration-dependent manner, which were abolished by pretreatment with prazosin. Effect of isoferulic acid on alpha1-AR was further characterized using the displacement of [3H]YM617 binding in C2C12 cells. The radioactive glucose uptake increasing action of isoferulic acid was abolished by tamsulosin or WB 4101 at concentration sufficient to block alpha1A-adrenoceptor (alpha1A-AR) but it was not modified by chlorethylclonidine (CEC) at the concentration sufficient to abolish alpha1B-AR. An activation of alpha1A-AR by isoferulic acid in C2C12 cells can thus be considered. Pharmacological inhibition of phospholipase C (PLC) by U73312 resulted in a concentration-dependent reduction of isoferulic acid-stimulated glucose uptake in C2C12 cells. This inhibition by U73112 was specific because the inactive congener, U73343, failed to modify the action of isoferulic acid. Also, chelerythrine and GF 109203X diminished the action of isoferulic acid at concentration sufficient to inhibit the activity of protein kinase C (PKC). The obtained data suggest that an activation of alpha1A-AR by isoferulic acid may increase the glucose uptake via PLC-PKC pathway in C2C12 cells. PMID:11474559

  16. Comparative study on pharmacokinetics and in vivo alpha1-adrenoceptor binding of [3H]tamsulosin and [3H]prazosin in rats.

    PubMed

    Ohkura, T; Yamada, S; Deguchi, Y; Kimura, R

    1999-04-01

    The plasma concentration, total radioactivity and in vivo alpha1-adrenoceptor binding in rat tissues after intravenous (i.v.) injection of [3H]tamsulosin were measured and they were compared with those obtained after the injection of [3H]prazosin. The plasma concentration of [3H]tamsulosin was consistently higher than that of [3H]prazosin, with 1.4 times greater areas under the curve (AUC(0-infinity)) of plasma concentration. As there was a significantly lower value of apparent volume of central compartment (Vd(c)) and distribution volume at steady state (Vd(ss)) for [3H]tamsulosin than [3H]prazosin with little difference in elimination rate constant (beta), the higher concentration of [3H]tamsulosin in plasma might be associated mainly with the smaller volume of distribution. The ratio of total radioactivity in tissues to the plasma unbound concentration of [3H]tamsulosin after i.v. injection of the ligand was consistently lower than that of [3H]prazosin. These observations suggest that [3H]tamsulosin is distributed in rat tissues in a more limited manner than [3H]prazosin. A significantly lower level of in vivo specific binding of [3H]tamsulosin than [3H]prazosin was observed in the spleen, heart and liver. Further, the apparent dissociation constant (Kd) and maximal number of binding sites (Bmax) for in vivo specific [3H]tamsulosin binding were considerably lower than those for [3H]prazosin binding. Therefore, these findings suggest that [3H]tamsulosin labels preferentially a subpopulation of the alpha1-adrenoceptor sites in rat tissues labeled by [3H]prazosin. In conclusion, the present study has shown that there is a significant difference in the pharmacokinetics and in vivo alpha1-adrenoceptor binding characteristics between tamsulosin and prazosin. PMID:10328564

  17. The alpha-2A-adrenoceptor agonist, guanfacine, increases regional cerebral blood flow in dorsolateral prefrontal cortex of monkeys performing a spatial working memory task.

    PubMed

    Avery, R A; Franowicz, J S; Studholme, C; van Dyck, C H; Arnsten, A F

    2000-09-01

    Research indicates that norepinephrine enhances the working memory functions of the prefrontal cortex (PFC) through actions at post-synaptic, alpha-2A adrenoceptors. The current study examined the effects of the alpha-2A adrenoreceptor agonist, guanfacine (0.7 mg/kg, i.m.), compared to saline on SPECT measures of regional cerebral blood flow (rCBF) in monkeys performing a spatial working memory task. Animals were infused with the SPECT blood flow tracer, Tcm-99m ECD, through an indwelling intravenous catheter while performing the working memory task. Guanfacine treatment significantly improved cognitive performance of the working memory task, and significantly increased rCBF values in the dorsolateral PFC, the brain region most tightly associated with performance of spatial working memory tasks. In contrast, guanfacine had no significant effect on rCBF in the superior temporal cortex, an auditory association area unrelated to task performance. These data are consistent with the hypothesis that alpha-2A adrenoceptor stimulation preferentially enhances functioning of the PFC. PMID:10942848

  18. Alpha2-adrenoreceptors profile modulation. 4. From antagonist to agonist behavior.

    PubMed

    Gentili, Francesco; Cardinaletti, Claudia; Vesprini, Cristian; Carrieri, Antonio; Ghelfi, Francesca; Farande, Aniket; Giannella, Mario; Piergentili, Alessandro; Quaglia, Wilma; Laurila, Jonne M; Huhtinen, Anna; Scheinin, Mika; Pigini, Maria

    2008-07-24

    The goal of the present study was to modulate the receptor interaction properties of known alpha 2-adrenoreceptor (AR) antagonists to obtain novel alpha 2-AR agonists with desirable subtype selectivity. Therefore, a phenyl group or one of its bioisosteres or aliphatic moieties with similar steric hindrance were introduced into the aromatic ring of the antagonist lead basic structure. The functional properties of the novel compounds allowed our previous observations to be confirmed. The high efficacy of 7, 12, and 13 as alpha 2-AR agonists and the significant alpha 2C-AR subtype selective activation displayed by 11 and 15 demonstrated that favorable interactions to induce alpha 2-AR activation were formed between the pendant groups of the ligands and the aromatic cluster present in transmembrane domain 6 of the binding site cavity of the receptors. PMID:18578476

  19. Design, Synthesis, and Biological Evaluation of Indoline and Indole Derivatives as Potent and Selective α1A-Adrenoceptor Antagonists.

    PubMed

    Zhao, Fei; Li, Jing; Chen, Ying; Tian, Yanxin; Wu, Chenglin; Xie, Yanan; Zhou, Yu; Wang, Jiang; Xie, Xin; Liu, Hong

    2016-04-28

    A series of indoline and indole derivatives were designed, synthesized, and evaluated as selective α1A-adrenergic receptor (α1A-AR) antagonists for the treatment of benign prostatic hyperplasia (BPH). In this study, two highly selective and potent α1A-AR antagonists, compounds (R)-14r (IC50 = 2.7 nM, α1B/α1A = 640.1, α1D/α1A = 408.2) and (R)-23l (IC50 = 1.9 nM, α1B/α1A = 1506, α1D/α1A = 249.6), which exhibited similar activities and better selectivities in cell-based calcium assays as compared with the marketed drug silodosin (IC50 = 1.9 nM, α1B/α1A = 285.9, α1D/α1A = 14.4), were identified. In the functional assays with isolated rat tissues, compounds (R)-14r and (R)-23l also showed high potency and uroselectivity. Most importantly, (R)-14r and (R)-23l can significantly decrease the micturition frequency and increase the mean voided volume of the BPH rats in a dose-dependent manner, making them worthy of further investigation for the development of anti-BPH agents. PMID:27031406

  20. alpha. -Adrenergic vasoconstriction and receptor subtypes in large coronary arteries of calves

    SciTech Connect

    Young, M.A.; Vatner, D.E.; Knight, D.R.; Graham, R.M.; Homcy, C.J.; Vatner, S.F. New England Regional Primate Research Center, Southborough, MA )

    1988-12-01

    The authors investigated {alpha}-adrenoceptor subtype distribution in large coronary arteries from both functional and biochemical perspectives. The effects of intracoronary administration of the selective {alpha}{sub 1}-adrenoceptor agonist phenylephrine, of the selective {alpha}{sub 2}-adrenoceptor agonist B-HT 920 and of the mixed {alpha}{sub 1+2}-adrenoceptor agonist norepinephrine were examined on measurements of left circumflex coronary artery diameter in conscious calves. After {beta}-adrenergic blockade, equivalent reductions in large coronary artery diameter were observed with phenylephrine, B-HT, and norepinephrine. Phenylephrine-induced constrictions were abolished by prazosin, an {alpha}{sub 1}-selective antagonist, but unaffected by rauwolscine, an {alpha}{sub 2}-selective antagonist. Conversely, the B-HT-induced constriction was abolished by rauwolscine but unaffected by prazosin. Coronary constriction with norepinephrine was attenuated with either prazosin or rauwolscine and abolished by the two antagonists combined. Ligand-binding studies in which ({sup 3}H)prazosin and ({sup 3}H)rauwolscine and sarcolemmal membranes were used revealed an {alpha}{sub 1}-adrenoceptor density of 15 {plus minus} 3.1 fmol/mg protein with a dissociation constant (K{sub D}) of 0.7 {plus minus} 0.2 nM and an {alpha}{sub 2}-adrenoceptor density of 68 {plus minus} 5.1 fmol/mg protein, with a K{sub D} of 7.4 {plus minus} 1.2 nM. Thus large coronary arteries of the calf contain both {alpha}{sub 1}- and {alpha}{sub 2}-adrenoceptor subtypes, each of which elicits constriction of the large coronary artery in the conscious animal.

  1. Pharmacological differentiation of presynaptic inhibitory alpha-adrenoceptors and opiate receptors in the cat nictitating membrane.

    PubMed

    Dubocovich, M L; Langer, S Z

    1980-11-01

    1 The action of morphine, naturally occurring and synthetic opiate peptides on [3H]-noradrenaline release induced by nerve stimulation was studied in the isolated nerve muscle preparation of the cat nictitating membrane under experimental conditions in which the alpha-presynaptic receptors were blocked by phentolamine 1 microM. 2 Morphine and the naturally occurring peptides: [Met5]-enkephalin, [Leu5]-enkephalin and beta-endorphin reduced 3H-transmitter overflow and responses to nerve stimulation from the cat nictitating membrane, effects which were completely antagonized by naloxone 0.3 microM. The relative order of potency for the inhibition of the stimulation-induced 3H-transmitter overflow at the level of the IC50 (microM) was as follows: [Met5]-enkephalin (0.020 microM) greater than or equal to [Leu5]-enkephalin (0.036 microM) > morphine (0.3 microM) > beta-endorphin (1 microM). 3 The synthetic opiate pentapeptides: BW 180 C (Tyr-D-Ala-Gly-Phe-D-Leu), and BW834 C (Tyr-D-Ala-Gly-pClPhe-DLeu), which are resistant to enzymatic degradation were more potent than the enkephalins in reducing the stimulation-evoked transmitter overflow from the cat nictitating membrane. On the other hand, the tetrapeptide BW832 C, which lacks the D-leucine terminal of BW180 C l was less potent than the enkephalins in inhibiting neurotransmission. 4 In the presence of phenoxybenzamine 1 microM, 3H-transmitter overflow was increased 8 fold and the inhibition of neurotransmission by methionine-enkephalin was not affected. Exposure to phenoxybenzamine 10 microM increased [3H]-noradrenaline overflow 15 fold and antagonized the effects of methionine enkephalin on transmitter release. 5 In the cat nictitating membrane the inhibitory presynaptic opiate receptors are different from the presynaptic alpha-autoreceptors which regulate the release of noradrenaline elicited by nerve depolarization through a negative feed-back mechanism. PMID:6254597

  2. The α2C-adrenoceptor antagonist, ORM-10921, has antipsychotic-like effects in social isolation reared rats and bolsters the response to haloperidol.

