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Adrenoceptors
Terms modified by Adrenoceptors Selected AbstractsBinding and functional affinity of some newly synthesized phenethylamine and phenoxypropanolamine derivatives for their agonistic activity at recombinant human ,3 -adrenoceptorJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2003Maruf Ahmed ABSTRACT ,3 -Adrenoceptor is the predominant ,-adrenoceptor in adipocytes and has drawn much attention during the investigation for anti-obesity and antidiabetes therapeutics. Thirteen new compounds have been evaluated for their potencies and efficacies as ,3 -adrenoceptor agonists on human ,3 - adrenoceptor expressed in COS-7 and Chinese hamster ovary (CHO) cells using radio ligand binding assay and cyclic AMP (cAMP) accumulation assay. Phenoxypropanolamine derivatives, SWR-0334NA (([E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl] phenoxy]acetic acid sodium salt), SWR-0335SA ((E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl] phenoxy] acetic acid ethanedioic acid), SWR-0342SA (S-(Z)-[4-[[1-[2-[(2-hydroxy,3-phenoxypropyl)]amino]ethyl]-1-pro-penyl]phenoxy] acetic acid ethanedioic acid), SWR-0348SA-SITA ((E)-[4-[5-[(3-phenoxy-2-hydroxy-propyl)amino]-2-hexene,3-yl] phenoxy]acetic acid ethanedioic acid) and SWR-0361SA ((E)-N-methyl-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl]phenoxy]acetoamide ethanedioic acid) showed higher agonistic activity for the ,3 -adrenoceptor. Among the compounds tested, SWR-0334NA exhibited full agonist activity (%Emax = 100.26) despite its lower binding affinity (pK1 = 6.11). Compounds SWR-0338SA((E)-[4-[5-[(2-phenyl-2-hydroxyethyl)amino]-2-pentene,3-yl]phenoxy]acetic acid ethanedioic acid), SWR-0339SA (S-(E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl] phenoxy] acetic acid ethanedioic acid), SWR-0345HA ((E)-2-methyl,3-[4-[2-(2-phenyl-2-hydroxyethyl-amino)ethoxy] phenyl]-2-propenoic acid ethyl ester hydrochloride), SWR-0358SA ((E)-(2-methoxy-ethyl)-[4-[5-[(3-phenoxy-2-hydroxypropyl) amino]-2-pentene,3-yl]phenoxy]acetoamide ethanedioic acid) and SWR-0362SA ((E)-1-[[[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene ,3-yl]phenoxy]-acetyl]carbonyl]piperidine ethanedioic acid) had moderate agonistic activity and were phenethylamine and phenoxypropanolamine derivatives. Compounds SWR-0065HA ([4-[2-[3-[[(3,4-dihydro-4-oxo-[1,2,4]-triazino(4,5-a)indol)-lyl]oxy]-2-hydroxypropylamino]ethoxy]phenyl]acetic acid methyl ester hydrochloride), SWR-0098NA ((E)-[4-[3-[(2-phenyl-2-hydroxyethyl)amino]-1-butenyl] phenoxy]-acetic acid sodium salt) and SWR-0302HA ([4-[[4-[2-(3-chlorophenoxy-2-hydroxypropyl)amino]-E-2-butenyl]oxy]phenoxy]acetic acid hydrochloride) had very low binding affinity towards ,3 -adreno-ceptors and they did not induce cAMP accumulation. We concluded that compounds SWR-0334NA, SWR-0335SA, SWR-0342SA, SWR-0348SA-SITA and SWR-0361SA were potential agonists of human ,3 - adrenoceptor. Further investigation on their selectivity towards ,3 -adrenoceptor could be useful for the exploration of the physiological properties of the ,3 -adrenoceptor. [source] Evidence of ,1 -adrenoceptor functional changes in omental arteries of patients with end-stage renal diseaseAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1 2008M. P. Cruz-Domínguez Summary 1,1 -Adrenoceptor (,1 -AR) subtypes were characterized in isolated omental arteries obtained after abdominal surgery in patients with end-stage renal disease (ESRD) or with Diabetes Mellitus type 2 plus ESRD (ESRD-DM). 2 Omental arteries from patients with ESRD and ESRD-DM elicited a significant increase in sensitivity to phenylephrine with a pD2 (,log EC50) of 6.7 and 6.6, respectively, vs. the control (5.8, P < 0.001). 3 Stimulation with phenylephrine was conducted in the presence or absence of selective ,1 -AR competitive antagonists: 5-methylurapidil (,1A -), AH11110A (1-[biphenyl-2-yloxy]-4-imino-4-piperidin-1-yl-butan-2-ol; ,1B -) and BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4.5] decane-7,9-dione; ,1D -). The relative abundance of mRNA for all three ,1 -ARs was determined. 4 The maximal contractile responses to phenylephrine were: Emax 1.59 ± 0.17, 1.48 ± 0.08 and 1.55 ± 0.14 g for the ESRD, ESRD-DM and control groups, respectively. 5 Functionally, there was an increment in the affinity for the ,1A -AR antagonist (pA2: control 7.45, ESRD 8.36, ESRD-DM 8.0; P < 0.01), and a reduction in the ,1B -AR antagonist affinity (8.3 for controls, 7.6 for ESRD and 7.3 for ESRD-DM; P < 0.01) associated with renal disease. The affinities for the ,1D -AR antagonist were similar among the studied groups (8.5 for the controls, 8.7 for the ESRD and 8.1 for the ESRD-DM groups). 6 Renal disease increased mRNA expression of ,1B -ARs and reduced both ,1A - and ,1D -ARs subtypes in ESRD and ESRD-DM patients. 7 The results suggest that human omental arteries exposed to chronic uraemia show vascular hypersensitivity to phenylephrine, because of functional ,1 -AR changes. [source] SPATIAL AND TEMPORAL ASPECTS OF cAMP SIGNALLING IN CARDIAC MYOCYTESCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 11 2008Radu V Iancu SUMMARY 1,1 -Adrenoceptor and M2 muscarinic receptor regulation of cAMP production plays a pivotal role in autonomic regulation of cardiac myocyte function. However, not all responses are easily explained by a uniform increase or decrease in cAMP activity throughout the entire cell. 2Adenovirus expression of fluorescence resonance energy transfer (FRET)-based biosensors can be used to monitor cAMP activity in protein kinase A (PKA) signalling domains, as well as the bulk cytoplasmic domain of intact adult cardiac myocytes. 3Data obtained using FRET-based biosensors expressed in different cellular microdomains have been used to develop a computational model of compartmentalized cAMP signalling. 