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Adrenoceptor Antagonist (adrenoceptor + antagonist)
Terms modified by Adrenoceptor Antagonist Selected AbstractsSensitivity to ,-adrenoceptor agonists of adipocytes from rats treated with an aqueous extract of Croton cajucara BenthJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2003Dora Maria Grassi-Kassisse ABSTRACT Aqueous extracts of Croton cajucara bark are used in folk medicine to treat hepatic and gastrointestinal disorders and as a coadjuvant in weight-loss programs. We examined the effect of treating rats for 15 days with a 5% aqueous extract of C. cajucara on body weight and food intake. The epididymal adipose pads were removed and the lipolytic responses of isolated adipocytes to isoprenaline, noradrenaline (norepinephrine), BRL37344 and adrenaline (epinephrine) were analysed in the absence or presence of metoprolol or ICI118,551. Treated rats had a significantly lower weight gain than control rats, with no difference in food and liquid intake, epididymal fat-pad weight or basal glycerol release. The sensitivity of the lipolytic response to isoprenaline and adrenaline was significantly higher in adipocytes from treated rats. The sensitivity to noradrenaline or BRL37344 was unaltered. Metoprolol shifted the dose-response curves to noradrenaline to the right in adipocytes from control and treated rats; the dose-response curve to isoprenaline in adipocytes from control rats was also shifted to the right. In adipocytes from treated rats, the dose-response curve to isoprenaline was unaltered by metoprolol but was shifted to the right by ICI118,551, a ,2 -adrenoceptor antagonist. We conclude that in adipocytes from treated rats there is an increase in the lipolytic response to non-selective agonists (isoprenaline and adrenaline) mediated by ,2 -adrenoceptors, with no alteration in the responses mediated by ,1 -adrenoceptors (noradrenaline) or ,3 -adrenoceptors (BRL37344). This effect could increase the role of adrenaline as an endogenous stimulator of lipolysis. [source] Conversion to Silodosin in Men on Conventional ,1 -Blockers for Symptomatic Benign Prostatic HyperplasiaLUTS, Issue 1 2010Masahiko TANAKA Objectives:,1 -blockers have commonly been used as first-line medical therapy for symptomatic benign prostatic hyperplasia (BPH). Recently, a highly selective ,1A -adrenoceptor antagonist, silodosin, was developed in Japan. We examined the efficacy and safety of conversion from conventional ,1 -blockers to silodosin in men with BPH. Methods: Conversion to silodosin was proposed to consecutive patients on conventional ,1 -blockers for symptomatic BPH for at least 6 months. The effects of conversion were examined by the International Prostate Symptom Score, quality of life index, overactive bladder symptom score, peak flow rate, residual urine volume, and adverse events at 12 weeks. The efficacy of silodosin was also evaluated by patients' impression. Results: Eighty-one men underwent conversion, for the most part because of dissatisfaction with the efficacy of their current treatment in improving nocturia or weak stream. The International Prostate Symptom Score total score significantly improved from 12.7 ± 5.9 at baseline to 10.6 ± 5.4 at 4 weeks (P < 0.001) and 10.9 ± 5.8 at 12 weeks (P < 0.01). The progress was mostly due to improvement in voiding symptoms, although reduction of storage symptoms was also significant. The quality of life index also significantly decreased with conversion to silodosin. Efficacy as judged by patients' impression was 76% (37/49) at 12 weeks of treatment. None of the overactive bladder symptom score, peak flow rate, and residual urine volume exhibited significant change. No serious adverse events were observed during the study period. Conclusion: Conversion to silodosin may be beneficial in men who are dissatisfied with conventional ,1 -blockers for BPH, and be particularly useful in improving voiding symptoms. [source] Nebivolol Dilates Human Penile Arteries and Reverses Erectile Dysfunction in Diabetic Rats through Enhancement of Nitric Oxide SignalingTHE JOURNAL OF SEXUAL MEDICINE, Issue 8 2010Javier Angulo PhD ABSTRACT Introduction., Traditional beta-blockers have sometimes been associated with erectile dysfunction (ED). Nebivolol is a cardioselective ,1 -adrenoceptor antagonist that promotes vasodilation through a nitric oxide (NO)-dependent mechanism. Aim., We evaluated the effects of nebivolol on the NO/cyclic guanosine monophosphate (cGMP) signaling pathway, on erectile function and dysfunction, and in human penile vascular tissues. Methods., Erectile response to cavernosal nerve electrical stimulation in control and diabetes-induced ED rats were evaluated, along with serum nitrite/nitrate (NOx) concentration and plasma/tissue cGMP levels. Endothelium-dependent and sildenafil-induced relaxation of isolated human corpus cavernosum (HCC) and human penile resistance arteries (HPRA) were also determined. Main Outcome Measures., The effects of nebivolol on erectile function and dysfunction and on NO/cGMP-mediated responses. Results., Treatment with nebivolol significantly potentiated erectile response in control rats, regardless of its effects on blood pressure. Nebivolol increased NOx and plasma cGMP by 3-fold and 2.75-fold, respectively, and significantly augmented the elevation of plasma cGMP produced by sildenafil. Nebivolol enhanced endothelium-dependent and sildenafil-induced relaxations of HCC tissue, and produced endothelium-dependent vasodilation of HPRA. Nebivolol, but not atenolol, significantly improved erectile response in diabetic rats (51.6%, 53.2%, and 87.1% of response at 3 Hz in nondiabetic rats, for vehicle-treated, atenolol-treated, and nebivolol-treated diabetic rats, respectively); after sildenafil administration, ED was completely reversed in nebivolol-treated diabetic rats (69.6% and 112% for diabetic rats treated with sildenafil and nebivolol plus sildenafil, respectively). Accordingly, nebivolol restored systemic NOx levels and cGMP content in penile tissue from these animals. Conclusions., Nebivolol in vivo activated the NO/cGMP pathway, enhanced erectile response and reversed ED in diabetic rats. Moreover, nebivolol in vitro potentiated NO/cGMP-mediated relaxation of human erectile tissues. These effects may account for the low incidence of ED in nebivolol-treated hypertensive patients. Nebivolol therefore may have utility in the treatment of ED, particularly ED associated with diabetes. Angulo J, Wright HM, Cuevas P, González-Corrochano R, Fernández A, Cuevas B, La Fuente JM, Gupta S, and de Tejada IS. Nebivolol dilates human penile arteries and reverses erectile dysfunction in diabetic rats through enhancement of nitric oxide signaling. J Sex Med 2010;7:2681,2697. [source] Influence of high dietary sodium intake on the functional subtypes of ,1 -adrenoceptors in the renal cortical vasculature of Wistar,Kyoto ratsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1-2 2009R. N. Kazi Summary 1,Increased renal vascular resistance is one renal functional abnormality that contributes to hypertension, and ,1 -adrenoceptors play a pivotal role in modulating this renal vascular resistance. This study investigates the functional contribution of ,1 -adrenoceptor subtypes in the renal cortical vasculature of Wistar,Kyoto rats on a normal sodium diet (WKYNNa) compared with those given saline to drink for 6 weeks (WKYHNa). 