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

These results suggest that an excessive response to sympathetic nerve stimulation, which is mainly mediated via alpha(1A)-adrenoceptor, in the hypertrophied prostate gives rise to detrusor overactivity. Furthermore, the alpha(1A)-adrenoceptor selective antagonist KMD-3213 would be suitable for improving irritative symptoms in patients with benign prostatic hyperplasia.

The selectivity of silodosin (KMD − 3213)， an antagonist of or1− adrenoceptor (AR) ， to the subtypes (α 且 A − ， α IB − and α ID − ARs)was examined by a receptor − binding study and a functional pharmacological study ， and we compared its sub − type − selectivity With those of other α 1 − AR antagonjsts ． In the receptor − binding study ， a replacement experiment using ［ 3H ］ − prazosin was conducted using the membrane fraction of mouse − derived LM (tk −)cells in which each of three hu − man ai − AR subtypes was expressed ． ln the functional pharmacological study ， the following isolated tissues were used as representative organs with high distribution densities of α 1 − AR subtypes (α 1A − AR ：rabbit prostate ， urethra and bladder trigone ；α 1B − AR ：rat spleen ；α 1D − AR ： rat thoracic aorta) ． Using the Magnus methQd ， we studied the inhibitory effect of silodosin on noradrenalille − induced contraction ， and compared it with those of tamsulosin hydrochloride ， naftopidil and prazosin hydrochloride ． Silodosin showed higher selectivity for the α 1A − AR subtype than tamsulosin hydrochloride ， naftopidil or prazosin hydrochloride(aMnity 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 trigon ¢ ， with pA20r pKb values of 9 ． 60， 8． 71 and 9． 35， respectively) 。 On the other hand ， the pA2 values for antagonism of noradrenaline ． induced contractions in rat iso − 1ated spleen and rat isolated thoracic aorta were 7 ． 15and 7 ， 88 ， respectively ． Seiectivity for lower urinary tract was higher for silodosin than for the other α 1 − AR antagonists ． Our data suggest that silodosin has a high selectivity for the α 1A − AR subtype and for the lower urinary tract ．

Background: Patients with diabetes experience lower urinary tract symptoms. Cystopathy may evolve into underactive bladder (UAB), depending on the degree and duration of the symptoms. In the present study, we aimed to investigate the effects of silodosin, an alpha 1A -adrenoceptor (AR) antagonist, on UAB in a rat model of diabetes mellitus (DM). Methods: Female Sprague-Dawley rats (6 weeks old) were administered streptozotocin (STZ) (50 mg/kg, i.v.) to establish a DM model. One week after STZ administration, vehicle or silodosin (0.3 or 1 mg/kg/day) was delivered subcutaneously through an osmotic pump. Nine weeks after STZ administration (8 weeks after drug treatment), a catheter was implanted into the bladder under urethane anesthesia. After the measurement of emptied bladder blood flow (BBF), saline was continuously infused into the bladder and intravesical pressure and micturition volume were measured. In another experiment, the bladder was isolated and nerve markers were quantified. Results: A cystometrogram showed that bladder capacity (BC), residual volume (RV), and bladder extension (BC/ bladder weight) increased by 7.43, 10.47, and 3.59 times, respectively, in vehicle rats in comparison with normal rats. These findings suggested the occurrence of UAB-like symptoms in this model. Silodosin (1 mg/kg/day) inhibited the increase in BC and RV by 49.0% and 46.8%, respectively, and caused a decrease in BBF of approximately 25.5% (when the difference between normal and vehicle was set as 100%) in STZ rats. The nerve marker expression levels tended to be decreased in the bladders of STZ rats and these effects were ameliorated by silodosin. Conclusions: The STZ rats showed increased bladder extension and RV, symptoms that were suggestive of UAB, and these symptoms were ameliorated by silodosin. These results suggested that the alpha 1A -AR antagonist would be useful for the prevention or treatment of UAB.