4A systems biology approach that uses quantitative computational modelling together with experimental data obtained using FRET-based biosensors has been used to provide evidence for the idea that compartmentation of cAMP signalling is necessary to explain the stimulatory responses to ,1 -adrenoceptor activation as well as the complex temporal responses to M2 muscarinic receptor activation. [source] Ventricular PKC-, and humoral signaling in DOCA-Salt rats treated with labedipinedilol-ADRUG DEVELOPMENT RESEARCH, Issue 3 2003Jwu-Lai Yeh Abstract Effects of oral antihypertensive monotherapy with labedipinedilol-A, labetalol, atenolol, amlodipine, prazosin (20 mg kg,1 day,1), and short-acting nifedipine (3 mg kg,1 day,1) on DOCA-salt-induced translocation of ventricular protein kinase C-,(PKC-,), humoral signaling, and the cardiovascular system were investigated in rats for 4 weeks. The triple blocking activities of labedipinedilol-A (,/,-adrenoceptor blockade and calcium entry blockade) were compared with single blocking activities of selective drugs. Cytosolic PKC-, immunoreactivity was decreased by labedipinedilol-A, short-acting nifedipine, amlodipine, prazosin, labetalol, atenolol, and losartan. Membranous PKC-, immunoreactivity was significantly decreased by labedipinedilol-A, amlodipine, prazosin, labetalol, and atenolol. Labedipinedilol-A and prazosin more potently decreased membranous than cytosolic PKC-, expression. Labedipinedilol-A, labetalol, and atenolol effectively inhibited DOCA-salt-induced increases in angiotensin II (Ang II). All antihypertensive agents reduced endothelin-1 (ET-1) levels in urine and cardiac weight growth. Treatments with labedipinedilol-A, labetalol, atenolol, and amlodipine normalized DOCA-salt-induced ANP increases. Prazosin did not decrease ANP. Short-acting nifedipine elevated ANP. During long-term antihypertensive therapy in DOCA-salt hypertensive rats, single blockade drugs did not fully inhibit ventricular PKC-, translocation or Ang II, ET-1, and ANP humoral signaling. However, triple blockade labedipinedilol-A therapy had a wide range of ,/,-adrenergic receptor and calcium channel inhibitory activities, including diminished reflux tachycardia, inhibition of PKC-, translocation, and reduction of Ang II, ET-1, and ANP formation. Drug Dev. Res. 59:307,315, 2003. 2003 Wiley-Liss, Inc. [source] ,2A and ,2C -adrenoceptor regulation in the brain: ,2A changes persist after chronic stressEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2003G. Flügge Abstract Stress-induced activation of the central nervous noradrenergic system has been suspected to induce depressive disorders. As episodes of depression often occur some time after a stress experience we investigated whether stress-induced changes in the ,2 -adrenoceptor (,2 -AR) system persist throughout a post-stress recovery period. Brains of male tree shrews were analysed after 44 days of chronic psychosocial stress and after a subsequent 10-day recovery period. Expression of RNA for ,2A and ,2C -adrenoceptors was quantified by in situ hybridization, and receptor binding was determined by in vitro receptor autoradiography. Activities of the sympathetic nervous system and of the hypothalamo,pituitary,adrenal axis were increased during chronic stress but normalized during recovery. ,2A -AR RNA in the glutamatergic neurons of the lateral reticular nucleus was elevated significantly after stress and after recovery (by 29% and 17%). In the dorsal motor nucleus of the vagus, subtype A expression was enhanced after recovery (by 33%). In the locus coeruleus, subtype A autoreceptor expression was not changed significantly. Subtype C expression in the caudate nucleus and putamen was elevated by stress (by 5 and 4%, respectively) but normalized during recovery. Quantification of 3H-RX821002 binding revealed receptor upregulation during stress and/or recovery. Our data therefore show: (i) that chronic psychosocial stress differentially regulates expression of ,2 -adrenoceptor subtypes A and C; (ii) that subtype A heteroreceptor expression is persistently upregulated whereas (iii), subtype C upregulation is only transient. The present findings coincide with post mortem studies in depressed patients revealing upregulation of ,2A -ARs. [source] The otic ganglion in rats and its parotid connection: cholinergic pathways, reflex secretion and a secretory role for the facial nerveEXPERIMENTAL PHYSIOLOGY, Issue 1 2006Nina Khosravani Otic ganglionectomy in rats was found to have affected the parotid gland more profoundly than section of the auriculotemporal nerve as assesssed by reduction in gland weight (by 33 versus 20%) and total acetylcholine synthesizing capacity (by 88 versus 76%) 1 week postoperatively and, when assessed on the day of surgery under adrenoceptor blockade, by reflex secretion (by 99 versus 88%). The facial nerve contributed to the acetylcholine synthesizing capacity of the gland. Section of the nerve only, at the level of the stylomastoid foramen, reduced the acetylcholine synthesis by 15% and, combined with otic ganglionectomy, by 98% or, combined with section of the auriculotemporal nerve, by 82%. The facial nerve was secretory to the gland, and the response was of a cholinergic nature. The nerve conveyed reflex secretion of saliva and caused secretion of saliva upon stimulation. Most of the facial secretory nerve fibres originated from the otic ganglion, since after otic ganglionectomy (and allowing for nerve degeneration) the secretory response to facial nerve stimulation was markedly reduced (from 23 to 4 ,l (5 min),1). The persisting secetory response after otic ganglionectomy, exaggerated due to sensitization, and the residual acetylcholine synthesizing capacity (mainly depending on the facial nerve) showed that a minor proportion of pre- and postganglionic nerve fibres relay outside the otic ganglion. The great auricular nerve, which like the facial nerve penetrates the gland, caused no secretion of saliva upon stimulation. Avulsion of the auriculotemporal nerve was more effective than otic ganglionectomy in reducing the acetylcholine synthesizing capacity (by 94 versus 88%) and as effective as otic ganglionectomy in abolishing reflex secretion (by 99%). When aiming at parasympathetic denervation, avulsion may be the preferable choice, since it is technically easier to perform than otic ganglionectomy. [source] Nitric oxide-dependent protein synthesis in parotid and submandibular glands of anaesthetized rats upon sympathetic stimulation or isoprenaline administrationEXPERIMENTAL PHYSIOLOGY, Issue 2 2004Shariel Sayardoust In anaesthetized female rats, the ,-adrenoceptor agonist isoprenaline was intravenously infused (20 ,g kg,1 min,1) for 30 min or the ascending cervical sympathetic nerve trunk was intermittently