2,The renal cortical vascular responses to the adrenergic agonists noradrenaline (NA), methoxamine (ME) and phenylephrine (PE) were measured in WKYHNa and WKYNNa rats either in the absence (the control phase) or presence of chloroethylclonidine (CEC), an ,1B -adrenoceptor antagonist, 5-methylurapidil (5-MeU), an ,1A antagonist, or BMY7378, an ,1D antagonist. 3,Results showed a greater renal cortical vascular sensitivity to NA, PE and ME in the WKYHNa compared with WKYNNa rats (P < 0.05). Moreover, 5-MeU and BMY7378 attenuated adrenergically induced renal cortical vasoconstriction in WKYHNa and WKYNNa rats; this response was largely blunted in CEC-treated WKYHNa rats (all P < 0.05) but not in CEC-treated WKYNNa rats. 4,The data suggest that irrespective of dietary sodium content, in Wistar,Kyoto rats ,1A - and ,1D -subtypes are the major ,1 -adrenoceptors in renal cortical vasculature; however, there appears to be a functional involvement of ,1B -adrenoceptors in the WKYHNa rats. [source] The ,1D -adrenoceptor antagonist BMY 7378 is also an ,2C -adrenoceptor antagonistAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2005L. Cleary Summary 1 We have investigated the actions of the ,1D -adrenoceptor selective antagonist BMY 7378 in comparison with yohimbine at ,1 - and ,2 -adrenoceptors. 2 In rat aorta (,1D -adrenoceptor), BMY 7378 (pA2 of 8.67) was about 100 times more potent than yohimbine (pA2 of 6.62) at antagonizing the contractile response to noradrenaline. 3 In human saphenous vein (,2C -adrenoceptor), BMY 7378 (pA2 of 6.48) was approximately 10 times less potent than yohimbine (pA2 of 7.56) at antagonizing the contractile response to noradrenaline. 4 In prostatic portions of rat vas deferens, BMY 7378 (10 ,m) did not significantly affect the concentration-dependent inhibition of single pulse nerve stimulation-evoked contractions by xylazine (an action at prejunctional ,2D -adrenoceptors). 5 In ligand-binding studies, BMY 7378 showed 10-fold selectivity for ,2C -adrenoceptors (pKi of 6.54) over other ,2 -adrenoceptors. 6 It is concluded that BMY 7378, in addition to ,1D -adrenoceptor selectivity in terms of ,1 -adrenoceptors, shows selectivity for ,2C -adrenoceptors in terms of ,2 -adrenoceptors. [source] Postjunctional ,1 -adrenoceptors in the vasculature of the pithed mouse are of the ,1A -subtypeAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2005J. J. López-Guerrero Summary 1 The pressor action of noradrenaline and its blockade by selective ,1 -adrenoceptor antagonists in the pithed mouse were evaluated. 2 Chloroethylclonidine (,1B/D -adrenoceptor alkylating agent) or BMY 7378 (,1D -adrenoceptor antagonist), both at 1 mg kg,1, did not block the increase in blood pressure induced by noradrenaline. 3 5-Methylurapidil (,1A -adrenoceptor antagonist), at 0.1 mg kg,1, displaced the dose,response curve approximately six-fold to the right. 4 The results support the idea that the pithed mouse vasculature express ,1A -adrenoceptors and suggest that it is a good model to study the roles of ,1 -adrenoceptors in gene knockout or overexpression. [source] Effects of atipamezole , a selective ,2 -adrenoceptor antagonist , on cardiac parasympathetic regulation in human subjectsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2004J. Penttilä Summary 1 This double-blind, cross-over, placebo-controlled study on six healthy male volunteers was designed to evaluate the effects of ,2 -adrenoceptor antagonism on cardiac parasympathetic regulation. 2 The subjects received atipamezole intravenously as a three-step infusion, which aimed at steady-state serum concentrations of 10, 30 and 90 ng ml,1 at 50-min intervals. 3 Drug effects were assessed with repeated recordings of blood pressure and electrocardiogram, in which the high-frequency (0.15,0.40 Hz) R-R interval variation is supposed to reflect cardiac parasympathetic efferent neuronal activity. 4 At the end of the three steps of the infusion, the mean (±SD) concentrations of atipamezole were 10.5 (3.9), 26.8 (5.6) and 81.3 (21.1) ng ml,1. 5 Within this concentration range, atipamezole appeared to reduce slightly the high-frequency R-R interval fluctuations, indicating a minor vagolytic effect in the heart. 6 Atipamezole increased systolic and diastolic arterial pressure, on average by 20 and 14 mmHg (maxima at the second step of the infusion), which evidently reflects an overall sympathetic augmentation. [source] Vascular responses to ,-adrenoceptor subtype-selective agonists with and without endothelium in rat common carotid arteriesAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2001S. Chiba 1 Using the cannula inserting method, vasodilator responses to ,-adrenoceptor agonists (isoprenaline, denopamine and procaterol) were investigated in isolated and perfused rat common carotid arteries. 2 Each ,-adrenoceptor agonist induced a vasodilation in preparations preconstricted by phenylephrine in a dose-related manner. The potencies were in the order of isoprenaline > procaterol >> denopamine. 3 Denopamine-induced dilations were significantly inhibited by 1 nmol betaxolol (a selective ,1 -adrenoceptor antagonist), but it was not influenced by 1 nmol ICI 118,551 (a selective ,2 -adrenoceptor antagonist). On the other hand, procaterol-induced vasodilations were significantly inhibited by 1 nmol ICI 118,551 but not modified by 10 nmol betaxolol. 4 ACh-induced vasodilations disappeared after intraluminal saponin injection to remove endothelium, but procaterol- and denopamine-induced dilations were not modified by removal of the endothelium. 