1 The possible existence of a b 3 -adrenergic receptor (b 3 -AR) in the human detrusor muscle was investigated by in vitro functional studies and analysis of mRNA expression. 2 Isoprenaline, noradrenaline and adrenaline each produced a concentration-dependent relaxation of the human detrusor. The rank order for their relaxing potencies was isoprenaline (pD 2 6.37+0.07) 5 noradrenaline (pD 2 6.07+0.12) 5 adrenaline (pD 2 5.88+0.11). 3 Neither dobutamine (b 1 -and b 2 -AR agonist) nor procaterol (b 2 -AR agonist) produced any signi®cant relaxation at concentrations up to 10 75 M. BRL37344A, CL316243 and CGP-12177A (b 3 -AR agonists), relaxed the preparations signi®cantly at concentrations higher than 10 76 M. The pD 2 values for BRL37344A, CL316243 and CGP-12177A were 6.42+0.25, 5.53+0.09 and 5.74+0.14, respectively. 4 CGP-20712A (10 77 ± 10 75 M), a b 1 -AR antagonist, did not a ect the isoprenaline-induced relaxation. On the other hand, ICI-118,551, a b 2 -AR antagonist, produced a rightward parallel shift of the concentration-relaxation curve for isoprenaline only at the highest concentration used (10 75 M) and its pK B value was 5.71+0.19. Moreover, SR58894A (10 77 ± 10 75 M), a b 3 -AR antagonist, caused a rightward shift of the concentration-relaxation curve for isoprenaline in a concentration-dependent manner. The pA 2 value and slope obtained from Schild plots were 6.24+0.20 and 0.68+0.31. 5 The b 1 -, b 2 -and b 3 -AR mRNAs were all positively expressed in detrusor smooth muscle preparations in a reverse transcription polymerase chain reaction assay. 6 In conclusion, the present results provide the ®rst evidence for the existence of the b 3 -AR subtype in the human detrusor. They also suggest that the relaxation induced by adrenergic stimulation of the human detrusor is mediated mainly through b 3 -AR activation.
1 The b-adrenoceptor (b-AR) subtypes mediating relaxation of the rabbit, rat and canine detrusors were subjected to functional investigation using selective b-AR agonists and antagonists. 2 In all three species, isoprenaline, noradrenaline and adrenaline each produced a concentrationdependent relaxation of the detrusor. The rank order for their relaxing potency was isoprenaline4 adrenaline4noradrenaline in rabbits and rats, but isoprenaline4noradrenaline4adrenaline in dogs. 3 Dobutamine did not produce relaxation of the detrusors at concentrations that are selective for b 1 -AR. The selective b 2 -AR agonist, procaterol, had a more potent relaxing e ect on rabbit and rat detrusors than on the canine detrusor. CGP-12177A, a selective b 3 -AR agonist, was more e ective in the rabbit than in the other two species. On the other hand, the relaxing e ect of another b 3 -AR agonist, CL316243, was more pronounced in dogs and rats than in rabbits. 4 CGP-20712A (10 79 to 10 77 M), a selective b 1 -AR antagonist, caused a slight rightward shift of the concentration-relaxation response curve for isoprenaline in the canine detrusor (pA 2 9.41), but not in the rabbit and rat detrusors. ICI-118,551, a selective b 2 -AR antagonist, antagonized the isoprenaline-induced relaxation in rabbits (pA 2 9.45) and rats (pA 2 9.05), but not in dogs. Bupranolol, a non-selective b-AR antagonist, caused a rightward shift of the concentration-relaxation curve for isoprenaline in the rabbit (pA 2 9.32) and rat (pA 2 8.98). However, higher concentrations (3610 78 to 10 75 M) were needed to induce a rightward shift of the curve for isoprenaline in the dog (pA 2 8.19) than in the other two species. 5. We have con®rmed that the distribution of b-AR subtypes in the detrusor muscle varies signi®cantly from species to species and we provide here the ®rst evidence of the presence of b 3 -AR in the detrusor. It is suggested that the relaxation induced by adrenoceptor agonists in urinary bladder smooth muscle may be mediated mainly via b 2 -AR in rabbits, via both b 2 -and b 3 -AR in rats, but mainly via b 3 -AR in dogs.
beta-adrenoceptor stimulation is an effective way of relaxing the human detrusor and the effect is similar in normal and neurogenic bladders. A major portion of the relaxant effect of isoproterenol is mediated via beta3-adrenoceptor stimulation. Clinical trials may reveal whether this method is useful for treating bladder overactivity.
The selectivity of silodosin , an antagonist of a 1 -adrenoceptor (AR), to the subtypes (a 1A -, a 1B -and a 1D -ARs) was examined by a receptor-binding study and a functional pharmacological study, and we compared its subtype-selectivity with those of other a 1 -AR antagonists. In the receptor-binding study, a replacement experiment using [ 3 H]-prazosin was conducted using the membrane fraction of mouse-derived LM (tk-) cells in which each of three human a 1 -AR subtypes was expressed. In the functional pharmacological study, the following isolated tissues were used as representative organs with high distribution densities of a 1 -AR subtypes (a 1A -AR: rabbit prostate, urethra and bladder trigone; a 1B -AR: rat spleen; a 1D -AR: rat thoracic aorta). Using the Magnus method, we studied the inhibitory eŠect of silodosin on noradrenaline-induced contraction, and compared it with those of tamsulosin hydrochloride, naftopidil and prazosin hydrochloride. Silodosin showed higher selectivity for the a 1A -AR subtype than tamsulosin hydrochloride, naftopidil or prazosin hydrochloride (a‹nity was highest for tamsulosin hydrochloride, followed by silodosin, prazosin hydrochloride and naftopidil in that order). Silodosin strong antagonized noradrenaline-induced contractions in rabbit lower urinary tract tissues (including prostate, urethra and bladder trigone, with pA 2 or pKb values of 9.60, 8.71 and 9.35, respectively). On the other hand, the pA 2 values for antagonism of noradrenaline-induced contractions in rat isolated spleen and rat isolated thoracic aorta were 7.15 and 7.88, respectively. Selectivity for lower urinary tract was higher for silodosin than for the other a 1 -AR antagonists. Our data suggest that silodosin has a high selectivity for the a 1A -AR subtype and for the lower urinary tract.Key words-silodosin (KMD-3213); a 1A -adrenoceptor subtype selectivity; lower urinary tract
The present results clearly demonstrated that the beta(3)-AR agonist prolonged the micturition interval without producing significant cardiovascular side effects. The human detrusor, like the rat detrusor, relaxes on beta(3)-AR stimulation. Provided that these results are valid in humans, selective beta(3)-AR agonists might be clinically useful for controlling a certain type of bladder overactivity.
These results indicate that in cerebral infarcted rats detrusor hyperreflexia can be suppressed by the selective beta3-adrenoceptor agonist CL316243 without increasing post-void residual volume and without significant cardiovascular side effects. If the current results hold true in humans, selective beta3-adrenoceptor agonists may prove useful for treating detrusor hyperreflexia associated with cerebral infarction.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.