stimulated (50 Hz, 1 s every tenth second) on one side for 30 min. The incorporation of [3H]leucine into trichloroacetic acid (TCA)-insoluble material was used as an index of protein synthesis. In response to isoprenaline, the [3H]leucine incorporation increased by 79% in the parotid glands and by 82% in the submandibular glands. The neuronal type NO-synthase inhibitor N-PLA, reduced (P < 0.001) this response to 26% and 20%, respectively. Sympathetic stimulation under ,-adrenoceptor blockade increased the [3H]leucine incorporation by 192% in the parotid glands and by 35% in the submandibular glands. N-PLA reduced the corresponding percentage figures to 86% (P < 0.01) and 8% (P < 0.05). When tested in the parotid glands, the non-selective NO-synthase inhibitor L -NAME reduced (P < 0.01) the nerve-evoked response to 91%. The increase in [3H]leucine incorporation in response to sympathetic stimulation under ,-adrenoceptor blockade was not affected by N-PLA in the parotid (139%versus 144%) and submandibular glands (39%versus 34%). In non-stimulated glands, the [3H]leucine incorporation was not influenced by the NO-synthase inhibitors. In conclusion, ,-adrenoceptor mediated salivary gland protein synthesis is largely dependent on NO generation by neuronal type NO-synthase, most likely of parenchymal origin. [source] Synthesis of (R)- and (S)-[O-methyl - 11C]N -[2-[3-(2-cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]- N,-(4-methoxy-phenyl)-urea as candidate high affinity ,1 -adrenoceptor PET radioligandsJOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 10 2005Stefan Wagner Abstract Molecular imaging and quantification of myocardial ,1 -adrenoceptor (AR) rather than total , -AR density is of great clinical interest since cardiac biopsy studies suggest that myocardial ,1 -AR density is reduced in patients with chronic heart failure whereas cardiac ,2 -AR density may vary. Positron emission tomography (PET), with appropriate radioligands, offers the possibility to assess , -AR density non-invasively in humans. However, no PET radioligand for the selective imaging of cardiac ,1 -ARs is clinically available. Here some derivatives of the well characterized ,1 -AR selective antagonist, ICI 89,406, namely the enantiomers of N -[2-[3-(2-cyano-phenoxy)-2-hydroxy-propylamino]-ethyl]- N,-(4-hydroxy-phenyl)-urea (5a and 5b) were synthesized and evaluated in vitro. The (R)-isomer 5a was more ,1 -selective but has lower affinity than its (S)-enantiomer 5b (,1 -AR selectivity: 6100 vs 1240; ,1 -affinity: K1 = 0.288 nM vs K1 = 0.067 nM). Etherification of the analogous desmethyl precursors, 5e and 5f, respectively, with [11C]iodomethane gave 11C-labelled versions of 5a and 5b, namely 5g and 5h, in 44 ± 5% radiochemical yield (decay-corrected) and 97.4 ± 1.3% radiochemical purity with specific radioactivities of 26.4 ± 9.4 GBq/µmol within 41.2 ± 3.4 min from the end of bombardment (n = 14). 5g and 5h are now being evaluated as candidate radioligands for myocardial ,1 -ARs. Copyright © 2005 John Wiley & Sons, Ltd. [source] Cardiovascular Actions of Orexin-A in the Rat Subfornical OrganJOURNAL OF NEUROENDOCRINOLOGY, Issue 1 2007P. M. Smith Orexin-A is a neuropeptide, primarily produced in the lateral hypothalamic/perifornical hypothalamus. Orexin receptors and immunoreactive neuronal fibres are widely distributed throughout the brain, suggesting integrative neurotransmitter roles in a variety of physiological systems. Intracerebroventricular injections of orexin-A increase blood pressure and stimulate drinking, and the subfornical organ (SFO), a circumventricular structure implicated in autonomic control, is a potential site at which orexin may act to exert these effects. We have therefore used microinjection techniques to examine the effects of orexin-A administered directly into the SFO on blood pressure and heart rate in urethane anaesthetised male Sprague-Dawley rats. Orexin-A microinjection (50 fmol) into the SFO caused site-specific decreases in blood pressure (SFO: mean area under curve (AUC) = ,681.7 ± 46.8 mmHg*s, n = 22 versus non-SFO: 63.68 ± 54.69 mmHg*s, n = 15, P < 0.001), and heart rate (SFO: mean AUC = ,26.7 ± 2.8 beats, n = 22, versus non-SFO: mean AUC = 1.62 ± 2.1 beats, n = 15, P < 0.001). Vagotomy did not alter the hypotensive or bradycardic responses elicited by orexin-A microinjection. Prior ,-adrenoceptor blockade with phenoxybenzamine (1 mg/kg, i.v.) masked the orexin-A induced blood pressure (mean AUC = ,122.6 ± 17.6 mmHg*s, n = 4, P < 0.01 paired t-test) and heart rate (mean AUC = ,6.7 ± 1.7 beats, n = 4, P < 0.05, paired test) response. The orexin-A induced heart rate response was attenuated when ,-adrenoceptors were blocked with propranolol (1 mg/kg, i.v.; mean AUC = 0.6 ± 2.8 beats, n = 5, P < 0.01 paired t-test). These studies demonstrate that microinjection of orexin-A into the SFO causes site specific decreases in blood pressure and heart rate which is mediated by a reduction in sympathetic tone. [source] Long-Term Modulation By Postnatal Oxytocin of the ,2 -Adrenoceptor Agonist Binding Sites in Central Autonomic Regions and the Role of Prenatal StressJOURNAL OF NEUROENDOCRINOLOGY, Issue 3 2004Z. Díaz-Cabiale Abstract The aim of this work was to evaluate whether oxytocin administered in male rats subcutaneously early in life in the absence or presence of food restriction during pregnancy has life-long effects on the ,2 -agonist binding sites in the nucleus of the solitarii tract (NTS), in the hypothalamus and the amygdala, as evaluated by quantitative receptor autoradiography. Maternal food restriction alone increased the affinity of the ,2 -agonist [3H]UK14.304 binding sites exclusively in the NTS. In offspring from ad libitum fed dams, oxytocin treatment significantly increased the density of ,2 -agonist binding sites in the NTS and in the hypothalamus. The Kd value of the ,2 -agonist binding sites in the hypothalamus of these rats, but not in the other regions studied, was also significantly increased. In offspring from food-restricted dams, oxytocin treatment produced a significant increase of the Bmax values in the hypothalamus and the amygdala and the Kd value of the ,2 -agonist binding sites in the NTS of these rats also was selectively and significantly increased. These results suggest that a