5 Pretreatment with L -NG -nitroarginine methyl ester (L -NAME) readily inhibited ACh-induced vasodilations. However, neither procaterol- or denopamine-induced vasodilation was modified by L -NAME treatment. 6 From these results, it is concluded that in the rat common carotid arteries (1) there are abundant ,2 - and a few ,1 -adrenoceptors, and (2) there is no participation of the endothelium-dependent mechanism in ,-adrenoceptor mediated vasodilations. [source] The ,-adrenoceptor antagonist, zolertine, inhibits ,1D- and ,1A-adrenoceptor-mediated vasoconstriction in vitroAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2000M. Ibarra 1 The antagonist effect of zolertine (4-phenyl-1-[2-(5-tetrazolyl)ethyl]piperazine trihydrochloride), on vascular contraction elicited by noradrenaline in aorta, carotid (,1D-adrenoceptors), mesenteric (,1A/D-adrenoceptors) and caudal arteries (,1A-adrenoceptors) from Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats and rabbit aorta (,1B-adrenoceptors), was investigated in endothelium-denuded arterial rings. 2 The selective ,1D-adrenoceptor agonist, noradrenaline, elicited concentration-dependent contractions in all arterial rings from both species. Noradrenaline selectivity was: carotid=aorta>>.Gt;mesenteric=rabbit aorta>caudal arteries. 3 The contractile responses induced by noradrenaline were competitively antagonized by zolertine in rat carotid and aorta arteries, yielding pA2 values of WKY, 7.48±0.18; SHR, 7.43±0.13 and WKY, 7.57±0.24; SHR, 7.40±0.08, respectively. Zolertine was a non-competitive antagonist in some blood vessels as Schild plot slopes were lower than unity. The pKb estimates for zolertine were WKY, 6.98±0.16; SHR, 6.81±0.18 in the mesenteric artery, WKY, 5.73±0.11; SHR, 5.87±0.25 in the caudal artery and 6.65±0.09 in rabbit aorta. 4 Competition binding experiments using the ,1-adrenoceptor antagonist [3H]prazosin showed a zolertine pKi of 6.81±0.02 in rat liver (,1B-adrenoceptors) and 6.35±0.04 in rabbit liver (,1A-adrenoceptors) membranes. 5 Zolertine showed higher affinity for ,1D-adrenoceptors compared to ,1A-adrenoceptors, while it had an intermediate affinity for ,1B-adrenoceptors. The ability of the ,1-adrenoceptor antagonist zolertine to block ,1D-adrenoceptor-mediated constriction in different vessels of WKY and SHR rats may explain its antihypertensive efficacy despite its low order of potency. [source] Antinociceptive Synergism of MD-354 and Clonidine.BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2010Part II. In the present investigation, a possible role for ,2 -adrenoceptors was examined. Mechanistic studies using yohimbine (a subtype non-selective ,2 -adrenoceptor antagonist), BRL 44408 (a preferential ,2A -adrenoceptor antagonist) and imiloxan (a preferential ,2B/C -adrenoceptor antagonist) on the antinociceptive actions of a MD-354/clonidine combination were conducted. Subcutaneous pre-treatment with all three antagonists inhibited the antinociceptive synergism of MD-354 and clonidine in the mouse tail-flick assay in a dose-dependent manner (AD50 = 0.33, 2.1, and 0.17 mg/kg, respectively). Enhancement of clonidine antinociception by MD-354 did not potentiate clonidine's locomotor suppressant activity in a mouse locomotor assay. When [ethyl- 3H]RS-79948-197 was used as radioligand, MD-354 displayed almost equal affinity to ,2A - and ,2B -adrenoceptors (Ki = 110 and 220 nM) and showed lower affinity at ,2C -adrenoceptors (Ki = 4,700 nM). MD-354 had no subtype-selectivity for the ,2 -adrenoceptor subtypes as an antagonist in functional [35S]GTP,S binding assays. MD-354 was a weak partial agonist at ,2A -adrenoceptors. Overall, in addition to the 5-HT3 receptor component, the present investigation found MD-354 to be a weak partial ,2A -adrenoceptor agonist that enhances clonidine's thermal antinociceptive actions through an ,2 -adrenoceptor-mediated mechanism without augmenting sedation. [source] Clonidine Attenuates Naloxone-Induced Opioid-Withdrawal Syndrome in Cholestatic Mice,,BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2001Ahmad Reza Dehpour Naloxone-precipitated withdrawal syndrome has been described in a mouse model of acute cholestasis. Thus we aimed at determining whether central noradrenergic hyperactivity is involved in manifestation of naloxone-precipitated withdrawal syndrome in mice with obstructive cholestasis. Acute cholestasis was induced by bile duct resection in mice and physical dependence was observed by precipitating a withdrawal syndrome with naloxone (2 mg/kg, intraperitoneally) 5 days after induction of cholestasis. Administration of clonidine (0.1 mg/kg, intraperitoneally), an ,2 -adrenoceptor agonist, 15 min. before naloxone injection significantly alleviates withdrawal severity in cholestatic mice. However, pretreatment of animals with yohimbine (3 mg/kg, intraperitoneally), an ,2 -adrenoceptor antagonist, 15 min. before clonidine blocked this ameliorative effect of clonidine. The results of this study support the evidence for involvement of the ,2 -adrenoceptors in the withdrawal syndrome of cholestasis in a mouse model. [source] RESEARCH PAPER: The antihyperalgesic effect of levetiracetam in an inflammatory model of pain in rats: mechanism of actionBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2010A Micov BACKGROUND AND PURPOSE Levetiracetam, a novel antiepileptic drug, has recently been shown to have antinociceptive effects in various animal models of pain. The purpose of this study was to investigate the antihyperalgesic effect of levetiracetam and its mechanism of action, by examining the involvement of GABAergic, opioidergic, 5-hydroxytryptaminergic (5-HTergic) and adrenergic systems in its effect, in a rat model of inflammatory pain. EXPERIMENTAL APPROACH Rats were intraplantarly injected with the pro-inflammatory compound carrageenan. A paw pressure test was used to determine: (i) the effect of levetiracetam on carrageenan-induced hyperalgesia; and (ii) the effects of bicuculline (selective GABAA receptor antagonist), naloxone (non-selective opioid receptor antagonist), methysergide (non-selective 5-HT receptor antagonist) and yohimbine (selective ,2 -adrenoceptor antagonist) on the antihyperalgesic action of levetiracetam. RESULTS Levetiracetam (10,200 mg·kg,1; p.o.) significantly reduced, in a dose-dependent manner, the inflammatory hyperalgesia induced by carrageenan. The antihyperalgesic effect of levetiracetam was significantly decreased after administration of bicuculline (0.5,2 mg·kg,1; i.p.), naloxone (1,3 