We evaluated the pharmacological profile of ritobegron [KUC-7483; (Ϫ)-ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)-2,5-dimethylphenyloxy]acetate monohydrochloride] and its effects on the bladder in cynomolgus monkeys by in vitro and in vivo experiments. In vitro, ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC 50 8.2 Ϯ 2.3 ϫ 10 Ϫ7 M; maximal relaxation 88.7 Ϯ 3.7%). The ␤ 3 -adrenoceptor (AR) antagonist 3-(2-allylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR58894A) produced a rightward shift of this concentration-response curve without altering the maximal response (pK B value 6.56 Ϯ 0.35). In isolated atria, ritobegron increased the atrial rate only at high concentrations (EC 50 6.5 Ϯ 1.2 ϫ 10 Ϫ5 M). Ritobegron had no effect on tracheal contraction at concentrations from 10 Ϫ9 to 10 Ϫ4 M, and even at the highest concentration tested, 10 Ϫ3 M, the maximal relaxation it induced was only 26.7 Ϯ 8.1%. Tests of the selectivity of ritobegron for the bladder gave values of 79.3-and 1200-fold higher versus atria and trachea, respectively. In the in vivo study ritobegron significantly decreased intravesical pressure (ED 50 1.44 mg/kg) without affecting either mean blood pressure or heart rate. In conclusion, ritobegron displayed potent and selective ␤ 3 -AR agonistic activity and relaxed the monkey isolated bladder, and in vivo it decreased intravesical pressure without affecting cardiovascular parameters. These results suggest that ritobegron may be a promising potential agent for the treatment of overactive bladder.

We performed in vitro and in vivo experiments to evaluate the pharmacological profile of ritobegron and its effects on the bladder in rats. β(3)-AR selectivity was assessed using CHO cells expressing various subtypes of the human β-adrenoceptor (AR). Effects on isolated organs were evaluated using the organ-bath method. Effects on intravesical pressure, heart rate, and mean blood pressure were evaluated in urethane-anesthetized rats. Ritobegron increased cAMP accumulation in a concentration-dependent manner in CHO cells expressing any one of three human β-AR, its selectivity for β(3)-AR being 301-fold and 32-fold higher versus β(1)-AR and β(2)-AR, respectively. Ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50), 7.7 × 10(-8) mol/L; maximal relaxation, 97.0 %), and the β(3)-AR antagonist SR58894A produced a parallel rightward-shift of this concentration-response curve without altering the maximal response [pK(B) value, 6.43]. Ritobegron concentration-dependently increased atrial rate and decreased myometrial contractions in vitro, and its selectivity for the bladder was 2,078-fold higher versus the atria and 14-fold higher versus the uterus. In vivo, ritobegron induced a dose-dependent decrease in intravesical pressure (ED(50) 0.4 mg/kg), without affecting heart rate and only slightly lowering mean blood pressure. Thus, ritobegron displayed potent and selective β(3)-AR agonistic activity toward transfected human β-AR and exhibited a high selectivity for the bladder versus other organs in rats. Moreover, it decreased intravesical pressure with minimal effects on the cardiovascular system in anesthetized rats. These results suggest that ritobegron shows promise as a potential agent for the treatment of overactive bladder.

Our results clearly demonstrate that silodosin is a potent and highly selective alpha(1A)-AR antagonist. A selective alpha(1A)-AR antagonist such as silodosin may have good potential as a less-hypotensive drug for the treatment of urinary dysfunction in benign prostatic hyperplasia patients.

This study aimed to characterize the β-adrenoceptor (β-AR) subtype mediating relaxation of isolated human bladder strips and to explore relaxation by the novel β3-AR-selective agonist KUC-7322 for its relaxant effect on the human isolated detrusor and for its effect on the carbachol (CCh)-induced contractile response. In two parallel studies, relaxation of isolated human bladder strips was tested for the β-AR agonists isoproterenol, clenbuterol, BRL 37344, and KUC-7322. For the isoproterenol and KUC-7322 responses, antagonism by CGP 20712A, ICI 118551, and SR59230A was determined. The potency and efficacy of the reference agonists for detrusor relaxation was in line with their known β3-AR activity. KUC-7322 relative to isoproterenol was a full agonist with a pEC(50) of 5.95 ± 0.09 and 5.92 ± 0.11 in the two studies. SR59230A exhibited antagonism of the expected potency against isoproterenol (apparent pK (B) 7.2) but not against KUC-7322. Neither isoproterenol nor KUC-7322 nor forskolin significantly attenuated CCh-induced contraction. These results suggest that KUC-7322 displays full agonistic activity in relaxing the human detrusor without inhibiting the contraction induced by cholinergic stimulation. These characteristics, if proven in vivo, may be beneficial for the treatment of overactive bladder, as increased bladder capacity with a negligible effect on voiding contractions may be anticipated.