postnatal, oxytocin-induced increase of regional ,2 -adrenoceptor function can be seen in adulthood by a persistent, regionally selective increase in the density of central ,2 -adrenoceptor agonist binding sites, in the absence of an affinity change in the NTS. Such a regional increase of ,2 -adrenoceptor signalling in adulthood may contribute to the anti-stress action of postnatal oxytocin. By contrast, after prenatal stress, the potential increase in ,2 -adrenoceptor signalling takes place via selective increases of density with no changes of affinity of the ,2 -agonist binding sites in the hypothalamus and the amygdala. [source] Binding and functional affinity of some newly synthesized phenethylamine and phenoxypropanolamine derivatives for their agonistic activity at recombinant human ,3 -adrenoceptorJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2003Maruf Ahmed ABSTRACT ,3 -Adrenoceptor is the predominant ,-adrenoceptor in adipocytes and has drawn much attention during the investigation for anti-obesity and antidiabetes therapeutics. Thirteen new compounds have been evaluated for their potencies and efficacies as ,3 -adrenoceptor agonists on human ,3 - adrenoceptor expressed in COS-7 and Chinese hamster ovary (CHO) cells using radio ligand binding assay and cyclic AMP (cAMP) accumulation assay. Phenoxypropanolamine derivatives, SWR-0334NA (([E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl] phenoxy]acetic acid sodium salt), SWR-0335SA ((E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl] phenoxy] acetic acid ethanedioic acid), SWR-0342SA (S-(Z)-[4-[[1-[2-[(2-hydroxy,3-phenoxypropyl)]amino]ethyl]-1-pro-penyl]phenoxy] acetic acid ethanedioic acid), SWR-0348SA-SITA ((E)-[4-[5-[(3-phenoxy-2-hydroxy-propyl)amino]-2-hexene,3-yl] phenoxy]acetic acid ethanedioic acid) and SWR-0361SA ((E)-N-methyl-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl]phenoxy]acetoamide ethanedioic acid) showed higher agonistic activity for the ,3 -adrenoceptor. Among the compounds tested, SWR-0334NA exhibited full agonist activity (%Emax = 100.26) despite its lower binding affinity (pK1 = 6.11). Compounds SWR-0338SA((E)-[4-[5-[(2-phenyl-2-hydroxyethyl)amino]-2-pentene,3-yl]phenoxy]acetic acid ethanedioic acid), SWR-0339SA (S-(E)-[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene,3-yl] phenoxy] acetic acid ethanedioic acid), SWR-0345HA ((E)-2-methyl,3-[4-[2-(2-phenyl-2-hydroxyethyl-amino)ethoxy] phenyl]-2-propenoic acid ethyl ester hydrochloride), SWR-0358SA ((E)-(2-methoxy-ethyl)-[4-[5-[(3-phenoxy-2-hydroxypropyl) amino]-2-pentene,3-yl]phenoxy]acetoamide ethanedioic acid) and SWR-0362SA ((E)-1-[[[4-[5-[(3-phenoxy-2-hydroxypropyl)amino]-2-pentene ,3-yl]phenoxy]-acetyl]carbonyl]piperidine ethanedioic acid) had moderate agonistic activity and were phenethylamine and phenoxypropanolamine derivatives. Compounds SWR-0065HA ([4-[2-[3-[[(3,4-dihydro-4-oxo-[1,2,4]-triazino(4,5-a)indol)-lyl]oxy]-2-hydroxypropylamino]ethoxy]phenyl]acetic acid methyl ester hydrochloride), SWR-0098NA ((E)-[4-[3-[(2-phenyl-2-hydroxyethyl)amino]-1-butenyl] phenoxy]-acetic acid sodium salt) and SWR-0302HA ([4-[[4-[2-(3-chlorophenoxy-2-hydroxypropyl)amino]-E-2-butenyl]oxy]phenoxy]acetic acid hydrochloride) had very low binding affinity towards ,3 -adreno-ceptors and they did not induce cAMP accumulation. We concluded that compounds SWR-0334NA, SWR-0335SA, SWR-0342SA, SWR-0348SA-SITA and SWR-0361SA were potential agonists of human ,3 - adrenoceptor. Further investigation on their selectivity towards ,3 -adrenoceptor could be useful for the exploration of the physiological properties of the ,3 -adrenoceptor. [source] Effect of Repeated Doses of Ethanol on Hepatic Mg2+ Homeostasis and MobilizationALCOHOLISM, Issue 7 2007Andrew Young The acute administration of a first dose of ethanol (EtOH) to rat liver cells reduces the amount of Mg2+ extruded by a second dose of EtOH or the subsequent addition of adrenergic agonists. In contrast, the Mg2+ extrusion normally elicited by the ,1 -adrenergic or , -adrenergic agonist does not impair the Mg2+ mobilization induced by the subsequent addition of EtOH. Inhibition of EtOH metabolism by 4-methylpyrazole abolishes almost completely the Mg2+ extrusion induced by the first dose of EtOH, and partially enlarges that elicited by the second dose of alcohol or the subsequent adrenergic stimulation. Ethanol-treated liver cells stimulated by the adrenergic agonist show a reduced level of membrane-bound G,s as well as a reduced cellular cAMP content. Analysis of cellular Mg2+ distribution indicates that EtOH administration decreases the Mg2+ content of the cytoplasm, mitochondria, and endoplasmic reticulum to a comparable extent. These data indicate that acute EtOH administration directly impairs cellular Mg2+ homeostasis and also prevents a further Mg2+ mobilization by additional doses of alcohol or ,1 -adrenoceptor and , -adrenoceptor agonist by decreasing cytosolic and intraorganelle Mg2+ content and by affecting G-protein membrane distribution/signaling. [source] ,3 -Adrenoceptors in urinary bladder,,NEUROUROLOGY AND URODYNAMICS, Issue 6 2007Osamu Yamaguchi Abstract The ,-adrenoceptor (AR) is currently classified into ,1, ,2, and ,3 subtypes. A third subtype, ,3 -AR, was first identified in adipose tissue, but has also been identified in smooth muscle tissue, particularly in the gastrointestinal tract and urinary bladder smooth muscle. There is a predominant expression of ,3 -AR messenger RNA (mRNA) in human bladder, with 97% of total ,-AR mRNA being represented by the ,3 -AR subtype and only 1.5 and 1.4% by the ,1 -AR and , 2 -AR subtypes, respectively. Moreover, the presence of ,1 -, ,2 -, and ,3 -AR mRNAs in the urothelium of human bladder has been identified. The distribution of ,-AR subtypes mediating detrusor muscle relaxation is species dependent, the predominant subtype being the ,3 -AR in humans. Recent studies have suggested that cAMP-dependent routes are not exclusive mechanisms triggering the ,-AR-mediated relaxation of smooth muscle. It has been demonstrated in rats detrusor muscle that cAMP plays a greater role in ,-adrenergic relaxation against basal tone than against KCl-induced tone and that conversely calcium-activated K+ channels (BKca channels) play a greater role under the latter circumstances. In rat models, ,3 -AR agonists increase bladder capacity without influencing bladder contraction and have only weak cardiovascular side effects. Although this evidence points toward the clinical utility of ,3 -AR agonists as therapy for overactive bladder (OAB), pharmacological differences exist between rat and human ,3 -ARs. Development of compounds with high selectivity for the human ,3 -AR, identified by screening techniques using cell lines transfected with the human ,1 -, ,2 -, and ,3 -AR genes, may mitigate against such problems. The association between the tryptophan 64 arginine polymorphism in the ,3 -AR gene and idiopathic OAB is discussed. Neurourol. Urodynam. 