mg·kg,1; i.p.), methysergide (0.25,1 mg·kg,1; i.p.) and yohimbine (1,3 mg·kg,1; i.p.). CONCLUSIONS AND IMPLICATIONS These results show that levetiracetam produced antihyperalgesia which is at least in part mediated by GABAA, opioid, 5-HT and ,2 -adrenergic receptors, in an inflammatory model of pain. The efficacy of levetiracetam in this animal model of inflammatory pain suggests that it could be a potentially important agent for treating inflammatory pain conditions in humans. [source] Cannabinoids inhibit noradrenergic and purinergic sympathetic cotransmission in the rat isolated mesenteric arterial bedBRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2007P Pakdeechote Background and purpose: Noradrenaline and ATP are sympathetic co-transmitters. In the rat perfused mesenteric bed cannabinoids have been shown to modify the overall response to sympathetic nerve stimulation. This study has assessed whether cannabinoid receptor activation modulates differentially the noradrenergic and purinergic components of sympathetic vasoconstriction. Experimental approach: Rat mesenteric beds were perfused with physiological salt solution and the effects of cannabinoids on responses to nerve stimulation, or exogenous noradrenaline or ,,, -methylene ATP (,,, -meATP; P2X receptor agonist) were determined after raising tone with U46619. The effects of cannabinoids on the noradrenaline and ATP components of sympathetic neurotransmission were assessed using the ,1 -adrenoceptor antagonist, prazosin, or after P2X receptor desensitization with ,,, -meATP. Key results: Anandamide, WIN 55,212-2 and CP55,940 attenuated sympathetic neurogenic vasoconstrictor responses. The inhibitory actions of anandamide and WIN 55,212-2 were blocked by LY320135, a CB1 receptor antagonist, but not by SR144528, a CB2 receptor antagonist. The inhibitory actions of CP55,940 were unaffected by LY320135 and SR144528. WIN 55,212-3, the inactive S(,) enantiomer of WIN 55,212-2, had no effect on sympathetic neurogenic responses. None of the cannabinoids affected contractile responses to exogenous noradrenaline or ,,, -meATP. Anandamide and WIN 55,212-2 inhibited both the noradrenaline and ATP components of the sympathetic neurogenic contractile responses, with effects on the ATP component being most marked. Conclusions and implications: These results indicate that prejunctional CB1 -like receptors mediate the sympathoinhibitory action of anandamide and WIN 55,212-2, but not CP55,940, in the rat mesenteric bed. Cannabinoids inhibit both the noradrenergic and purinergic components of sympathetic neurotransmission. British Journal of Pharmacology (2007) 152, 725,733; doi:10.1038/sj.bjp.0707397; published online 16 July 2007 [source] Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious ratsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2004S M Gardiner The observation that the immunosuppressants, cyclosporine A (CsA) and tacrolimus, have pressor effects, but sirolimus does not, has led to an hypothesis that generalised sympathoexcitation, resulting from inhibition of calcineurin by CsA and tacrolimus underlies their pressor effects, because sirolimus does not inhibit calcineurin. It is unknown if sirolimus has haemodynamic actions not accompanied by a pressor effect, and whether or not the pressor effects of CsA and tacrolimus are accompanied by similar haemodynamic changes. Therefore, the first aim of our studies was to investigate these possibilities in conscious, chronically-instrumented, male, Sprague-Dawley rats. CsA (5.9 mg kg,1 bolus i.v.) caused rapid-onset, prolonged hypertension, tachycardia and mesenteric vasoconstriction. There was a slower onset renal vasoconstriction, but no significant change in hindquarters vascular conductance; all the effects of CsA were significantly greater than those of vehicle. CsA given by infusion (over 30 min or 2 h) caused changes qualitatively similar to those above. Repeated administration of CsA over 4 days did not enhance its cardiovascular effects. Pretreatment with the angiotensin (AT1) receptor antagonist, losartan, and the endothelin (ETA and ETB) receptor antagonist, SB 209670, reduced the pressor and mesenteric vasoconstrictor effects of CsA. Additional administration of the , -adrenoceptor antagonist, phentolamine, completely inhibited the cardiovascular effects of CsA. Tacrolimus (450 ,g kg,1 bolus i.v.) caused similar peak pressor and tachycardic effects to CsA, but these were much slower in onset, and were maximal when there were no significant regional vasoconstrictions, indicating that the pressor effect was probably due to a rise in cardiac output. However, although propranolol reversed the tachycardic effect of tacrolimus, it did not influence the pressor response. Sirolimus (450 ,g kg,1 bolus i.v.) had no tachycardic action, and only a modest, transient pressor effect, accompanied by equally brief reductions in renal, mesenteric, and hindquarters vascular conductances. The differences between the regional haemodynamic profiles of equipressor doses of CsA and tacrolimus, and the finding that sirolimus has significant cardiovascular actions, indicate that generalised sympathoexcitation, resulting from calcineurin inhibition (with CsA and tacrolimus), is unlikely to be the sole explanation of their pressor effects. British Journal of Pharmacology (2004) 141, 634,643. doi:10.1038/sj.bjp.0705659 [source] Bimatoprost: A Novel Antiglaucoma AgentCARDIOVASCULAR THERAPEUTICS, Issue 2 2004D. F. Woodward ABSTRACT The aim of glaucoma therapy is to preserve vision by reducing intraocular pressure (IOP). Following recent National Eye Institute sponsored studies, it is becoming increasingly apparent that every mmHg of extra IOP lowering counts. Bimatoprost is the newest and most effective addition to the physician's armamentarium of ocular hypotensive drugs. Direct clinical comparisons have demonstrated that it is more efficacious than the prostaglandin (PG) FP receptor agonist prodrugs, latanoprost and travoprost, as well as a ,-adrenoceptor antagonist, timolol, alone or in fixed combination with the carbonic anhydrase inhibitor, dorzolamide. Moreover, patients that are refractory to latanoprost therapy may be successfully treated with bimatoprost. Such evidence provides support, at the clinical level, for the contention that bimatoprost is pharmacologically distinct from PG FP receptor agonist prodrugs. Bimatoprost is a structural analog of PGF2, -ethanolamide (prostamide F2,), which is formed from the endocannabinoid