    PubMed

    Uys, Madeleine; Shahid, Mohammed; Sallinen, Jukka; Dreyer, Walter; Cockeran, Marike; Harvey, Brian H

    2016-11-01

    Early studies suggest that selective α2C-adrenoceptor (AR)-antagonism has anti-psychotic-like and pro-cognitive properties. However, this has not been demonstrated in an animal model of schizophrenia with a neurodevelopmental construct. The beneficial effects of clozapine in refractory schizophrenia and associated cognitive deficits have, among others, been associated with its α2C-AR modulating activity. Altered brain-derived neurotrophic factor (BDNF) has been linked to schizophrenia and cognitive deficits. We investigated whether the α2C-AR antagonist, ORM-10921, could modulate sensorimotor gating and cognitive deficits, as well as alter striatal BDNF levels in the social isolation reared (SIR) model of schizophrenia, comparing its effects to clozapine and the typical antipsychotic, haloperidol, the latter being devoid of α2C-AR-activity. Moreover, the ability of ORM-10921 to augment the effects of haloperidol on the above parameters was also investigated. Animals received subcutaneous injection of either ORM-10921 (0.01mg/kg), clozapine (5mg/kg), haloperidol (0.2mg/kg), haloperidol (0.2mg/kg)+ORM-10921 (0.01mg/kg) or vehicle once daily for 14days, followed by assessment of novel object recognition (NOR), prepulse inhibition (PPI) of startle response and striatal BDNF levels. SIR significantly attenuated NOR memory as well as PPI, and reduced striatal BDNF levels vs. social controls. Clozapine, ORM-10921 and haloperidol+ORM-10921, but not haloperidol alone, significantly improved SIR-associated deficits in PPI and NOR, with ORM-10921 also significantly improving PPI deficits vs. haloperidol-treated SIR animals. Haloperidol+ORM-10921 significantly reversed reduced striatal BDNF levels in SIR rats. α2C-AR-antagonism improves deficits in cognition and sensorimotor gating in a neurodevelopmental animal model of schizophrenia and bolsters the effects of a typical antipsychotic, supporting a therapeutic role for α2C-AR-antagonism in schizophrenia. PMID:27381554

  3. Adrenoceptors in renal medullary collecting duct (RMCD) cells

    SciTech Connect

    Clarke, D.; Garg, L.C. )

    1990-02-26

    Recently, the authors have reported that specific, saturable and high affinity alpha{sub 1} adrenoceptors, linked to phosphoinositide messenger system, are present in the RMCD cells. In order to determine if alpha{sub 2} adrenoceptors are also present in RMCD cells, the authors measured the specific binding of ({sup 3}H)rauwolscine, an d{sub 2} adrenergic antagonist, to RMCD cells isolated from the inner medulla of the rabbit kidney. Binding of ({sup 3}H)rauwolscine to the homogenates of RMCD cells was measured in the absence (total binding) and the presence (non-specific binding) of 100 {mu}M phentolamine. The specific binding (the difference between total and non-specific binding) was measured at various concentrations of ({sup 3}H)rauwolscine. The interpolated values (fmol/mg protein) are from a curve generated using the EBDA program to analyze data from 3 animals. The apparent K{sub d} and B{sub max} of({sup 3}H)rauwolscine was 3.56 nM and 29 fmol/mg, respectively. Yohimbine inhibited binding of ({sup 3}H)rauwolscine with an IC{sub 50} of 5 {times} 10{sup {minus}9} M. Prazosin which was much less effective in displacing ({sup 3}H) rauwolscine, had a IC{sub 50} of 10{sup {minus}5} M. The authors conclude that in addition to alpha{sub 1} adrenoceptors, the specific, saturable and high affinity alpha{sub 2} adrenoceptors are also present on RMCD cells.

  4. Ketanserin in essential hypertension: use as monotherapy and in combination with a diuretic or beta-adrenoceptor antagonist.

    PubMed Central

    Cameron, H A; Waller, P C; Ramsay, L E

    1987-01-01

    1. The antihypertensive efficacy and tolerability of twice-daily treatment with the 5-hydroxytryptamine antagonist ketanserin were examined in a double-blind, placebo-controlled trial of 7 weeks duration in 56 hypertensive patients. Twenty were untreated, 20 were already taking bendrofluazide 5 mg daily, and 16 were already taking atenolol 100 mg daily. Randomisation was stratified to compare ketanserin with placebo as monotherapy (n = 20), when added to bendrofluazide (n = 20), and when added to atenolol (n = 16). 2. The antihypertensive effect of ketanserin in all patients completing the study (mean daily dose 71 mg) was 10/6 mm Hg supine (P less than 0.01/P less than 0.01) and 6/6 mm Hg standing (NS/P less than 0.01) when blood pressure was measured 2 h after the morning dose. Responses were similar in patients taking ketanserin as monotherapy, in addition to bendrofluazide, and in addition to atenolol, with reductions in mean arterial pressure of 4.6, 7.4 and 8.9 mm Hg respectively. 3. Ketanserin had no antihypertensive effect when measured 14 h after the last dose. The rise in blood pressure between 2 and 14 h after dosing was 11/4 mm Hg supine (P less than 0.01/NS) and 8/5 mm Hg standing (P less than 0.05/P less than 0.05). 4. The antihypertensive response to ketanserin was positively related to initial blood pressure and, independent of this, to age. It was not related to plasma concentrations of ketanserin or ketanserinol. 5. Five of 28 patients taking ketanserin discontinued treatment because of side-effects, compared with one of 28 patients taking placebo.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2894215

  5. The cytotoxicity of the α1-adrenoceptor antagonist prazosin is linked to an endocytotic mechanism equivalent to transport-P.

    PubMed

    Fuchs, Robert; Stracke, Anika; Ebner, Nadine; Zeller, Christian Wolfgang; Raninger, Anna Maria; Schittmayer, Matthias; Kueznik, Tatjana; Absenger-Novak, Markus; Birner-Gruenberger, Ruth

    2015-12-01

    Since the α1-adrenergic antagonist prazosin (PRZ) was introduced into medicine as a treatment for hypertension and benign prostate hyperplasia, several studies have shown that PRZ induces apoptosis in various cell types and interferes with endocytotic trafficking. Because PRZ is also able to induce apoptosis in malignant cells, its cytotoxicity is a focus of interest in cancer research. Besides inducing apoptosis, PRZ was shown to serve as a substrate for an amine uptake mechanism originally discovered in neurones called transport-P. In line with our hypothesis that transport-P is an endocytotic mechanism also present in non-neuronal tissue and linked to the cytotoxicity of PRZ, we tested the uptake of QAPB, a fluorescent derivative of PRZ, in cancer cell lines in the presence of inhibitors of transport-P and endocytosis. Early endosomes and lysosomes were visualised by expression of RAB5-RFP and LAMP1-RFP, respectively; growth and viability of cells in the presence of PRZ and uptake inhibitors were also tested. Cancer cells showed co-localisation of QAPB with RAB5 and LAMP1 positive vesicles as well as tubulation of lysosomes. The uptake of QAPB was sensitive to transport-P inhibitors bafilomycin A1 (inhibits v-ATPase) and the antidepressant desipramine. Endocytosis inhibitors pitstop(®) 2 (general inhibitor of endocytosis), dynasore (dynamin inhibitor) and methyl-β-cyclodextrin (cholesterol chelator) inhibited the uptake of QAPB. Bafilomycin A1 and methyl-β-cyclodextrin but not desipramine were able to preserve growth and viability of cells in the presence of PRZ. In summary, we confirmed the hypothesis that the cellular uptake of QAPB/PRZ represents an endocytotic mechanism equivalent to transport-P. Endocytosis of QAPB/PRZ depends on a proton gradient, dynamin and cholesterol, and results in reorganisation of the LAMP1 positive endolysosomal system. Finally, the link seen between the cellular uptake of PRZ and cell death implies a still unknown pro

  6. Regulation of renal artery smooth muscle tone by alpha1-adrenoceptors: role of voltage-gated calcium channels and intracellular calcium stores.

    PubMed

    Eckert, R E; Karsten, A J; Utz, J; Ziegler, M

    2000-04-01

    The ischemia induced vasospasm of the renal arterial blood vessels mediated by alpha1-adrenoceptors is of importance for the loss of kidney function. This is based on reduced perfusion of the kidney cortex occurring in kidney transplant and organ preserving surgery. The present study considered the intracellular mechanism of the norepinephrine (NE) induced renal artery vasospasm by using swine renal artery smooth muscle ring. Norepinephrine and phenylephrine (PE) induced dose-dependent and fully reversible isometric contractions with a threshold concentration of 10 nM (n = 7) and 10 nM (n = 4), and an EC50 of 0.3 microM and 1 microM, respectively. The receptor was identified as alpha1A-subtype. The contraction was completely inhibited by verapamil (IC50 = 1.51 microM; n = 11) and diltiazem (IC50 = 9.49 microM; n = 8) and 85% by nifedipine (IC50 = 0.13 microM; n = 21). Blockade of the intracellular inositol- 1,4,5-trisphosphate (IP3)-sensitive Ca2+ store by thapsigargin (1 microM, n = 7) or suppression of Ca2+ release from the intracellular Ca2+-sensitive Ca2+ store by ryanodine (100 microM, n = 4) inhibited the PE induced contraction by 39.5% and 47.6%, respectively. The results suggest a key role of voltage-dependent Ca2+ channels and intracellular Ca2+ stores in the alpha1A-adrenoceptor induced contraction of the renal artery. PMID:10850635

  7. Characterization and autoradiographical localization of non-adrenoceptor idazoxan binding sites in the rat brain.

    PubMed Central

    Mallard, N. J.; Hudson, A. L.; Nutt, D. J.

    1992-01-01

    1. In rat whole brain homogenates, saturation analysis revealed that both [3H]-idazoxan and [3H]-RX821002, a selective alpha 2-adrenoceptor ligand, bound with high affinity to an apparent single population of sites. However, the Bmax for [3H]-idazoxan was significantly (P less than 0.01) greater than that for [3H]-RX821002. 2. In competition studies, (-)-adrenaline displaced 3 nM [3H]-idazoxan binding with an affinity consistent with [3H]-idazoxan labelling alpha 2-adrenoceptors. However, this displacement was incomplete since 23.68 +/- 1.11% of specific [3H]-idazoxan binding remained in the presence of an excess concentration (100 microM) of (-)-adrenaline. In contrast, unlabelled idazoxan promoted a complete displacement of [3H]-idazoxan binding with a Hill slope close to unity and an affinity comparable with its KD determined in saturation studies. 3. Displacement of [3H]-idazoxan binding by the alpha 2-adrenoceptor antagonists yohimbine, RX821002 (2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline) and RX811059 (2-(2-ethoxy-1,4-benzodioxan-2-yl)-2-imidazoline) was more complex, with Hill slopes considerably less than unity, and best described by a two-site model of interaction comprising a high and low affinity component. The proportion of sites with high affinity for each antagonist was similar (60-80%). 4. The rank order of antagonist potency for the high affinity component in each displacement curve (RX821002 greater than RX811059 greater than yohimbine) is similar to that determined against the binding of [3H]-RX821002 to rat brain, suggesting that these components reflect the inhibition of [3H]-idazoxan binding to alpha 2-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 4 Figure 5 Figure 6 PMID:1356565

  8. [Additional administration of dutasteride in patients with benign prostatic hyperplasia who did not respond sufficiently to α1-adrenoceptor antagonist : investigation of clinical factors affecting the therapeutic effect of dutasteride].

    PubMed

    Masuda, Mitsunobu; Murai, Tetsuo; Osada, Yutaka; Kawai, Masaki; Kasuga, Jun; Yokomizo, Yumiko; Kuroda, Shinnosuke; Nakamura, Mami; Noguchi, Go

    2014-02-01

    We performed additional administration of dutasteride in patients who did not respond sufficiently to α1-adrenoceptor antagonist treatment for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) (LUTS/BPH). Among 76 registered patients, efficacy was analyzed in 58 patients. International Prostate Symptom Score (IPSS), subscores for voiding and storage symptoms and quality of life (QOL) on the IPSS, and Overactive Bladder Symptom Score (OABSS) were all significantly improved from the third month of administration compared to the time of initiating additional administration of dutasteride. Additional administration of dutasteride also significantly reduced prostate volume, and residual urine with the exception of the sixth month after administration. Age at initiation of administration and voiding symptom subscore on the IPSS were clinical factors affecting the therapeutic effects of dutasteride. The rate of improvement with treatment decreased with increasing age at initiation of dutasteride administration, and increased as voiding symptom subscore on the IPSS increased. Therefore, additional administration of dutasteride appears useful for cases of LUTS/BPH in which a sufficient response is not achieved with α1-adrenoceptor antagonist treatment. Because patients who have severe voiding symptoms or begin dutasteride at an early age may be expected to respond particularly well to dutasteride in terms of clinical efficacy, they were considered to be suitable targets for additional administration. PMID:24755815

  9. PKC regulates alpha(1)-adrenoceptor-mediated contractions and baseline Ca(2+) sensitivity in the uterine arteries of nonpregnant and pregnant sheep acclimatized to high altitude hypoxia.