26:752,756, 2007. © 2007 Wiley-Liss, Inc. [source] Norepinephrine transporter and ,2c adrenoceptor allelic variants and personality factors,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 6 2002Shih-Jen Tsai Abstract It has been suggested that reward dependence, as measured by the Tridimensional Personality Questionnaire (TPQ), is related to central noradrenergic activity, a proposition supported by two studies of urinary norepinephrine metabolite. In the current investigation, 190 normal young Han Chinese were examined, with genetic polymorphisms determined for the norepinephrine transporter (1287G/A) and the ,2c -adrenoceptor (Del322,325) to test the association with TPQ personality traits. No significant association was demonstrated for these two polymorphisms and any of the TPQ personality-factor scores, including reward dependence and its subscales. Our negative findings suggest that the investigated polymorphisms of the norepinephrine transporter and the ,2c adrenoceptor do not play a major role in the reward-dependence personality trait as assessed by TPQ. © 2002 Wiley-Liss, Inc. [source] cGMP-enhancing- and ,1A/,1D -adrenoceptor blockade-derived inhibition of Rho-kinase by KMUP-1 provides optimal prostate relaxation and epithelial cell anti-proliferation efficacyTHE PROSTATE, Issue 13 2007Chi-Ming Liu Abstract Background Soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) and Rho kinase (ROCK2) pathways are important in the regulation of prostate smooth muscle tone. This study is aimed to examine the relaxation activities of a sGC activator and PDE5A/ROCK2 inhibitor KMUP-1 in rat prostate and associated anti-proliferation activity in human prostatic epithelial cells. Methods The action characteristics of KMUP-1 were identified by isometric tension measurement, receptor binding assay, Western blotting and radioimmunoassay in rat prostate. Anti-proliferation activity of KMUP-1 in human prostatic epithelial PZ-HPV-7 cells was identified using flow cytometry and real time QRT-PCR. Results KMUP-1 inhibited phenylephrine-induced contractility in a concentration-dependent manner. KMUP-1 possessed potent ,1A/,1D -adrenoceptor binding inhibition activity, increased cAMP/cGMP levels and increased the expression of sGC, PKG, and PKA protein in rat prostate. Moreover, KMUP-1 inhibited phenylephrine-induced ROCK2 expression. KMUP-1 inhibited cell growth, arrested the cell cycle at G0/G1 phase and increased the expression of p21 in PZ-HPV-7 cells. Conclusions These results broaden our knowledge of sGC/cGMP/PKG and ROCK2 regulation on the relaxation and proliferation of prostate, which may help in the design of benign prostate hyperplasia (BPH) therapies that target these signaling pathways. KMUP-1 possesses the potential benefit in the treatment of BPH by its ,1A/,1D -adrenoceptor blockade, sGC activation, inhibition of PDE5A and ROCK2 and p21 protein enhancement, leading to attenuation of the smooth muscle tone and the proliferation of epithelial PZ-HPV-7 cells. The synergistic contribution of these pathways by KMUP-1 may benefit BPH patients with lower urinary tract symptoms. Prostate 67: 1397,1410, 2007. © 2007 Wiley-Liss, Inc. [source] Unresponsive asystolic cardiac arrest responding to external cardiac pacing in a patient with phaeochromocytomaANAESTHESIA, Issue 8 2007M. J. Taylor Summary An anaesthetised 48-year-old woman became haemodynamically unstable following biopsy of a thoracic mass suggesting a diagnosis of a thoracic phaeochromocytoma. Surgery was postponed to allow confirmatory investigations and pre-operative adrenoceptor blockade with phenoxybenzamine and labetalol. Nine days later, following resection of her phaeochromocytoma, she suffered an intra-operative asystolic cardiac arrest which was unresponsive to standard resuscitation protocols and required external cardiac pacing. We discuss the issues involved and suggest that the competitive ,1 adrenoceptor antagonist doxazosin may be preferable to the covalently bound mixed alpha adrenoceptor antagonist phenoxybenzamine in the pre-operative preparation of patients with phaeochromocytoma. [source] Effect of inhibitors of mitogen-activated protein kinase kinase on ,1B -adrenoceptor phosphorylationAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 1-2 2009R. Alcántara-Hernández Summary 1,Mitogen-activated protein kinases mediate hormone/neurotransmitter action on proliferation and differentiation and participate in receptor regulation. The effect of inhibitors of mitogen-activated kinase kinase (MEK) on ,1B -adrenoceptor phosphorylation state and function was studied using different cell lines. It was observed that at nanomolar concentrations the MEK inhibitors, PD98059 (2,-amino-3,-methoxyflavone) and UO126 [1,4-(diamino-2,3-dicyano/1,4-bis-(2-aminophenylthio)-butadiene], increased ,1B -adrenoceptor phosphorylation and diminished the functional response of this receptor to noradrenaline. These agents did not alter the action of lysophosphatidic acid. 2,Staurosporine (IC50 , 0.8 nm) (a general protein kinase inhibitor) and bis-indolyl-maleimide I (IC50 , 200 nm) (a selective protein kinase C inhibitor) inhibited PD98059-induced ,1B -adrenoceptor phosphorylation. In contrast, neither wortmannin (phosphoinositide 3-kinase inhibitor) nor genistein (protein tyrosine kinase inhibitor) had any effect. The data suggest the possibility that MEK might exert control on the activity of the enzymes that regulate receptor phosphorylation, such as G-protein-coupled receptor kinases, protein kinase C or serine/threonine protein phosphatases. 