anandamide by a biosynthetic pathway involving cyclooxygenase-2 (COX-2). Their pharmacology is remarkably similar, such that bimatoprost may be regarded as a prostamide mimetic. The target receptor for bimatoprost and the prostamides appears unique and unrelated to PG- and endocannabinoid-sensitive receptors. Extensive ocular distribution/metabolism studies in non-human primates demonstrate that bimatoprost is not a prodrug, it remains essentially intact. Its profound ocular hypotensive effects may, therefore, be attributed to its prostamide-mimetic properties. [source] ROLE OF HYPOTHALAMIC ,2 -ADRENOCEPTOR ACTIVITY IN FRUCTOSE-INDUCED HYPERTENSIONCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 10 2006Marcos A Mayer SUMMARY 1The aim of the present study was to investigate the effects of the ,2 -adrenoceptor antagonist yohimbine on blood pressure and heart rate (HR) regulation, as well as on adrenergic and serotoninergic neurotransmission, in fructose hypertensive (F) rats. 2The anterior hypothalamic area of control (C) and F rats was perfused with Ringer's solution containing 10 and 100 µg/mL yohimbine through a microdialysis concentric probe. The effects of yohimbine on mean arterial pressure (MAP) and HR, as well as on hypothalamic dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) levels, were measured according to perfusion time. 3Although intrahypothalamic perfusion of yohimbine increased blood pressure in C rats (,MAP 9 ± 1 and 11 ± 2 mmHg for 10 and 100 µg/mL yohimbine, respectively; P < 0.05 vs Ringer's perfusion), the ,-adrenoceptor antagonist did not modify MAP in F. Intrahypothalamic yohimbine had no effect on HR at either concentration tested. Intrahypothalamic perfusion of 10 and 100 µg/mL yohimbine increased DOPAC levels in C rats (135 ± 6 and 130 ± 5% of basal levels, respectively; both n = 6; P < 0.05 vs Ringer's perfusion), but not in F animals (115 ± 6 and 102 ± 6% of basal levels, respectively; both n = 6). In both C and F rats, yohimbine administration induced an increase in 5-HIAA dialysate levels. 4The results of the present study support the notion that ,2 -adrenoceptor tone of the anterior hypothalamus of normotensive rats, which contributes to normal blood pressure regulation, is not involved in the control of HR in either normotensive C or hypertensive F rats. The absence of changes in MAP after yohimbine perfusion in F rats suggests that the ,2 -adrenoceptor tone could be decreased in this group of rats and that this may be responsible for the maintenance of hypertension in this model. Intrahypothalamic perfusion of yohimbine increased DOPAC in the dialysate only in C rats, suggesting changes in presynaptic ,2 -adrenoceptor activity in fructose-overloaded rats. Conversely, increased 5-HIAA levels did not differ between C and F groups. [source] Ketanserin stabilizes blood pressure in conscious spontaneously hypertensive ratsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2003Chao-Yu Miao Summary 1.,It has been demonstrated that blood pressure variability (BPV) is increased in hypertension and related to organ damage. It will be important to lower BPV in the treatment of hypertension. The present study was designed to investigate the effect of ketanserin, a 5-HT2A receptor antagonist with a weak ,1 -adrenoceptor blocking effect, on BPV in conscious spontaneously hypertensive rats (SHR). 2.,It was found that ketanserin decreased blood pressure (BP) and BPV in SHR when administered intravenously (3 mg/kg, i.v.). Ketanserin decreased BPV, but not the BP level, when administered intracerebroventricularly (50 µg/rat, i.c.v.). 3.,Prazosin, an ,1 -adrenoceptor antagonist, lowered BP but did not affect BPV when given either i.v. (0.5 mg/kg) or i.c.v. (30 ug/rat). Ritanserin (0.625 mg/kg, i.v.; 40 'ug/rat, i.c.v.), a 5-HT2A receptor antagonist, decreased BPV only when administered i.c.v. and did not modify the BP level. 4.,Ketanserin enhanced arterial baroreflex function in SHR when given either i.v. or i.c.v. 5.,The stabilizing effect of ketanserin on BP was persistent when administered intragastrically. This administration route is similar to oral administration clinically. 6.,It is concluded that ketanserin is an antihypertensive agent with an effect of reducing BPV. This effect is mainly mediated by central 5-HT2A receptors and is probably attributable to the restoration of arterial baroreflex function. [source] Existence Of ,1A - and ,1B -Adrenoceptor Subtypes In Canine Mandibular Alveolar ArteriesCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 9 2001Yuichi Taguchi SUMMARY 1. The present study attempted to pharmacologically characterize the , -adrenoceptor subtypes mediating vasoconstriction in canine isolated and perfused mandibular alveolar artery (MAA). 2. Noradrenaline (NA) and phenylephrine (PE) induced a strong vasoconstriction in a dose-dependent manner. The PE-induced vascular constriction was significantly inhibited by treatment with prazosin. Xylazine evoked a moderate vascular constriction and the xylazine-induced response was suppressed by rauwolscine. The NA-induced response was partially inhibited by rauwolscine and the remaining response to NA was abolished by subsequent administration of prazosin. 3. Treatment of MAA with WB4101 produced a dose- dependent inhibition of NA-induced vasoconstriction. Pretreatment of tissues with 10 ,mol/L chloroethylclonidine produced a slight and statistically significant inhibition of NA-induced responses. BMY 7378, a selective ,1D -adrenoceptor antagonist, failed to significantly affect vasoconstrictor responses to NA. 4. The present results suggests that: (i) both ,1 - and ,2 -adrenoceptors are involved in vasoconstrictor responses in the canine MAA; and (ii) the ,1 -adrenoceptors involved in the vasoconstrictor responses in the MAA are characterized as mainly of the ,1A - and partially of the ,1B -adrenoceptor subtype. [source] New Glaucoma Medications in the Geriatric Population: Efficacy and SafetyJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 5 2002Gary D. Novack PhD Glaucoma can be considered a disease of the aging eye. Most medications used to treat glaucoma are in topical eyedrop form and may cause numerous untoward systemic effects in older persons. In recent years, several new ocular hypotensive medications have become available. These medications are being used more commonly because there is a growing trend by ophthalmologists to aggressively lower intraocular pressure. Therefore, geriatricians require a comprehensive