    PubMed

    Xiao, Daliao; Huang, Xiaohui; Longo, Lawrence D; Zhang, Lubo

    2010-01-01

    Chronic hypoxia has a profound effect on uterine artery adaptation to pregnancy. The present studies tested the hypothesis that pregnant kinase C (PKC) differentially regulates alpha(1)-adrenoceptor-mediated contractions and Ca(2+) sensitivity in the uterine arteries of nonpregnant and pregnant sheep acclimatized to high altitude hypoxia. Uterine arteries were isolated from nonpregnant (NPUA) and near-term pregnant (PUA) ewes maintained at high altitude (3801 m, Pao(2) approximately 60 torr) for 110 days. Phorbol 12,13-dibutyrate (PDBu) decreased phenylephrine-induced contractions in PUA but not in NPUA, which was partly inhibited by the PKC inhibitor GF109203X. Additionally, GF109203X shifted the concentration-response curve of phenylephrine-induced contractions to the right in PUA. In beta-escin-permeabilized arteries, Ca(2+)-induced increases in 20-kDa myosin light chain phosphorylation (MLC(20)-P) were similar in NPUA and PUA. However, Ca(2+) produced a concentration-dependent increase in the ratio of tension to MLC(20)-P in PUA, as compared with NPUA. PKC inhibition decreased Ca(2+)-induced contractions in both NPUA and PUA. PDBu induced contractions of PUA in the absence of changes in MLC(20)-P, which was not affected by PD098059. There was a significant increase in the basal activity of PKCvarepsilon in PUA, but not in NPUA, in hypoxic sheep, as compared with normoxic animals. The results demonstrate that the inhibitory effect of PKC on alpha(1)-adrenoceptor-mediated contractions of uterine arteries is preserved in pregnant sheep at high altitude. However, the PKC-mediated thin-filament regulatory pathway is upregulated, resulting in increased baseline Ca(2+) sensitivity in the uterine artery during pregnancy at high altitude. PMID:20586600

  10. Accumbal α-adrenoceptors, but not β-adrenoceptors, regulate behaviour that is mediated by reserpine-sensitive storage vesicles.

    PubMed

    Verheij, Michel M M; Saigusa, Tadashi; Koshikawa, Noriaki; Cools, Alexander R

    2015-02-01

    It has previously been demonstrated that mesolimbic α-adrenoceptors, but not β-adrenoceptors, control the release of dopamine that is derived from reserpine-sensitive storage vesicles. The aim of the present study was to investigate whether these storage vesicles also regulate α-adrenoceptor-mediated or β-adrenoceptor-mediated changes in behaviour. Accordingly, rats were pretreated with reserpine before the α-adrenoceptor antagonist phentolamine or the β-adrenoceptor agonist isoproterenol was locally applied to the nucleus accumbens. Both phentolamine and isoproterenol increased the duration of walking, rearing and grooming and decreased the duration of sitting. Reserpine counteracted the behavioural response elicited by phentolamine but not by isoproterenol. The results of the present study demonstrate that mesolimbic α-adrenoceptors, but not β-adrenoceptors, regulate behaviour that is mediated by reserpine-sensitive storage pools. It is hypothesized that the observed α-adrenoceptor-mediated increase in locomotor activity is due to the α-adrenoceptor-mediated increase in the release of accumbal intravesicular dopamine. Our finding that α-adrenoceptors inhibit, whereas β-adrenoceptors stimulate, locomotor activity may help explain why noradrenaline or environmental stressors have previously been found to have opposing effects on the regulation of behaviour. PMID:25325287

  11. Agonist and antagonist effects of nicotine on chick neuronal nicotinic receptors are defined by alpha and beta subunits.

    PubMed

    Hussy, N; Ballivet, M; Bertrand, D

    1994-09-01

    1. Functional neuronal nicotinic receptors were reconstituted in Xenopus oocytes by the nuclear injection of different combinations of chick and rat cDNAs encoding alpha and beta subunits. The pharmacology of these nicotinic receptors was investigated using two-electrode voltage clamp. 2. The sensitivity of the chick alpha 3/beta 2, alpha 3/beta 4, and alpha 4/beta 2 receptors to acetylcholine (ACh) and neuronal bungarotoxin differed markedly, indicating that both subunits contribute to the pharmacological properties of the receptors. 3. Nicotine acted as an agonist on the chick alpha 3/beta 4 and alpha 4/beta 2 receptors and rat alpha 3/beta 2 receptor. In contrast, nicotine (at concentrations > 3 microM) was only a weak partial agonist of the chick alpha 3/beta 2 receptor. Moreover, nicotine coapplied with 3 microM ACh on the chick alpha 3/beta 2 receptor acted as a potent competitive antagonist, with an IC50 of 0.43 microM. No antagonist effect of nicotine could be revealed on the other nicotinic receptors. 4. The effect of nicotine was tested on hybrid receptors obtained by coinjection of chick and rat cDNAs encoding the alpha 3 and beta 2 subunits (yielding the rat alpha 3/chick beta 2 and chick alpha 3/rat beta 2 receptors). Nicotine (10 microM) strongly inhibited both hybrid receptors. 5. Chimeric subunits were constructed by exchanging a segment located in the extracellular N-termini of chick alpha 3 and alpha 4 subunits and chick alpha 3 and rat alpha 3 subunits. These subunits were coexpressed in oocytes with chick or rat beta 2 subunits. The effect of nicotine on these receptors pointed to the importance of a 15 amino acid stretch located 3' of the first transmembrane segment in the determination of the agonist and antagonist action of nicotine. 6. Within this 15 amino acid segment, a single residue differs in chick and rat alpha 3 subunits, at position 198, within the ligand binding site of alpha subunits. Gln198 of the rat alpha 3 subunit was replaced

  12. Ontogeny of the rat hepatic adrenoceptors

    SciTech Connect

    McMillian, M.K.

    1985-01-01

    Hepatic alpha-1, alpha-2, and beta-2 adrenoceptors were characterized during development of the rat through Scatchard analysis of (/sup 3/H)-prazosin, (/sup 3/H)-rauwolscine and (/sup 125/I)-pindolol binding to washed particle membrane preparations. Major changes in adrenoceptor number occur shortly before birth and at weaning. The fetal rat liver is characterized by a large number of alpha-2 adrenoceptors which falls 10-20 fold at birth. The number of hepatic beta adrenoceptors decreases 30-50% during the third week after birth increases slightly at weaning, then decreases gradually in the adult. Hepatic alpha-1 adrenoceptor number increases 3-5 fold at weaning to become the predominant adrenoceptor in the adult rat liver. The basis for the fall in alpha-2 number at birth remains unclear. The fall in beta receptor number at the end of the second week post-natally appears dependent on increased insulin and corticosterone secretion as well as increased NE release form nerve terminals. The basis for the increase in beta number at weaning and the sex-dependent loss of beta function but not receptor number in the adult rat remains unknown. The dramatic increases in alpha-1 number and function at weaning are dependent on increased adrenocortical secretion, adrenalectomy prevents the normal. This effect of adrenocorticoids might be mediated through glycogen, as glycogen depletion during fasting decreases alpha-1 receptor number and function at weaning are dependent on increased adrenocortical secretion, adrenalectomy prevents the normal. This effect of adrenocorticoids might be mediated through glycogen, as glycogen depletion during fasting decreases alpha-1 receptor number and function. These findings suggest that hepatic adrenoceptor number adapts from the low carbohydrate diet of the suckling rat to the high carbohydrate diet of the adult at weaning.

  13. Structural insights into Resveratrol’s antagonist and partial agonist actions on estrogen receptor alpha

    PubMed Central

    2013-01-01

    Background Resveratrol, a naturally occurring stilbene, has been categorized as a phytoestrogen due to its ability to compete with natural estrogens for binding to estrogen receptor alpha (ERα) and modulate the biological responses exerted by the receptor. Biological effects of resveratrol (RES) on estrogen receptor alpha (ERα) remain highly controversial, since both estrogenic and anti-estrogenic properties were observed. Results Here, we provide insight into the structural basis of the agonist/antagonist effects of RES on ERα ligand binding domain (LBD). Using atomistic simulation, we found that RES bound ERα monomer in antagonist conformation, where Helix 12 moves away from the ligand pocket and orients into the co-activator binding groove of LBD, is more stable than RES bound ERα in agonist conformation, where Helix 12 lays over the ligand binding pocket. Upon dimerization, the agonistic conformation of RES-ERα dimer becomes more stable compared to the corresponding monomer but still remains less stable compared to the corresponding dimer in antagonist conformation. Interestingly, while the binding pocket and the binding contacts of RES to ERα are similar to those of pure agonist diethylstilbestrol (DES), the binding energy is much less and the hydrogen bonding contacts also differ providing clues for the partial agonistic character of RES on ERα. Conclusions Our Molecular Dynamics simulation of RES-ERα structures with agonist and antagonist orientations of Helix 12 suggests RES action is more similar to Selective Estrogen Receptor Modulator (SERM) opening up the importance of cellular environment and active roles of co-regulator proteins in a given system. Our study reveals that potential co-activators must compete with the Helix 12 and displace it away from the activator binding groove to enhance the agonistic activity. PMID:24160181

  14. Enhancement by neuropeptide Y (NPY) of the dihydropyridine-sensitive component of the response to alpha 1-adrenoceptor stimulation in rat isolated mesenteric arterioles.

    PubMed Central

    Andriantsitohaina, R.; Stoclet, J. C.

    1990-01-01

    1. The mechanism by which neuropeptide Y (NPY) potentiates the vasoconstriction induced by alpha 1-adrenoceptor agonists was investigated in 3rd generation mesenteric arterioles of the rat. 2. At a maximally active concentration, nitrendipine (10(-6) M) displaced to the right the concentration-response curves to noradrenaline (pD2 decreased from 6.2 +/- 0.06 to 5.7 +/- 0.03) and phenylephrine (pD2 decreased from 5.6 +/- 0.03 to 5.3 +/- 0.03). Diltiazem (10(-5) M) also shifted to the right the concentration-response curve to phenylephrine (pD2 decreased from 6.0 +/- 0.06 to 5.5 +/- 0.04). In addition, the maximal response to phenylephrine was significantly decreased in the presence of either nitrendipine or diltiazem. 3. In the absence of a calcium channel blocking agent, NPY (100 nM) produced a leftward shift of the concentration-response curves to noradrenaline (pD2 increased from 6.2 +/- 0.06 to 6.5 +/- 0.05) and phenylephrine (pD2 increased from 5.6 +/- 0.03 to 6.0 +/- 0.06 and from 6.0 +/- 0.06 to 6.3 +/- 0.11). In the presence of either nitrendipine (10(-6) M) or diltiazem (10(-5) M), NPY (100 nM) did not alter the concentration-response curves to either noradrenaline or phenylephrine. 4. NPY was added to arterioles brought to the same level of tension (40% of the maximal contraction) either by phenylephrine alone (1.5 x 10(-6) M) or by a higher concentration of phenylephrine (3 x 10(-6) M) followed by the addition of prazosin (1.3 x 10(-9) M; a concentration at which it partially blocks alpha 1-adrenoceptors).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1970270

  15. Highly Potent, Water Soluble Benzimidazole Antagonist for Activated (alpha)4(beta)1 Integrin

    SciTech Connect

    Carpenter, R D; Andrei, M; Lau, E Y; Lightstone, F C; Liu, R; Lam, K S; Kurth, M J

    2007-08-29

    The cell surface receptor {alpha}{sub 4}{beta}{sub 1} integrin, activated constitutively in lymphoma, can be targeted with the bisaryl urea peptidomimetic antagonist 1 (LLP2A). However, concerns on its preliminary pharmacokinetic (PK) profile provided an impetus to change the pharmacophore from a bisaryl urea to a 2-arylaminobenzimidazole moiety resulting in improved solubility while maintaining picomolar potency [5 (KLCA4); IC{sub 50} = 305 pM]. With exceptional solubility, this finding has potential for improving PK to help diagnose and treat lymphomas.

