α1-Adrenoceptor Subtype Selectivity and Organ Specificity of Silodosin (KMD-3213)

Abstract

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

Effects of four different .ALPHA.1-adrenoceptor antagonists on .ALPHA.-adrenoceptor agonist-induced contractions in isolated mouse and hamster ureters

“…The potencies of the various α1-adrenoceptor antagonists in our study would presumably be reflected by their clinical efficacies towards stone passage. The efficacies displayed by silodosin in the present experiments on the mouse ureter (pKB value = 9.47) and hamster ureter (10.09) were much greater than those reported for the mouse aorta (α1D-adrenoceptor-mediated response; pA2 value = 8.25) (Hosoda et al, 2005), rat aorta (α1D-adrenoceptor-mediated response; pA2 value = 7.88) (Tatemichi et al, 2006a), dog carotid artery (α1B-adrenoceptor-mediated response; pKB value = 7.54) (Tatemichi et al, 2006b), or human mesenteric artery (α1B-adrenoceptor-mediated response; pA2 value = 7.47) (Murata et al, 2000). Moreover, Akiyama et al (1999) demonstrated in anesthetized rats that silodosin suppressed an α1A-adrenoceptor-mediated response (the increase in intraurethral pressure induced by phenylephrine) without seriously altering mean blood pressure, with selectivity (α1A-adrenoceptor-mediated response against hypotensive effect) being markedly greater for silodosin (29.7) than for terazosin (0.52).…”

A Study on Efficacy and Safety of Silodosin in Geriatric Patients with Benign Prostatic Hyperplasia

“…Moreover, tamsulosin has a higher selectivity for the α1B-adrenoreceptors than silodosin, and thus, the decrease in blood pressure induced by tamsulosin may be mediated by its blocking α1B-adrenoreceptors action on the participating in blood vessel contraction and baroreceptor-induced inotropic effects. [9,16] Therefore, the lack of cardiovascular side effects may be a major advantage of silodosin. Our study statistically proved that silodosin is effective in improving the IPSS, PFR with fewer cardiovascular side effects.…”

“…Silodosin is an emerging agent with high selectivity for α1A-ARs recently developed in Japan. In vitro studies have showed that silodosin's α1A-to-α1B binding ratio is extremely high (162:1) [9]. Schwinn DA et al [10] , Forray C et al [11] compared silodosin with non-selective alpha1A-adrenoceptor (AR) blockers and demonstrated that drugs with a high selectivity for α1A-Adrenoreceptors may be more prostatespecific and maintain a therapeutic response in the treatment of symptomatic BPH with minimal effect on blood pressure and fewer cardiovascular side effects .…”

Silodosin is effective for treatment of LUTS in men with BPH: a systematic review

“…Silodosin was demonstrated to have a higher selectivity for the alpha 1A -AR subtype than tamsulosin hydrochloride, naftopidil or prazosin hydrochloride, and the alpha 1A -to-alpha 1B binding ratio of silodosin is 162 : 1. 13 These results suggested that silodosin may have more beneficial effects on the symptoms associated with BPH and minimal effects on blood pressure. Several randomized controlled trials have reported the clinical effectiveness and safety of silodosin for BPH.…”

“…[32][33][34] Moreover, tamsulosin has a higher selectivity for the alpha 1B -AR than silodosin, and thus, the decrease in blood pressure induced by tamsulosin may be mediated by its blocking action on the alpha 1B -AR participating in blood vessel contraction and baroreceptor-induced inotropic effects. 13,24 Therefore, the lack of cardiovascular side effects may be a major advantage of silodosin.…”