3,Coimmunoprecipitation studies showed a constant association of total extracellular signal-regulated kinase 2 (ERK2) with ,1B -adrenoceptors. Association of phospho-ERK 1/2 to ,1B -adrenoceptors increased not only in response to agonist but also in response to agents that increase ,1B -adrenoceptor and ERK1/2 phosphorylation [such as endothelin-1, phorbol 12-myristate-13-acetate (PMA) and epidermal growth factor (EGF)]; not surprisingly, PD98059 decreased this effect. 4,Our data show that blockade of MEK activity results in increased ,1B -adrenoceptor phosphorylation, diminished adrenoceptor function and perturbation of receptor,ERK1/2 interaction. [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] Alpha1A/L -adrenoceptors mediate contraction of the circular smooth muscle of the pig urethraAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2006K. Bagot Summary 1 Sympathetically mediated urethral tone is essential for the maintenance of continence and involves the activation of postjunctional ,1 -adrenoceptors. This study characterizes the ,1 -adrenoceptor subtypes responsible for mediating contraction of the urethral circular smooth muscle of the pig. 2 The potency order of a number of agonists and the affinities of several receptor selective antagonists were determined on pig-isolated circular smooth muscle strips in the presence of cocaine (1 ,m) and corticosterone (10 ,m) to inhibit amine uptake and propranolol (1 ,m) to antagonize , -adrenoceptors. 3 The potency order for agonists was N -[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulphonamide (A61603) > noradrenaline = phenylephrine = M6434 > methoxamine with pEC50 values of 7.3, 5.8, 5.7, 5.6 and 5.0 respectively. 4 The ,1D -adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione (BMY7378) caused rightward shifts of the concentration,response curves to noradrenaline, yielding a low affinity estimate (6.6) for the urethral receptor. The ,1A -adrenoceptor-selective antagonists, RS100329 and 5-methylurapidil, gave relatively high affinity estimates (9.6 and 8.8 respectively) for this receptor. All three antagonists produced Schild plots with slopes close to unity but did reduce maximum responses at higher concentrations. Prazosin antagonized responses of the urethra to noradrenaline, yielding a mean affinity estimate of 9.0. Although the Schild plot for prazosin again had a slope of unity, this drug also reduced maximum responses to noradrenaline at all concentrations examined (10,100 nm). N -[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro- ,,, -dimethyl-1H-indole-3-ethanamide (RS17053), which discriminates between responses mediated via ,1A (high affinity) and ,1L -adrenoceptors (low affinity) at concentrations up to 3 ,m, failed to antagonize responses of the urethra. 5 These results suggest that contraction of urethral circular smooth muscle in the pig is mediated via a single population of adrenoceptors with the pharmacological characteristics of the ,1A/L -adrenoceptor, most probably the ,1L -adrenoceptor. [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] Evidence showing that ,-adrenoceptor subtype responsible for the relaxation induced by isoprenaline is principally ,2 but not ,1 in guinea-pig tracheal smooth muscleAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 2 2004Y. Tanaka Summary 1 The present study was carried out to pharmacologically identify the ,-adrenoceptor subtype that mediates isoprenaline-elicited relaxation in the isolated guinea-pig tracheal smooth muscle, to answer the question whether it is ,1 - or ,2 -subtype? 2 Isoprenaline as well as salbutamol, a well-known ,2 -selective adrenoceptor agonist, produced a concentration-dependent relaxation with a pD2 value of 8.12 vs. 7.54 for salbutamol. 3 Isoprenaline-elicited relaxation was not affected by ,1 -selective antagonists, atenolol and CGP-20,712A, within the concentration ranges supposed to antagonize ,1 -subtype: atenolol, ,10,6 m; CGP-20,712A, ,10,8 m. 4 By contrast, the concentration,response curves for isoprenaline as well as salbutamol were shifted rightwards in a competitive fashion by atenolol at the concentrations ,3 × 10,6 m. However, pA2 values of atenolol against isoprenaline (5.86) and salbutamol (5.71) were consistent with the value corresponding to ,2 - but not to ,1 -subtype (around 7.00), and these values were not significantly different from each other. 5 Competitive antagonism of the relaxations to isoprenaline and salbutamol were also obtained with ,2 -selective antagonists, butoxamine and ICI-118,551. Against isoprenaline and salbutamol, the pA2 values of butoxamine (6.51 vs. 6.81) and ICI-118,551 (8.83 vs. 8.90) were substantially identical. Thus the primary mediation of ,2 -receptor in the relaxations was strongly supported. 6 The present findings provide evidence that the ,-adrenoceptor which mediates isoprenaline-elicited relaxation of guinea-pig tracheal smooth muscle is essentially ,2 - but not ,1 -subtype. The present study also indicates the importance of using multiple receptor antagonists with different pA2 values to pharmacologically identify the responsible receptor subtype in smooth muscle mechanical responses. [source] The functional ,-adrenoceptor in dog caudal vesical arteries is mainly an ,1A subtypeAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 5-6 2002M. Nakazawa Summary 1 The present study attempted to pharmacologically characterize the subtypes of ,-adrenoceptors mediating the vasoconstriction in the isolated and perfused canine vesical artery. 2 Noradrenaline (NA) and phenylephrine (PE, an ,1 -adrenoceptor agonist) induced a dose-dependent vasoconstriction, whereas xylazine (an ,2 -agonist) did not induce any clear vascular constrictor response. 3 Prazosin at 0.01 ,m and rauwolscine at 0.1 ,m failed to affect the NA-induced vasoconstriction. Prazosin at 0.1 ,m antagonized the vasoconstrictor responses to NA, with pKB value of 7.8. 4 WB 4101 at 0.01,0.1 ,m dose-dependently inhibited the responses to NA, with a pKB value of 8.9. The vasoconstrictor responses to NA were not significantly affected by chloroethylclonidine (10,30 ,m) or BMY 7378 (0.1 ,m). 