knowledge of medications used to treat glaucoma, in addition to an understanding of their mechanism of action profiles of untoward effects and possible interactions with other diseases or medications. Therefore, we performed a review of the medications recently introduced into clinical practice. We selected drugs approved by the U.S. Food and Drug Administration between 1996 and September 2001. The safety profiles of these agents and their untoward side effects were reviewed by class: topical carbonic anhydrase inhibitors (brinzolamide: ocular tolerance, taste perversion), ,-adrenoceptor antagonists (timolol: bradycardia and bronchospasm), ,-adrenergic agonists (brimonidine: oral dryness, headache, and fatigue), and prostaglandin analogs (latanoprost, bimatoprost, travoprost, and unoprostone isopropyl: ocular hyperemia, iris color changes). The function of this review is to make geriatricians more aware of the efficacy and untoward effects of medications recently introduced into clinical practice. We recommend that geriatricians perform a medication review on all medications their patients use, including eye drops. [source] Role of Endothelium/Nitric Oxide and Cyclic AMP in Isoproterenol Potentiation of 17ß-Estradiol-Mediated VasorelaxationJOURNAL OF CARDIAC SURGERY, Issue 6 2002HY Chan Estrogen exerts vasorelaxation and cardiac protection via multiple cellular mechanisms. Estrogen modifies vasodilatation induced by certain relaxants such as ß-adrenoceptor agonists. However, little is known whether low concentrations of ß-adrenoceptor agonists would also influence the acute relaxant response to estrogen. The present study was designed to investigate the synergistic interaction between isoproterenol and 17ß-estradiol, and to study the role of endothelium and cyclic AMP-dependent pathway in this interaction. Changes in vessel tone of the isolated rat mesenteric artery rings were measured by force-displacement Grass transducer. In 9,11-dideoxy-11,, 9,-epoxy-methanoprostaglandin F2, - preconstricted endothelium-intact rings, 17ß-estradiol induced concentration-dependent relaxation with pD2 of 5.074 ± 0.043. Pretreatment of endothelium-intact rings with isoproterenol (1-3 × 10 -9 M, 1-h incubation time) significantly enhanced 17,-estradiol-induced relaxation. Longer incubation (2.5 h) did not produce further amplifying effect. This effect was inhibited by Rp-cGMPS triethylamine (3 × 10 -6 M), and disappeared in the presence of 3 × 10 -5 M NG -nitro-L-arginine methyl ester or in the endothelium-denuded rings. The effect of isoproterenol was partially antagonized by propranolol (3 × 10 -6 M), ICI 118,551 (3 × 10 -6 M) but not by atenolol (10 -5 M). None of three ,-adrenoceptor antagonists affected 17ß-estradiol-induced relaxation in the absence of isoproterenol. Rp-cAMPS triethylamine (3 × 10 -6 M) abolished the effect of isoproterenol. Besides, exposure to 3 × 10 -9 M forskolin for 1 h also potentiated the relaxant response to 17,-estradiol. In summary, this isoproterenol enhancement was dependent on the presence of endothelium and abolished by L-NAME via a ,2 -adrenoceptor-mediated cyclic AMP-dependent mechanism. These data also indicate the possible existence of cyclic AMP-dependent nitric oxide-producing pathway in the regulation of the vascular response to vasodilators. (supported by UPGC Direct Grant) [source] Do ,1 -adrenoceptor antagonists improve lower urinary tract symptoms by reducing bladder outlet resistance?,NEUROUROLOGY AND URODYNAMICS, Issue 3 2008Maurits M. Barendrecht Abstract Aims To test the hypothesis that improvements of lower urinary tract symptoms (IPSS) upon treatment with an ,-blocker are due to reduction of bladder outlet obstruction (assessed as the bladder outlet obstruction index, BOOI); relationships of either with free flow Qmax were also explored. Methods The database of a large placebo-controlled, randomized, double-blind study with the ,-blocker tamsulosin was analyzed retrospectively. Patients were stratified into lower and upper halves according to baseline IPSS, Qmax or BOOI and treatment-associated alterations thereof. In these strata differences between values for the other two parameters were analyzed, for example, improvement of IPSS and Qmax were compared in patients with below and above median improvement of BOOI. Results Patients with below and above median baseline for one parameter, for example, IPSS had rather similar values for the other two parameters, for example, Qmax and BOOI. Likewise, patients based upon baseline strata for one parameter had rather similar improvements of the other two parameters. Most importantly, patients with below and above median treatment-associated improvements of one parameter, for example, BOOI exhibited only small if any difference for alterations of the other two parameters, for example, IPPS and Qmax. Conclusions We conclude that IPSS, free flow Qmax and BOOI are only loosely related at baseline. More importantly, treatment-induced improvements of these parameters are also only loosely related. These data do question the hypothesis that ,-blockers largely improve lower urinary tract symptoms by reducing bladder outlet obstruction and suggest that they may also act independent of prostatic smooth muscle tone. Neurourol. Urodynam. 27:226,230, 2008. © 2007 Wiley-Liss, Inc. [source] Effect of ,-adrenoceptor antagonists on autonomic control of ciliary smooth muscleOPHTHALMIC AND PHYSIOLOGICAL OPTICS, Issue 5 2002Barry Winn Abstract Purpose: Pharmacological intervention with peripheral sympathetic transmission at ciliary smooth muscle neuro-receptor junctions has been used against a background of controlled parasympathetic activity to investigate the characteristics of autonomic control of ocular accommodation. Methods: A continuously recording infra-red optometer was used to measure accommodation on a group of five visually normal emmetropic subjects under open- and closed-loop conditions. A double-blind protocol between saline, timolol and betaxolol was used to differentiate between the localised action on ciliary smooth muscle and effects induced by changes in stimulus conditions. Data were collected before and 45 min following the instillation of saline, timolol or betaxolol. Open-loop post-task decay was investigated following 3 min sustained near fixation of a stimulus placed 3 D above the subject's pre-task tonic accommodation level. Closed-loop dynamic responses were recorded for each treatment condition while subjects viewed sinusoidally (0.05,0.6 