  16. Relationship between phosphatidylinositol (PI) turnover and Ca/sup 2 +/ utilization induced by. cap alpha. /sub 1/-adrenoceptor stimulation in rat aorta

    SciTech Connect

    Chiu, A.T.; P.B.M.W.M. Timmermans

    1986-03-05

    The authors have recently demonstrated that stimulation of ..cap alpha../sub 1/-adrenoceptors in rat aorta can activate two distinct processes of Ca/sup 2 +/ utilization for contraction. Sgd 101/75 (indanidine) was found to exclusively facilitate an influx of extracellular Ca/sup 2 +/ which was sensitive to nifedipine inhibition, whereas norepinephrine (NE) elicited both influx and intracellular release of Ca/sup 2 +/. The latter process was insensitive to nifedipine. In this study, the causal relationship between ..cap alpha../sub 1/-receptor activation and the mediatory responses, such as PI turnover has been evaluated. NE (1 x 10/sup -5/ M) maximally induced a /sup 45/Ca/sup 2 +/ efflux and also maximally increased the accumulation of /sup 3/H-inositol-1-PO/sub 4/ (IP) in the presence of 10 mM LiCl in a time-dependent fashion (0-60 min). This accumulation reached 1000% over control at 60 min of stimulation which could be abolished by 10/sup -6/ M prazosin and partially by 10/sup -6/ M yohimbine, while it was unaffected by nifedipine. Potassium depolarization as well as Sgd 101/75 (1 x 10/sup -5/ M) only slightly invoked IP production. However, the effect of NE on IP formation was antagonized by Sgd 101/75. These results support the concept that PI turnover mediates primarily the process of intracellular Ca/sup 2 +/ release subsequent to ..cap alpha../sub 1/-receptor activation in rat aorta.

  17. α1-Adrenoceptors are required for normal male sexual function

    PubMed Central

    Sanbe, A; Tanaka, Y; Fujiwara, Y; Tsumura, H; Yamauchi, J; Cotecchia, S; Koike, K; Tsujimoto, G; Tanoue, A

    2007-01-01

    Background and purpose: α1-Adrenoceptor antagonists are extensively used in the treatment of hypertension and lower urinary tract symptoms associated with benign prostatic hyperplasia. Among the side effects, ejaculatory dysfunction occurs more frequently with drugs that are relatively selective for α1A-adrenoceptors compared with other drugs of this class. This suggests that α1A-adrenoceptors may contribute to ejaculation. However, this has not been studied at the molecular level. Experimental approach: The physiological contribution of each α1-adrenoceptor subtype was characterized using α1-adrenoceptor subtype-selective knockout (KO) mice (α1A-, α1B- and α1D-AR KO mice) since the subtype-specific drugs available are only moderately selective. We analysed the role of α1-adrenoceptors in the blood pressure and vascular response as well as ejaculation by determining these variables in α1-adrenoceptor subtype-selective KO mice and in mice with all their α1-adrenoceptor subtypes deleted (α1-AR triple-KO mice). Key results: The pregnancy rate was reduced by 50% in α1A-adrenoceptor KO mice, and this reduction was dramatically enhanced in α1-adrenoceptor triple-KO mice. Contractile tension of the vas deferens in response to noradrenaline was markedly decreased in α1A-adrenoceptor KO mice, and this contraction was completely abolished in α1-adrenoceptor triple-KO mice. This attenuation of contractility was also observed in the electrically stimulated vas deferens. Conclusions and implications: These results demonstrate that α1-adrenoceptors, particularly α1A-adrenoceptors, are required for normal contractility of the vas deferens and consequent sperm ejaculation as well as having a function in fertility. PMID:17603545

  18. Dihydroergocryptine: a pseudo-irreversible alpha-adrenergic antagonist in the guinea pig vas deferens

    SciTech Connect

    Wilberding, C.A.; Marks, B.H.

    1981-03-01

    The ergot alkaloid, dihydroergocryptine, exhibits some of the characteristics of a competitive alpha-adrenergic antagonist. Dihydroergocryptine physiological antagonism is surmountable by high concentrations of alpha-adrenergic agonists and (/sup 3/H)-dihydroergocryptine readily binds and dissociates from crude membranes with the characteristics expected of an alpha-adrenoreceptor ligand. However, during physiological studies, dihydroergocryptine antagonism is not readily reversible by washing. To explain this apparently paradoxical behavior of dihydroergocryptine, the characteristic of (/sup 3/H)-dihydroergocryptine accumulation and efflux in the guinea pig vas deferens were studied. Vas deferens segments accumulated 0.99 pmol (/sup 3/H)-dihydroergocryptine/mg protein. Most of the radioligand was extractable by acid-ethanol. About 5-6% of the radioligand remained bound to extracted tissue residues and appeared to be associated with crude membrane fractions prepared from vas deferens segments. Kinetic analysis of (/sup 3/H)-dihydroergocryptine efflux from vas deferens segments indicated the presence of three compartments of radioligand in this tissue. A large compartment of (/sup 3/H)-dihydroergocryptine emptied slowly and may represent radioligand accumulated into the intracellular space. (/sup 3/H)-Dihydroergocryptine also was released from a compartment which exhibited the size and kinetics characteristic of alpha-adrenoreceptor sites on guinea pig vas deferens crude membranes. A small compartment of (/sup 3/H)-dihydroergocryptine was nonexchangeable and nonextractable by acid-ethanol; this nonextractable radioligand may be bound covalently to membrane sites and/or other tissue components.

  19. Effects of β(3)-adrenoceptor activation on expression of pancreatic adrenoceptors and angiotensin II receptors in ApoE(-/-) mice.

    PubMed

    Song, Jun-Ying; Li, Yan-Fang; Jiang, Zhi-Li; Guo, Yan-Qing

    2015-10-01

    Hyperlipidemia can be harmful to the pancreas and β3-adrenoceptor agonist can improve lipid metabolism disorder. We aimed to study the effects of β3-adrenoceptor activation on glucose, insulin and the expression of pancreatic adrenoceptors and angiotensin II receptors. Ten C57BL/6J mice at the age of 10 weeks served as normal control, and forty age-matched apolipoprotein E knockout (ApoE(-/-)) mice were randomly divided into hyperlipidaemia model group, low-dose and high-dose β3-adrenoceptor agonist group and β3-adrenoceptor antagonist group. After 26 weeks of high-fat diet, treatments were given for 12 weeks. Serum glucose and insulin levels in 48 weeks old mice were measured using an automatic biochemical detector. Quantitative rt-PCR and Western blot were used to analyze the mRNA and protein expression of α1A-, α2A-, β2-, β3-adrenoceptors and angiotensin II type 1 and type 2 receptors in pancreas. We found that β3-adrenoceptor agonist could decrease serum glucose and insulin levels in aged ApoE(-/-) mice (P<0.01) and down-regulate the expression of α1A-adrenoceptor and angiotensin II type 1 receptor which were significantly increased in model mice (P<0.05, P<0.01). Compared with the model mice, α2A-, β2-, β3-adrenoceptor and angiotensin II type 2 receptor expression were up-regulated in β3-adrenoceptor agonist treat mice (P<0.05, P<0.01). These results suggest that chronic β3-adrenoceptor activation regulated the expression of adrenoceptors and angiontensin II receptors towards contrary direction, which indicates that there are interactions between β3-adrenoceptor and subtypes of adrenoceptor and angiotensin II receptor, and these interactions may play a protective role in pancreas and improve glucose metabolism disorders. PMID:26102566

  20. Bindings of /sup 3/H-prazosin and /sup 3/H-yohimbine to alpha adrenoceptors in the guinea-pig stomach

    SciTech Connect

    Taniguchi, T.; Nishikawa, H.

    1988-01-01

    Alpha adrenoceptor subtypes have been investigated by radioligand binding study in guinea-pig stomach using /sup 3/H-prazosin and /sup 3/H-yohimbine. The specific /sup 3/H-prazosin binding to guinea-pig stomach was saturable and of high affinity with a Bmax of 33 fmol/mg protein. Specific /sup 3/H-yohimbine binding to the tissue was also saturable and of high affinity with a Bmax of 150 fmol/mg protein. Adrenergic drugs competed for /sup 3/H-prazosin binding in order of prazosin > phentolamine > methoxamine > norepinephrine > clonidine > epinephrine > yohimbine. These drugs competed for /sup 3/H-yohimbine binding in order of yohimbine > phentolamine > clonidine > epinephrine > norepinephrine > prazosin > methoxamine. They also examined whether dopamine receptors exist in guinea-pig stomach, using radioligand binding study. Specific binding of /sup 3/H-spiperone, /sup 3/H-apomorphine, /sup 3/H-dopamine and /sup 3/H-domperidone was not detectable in the stomach. Dopaminergic drugs such as dopamine, haloperidol, domperidone and sulpiride competed for /sup 3/H-prazosin binding in order of haloperidol > domperidone > dopamine > sulpiride. Metoclopramide, sulpiride and dopamine competed for /sup 3/H-yohimbine binding in order of metoclopramide > sulpiride > dopamine.

  1. From the cell to the clinic: a comparative review of the partial D₂/D₃receptor agonist and α2-adrenoceptor antagonist, piribedil, in the treatment of Parkinson's disease.

    PubMed

    Millan, Mark J

    2010-11-01

    Though L-3,4-dihydroxyphenylalanine (L-DOPA) is universally employed for alleviation of motor dysfunction in Parkinson's disease (PD), it is poorly-effective against co-morbid symptoms like cognitive impairment and depression. Further, it elicits dyskinesia, its pharmacokinetics are highly variable, and efficacy wanes upon long-term administration. Accordingly, "dopaminergic agonists" are increasingly employed both as adjuncts to L-DOPA and as monotherapy. While all recognize dopamine D(2) receptors, they display contrasting patterns of interaction with other classes of monoaminergic receptor. For example, pramipexole and ropinirole are high efficacy agonists at D(2) and D(3) receptors, while pergolide recognizes D(1), D(2) and D(3) receptors and a broad suite of serotonergic receptors. Interestingly, several antiparkinson drugs display modest efficacy at D(2) receptors. Of these, piribedil displays the unique cellular signature of: 1), signal-specific partial agonist actions at dopamine D(2)and D(3) receptors; 2), antagonist properties at α(2)-adrenoceptors and 3), minimal interaction with serotonergic receptors. Dopamine-deprived striatal D(2) receptors are supersensitive in PD, so partial agonism is sufficient for relief of motor dysfunction while limiting undesirable effects due to "over-dosage" of "normosensitive" D(2) receptors elsewhere. Further, α(2)-adrenoceptor antagonism reinforces adrenergic, dopaminergic and cholinergic transmission to favourably influence motor function, cognition, mood and the integrity of dopaminergic neurones. In reviewing the above issues, the present paper focuses on the distinctive cellular, preclinical and therapeutic profile of piribedil, comparisons to pramipexole, ropinirole and pergolide, and the core triad of symptoms that characterises PD-motor dysfunction, depressed mood and cognitive impairment. The article concludes by highlighting perspectives for clarifying the mechanisms of action of piribedil and other

  2. Neuroprotective and memory-related actions of novel alpha-7 nicotinic agents with different mixed agonist/antagonist properties.