5 The present results indicate that the canine vesical arteries dominantly contain ,1 -adrenoceptors but have no ,2 -adrenoceptors, and the functional subtype of ,1 -adrenoceptor is characterized as an ,1A -adrenoceptor subtype. [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] Urodynamic evaluation of fesoterodine metabolite, doxazosin and their combination in a rat model of partial urethral obstructionBJU INTERNATIONAL, Issue 2 2010Claudius Füllhase OBJECTIVE To evaluate the urodynamic effects of fesoterodine, a new antimuscarinic agent, alone and combined with doxazosin, in a rat model of partial urethral obstruction (PUO), as 35,83% of men with bladder outlet obstruction (BOO) secondary to benign prostatic hyperplasia (BPH) have overactive bladder (OAB) syndrome, and as the combination of ,1 -adrenoceptor- and muscarinic-receptor antagonists has been proposed to be beneficial for these patients. MATERIALS AND METHODS Thirty-seven male Sprague-Dawley rats (250 g) had surgically induced PUO; 2 weeks later they were evaluated by cystometry with no anaesthesia or any restraint. After a 1-h period either 5-hydroxymethyl tolterodine (5-HMT, the active metabolite of fesoterodine, previously known as SPM 7605), doxazosin or a combination of both, was given intravenously (0.1 mg/kg body weight), and cystometry was continued for another 45 min. Fifteen healthy, age-matched rats served as a control. RESULTS At 2 weeks after surgery the obstructed rats had an greater bladder weight, threshold pressure (TP) and micturition frequency (MF), and lower bladder capacity (BCap) and micturition volume (MV) than the controls. 5-HMT did not cause urinary retention in obstructed rats, but decreased TP, maximum pressure (MP), spontaneous bladder activity (SA) and, paradoxically, increased MF. Doxazosin alone decreased TP, MP, MF and increased BCap and MV. 5-HMT and doxazosin together did not depress the ability to empty the bladder, and showed decreased TP, MP and SA. CONCLUSIONS 5-HMT, alone and in combination, did not impair the voiding ability in obstructed rats. Doxazosin counteracted some of the ,negative' effects of 5-HMT in this model (increase of MF) and did not attenuate the ,positive' effects (decrease of bladder SA). In this model, the combination of 5-HMT and doxazosin appeared to be urodynamically safe and well tolerated. [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] Comparison of tamsulosin and naftopidil for efficacy and safety in the treatment of benign prostatic hyperplasia: a randomized controlled trialBJU INTERNATIONAL, Issue 4 2005Momokazu Gotoh OBJECTIVES To compare the efficacy and safety of two ,1a/,1d adrenoceptor (AR) antagonists with different affinity for the ,1AR subtypes, tamsulosin and naftopidil, in the treatment of benign prostatic hyperplasia (BPH). PATIENTS AND METHODS Patients with BPH were randomized to receive either tamsulosin or naftopidil. The primary efficacy variables were the changes in the total International Prostate Symptom Score (IPSS), maximum flow rate on free uroflowmetry, and residual urine volume. The secondary efficacy variables were average flow rate, changes in the IPSS storage score, IPSS voiding score, and quality-of-life (QoL) Index score, from baseline to endpoint (12 weeks). Data on all randomized patients were included in the safety analyses for adverse effects and changes in blood pressure. RESULTS Of the 185 patients enrolled data for 144 who were eligible for inclusion in the efficacy analysis were analysed (75 from the tamsulosin and 69 from the naftopidil group). There was no significant difference in any variable at baseline between the groups. There were satistically significant improvements for all primary and secondary variables in both groups, except for residual urine in the tamsulosin group. However, there was no significant intergroup difference in the improvement of any efficacy variable between the groups. The adverse effects were comparable, with no significant differences in systolic and diastolic blood pressure after treatment in both groups. CONCLUSIONS This study suggests that naftopidil is as effective and safe as tamsulosin. Both drugs were effective in improving storage and voiding symptoms. However, there was no difference in clinical efficacy or adverse effects between the ,1 AR antagonists with different affinity to ,1 subtypes, ,1a and ,1d. [source] Treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia in relation to the patient's risk profile for progressionBJU INTERNATIONAL, Issue 2005John Trachtenberg SUMMARY Lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) is a slowly progressing disease, with some patients progressing more rapidly than others. In 80% of patients who progress this is caused by the worsening of symptoms. The physician can predict the risk of progression from the patient's clinical profile; increased symptom severity, a poor maximum urinary flow rate (Qmax), and a high postvoid residual urine volume (PVR), are major risk factors for overall clinical progression of LUTS/BPH. A large baseline prostate volume and a high serum prostate-specific antigen (PSA) level are the predominant risk factors for developing acute urinary retention. After predicting risk, the most appropriate treatment should be established by balancing the benefits of treatment against the possible risks and bother resulting from adverse events. From the Medical Therapy Of Prostatic Symptoms study it can be concluded that monotherapy with an ,1 -adrenoceptor (AR) antagonist is an appropriate treatment for many patients with LUTS/BPH. However, for those at high risk of progression (those with a large prostate volume and high PSA level), it appears more appropriate to add a 5,-reductase inhibitor to the ,1 -AR antagonist to obtain maximum relief of symptoms, and ideally to halt the progression of the disease. This was confirmed by the RAND Appropriateness Method study, in which 12 urologists determined the most appropriate treatment for patients with LUTS/BPH based on their clinical profile, combination of clinical variables and/or risk factors. This study also indicates that patients at very high risk of progression, with severe obstruction (poor Qmax and high PVR), are potential candidates for immediate surgery. [source] Antagonism of long-acting ,2 -adrenoceptor agonismBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2002Brian J. Lipworth The established place of regular long-acting ,2 -adrenoceptor agonists at step 3 in asthma management guidelines has evolved as a consequence of evidence showing additive effects