Hz) or stepwise vergence-modulated targets over a 2 D range (2,4 D). Results: Open-loop data demonstrate a rapid post-task regression to pre-task tonic accommodation levels for saline and betaxolol control conditions. A slow positive post-task shift was induced by timolol indicating that sympathetic inhibition contributes to accommodative adaptation during sustained near vision. Closed-loop accommodation responses to temporally modulated sinusoidal stimuli showed characteristic features for both saline and betaxolol control conditions. Timolol induced a reduced gain for low- and mid-temporal frequencies (< 0.3 Hz) but did not affect the response at higher temporal frequencies. Response times to stepwise stimuli increased following the instillation of timolol for the near-to-far fixation condition compared with the controls and was related to the period of sustained prior fixation. Conclusions: Modulation of accommodation under open- and closed-loop conditions by a non-selective ,-blocker is consistent with the temporal and inhibitory features of sympathetic innervation to ciliary smooth muscle. Although parasympathetic innervation predominates there is evidence to support a role for sympathetic innervation in the control of ocular accommodation. [source] ,1A -Adrenoceptors predominate in the control of blood pressure in mouse mesenteric vascular bedAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2007S. G. Martínez-Salas Summary 1,The pressor action of the ,1A -adrenoceptor agonist, A61603 (N -[5-(4,5-dihydro-1H -imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulfonamide) or the ,1 -adrenoceptor agonist phenylephrine, and their blockade by selective ,1 -adrenoceptor antagonists in the mouse isolated mesenteric vascular bed were evaluated. 2,A61603 showed a , 235-fold higher potency in elevating perfusion pressure in mesenteric bed compared to phenylephrine. 3,The ,1A -adrenoceptor selective antagonist RS 100329 (5-methyl-3-[3-[4-[2-(2,2,2,-trifluoroethoxy) phenyl]-1-piperazinyl] propyl]-2,4-(1H)-pyrimidinedione), displaced with high affinity agonist concentration,response curves to the right in a concentration-dependent manner. 4,The ,1D -adrenoceptor selective antagonist BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5] decane-7,9-dione), did not displace A61603 nor did it block the phenylephrine-induced pressor response. 5,The ,1B/D -adrenoceptor alkylating antagonist chloroethylclonidine (CEC), caused a rightward shift of the phenylephrine concentration,response curve and reduced its maximum response; however, CEC only slightly modified A61603 evoked contraction. 6,The results indicate that the isolated mouse mesenteric vascular bed expresses ,1A -adrenoceptors and suggest a very discrete role for 1B -adrenoceptors. [source] Vascular ,1 -adrenoceptors in isolated perfused rat kidney: influence of ageingAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2007S. O. Awe Summary 1 The present study identifies ,1 -adrenoceptor subtype(s) involved in constrictor responses of the kidney and how ageing influences it. 2 The study was conducted on kidneys from F344BNF1 rats, which unlike F344 or Wistar rats used by many previous investigators do not exhibit glomerulonephritis at advanced age. 3 Noradrenaline (NA) and phenylephrine (PHE) (non-selective ,1) and A61063 (selective ,1A) adrenoceptor agonists elicited constriction of perfused kidneys of young and old rats. The pD2 values (index of renovascular reactivity) were significantly higher for A61603 than for either PHE or NA, and significantly decrease across age groups. 4 BMY 7378 or RS 100329, ,1D - or ,1A -adrenoceptor antagonists, respectively antagonized the constrictor responses and suppressed the maximal responses to all agonists in young adult rat kidneys. However, antagonism of PHE or A61063 by BMY 7378 in old rat kidneys was surmountable. 5 This study suggests that: (i) ,1A and ,1D -adrenoceptor subtypes mediate vasoconstriction of perfused rat kidney; (ii) ,1A -adrenoceptor subtype appears to predominate in renal vasculature based on agonist relative potencies. (iii) Ageing significantly decreases ,1 -adrenoceptor-mediated vasoconstriction of rat kidney. [source] Postjunctional ,1 -adrenoceptors in the vasculature of the pithed mouse are of the ,1A -subtypeAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 3 2005J. J. López-Guerrero Summary 1 The pressor action of noradrenaline and its blockade by selective ,1 -adrenoceptor antagonists in the pithed mouse were evaluated. 2 Chloroethylclonidine (,1B/D -adrenoceptor alkylating agent) or BMY 7378 (,1D -adrenoceptor antagonist), both at 1 mg kg,1, did not block the increase in blood pressure induced by noradrenaline. 3 5-Methylurapidil (,1A -adrenoceptor antagonist), at 0.1 mg kg,1, displaced the dose,response curve approximately six-fold to the right. 4 The results support the idea that the pithed mouse vasculature express ,1A -adrenoceptors and suggest that it is a good model to study the roles of ,1 -adrenoceptors in gene knockout or overexpression. [source] Pharmacological characterization of ,2 -adrenoceptor-mediated responses in pig nasal mucosaAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2003M. R. Corboz Summary 1 Pig nasal mucosal strips were incubated with ,-adrenoceptor antagonists followed by ,2 -adrenoceptor agonist concentration,response curves. 2 Contractions elicited by the ,2 -adrenoceptor agonists BHT-920 (pD2 = 6.16 ± 0.07), UK 14,304 (pD2 = 6.89 ± 0.13) and PGE-6201204 (pD2 = 7.12 ± 0.21) were blocked by the ,2 -adrenoceptor antagonist yohimbine (0.1 ,m). In contrast, the ,1 -adrenoceptor antagonist prazosin (0.03 ,m) had no effect on the BHT-920-, UK 14,304- and PGE-6201204-induced contractions, but blocked the contractile response to the ,1 -adrenoceptor agonist phenylephrine (pD2 = 5.38 ± 0.04) and the mixed ,1 - and ,2 -adrenoceptor agonist oxymetazoline (pD2 = 6.30 ± 0.22). 3 The ,2 -adrenoceptor antagonist yohimbine (0.01,0.1 ,m, pA2 = 8.04), ,2B/C -adrenoceptor antagonist ARC 239 (10 ,m, pKb = 6.33 ± 0.21), ,2A/C -adrenoceptor antagonist WB 4101 (0.3 ,m, pKb = 8.01 ± 0.24), ,2A -adrenoceptor antagonists BRL44408 (0.1 ,m, pKb = 6.82 ± 0.34) and RX 821002 (0.1 ,m, pKb = 8.31 ± 0.35), ,2C -adrenoceptor antagonists spiroxatrine (1 ,m, pKb = 7.32 ± 0.32), rauwolscine (0.1 ,m, pKb = 8.16 ± 0.14) and HV 723 (0.3 ,m, pKb = 7.68 ± 0.14) inhibited BHT-920-induced contractions in pig nasal mucosa. 