    PubMed

    Meyer, E M; Tay, E T; Zoltewicz, J A; Meyers, C; King, M A; Papke, R L; De Fiebre, C M

    1998-03-01

    The goals of this study were to develop compounds that were selective and highly efficacious agonists at alpha-7 receptors, while varying in antagonist activity; and to test the hypothesis that these compounds had memory-related and neuroprotective actions associated with both agonist and antagonist alpha-7 receptor activities. Three compounds were identified; E,E-3-(cinnamylidene)anabaseine (3-CA), E,E-3-(2-methoxycinnamylidene) anabaseine (2-MeOCA) and E,E-3-(4-methoxycinnamylidene) anabaseine (4-MeOCA) each displaced [125I]alpha-bungarotoxin binding from rat brain membranes and activated rat alpha-7 receptors in a Xenopus oocyte expression system fully efficaciously. The potency series for binding and receptor activation was 2-MeOCA > 4-MeOCA = 3-CA and 2-MeOCA = 3-CA > 4-MeOCA, respectively. No compound significantly activated oocyte-expressed alpha-4beta-2 receptors. Although each cinnamylidene-anabaseine caused a long-term inhibition of alpha-7 receptors, as measured by ACh-application 5 min later, this inhibition ranged considerably, from less than 20% (3-CA) to 90% (2-MeOCA) at an identical concentration (10 microM). These compounds improved passive avoidance behavior in nucleus basalis lesioned rats, with 2-MeOCA most potent in this respect. In contrast, only 3-CA was neuroprotective against neurite loss during nerve growth factor deprivation in differentiated rat pheochromocytoma (PC12) cells. Choline, an efficacious alpha-7 agonist without antagonist activity, was also protective in this model. These results suggest that the neurite-protective action of alpha-7 receptor agonists may be more sensitive to potential long-term antagonist properties than acute behavioral actions are. PMID:9495863

  3. Genetically engineered bacteriophage delivers a tumor necrosis factor alpha antagonist coating on neural electrodes.

    PubMed

    Kim, Young Jun; Jin, Young-Hyun; Salieb-Beugelaar, Georgette B; Nam, Chang-Hoon; Stieglitz, Thomas

    2014-02-01

    This paper reports a novel approach for the formation of anti-inflammatory surface coating on a neural electrode. The surface coating is realized using a recombinant f88 filamentous bacteriophage, which displays a short platinum binding motif and a tumor necrosis factor alpha antagonist (TNF-α antagonist) on p3 and p8 proteins, respectively. The recombinant bacteriophages are immobilized on the platinum surface by a simple dip coating process. The selective and stable immobilization of bacteriophages on a platinum electrode is confirmed by quartz crystal microbalance with dissipation monitoring, atomic force microscope and fluorescence microscope. From the in vitro cell viability test, the inflammatory cytokine (TNF-α) induced cell death was prevented by presenting recombinant bacteriophage coating, albeit with no significant cytotoxic effect. It is also observed that the bacteriophage coating does not have critical effects on the electrochemical properties such as impedance and charge storage capacities. Thus, this approach demonstrates a promising anti-apoptotic as well as anti-inflammatory surface coating for neural implant applications. PMID:24448635

  4. The odd sibling: features of β3-adrenoceptor pharmacology.

    PubMed

    Cernecka, Hana; Sand, Carsten; Michel, Martin C

    2014-11-01

    β3-Adrenoceptor agonists have recently been introduced for the treatment of overactive urinary bladder syndrome. Their target, the β3-adrenoceptor, was discovered much later than β1- and β2-adrenoceptors and exhibits unique properties which make extrapolation of findings from the other two subtypes difficult and the β3-adrenoceptor a less-understood subtype. This article discusses three aspects of β3-adrenoceptor pharmacology. First, the ligand-recognition profile of β3-adrenoceptors differs considerably from that of the other two subtypes, i.e., many antagonists considered as nonselective actually are β3-sparing, including propranolol or nadolol. Many agonists and antagonists classically considered as being β3-selective actually are not, including BRL 37,344 ((±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate) or SR 59,230 (3-(2-ethylphenoxy)-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol oxalate). Moreover, the binding pocket apparently differs between the human and rodent β3-adrenoceptor, yielding considerable species differences in potency. Second, the expression pattern of β3-adrenoceptors is more restricted than that of other subtypes, particularly in humans; this makes extrapolation of rodent findings to the human situation difficult, but it may result in a smaller potential for side effects. The role of β3-adrenoceptor gene polymorphisms has insufficiently been explored and may differ even between primate species. Third, β3-adrenoceptors lack the phosphorylation sites involved in agonist-induced desensitization of the other two subtypes. Thus, they exhibit downregulation and/or desensitization in some, but not other, cell types and tissues. When desensitization occurs, it most often is at the level of mRNA or signaling molecule expression. All three of these factors have implications for future studies to better understand the β3-adrenoceptor as a novel pharmacological target

  5. A deletion variant of the alpha2b-adrenoceptor is related to emotional memory in Europeans and Africans.

    PubMed

    de Quervain, Dominique J-F; Kolassa, Iris-Tatjana; Ertl, Verena; Onyut, P Lamaro; Neuner, Frank; Elbert, Thomas; Papassotiropoulos, Andreas

    2007-09-01

    Emotionally arousing events are recalled better than neutral events. This phenomenon, which helps us to remember important and potentially vital information, depends on the activation of noradrenergic transmission in the brain. Here we show that a deletion variant of ADRA2B, the gene encoding the alpha2b-adrenergic receptor, is related to enhanced emotional memory in healthy Swiss subjects and in survivors of the Rwandan civil war who experienced highly aversive emotional situations. PMID:17660814

  6. Clonidine, an alpha-2 adrenoceptor agonist relieves mechanical allodynia in oxaliplatin-induced neuropathic mice; potentiation by spinal p38 MAPK inhibition without motor dysfunction and hypotension.

    PubMed

    Yeo, Ji-Hee; Yoon, Seo-Yeon; Kim, Sol-Ji; Oh, Seog-Bae; Lee, Jang-Hern; Beitz, Alvin J; Roh, Dae-Hyun

    2016-05-15

    Cancer chemotherapy with platinum-based antineoplastic agents including oxaliplatin frequently results in a debilitating and painful peripheral neuropathy. We evaluated the antinociceptive effects of the alpha-2 adrenoceptor agonist, clonidine on oxaliplatin-induced neuropathic pain. Specifically, we determined if (i) the intraperitoneal (i.p.) injection of clonidine reduces mechanical allodynia in mice with an oxaliplatin-induced neuropathy and (ii) concurrent inhibition of p38 mitogen-activated protein kinase (MAPK) activity by the p38 MAPK inhibitor SB203580 enhances clonidine's antiallodynic effect. Clonidine (0.01-0.1 mg kg(-1), i.p.), with or without SB203580(1-10 nmol, intrathecal) was administered two weeks after oxaliplatin injection(10 mg kg(-1), i.p.) to mice. Mechanical withdrawal threshold, motor coordination and blood pressure were measured. Postmortem expression of p38 MAPK and ERK as well as their phosphorylated forms(p-p38 and p-ERK) were quantified 30 min or 4 hr after drug injection in the spinal cord dorsal horn of treated and control mice. Clonidine dose-dependently reduced oxaliplatin-induced mechanical allodynia and spinal p-p38 MAPK expression, but not p-ERK. At 0.1 mg kg(-1), clonidine also impaired motor coordination and decreased blood pressure. A 10 nmol dose of SB203580 alone significantly reduced mechanical allodynia and p-p38 MAPK expression, while a subeffective dose(3 nmol) potentiated the antiallodynic effect of 0.03 mg kg(-1) clonidine and reduced the increased p-p38 MAPK. Coadministration of SB203580 and 0.03 mg kg(-1) clonidine decreased allodynia similar to that of 0.10 mg kg(-1) clonidine, but without significant motor or vascular effects. These findings demonstrate that clonidine treatment reduces oxaliplatin-induced mechanical allodynia. The concurrent administration of SB203580 reduces the dosage requirements for clonidine, thereby alleviating allodynia without producing undesirable motor or cardiovascular effects. PMID

  7. A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility "in vitro".

    PubMed

    Colciago, Alessandra; Mornati, Ornella; Ferri, Nicola; Castelnovo, Luca Franco; Fumagalli, Laura; Bolchi, Cristiano; Pallavicini, Marco; Valoti, Ermanno; Negri-Cesi, Paola

    2016-01-01

    The progression of prostate cancer (PC) to a metastatic hormone refractory disease is the major contributor to the overall cancer mortality in men, mainly because the conventional therapies are generally ineffective at this stage. Thus, other therapeutic options are needed as alternatives or in addition to the classic approaches to prevent or delay tumor progression. Catecholamines participate to the control of prostate cell functions by the activation of alpha1-adrenoreceptors (alpha1-AR) and increased sympathetic activity has been linked to PC development and evolution. Molecular and pharmacological studies identified three alpha1-AR subtypes (A, B and D), which differ in tissue distribution, cell signaling, pharmacology and physiological role. Within the prostate, alpha1A-ARs mainly control stromal cell functions, while alpha1B- and alpha1D- subtypes seem to modulate glandular epithelial cell growth. The possible direct contribution of alpha1D-ARs in tumor biology is supported by their overexpression in PC. The studies here presented investigate the "in vitro" antitumor action of A175, a selective alpha1D-AR antagonist we have recently obtained by modifying the potent, but not subtype-selective alpha1-AR antagonist (S)-WB4101, in the hormone-refractory PC3 and DU145 PC cell lines. The results indicate that A175 has an alpha1D-AR-mediated significant and dose-dependent antiproliferative action that possibly involves the induction of G0/G1 cell cycle arrest, but not apoptosis. In addition, A175 reduces cell migration and adhesiveness to culture plates. In conclusion, our work clarified some cellular aspects promoted by alpha1D-AR activity modulation and supports a further pharmacological approach in the cure of hormone-refractory PC, by targeting specifically this AR subtype. PMID:26621245

  8. Effect of the α(2)-adrenoceptor antagonist yohimbine on vascular regulation of the middle cerebral artery and the ophthalmic artery in healthy subjects.

    PubMed

    Kaya, S; Kolodjaschna, J; Berisha, F; Polska, E; Pemp, B; Garhöfer, G; Schmetterer, L

    2011-01-01

    There is evidence that vascular beds distal to the ophthalmic artery (OA) show vasoconstriction in response to a step decrease in systemic blood pressure (BP). The mediators of this response are mostly unidentified. The aim of the current study was to test the hypothesis that α2-adrenoreceptors may contribute to the regulatory process in response to a decrease in BP. In this randomized, double-masked, placebo-controlled study 14 healthy male volunteers received either 22mg yohimbine hydrochloride or placebo. Beat-to-beat BP was measured by analysis of arterial pressure waveform; blood flow velocities in the middle cerebral artery (MCA) and the OA were measured with Doppler ultrasound. Measurements were done before, during and after a step decrease in BP. The step decrease in BP was induced by bilateral thigh cuffs at a suprasystolic pressure followed by a rapid cuff deflation. After cuff deflation, BP returned to baseline after 7-8 pulse cycles (PC). Blood velocities in the MCA returned to baseline earlier (4 PC) than BP indicating peripheral vasodilatation. Blood velocities in the OA returned to baseline later (15-20 PC) indicating peripheral vasoconstriction. Yohimbine did not affect the blood velocity response in the MCA, but significantly shortened the time of OA blood velocities to return to baseline values (6-7 PC, p<0.05). In conclusion, our results indicate that yohimbine did not alter the regulatory response in the MCA, but modified the response of vascular beds distal to the OA. This suggests that α2-adrenoceptors play a role in the vasoconstrictor response of the vasculatures distal to the OA. PMID:20934440

  9. Duodenal mucosal bicarbonate secretion in man. Stimulation by acid and inhibition by the alpha 2-adrenoceptor agonist clonidine.