of salmeterol and formoterol on exacerbation rates, resulting in a putative inhaled corticosteroid sparing effect. There is however, evidence to show that although long-acting ,2 -adrenoceptor agonists facilitate using a lower dose of inhaled corticosteroid, this may occur at the expense of suboptimal anti-inflammatory control. This is likely to be the case especially with fixed dose combination inhalers where it is not possible to properly titrate anti-inflammatory therapy with inhaled corticosteroids without also inadvertently overtreating with unnecessarily high doses of long-acting ,2 -adrenoceptor agonists. Most patients with mild to moderate persistent asthma can be adequately controlled on monotherapy with inhaled corticosteroid in low or medium dosage, which is considerably cheaper than concomitant ,,use ,,of ,,a ,,long-acting ,,,2 -adrenoceptor ,,agonist. ,,Subsensitivity ,,to ,,long-acting ,2 -adrenoceptor ,agonists ,is ,a ,predictable ,pharmacological ,phenomenon, which occurs despite concomitant inhaled corticosteroid therapy and occurs more readily for bronchoprotective ,than ,bronchodilator ,effects. ,Subsensitivity ,of ,salbutamol, protection against bronchoconstrictor stimuli occurs in patients receiving concomitant long-acting ,2 -adrenoceptor agonists, which may be due to ,2 -adrenoceptor down-regulation or prolonged receptor occupancy. Prospective large scale long-term studies are required to further define the clinical relevance of ,2 -adrenoceptor polymorphisms, to look at clinical control outcomes as well as propensity for subsensitivity. It would therefore make more sense to first of all optimize the dose of anti-inflammatory therapy with inhaled corticosteroid and to then consider adding a long-acting ,2 -adrenoceptor agonist for patients who are poorly controlled. [source] Comparison of clozapine and haloperidol on some autonomic and psychomotor functions, and on serum prolactin concentration, in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2001J. L. Pretorius Aims To compare the autonomic, neuroendocrine and psychomotor effects of single doses of the ,atypical' antipsychotic clozapine and the ,classical' antipsychotic haloperidol, in healthy male volunteers. Methods Clozapine (50 mg), haloperidol (3 mg) and placebo were administered to 12 healthy male volunteers at weekly intervals, according to a balanced double-blind design. Resting pupil diameter, salivary output, heart rate, blood pressure, plasma prolactin concentration, critical flicker fusion frequency and subjective ,alertness', ,contentedness' and ,anxiety' were measured at baseline and 2, 3, 4 and 5 h after drug ingestion. Data were analysed by analysis of variance with individual comparisons (Dunnett's test) with a significance criterion of P < 0.05. Results Significant treatment effects (difference from placebo [mean, 95% CI] 5 h after drug ingestion) were as follows: clozapine reduced pupil diameter (mm; ,3.02 [,3.56, ,2.47]), salivary output (g; ,0.34 [,0.60, ,0.08]), mean arterial blood pressure (mm Hg; ,8.7 [,14.3, ,3.1]), critical flicker fusion frequency (Hz; ,3.26 [,3.94, ,2.58]), and subjectively-rated ,alertness' (mm; ,20.94 [,29.21, ,12.67]) and ,contentedness' (mm; ,12.98 [,17.90, ,8.06]), whereas haloperidol increased prolactin concentration (mU l,1; 301.3 [196.7, 405.8]) and caused small reductions in pupil diameter (mm; ,0.68 [,1.23, ,0.14]), mean arterial blood pressure (mm Hg; ,7.0 [,12.6, ,1.4]) and critical flicker fusion frequency (Hz; ,1.15 [,1.83, ,0.47]). Conclusions The effects of the antipsychotics are in agreement with their receptor binding profiles: ,1 -adrenoceptor blockade by clozapine may contribute to reductions in pupil diameter, salivation, mean arterial blood pressure and sedation, and muscarinic cholinoceptor blockade by the drug may underlie the reduction in salivation. Conversely, D2 dopamine receptor blockade by haloperidol is likely to be responsible for the increase in prolactin secretion evoked by the drug. [source] The signal transduction cascade regulating the expression of the gap junction protein connexin43 by ,-adrenoceptorsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009A Salameh Background and purpose:, In mammalian heart, connexin43 (Cx43) represents the predominant connexin in the working myocardium. As the ,-adrenoceptor is involved in many cardiac diseases, we wanted to clarify the pathway by which ,-adrenoceptor stimulation may control Cx43 expression. Experimental approach:, Cultured neonatal rat cardiomyocytes were stimulated with isoprenaline. Cx43 expression as well as activation of p38 mitogen-activated protein kinase (MAPK), p42/44 MAPK, JUN NH2 -terminal kinase (JNK) and nuclear translocation of the transcription factors activator protein 1 (AP1) and CRE-binding protein (CREB) were investigated. Additionally, we assessed Cx43 expression and distribution in left ventricular biopsies from patients without any significant heart disease, and from patients with either congestive heart failure [dilated cardiomyopathy (DCM)] or hypertrophic cardiomyopathy (HCM). Key results:, Isoprenaline exposure caused about twofold up-regulation of Cx43 protein with a pEC50 of 7.92 ± 0.11, which was inhibited by propranolol, SB203580 (4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl)-1H-imidazole) (p38 inhibitor), PD98059 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one) (MAPK 1 kinase inhibitor) (Alexis Biochemicals, San Diego, CA, USA) or cyclosporin A. Similar findings were obtained for Cx43 mRNA. Furthermore, Cx43 up-regulation was accompanied by phosphorylation of p38, p42/44 and JNK, and by translocation of AP1 and CREB to the nucleus. Analysis of Cx43 protein and mRNA in ventricular biopsies revealed that in patients with DCM, Cx43 content was significantly lower, and in patients with HCM, Cx43 content was significantly higher, relative to patients without any cardiomyopathy. More importantly, Cx43 distribution also changed with more Cx43 being localized at the lateral border of the cardiomyocytes. Conclusion and implication:, ,-adrenoceptor stimulation up-regulated cardiac Cx43 expression via a protein kinase A and MAPK-regulated pathway, possibly involving AP1 and CREB. Cardiomyopathy altered Cx43 expression and distribution. [source] | ||||||||||||||||||||||||||||||||||