4 The present antagonist potencies showed correlations with binding affinity estimates (pKi) obtained for these antagonists at the human recombinant ,2A - and ,2C -adrenoceptors (r = 0.78 and 0.83, respectively) and with binding affinity estimates (pKd) obtained in pig native ,2A - and ,2C -monoreceptor assays (r = 0.85 and 0.78, respectively). No correlation was observed for the ,2B -subtype. 5 In conclusion, contractile responses to phenylephrine, BHT-920, UK 14,304, PGE-6201204 and oxymetazoline indicate that ,1 - and ,2 -adrenoceptors are present and mediate vasoconstriction in pig nasal mucosa. Furthermore, correlation analysis comparing antagonist potency in pig nasal mucosa with affinities for human recombinant ,2 -adrenoceptors and native pig ,2 -adrenoceptors suggest that ,2A - and ,2C -adrenoceptor subtypes constrict pig nasal mucosa vasculature. [source] Role of the cholinergic system and of apamin-sensitive Ca2+ -activated K+ channels on rabbit jejunum spontaneous activity and on the inhibitory effects of adrenoceptor agonistsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2003L. Romanelli Summary 1 One reason why rabbit jejunum is suitable for studying the mechanisms underlying the actions of the various neurotransmitters and their interactions is its spontaneous motility. The main regulator of spontaneous motility is the cholinergic system. How the cholinergic system regulates the spontaneous activity in the rabbit jejunum and how it affects the inhibitory action of , - and , -adrenoceptor agonists remains unclear. 2 We studied the influence of the cholinergic system and apamin-sensitive Ca2+ -activated K+ channels on spontaneous contractions in the rabbit jejunum and on the inhibitory effects of,1 - and , -adrenoceptor agonists. 3 In naïve tissues, atropine (ATR, 7.4 × 10,8 m) and tetrodotoxin (8 × 10,8 m) almost completely inhibited , to a similar extent , the amplitude of spontaneous activity. Despite the presence of ATR or TDX, tissue contraction gradually recovered to about 50% of the baseline amplitude within 5,10 min. When ATR or TDX, respectively, were added to the TDX- or ATR-treated tissues, the recovered activity decreased weakly but significantly. After washout and a 45-min rest the contraction amplitude returned to baseline values. A further exposure to ATR or TDX reduced the contraction to a level significantly lower than the one obtained after TDX or ATR added 5 min after ATR or TDX, respectively. In preparations prestimulated for 10 min with acetylcholine (ACh), ATR abolished the TDX-resistant recovered spontaneous activity. 4 Adrenaline (ADR, 0.5,5 × 10,7 m) and phenylephrine (PHE, 1,10 × 10,7 m) inhibited tissue motility in naïve and in ATR- and in TDX-exposed preparations. But whereas in naïve preparations the ,1 -adrenoceptor antagonists completely antagonized inhibition induced by both drugs, in ATR- and TDX-exposed tissues they did so only partially for ADR. Agonist-induced inhibition had a rapid onset but rapidly faded; pendular movements took significantly longer to recover in ATR- and TDX-treated tissues than in naïve tissues. In tissues exposed for 2 min to ADR (0.5,5 × 10,7 m) or PHE (1,10 × 10,7 m), washout or addition of ,1 -adrenoceptor antagonists caused an immediate short-lasting increase in contraction amplitude. 5 Apamin (APAM, 5 × 10,9 m) caused a rapid and persistent increase in the amplitude of contractions. It also blocked the inhibitory responses to ADR and PHE, and removed washout-induced contractions. The APAM-induced increase in the contraction amplitude correlated with the increase obtained by washing out ADR or PHE. 6 Isoprenaline (at concentrations up to 2.8 × 10,7 m) produced no inhibitory response in naïve tissues, but it invariably blocked (at a concentration of 0.7 × 10,7 m) the recovered spontaneous activity (and sometimes depressed muscletone) in tissues exposed to ATR or TDX. Neither propranolol (3.4 × 10,7 m) nor APAM (5 × 10,9 m) counteracted these inhibitory effects. 7 These results indicate that spontaneous motility in the rabbit jejunum is predominantly mediated by neuronal release of ACh and by some other unidentified neuronal activity. Released ACh inhibits myogenic activity and strongly antagonizes , -adrenoceptor-induced APAM-insensitive inhibition but leaves ,1 agonist-induced APAM-sensitive inhibition unchanged. [source] Polymorphisms in the ,1A -adrenoceptor gene do not modify the short- and long-term efficacy of ,1 -adrenoceptor antagonists in the treatment of benign prostatic hyperplasiaBJU INTERNATIONAL, Issue 4 2006CHAIDIR A. MOCHTAR OBJECTIVE To determine whether a common single nucleotide polymorphism (SNP) in the ADRA1A gene encoding the ,1A -adrenoceptor modifies the short- and long-term efficacy of ,1 -adrenoceptor antagonists in the treatment of benign prostatic hyperplasia (BPH). PATIENTS AND METHODS For 254 patients with BPH and/or lower urinary tract symptoms who received ,1 -adrenergic antagonists for ,,3 months, the ADRA1A genotype at position 1475 of the coding region was determined. The patients' short-term response to treatment was determined for four outcome measures, i.e. the International Prostate Symptom Score (IPSS), the IPSS quality-of-life score, peak urinary flow rate, and obstruction grade, stratified by genotype. Eventual BPH-related invasive therapy was used as the outcome for assessing the long-term response to treatment. Genetic variants at positions 834, 896, 898 and 1831 were too rare to be considered in the analysis. RESULTS There were no significant differences for the genotype strata in three of the four outcome measures. Patients with the CC genotype responded significantly better in quality-of-life perception than patients with the CT or TT genotype. There were also no significant differences in the risk of BPH-related invasive therapy among the three genotypes. CONCLUSIONS The 1475C,T SNP in the ADRA1A gene does not modify the short- and long-term efficacy of ,1 -adrenoceptor antagonists for treating BPH. There was a small effect on perceived quality of life but this was not reflected in other variables that measured the treatment response more directly. [source] Lower urinary tract symptoms suggestive of benign prostatic hyperplasia: latest update on ,1 -adrenoceptor antagonistsBJU INTERNATIONAL, Issue 1 2006Article first published online: 6 DEC 200 No abstract is available for this article. [source] Ejaculatory dysfunction and ,1 -adrenoceptor antagonistsBJU INTERNATIONAL, Issue 3 2004Michel Martin C. No abstract is available for this article. [source] | |||||||||||||||||||||||||