    PubMed Central

    Knutson, L; Flemström, G

    1989-01-01

    A multi-channel small diameter tube was used to study the secretion of bicarbonate by 3 cm long segments of the proximal duodenum isolated between balloons. The tube had an outer diameter of 5.3 mm and two central and four smaller, peripheral channels. Measurements of infused phenol red, 14C-PEG and vitamin B12 and of trypsin activity were performed to rule out contamination of the perfusate by gastric and pancreatic secretions. Basal secretion of bicarbonate by the duodenal mucosa in healthy subjects varied between 135 and 220 mumol/cm of intestine per hour. Perfusion of the lumen with acid (100 mM HCl for five minutes) increased the secretion to greater than 400 mumol/cm/h and the alpha 2-adrenoreceptor agonist clonidine (150 micrograms iv) decreased the HCO3- secretion by 70 mumol/cm/h. Clonidine simultaneously reduced the mean arterial blood pressure and plasma noradrenaline concentration, but did not affect the plasma glucose or adrenaline concentration. Duodenal bicarbonate secretion is important in the protection of this mucosa against acid discharged from the stomach. Increased sympathetic activity may, by inhibiting the bicarbonate secretion, decrease the protection in proximal duodenum in man and facilitate ulceration. Images Fig. 2 PMID:2558985

  10. Protein kinase C-alpha and -beta play antagonistic roles in the differentiation process of THP-1 cells.

    PubMed

    Dieter, P; Schwende, H

    2000-05-01

    The roles of protein kinase C (PKC) isoenzymes in the differentiation process of THP-1 cells are investigated. Inhibition of PKC by RO 31-8220 reduces the phagocytosis of latex particles and the release of superoxide, prostaglandin E(2) (PGE(2)), and tumour necrosis factor (TNF)-alpha. The proliferation of THP-1 cells is slightly enhanced by RO 31-8220. Stable transfection of THP-1 cells with asPKC-alpha, and incubation of THP-1 cells with antisense (as) PKC-alpha oligodeoxynucleotides reduces PKC-alpha levels and PKC activity. asPKC-alpha-transfected THP-1 cells show a decreased phagocytosis and a decreased release of superoxide, PGE(2) and TNF-alpha. The proliferation of asPKC-alpha-transfected THP-1 cells is enhanced. Stable transfection of THP-1 cells with asPKC-beta, and incubation of THP-1 cells with asPKC-beta oligodeoxynucleotides, reduces PKC-beta levels and PKC activity. asPKC-beta-transfected THP-1 cells show a decreased phagocytosis, a decreased TNF-alpha release, and a decreased proliferation. However, no difference is measured in the release of superoxide and PGE(2). These results suggest that: (1) PKC-alpha but not PKC-beta is involved in the release of superoxide and PGE(2); (2) TNF-alpha release and the phagocytosis of latex particles are mediated by PKC-alpha, PKC-beta, and other PKC isoenzymes; and (3) PKC-alpha and PKC-beta play antagonistic roles in the differentiation process of THP-1 cells. PKC-alpha promotes the differentiation process of THP-1 cells, PKC-beta retards the differentiation of THP-1 cells into macrophage-like cells. PMID:10822170

  11. Differential effects of K+ channel blockers on antinociception induced by alpha 2-adrenoceptor, GABAB and kappa-opioid receptor agonists.

    PubMed Central

    Ocaña, M.; Baeyens, J. M.

    1993-01-01

    1. The effects of several K+ channel blockers (sulphonylureas, 4-aminopyridine and tetraethylammonium) on the antinociception induced by clonidine, baclofen and U50,488H were evaluated by use of a tail flick test in mice. 2. Clonidine (0.125-2 mg kg-1, s.c.) induced a dose-dependent antinociceptive effect. The ATP-dependent K+ (KATP) channel blocker gliquidone (4-8 micrograms/mouse, i.c.v.) produced a dose-dependent displacement to the right of the clonidine dose-response line, but neither 4-aminopyridine (4-AP) (25-250 ng/mouse, i.c.v.) nor tetraethylammonium (TEA) (10-20 micrograms/mouse, i.c.v.) significantly modified clonidine-induced antinociception. 3. The order of potency of sulphonylureas in antagonizing clonidine-induced antinociception was gliquidone > glipizide > glibenclamide > tolbutamide, which is the same order of potency as these drugs block KATP channels in neurones of the CNS. 4. Baclofen (2-16 mg kg-1, s.c.) also induced a dose-dependent antinociceptive effect. Both 4-AP (2.5-25 ng/mouse, i.c.v.) and TEA (10-20 micrograms/mouse, i.c.v.) dose-dependently antagonized baclofen antinociception, producing a displacement to the right of the baclofen dose-response line. However, gliquidone (8-16 micrograms/mouse, i.c.v.) did not significantly modify the baclofen effect. 5. None of the K+ channel blockers tested (gliquidone, 8-16 micrograms/mouse; 4-AP, 25-250 ng/mouse and TEA, 10-20 micrograms/mouse, i.c.v.), significantly modified the antinociception induced by U50,488H (8 mg kg-1, s.c.). 6. These results suggest that the opening of K+ channels is involved in the antinociceptive effect of alpha 2 and GABAB, but not kappa-opioid, receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7905339

  12. Antagonists of the Vasopressin V1 Receptor and of the β1-Adrenoceptor Inhibit Cytotoxic Brain Edema in Stroke by Effects on Astrocytes – but the Mechanisms Differ

    PubMed Central

    Hertz, Leif; Xu, Junnan; Chen, Ye; Gibbs, Marie E; Du, Ting; Hertz, Leif; Xu, Junnan; Chen, Ye; Gibbs, Marie E; Du, Ting

    2014-01-01

    Brain edema is a serious complication in ischemic stroke because even relatively small changes in brain volume can compromise cerebral blood flow or result in compression of vital brain structures on account of the fixed volume of the rigid skull. Literature data indicate that administration of either antagonists of the V1 vasopressin (AVP) receptor or the β1-adrenergic receptor are able to reduce edema or infarct size when administered after the onset of ischemia, a key advantage for possible clinical use. The present review discusses possible mechanisms, focusing on the role of NKCC1, an astrocytic cotransporter of Na+, K+, 2Cl- and water and its activation by highly increased extracellular K+ concentrations in the development of cytotoxic cell swelling. However, it also mentions that due to a 3/2 ratio between Na+ release and K+ uptake by the Na+,K+-ATPase driving NKCC1 brain extracellular fluid can become hypertonic, which may facilitate water entry across the blood-brain barrier, essential for development of edema. It shows that brain edema does not develop until during reperfusion, which can be explained by lack of metabolic energy during ischemia. V1 antagonists are likely to protect against cytotoxic edema formation by inhibiting AVP enhancement of NKCC1-mediated uptake of ions and water, whereas β1-adrenergic antagonists prevent edema formation because β1-adrenergic stimulation alone is responsible for stimulation of the Na+,K+-ATPase driving NKCC1, first and foremost due to decrease in extracellular Ca2+ concentration. Inhibition of NKCC1 also has adverse effects, e.g. on memory and the treatment should probably be of shortest possible duration. PMID:25342939

  13. Synthesis and secretion of interleukin-1 alpha and interleukin-1 receptor antagonist during differentiation of cultured keratinocytes.

    PubMed

    Corradi, A; Franzi, A T; Rubartelli, A

    1995-04-01

    Keratinocytes produce interleukin-1 alpha (IL-1 alpha) and the epithelial variant of its inhibitor, interleukin-1 receptor antagonist (icIL-1ra). Both IL-1 alpha and icIL-1ra lack a secretory signal peptide; however, some icIL-1ra is found in the supernatants of cultured keratinocytes. The lack of correlation with the release of the cytosolic enzyme lactate dehydrogenase suggests that icIL-1ra can be actively secreted. Brefeldin A fails to block icIL-1ra release, suggesting that this protein may be externalized by keratinocytes through a leaderless pathway of secretion. Only minute amounts of soluble extracellular IL-1 alpha are detected: however, both IL-1 alpha and icIL-1ra can be released from the external face of the keratinocyte plasma membrane by mild acidic treatment, suggesting that IL-1 alpha can also be secreted by keratinocytes. The observation of membrane-associated IL-1 alpha and icIL-1ra might reflect an autocrine loop of regulation. Support for this hypothesis comes from the finding that keratinocytes, when exposed to exogenous recombinant IL-1 alpha, increase their content in both IL-1 alpha and IL-1ra mRNA. When keratinocytes are subjected to counterflow centrifugal elutriation, three major cell populations are obtained, representing three different degrees of keratinocyte differentiation. Cells from all populations synthesize IL-1 alpha and IL-1ra: however, while IL-1 alpha is uniformly distributed in cells from all maturational stages, IL-1ra accumulates in large, more differentiated keratinocytes. Changes in the ratio of IL-1ra to IL-1 alpha production and secretion by keratinocytes at different degrees of maturation might contribute to the control of growth and differentiation of human skin. PMID:7698236

  14. Rational design of alpha-conotoxin analogues targeting alpha7 nicotinic acetylcholine receptors: improved antagonistic activity by incorporation of proline derivatives.

    PubMed

    Armishaw, Christopher; Jensen, Anders A; Balle, Thomas; Clark, Richard J; Harpsøe, Kasper; Skonberg, Christian; Liljefors, Tommy; Strømgaard, Kristian

    2009-04-01

    Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that belong to the superfamily of Cys loop receptors. Valuable insight into the orthosteric ligand binding to nAChRs in recent years has been obtained from the crystal structures of acetylcholine-binding proteins (AChBPs) that share significant sequence homology with the amino-terminal domains of the nAChRs. alpha-Conotoxins, which are isolated from the venom of carnivorous marine snails, selectively inhibit the signaling of neuronal nAChR subtypes. Co-crystal structures of alpha-conotoxins in complex with AChBP show that the side chain of a highly conserved proline residue in these toxins is oriented toward the hydrophobic binding pocket in the AChBP but does not have direct interactions with this pocket. In this study, we have designed and synthesized analogues of alpha-conotoxins ImI and PnIA[A10L], by introducing a range of substituents on the Pro(6) residue in these toxins to probe the importance of this residue for their binding to the nAChRs. Pharmacological characterization of the toxin analogues at the alpha(7) nAChR shows that although polar and charged groups on Pro(6) result in analogues with significantly reduced antagonistic activities, analogues with aromatic and hydrophobic substituents in the Pro(6) position exhibit moderate activity at the receptor. Interestingly, introduction of a 5-(R)-phenyl substituent at Pro(6) in alpha-conotoxin ImI gives rise to a conotoxin analogue with a significantly higher binding affinity and antagonistic activity at the alpha(7) nAChR than those exhibited by the native conotoxin. PMID:19131337

  15. Solution conformation of alpha-conotoxin GIC, a novel potent antagonist of alpha3beta2 nicotinic acetylcholine receptors.

    PubMed Central

    Chi, Seung-Wook; Kim, Do-Hyoung; Olivera, Baldomero M; McIntosh, J Michael; Han, Kyou-Hoon

    2004-01-01

    Alpha-conotoxin GIC is a 16-residue peptide isolated from the venom of the cone snail Conus geographus. Alpha-conotoxin GIC potently blocks the alpha3beta2 subtype of human nicotinic acetylcholine receptor, showing a high selectivity for neuronal versus muscle subtype [McIntosh, Dowell, Watkins, Garrett, Yoshikami, and Olivera (2002) J. Biol. Chem. 277, 33610-33615]. We have now determined the three-dimensional solution structure of alpha-conotoxin GIC by NMR spectroscopy. The structure of alpha-conotoxin GIC is well defined with backbone and heavy atom root mean square deviations (residues 2-16) of 0.53 A and 0.96 A respectively. Structure and surface comparison of alpha-conotoxin GIC with the other alpha4/7 subfamily conotoxins reveals unique structural aspects of alpha-conotoxin GIC. In particular, the structural comparison between alpha-conotoxins GIC and MII indicates molecular features that may confer their similar receptor specificity profile, as well as those that provide the unique binding characteristics of alpha-conotoxin GIC. PMID:14992691

  16. Effects of Spinal and Peripheral Injection of α1A or α1D Adrenoceptor Antagonists on Bladder Activity in Rat Models with or without Bladder Outlet Obstruction

    PubMed Central

    Kim, Jae Heon; Shim, Ji Sung; Kang, Seung Chul; Shim, Kang Soo; Park, Jae Young; Moon, Du Geon; Lee, Jeong Gu

    2011-01-01

    Purpose Antagonists of α1-adrenergic receptors (α1ARs) relax prostate smooth muscle and relieve voiding and storage symptoms. Recently, increased expression of α1ARs with change of its subtype expression has been proved in bladder outlet obstruction (BOO). To search for the evidence of changes in α1ARs subtype expression and activity in the peripheral and spinal routes, the effects of spinal and peripheral administration of tamsulosin (an α1A/D-selective AR), naftopidil (an α1A/D-selective AR), and doxazosin (non-selective AR) on bladder activity were investigated in a rat model with or without BOO. Methods A total of 65 female Sprague-Dawley rats were divided into the BOO surgery group (n=47) and the sham surgery group (n=18). After 6 weeks, cystometry was assessed before and after intrathecal and intra-arterial administrations of tamsulosin, naftopidil, and doxazosin. Results After intra-arterial administrations of all three drugs, bladder capacity (BC) was increased and maximal intravesical pressure (Pmax) was decreased in both BOO and the sham rat models (P<0.05). After intrathecal administration of all three drugs, BC was increased and Pmax was decreased in only the BOO group. The episodes of involuntary contraction in the BOO rat models were decreased by intra-arterial administration (P=0.031). The increase of BC after intrathercal and intra-arterial administrations of α1ARs was significantly greater in the BOO group than in the sham group (P=0.023, P=0.041). In the BOO group, the increase of BC and decrease in Pmax were greater by intra-arterial administration than by intrathecal administration (P=0.035). There were no significant differences of the degrees of changes in the cystometric parameters among the three different α1ARs. Conclusions Up-regulations of the α1ARs in BOO were observed by the greater increases of BC after α1AR antagonist administrations in the BOO group than in the sham group. However, there were no subtype differences of the

  17. Effects of combined alpha and beta adrenoceptor blockade in patients with angina pectoris. A double blind study comparing labetalol with placebo.

    PubMed

    Quyyumi, A A; Wright, C; Mockus, L; Shackell, M; Sutton, G C; Fox, K M

    1985-01-01

    The effects of a combined alpha and beta receptor antagonist, labetalol, were investigated in 10 patients with chronic stable angina pectoris. The optimal dose was determined during an initial dose titration study when the patients were treated with 200 mg, 400 mg, and 600 mg (six patients) of labetalol a day. The effective dose was then compared with placebo in a double blind randomised study. The effects of the drug were monitored with angina diaries, treadmill exercise testing, and 48 hour ambulatory electrocardiographic ST segment monitoring. Plasma labetalol concentrations were measured during each treatment period. The mean effective antianginal dose of labetalol was 480 (SD 140) mg/day given by mouth twice a day. There was a dose related reduction in daytime and nocturnal heart rate, the frequency of pain was significantly reduced by 41%, and exercise duration was significantly increased by 44% with labetalol when compared with placebo. The frequency and duration of the episodes of ST segment depression were significantly reduced by 56% and 73% respectively with labetalol. Adverse effects resulted in a reduction of the dose of labetalol in two patients. Thus labetalol is an effective agent in the treatment of angina pectoris. PMID:3881105

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

    SciTech Connect

    Spina, D.; Rigby, P.J.; Paterson, J.W.; Goldie, R.G. )

    1989-11-01

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

  19. The effects of (RS)-alpha-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG), a potent and selective metabotropic glutamate receptor antagonist.

    PubMed Central

    Toms, N. J.; Jane, D. E.; Kemp, M. C.; Bedingfield, J. S.; Roberts, P. J.

    1996-01-01

    1. In this study we describe the potent antagonist activity of a novel metabotropic glutamate (mGlu) receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG) which exhibits selectivity for mGlu receptors (group II and III) negatively coupled to adenylyl cyclase in the adult rat cortex. 2. Both the L-2-amino-4-phosphonobutyrate (L-AP4) and (2S, 1'S, 2'S)-2-(carboxycyclopropyl)glycine (L-CCG-1) inhibition of forskolin-stimulated cyclic AMP accumulation were potently reversed by (RS)-CPPG (IC50 values: 2.2 +/- 0.6 nM and 46.2 +/- 18.2 nM, respectively). 3. In contrast, (RS)-CPPG acted as a weak antagonist against group I mGlu receptors. In neonatal rat cortical slices, (RS)-CPPG antagonized (KB = 0.65 +/- 0.07 mM) (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD)-stimulated phosphoinositide hydrolysis. (RS)-CPPG (100 microM) failed to influence L-quisqualate-stimulated phosphoinositide hydrolysis in cultured cerebellar granule cells. 4. In the rat cerebral cortex, (RS)-CPPG is the most potent antagonist of group II/III mGlu receptors yet described (with 20 fold selectivity for group III mGlu receptors), having negligible activity at group I mGlu receptors. PMID:8922731

  20. Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists.

    PubMed

    Chen, Chen; Tucci, Fabio C; Jiang, Wanlong; Tran, Joe A; Fleck, Beth A; Hoare, Sam R; Wen, Jenny; Chen, Takung; Johns, Michael; Markison, Stacy; Foster, Alan C; Marinkovic, Dragan; Chen, Caroline W; Arellano, Melissa; Harman, John; Saunders, John; Bozigian, Haig; Marks, Daniel

    2008-05-15

    A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia. PMID:18417348

  1. Yohimbine antagonises α1A- and α1D-adrenoceptor mediated components in addition to the α2A-adrenoceptor component to pressor responses in the pithed rat.

    PubMed

    Docherty, James R

    2012-03-15

    We have recently shown that responses to pressor nerve stimulation in the pithed rat are mediated by α(1A)- and α(1D)-adrenoceptors, with no evidence for α(2)-adrenoceptor involvement, and that responses previously identified as α(2)-adrenoceptor mediated are actually α(1D)-adrenoceptor mediated. We have now re-examined the subtypes of α-adrenoceptor involved in pressor responses produced by exogenous agonists in the pithed rat preparation to confirm whether α(2)-adrenoceptors are involved in these responses. The α(2)-adrenoceptor and α(1D)-adrenoceptor antagonist yohimbine (1mg/kg) and the α(2A)-adrenoceptor antagonist methoxy-idazoxan (5 mg/kg) significantly shifted, but the α(1D)-adrenoceptor antagonist BMY 7378 (8-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspir o[4.5]decane-7,9-dione dihydrochloride) (1 mg/kg) did not affect, the pressor potency of the α(2)-adrenoceptor agonist xylazine. α(1)-adrenoceptor antagonists showed low potency against pressor responses to xylazine. The pressor potency of the α(1)-adrenoceptor agonist amidephrine was not affected by BMY 3778 (1 mg/kg) but significantly shifted by prazosin (0.01 mg/kg) and by yohimbine (1 mg/kg). In contrast, the pressor potency of phenylephrine was significantly shifted by both yohimbine and BMY 7378 (1 mg/kg), but to a greater extent by the α(1A)-adrenoceptor antagonist RS 100329 (5-Methyl-3-[3-[3-[4-[2-(2,2,2,trifluroethoxy) phenyl]-1-piperazinyl]propyl]-2,4-(1H,3H)-pyrimidinedione] hydrochloride) (0.1 mg/kg). In conclusion, we have identified and separated α(1A)-, α(1D)- and α(2A)-adrenoceptor antagonist actions of yohimbine against pressor responses. Pressor responses to exogenous agonists in the pithed rat involve both α(1A)- and α(1D)-adrenoceptors and in addition, α(2A)-adrenoceptors. PMID:22290390

  2. Solution conformation of a neuronal nicotinic acetylcholine receptor antagonist {alpha}-conotoxin OmIA that discriminates {alpha}3 vs. {alpha}6 nAChR subtypes

    SciTech Connect

    Chi, Seung-Wook; Kim, Do-Hyoung; Olivera, Baldomero M.; McIntosh, J. Michael; Han, Kyou-Hoon . E-mail: khhan600@kribb.re.kr

    2006-06-23

    {alpha}-Conotoxin OmIA from Conus omaria is the only {alpha}-conotoxin that shows a {approx}20-fold higher affinity to the {alpha}3{beta}2 over the {alpha}6{beta}2 subtype of nicotinic acetylcholine receptor. We have determined a three-dimensional structure of {alpha}-conotoxin OmIA by nuclear magnetic resonance spectroscopy. {alpha}-Conotoxin OmIA has an '{omega}-shaped' overall topology with His{sup 5}-Asn{sup 12} forming an {alpha}-helix. Structural features of {alpha}-conotoxin OmIA responsible for its selectivity are suggested by comparing its surface characteristics with other functionally related {alpha}4/7 subfamily conotoxins. Reduced size of the hydrophilic area in {alpha}-conotoxin OmIA seems to be associated with the reduced affinity towards the {alpha}6{beta}2 nAChR subtype.

  3. Allosteric interactions between the antagonist prazosin and amiloride analogs at the human alpha(1A)-adrenergic receptor.

    PubMed

    Leppik, R A; Mynett, A; Lazareno, S; Birdsall, N J

    2000-03-01

    It has been demonstrated previously that amilorides can interact with a well defined allosteric site on the human alpha(2A)-adrenergic receptor. In this study, the question was explored as to whether the human alpha(1A)-adrenergic receptor also possesses an equivalent allosteric site. The six amilorides examined strongly increased the dissociation rate of the antagonist [(3)H]prazosin from the alpha(1A)-adrenergic receptor in a concentration-dependent manner. With the parent amiloride, the dissociation data were well fitted by an equation derived from the ternary complex allosteric model, compatible with amiloride acting at a defined allosteric site on the alpha(1A)-adrenergic receptor. In contrast, the dissociation data for [(3)H]prazosin in the presence of the amiloride analogs were not compatible with the equation derived from a one-allosteric-site model, but could be fitted well by an equation derived from a two-allosteric-site model. However, certain individual parameters could not be resolved. The observed dissociation rate constants increased steeply with increasing amiloride analog concentration, and in some cases the data could be fitted with a logistic equation. The slope factors calculated from such fits were 1.2 to 2.1. It is concluded that the structure-binding relationships of the amilorides at the alpha(1A)- and alpha(2A)-adrenergic receptors are different. The interactions of the five amiloride analogs, but not the parent amiloride, with the alpha(1A)-adrenergic receptor are compatible with the presence of two (but not one) allosteric sites, and is thus more complex than that found for the alpha(2A)-adrenergic receptor. PMID:10692482

  4. Tumor necrosis factor-alpha antagonists improve aortic stiffness in patients with inflammatory arthropathies: a controlled study.

    PubMed

    Angel, Kristin; Provan, Sella Aarrestad; Gulseth, Hanne Løvdahl; Mowinckel, Petter; Kvien, Tore Kristian; Atar, Dan

    2010-02-01

    The chronic inflammatory state of rheumatoid arthritis and other inflammatory arthropathies, such as ankylosing spondylitis and psoriatic arthritis, contributes to the accelerated atherosclerosis associated with these conditions. This study evaluates the effect of treatment with tumor necrosis factor (TNF)-alpha antagonists on arterial stiffness in patients with inflammatory arthropathies. A total of 60 patients with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and clinical indication for anti-TNF-alpha therapy were included. Thirty-five patients started with anti-TNF-alpha therapy and were compared with a nontreatment group of 25 patients. Aortic stiffness (aortic pulse wave velocity), augmentation index, and disease activity were assessed at baseline and after 3 months. Aortic pulse wave velocity (mean+/-SD) was reduced in the treatment group but not in the control group (-0.50+/-0.78 m/s versus 0.05+/-0.54 m/s, respectively; P=0.002). Concomitantly, C-reactive protein and the disease activity score were reduced in the treatment group (-9.3+/-20.2 mg/L [P<0.001] and -0.74+/-0.91 [P=0.004]). Augmentation index remained unchanged in both groups (0.1+/-7.1% versus -1.0+/-5.8%, respectively; P=0.53). In a multivariate linear regression model, only treatment with TNF-alpha antagonist and change in mean arterial pressure predicted alterations in aortic pulse wave velocity. In summary, anti-TNF-alpha therapy improved aortic stiffness in patients with inflammatory arthropathies. These findings support the idea that anti-inflammatory treatment has a favorable effect on cardiovascular risk in patients with inflammatory arthropathies. PMID:20038753

  5. The effects of intraperitoneal administration of antagonists and development of morphine tolerance on the antinociception induced by stimulating the anterior pretectal nucleus of the rat.

    PubMed Central

    Rees, H.; Prado, W. A.; Rawlings, S.; Roberts, M. H.

    1987-01-01

    1 The effects of intraperitoneal administration of antagonists to morphine, 5-hydroxytryptamine (5-HT), noradrenaline and dopamine have been studied on the antinociceptive effects of electrical stimulation of the anterior pretectal nucleus (APtN) of the rat. 2 A 15 s period of 35 microA sine wave stimulation of APtN significantly increased the latency of the tail flick reflex to noxious heat for periods up to 1 h. 3 Naloxone (0.25-1.0 mg kg-1) attenuated the effects of APtN stimulation in a dose-dependent manner. In rats made tolerant to morphine by daily administration of morphine, the antinociceptive effects of APtN stimulation were significantly reduced. 4 The 5-HT receptor antagonists methysergide (5 mg kg-1) and ketanserin (1 mg kg-1), the dopamine receptor antagonist haloperidol (1 mg kg-1) and the beta-adrenoceptor antagonist propranolol (1 mg kg-1) had little effect on the antinociceptive effects of stimulating the APtN. 5 alpha-Adrenoceptor antagonists caused a dose-dependent antagonism of the response. The order of potency was; idazoxan greater than prazosin greater than phenoxybenzamine, the respective ED50 for each drug being 0.08: 0.45: 1.5 mg kg-1. 6 It is concluded that antagonism at opioid receptors and alpha-adrenoceptors but not beta-adrenoceptors, dopamine or 5-HT receptors reduces the antinociceptive effects of APtN stimulation. This differs from the reported effects of these antagonists on the antinociception caused by stimulating other sites in the brain. PMID:2892554

  6. Differential effects of calcium antagonists and Bay K 8644 on contractile responses to exogenous noradrenaline and adrenergic nerve stimulation in the rabbit ear artery.

    PubMed Central

    Skärby, T. V.; Högestätt, E. D.

    1990-01-01

    1. The effects of three calcium antagonists (nifedipine, verapamil, diltiazem) and the calcium agonist Bay K 8644 were compared on contractile responses of similar amplitude elicited by noradrenaline (NA) and electrical nerve stimulation (ENS) in the rabbit isolated ear artery. 2. Contractions induced by both NA (3 x 10(-7) M) and ENS (10 Hz, 10s) were almost exclusively mediated by alpha 1-adrenoceptors, since 10(-7) M prazosin abolished (NA) or almost abolished (ENS) the responses, and prazosin was more than three orders of magnitude more potent than rauwolscine on both types of response. 3. ENS-induced contractions were considerably less inhibited by nifedipine, verapamil and diltiazem than were those elicited by NA. Bay K 8644 enhanced responses to NA more than those to ENS. 4. The inhibitory effect of nifedipine and Ca2+ deprivation on NA-induced contractions decreased with increasing NA concentration. Reduction of the NA response by prazosin or phenoxybenzamine increased the nifedipine inhibition. 5. Reduction of the ENS-induced contractions by prazosin or phenoxybenzamine, or by use of a lower stimulation frequency did not increase the inhibitory effect of nifedipine. 6. In conclusion, the differential effects of the calcium antagonists on NA- and ENS-induced contractions were not related to differences in alpha-adrenoceptor subtype (alpha 1/alpha 2), receptor reserve or response amplitude, but may rather reflect temporal and spatial differences in alpha-adrenoceptor activation between the responses. PMID:1707708

  7. Molecular and functional characteristics of β3-adrenoceptors in late pregnant mouse uterus: a comparison with β2-adrenoceptors.

    PubMed

    Parida, Subhashree; Uttam Singh, Thakur; Ravi Prakash, Vellanki; Mishra, Santosh K

    2013-01-30

    β(3)-adrenoceptor is a potential target for uterine relaxant drugs for the treatment of preterm labor. Mouse is an ideal experimental model for preterm labor. However, there is limited information on the molecular and functional characteristics of β(3)-adrenoceptors in mouse uterus. Therefore, the current study was undertaken to characterize the β(3)-adrenoceptors in late pregnant mouse uterus by molecular and functional experiments and to compare their expression and function with the β(2)-adrenoceptors. Using RT-PCR, we demonstrated the presence of β(3)-adrenoceptor mRNA in the mouse uterus. Accordingly, selective β(3)-adrenoceptor agonist SAR150640 (ethyl-4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-3[(methylsulfonyl)amino]-phenoxy}propyl)amino]cyclohexyl}benzoate hydrochloride) caused concentration-dependent relaxation of the isolated tissue. SR59230A (1 μM), a selective antagonist of β(3)-adrenoceptors, antagonized the relaxant response to SAR150640. Using real-time PCR we found that in comparison to β(3)-adrenoceptor mRNA, β(2)-adrenoceptor mRNA is predominantly expressed in the late pregnant mouse uterus. We then assessed the comparative efficiency of different β-adrenoceptor agonists, such as SAR150640, salbutamol and isoprenaline to relax the tissue. SAR150640 (pD(2) 6.64±0.21, E(max) 104.9±7.95), salbutamol (pD(2) 8.57±0.062, E(max) 103.1±3.22) and isoprenaline (pD(2) 9.48±0.084, E(max) 102.9±5.18) caused concentration-dependent inhibition of uterine rhythmic contractions. While the maximal relaxation to these agonists was comparable, the order of potency was isoprenaline>salbutamol>SAR. These results suggest that β(3)-adrenoceptor mRNA is present in the pregnant mouse uterus and is functionally active. The predominance of β(2)- over β(3)-adrenoceptor expression may explain variable potency amongst the β-adrenoceptor agonists. PMID:23219791

  8. Closed headpiece of integrin [alpah]IIb[beta]3 and its complex with an [alpha]IIb[beta]3-specific antagonist that does not induce opening

    SciTech Connect

    Zhu, Jieqing; Zhu, Jianghai; Negri, Ana; Provasi, Davide; Filizola, Marta; Coller, Barry S.; Springer, Timothy A.

    2011-08-24

    The platelet integrin {alpha}{sub IIb}{beta}{sub 3} is essential for hemostasis and thrombosis through its binding of adhesive plasma proteins. We have determined crystal structures of the {alpha}{sub IIb}{beta}{sub 3} headpiece in the absence of ligand and after soaking in RUC-1, a novel small molecule antagonist. In the absence of ligand, the {alpha}{sub IIb}{beta}{sub 3} headpiece is in a closed conformation, distinct from the open conformation visualized in presence of Arg-Gly-Asp (RGD) antagonists. In contrast to RGD antagonists, RUC-1 binds only to the {alpha}{sub IIb} subunit. Molecular dynamics revealed nearly identical binding. Two species-specific residues, {alpha}{sub IIb} Y190 and {alpha}{sub aIIb} D232, in the RUC-1 binding site were confirmed as important by mutagenesis. In sharp contrast to RGD-based antagonists, RUC-1 did not induce {alpha}{sub IIb}{beta}{sub 3} to adopt an open conformation, as determined by gel filtration and dynamic light scattering. These studies provide insights into the factors that regulate integrin headpiece opening, and demonstrate the molecular basis for a novel mechanism of integrin antagonism.

  9. Scorpion venom-induced neutrophilia is inhibited by a PAF receptor antagonist in the rat.

    PubMed

    Borges, C M; Silveira, M R; Aparecida, M; Beker, C L; Freire-Maia, L; Teixeira, M M

    2000-04-01

    A dramatic blood neutrophilia is an important feature of the severe envenoming caused by the Brazilian scorpion Tityus serrulatus and may contribute to the development of lung injury in children. We examined the effects of an intravenous injection of T. serrulatus scorpion venom (TsV) on the total number of leukocytes and neutrophils in the blood of anesthetized rats. Injection of TsV (250 microg/kg) induces a significant leukocytosis 2 and 3 h after its injection, explained by an increase in the number of neutrophils. The release of catecholamines and action on adrenoceptors is responsible for most of the systemic manifestations of TsV. However, pretreatment with the beta-adrenoceptor antagonists metoprolol and propranolol or the alpha1-adrenoceptor antagonist prazosin (0.25 mg/kg) did not prevent TsV-induced neutrophilia. Blood neutrophilia induced by TsV occurred simultaneously with a significant reduction of mature neutrophils in bone marrow. Pretreatment with the platelet-activating factor (PAF) receptor antagonists UK-74505 or WEB-2086 prevented TsV-induced increase in blood neutrophils and reduction in the number of neutrophils in the bone marrow. It is concluded that scorpion venom induces blood neutrophilia in rats, explained by a PAF receptor-dependent mobilization of neutrophils from the bone marrow. PMID:10770284

  10. Functional effects of β3-adrenoceptor on pacemaker activity in interstitial cells of Cajal from the mouse colon.

    PubMed

    Wu, Mei Jin; Shin, Dong Hoon; Kim, Man Yoo; Park, Chan Guk; Kim, Young Dae; Lee, Jun; Park, Il Koo; Choi, Seok; So, Insuk; Park, Jong Seong; Jun, Jae Yeoul

    2015-05-01

    We investigated the presence of β3-adrenoceptor and its functional effects on pacemaker potentials in colonic interstitial cells of Cajal (ICCs) from mice. The whole-cell patch clamp technique was used to record pacemaker potentials in cultured ICCs and reverse transcription polymerase chain reaction (RT-PCR) was performed to detect the mRNA transcript levels β-adrenoceptors. The β3-adrenoceptor agonist, BRL37344, reduced the frequency of pacemaker potentials in a concentration-dependent manner. The inhibitory effects of BRL37344 were blocked by the pretreatment of propranolol, a nonspecific β-adrenoceptor antagonist, but not by the selective β1-adrenoceptor antagonist atenolol and the selective β2-adrenoceptor antagonist butoxamine. β3-adrenoceptor antagonists SR59230A and L748337 blocked the inhibitory effects of BRL37344. RT-PCR revealed mRNA transcripts of β1- and β3-adrenoceptor, but not β2-adrenoceptor, in c-kit- and Ano-1-positive colonic ICCs. The K(+) channel blockers tetraethylammonium, apamin, and glibenclamide did not block the effects of BRL37344. N(ω)-Nitro-l-arginine methyl ester hydrochloride (L-NAME), an NO synthase inhibitor, and chelerythrine, a protein kinase C inhibitor, also did not block the effects of BRL37344. Noradrenaline mimicked the effects of BRL37344 in colonic ICCs. However, the inhibitory effects of noradrenaline on pacemaker potentials were blocked only by pretreatment with atenolol but not by butoxamine, SR59230A, or L748337. In small intestinal ICCs, BRL37344 had no effect on pacemaker potentials and mRNA transcripts of β1-and β2-adrenoceptor, but not β3-adrenoceptor were detected. These results suggest that β3-adrenoceptors are present in colonic ICCs and may play a role in regulating gastrointestinal motility by the inhibition of pacemaker potentials. PMID:25725113