Pharmacological evidence of distinct oci‐adrenoceptor subtypes mediating the contraction of human prostatic urethra and peripheral artery

Abstract

1 The a,-adrenoceptor subtypes mediating contractions of the smooth muscle in human prostatic urethra and branches of internal iliac artery were characterized in isometric contraction experiments. 2 Phenylephrine produced concentration-dependent contractions in both the urethra and artery. These responses were competitively inhibited by prazosin, WB4101 and 5-methyl-urapidil, and the slopes of Schild plots for all these antagonists were close to unity. 3 The pA2 values for prazosin were not significantly different between the urethra (9.42 ± 0.11; mean ± s.d.) and artery (9.50 0.27), while the pA2 values for WB4101 and 5-methyl-urapidil in the human prostatic urethra (8.94 0.19 and 8.42 0.14, respectively) were significantly greater than in the branches of human internal iliac artery (7.94 0.21 and 7.43 ± 0.22, respectively; P<0.01).4 Pretreatment with chlorethylclonidine (CEC) at concentrations ranging from 0.1 IJM to 1I00 1M attenuated the maximum contraction to phenylephrine in a concentration-dependent manner in both the urethra and artery. However, the urethra was significantly less affected by CEC than the artery. The pD'2 values (negative logarithm of the molar concentration of antagonist which reduced the maximum contraction to one half) in the urethra and artery were 4.35 ± 0.27 and 5.20 ± 0.37, respectively (P<0.0 1). 5 The present results indicate that there are distinct populations of a,-adrenoceptor subtypes in the human prostatic urethra and branches of the internal iliac artery. The a1-adrenoceptors responsible for the contraction of the human internal iliac artery branches are predominantly ax1-subtype, whereas those in the human prostatic urethra are considered to be not a,3, but atc or possibly O1A or a1A/D-subtype.

Effects of KMD-3213, a Uroselective α1A-Adrenoceptor Antagonist, on the Tilt-Induced Blood Pressure Response in Normotensive Rats

“…There are a number of reports indicating that the a 1a-AR subtype is the predominant a1-AR subtype in the human prostate (3 -5). Moreover, the contractile response of human prostate to norepinephrine is mediated by the a 1A-AR (6), while a 1B-AR is predominant in human peripheral arteries and aorta (7,8). These findings suggest a possibility for the development of an a 1A -AR antagonist specific for the prostate.…”

In vitroα1‐adrenoceptor pharmacology of Ro 70–0004 and RS‐100329, novel α1A‐adrenoceptor selective antagonists

“…The discovery and de®nition of a 1 -adrenoceptor subtypes o ers the potential for more selective agents. Recently, interest has focused on the role of the a 1A -adrenoceptor subtype in BPH, as a result of studies demonstrating that this subtype predominates in the urethra and prostate of man (Price et al, 1993;Faure et al, 1994;Taniguchi et al, 1997), and has been claimed to be the receptor mediating noradrenaline (NA) induced smooth muscle contraction in these tissues (Forray et al, 1994;Hatano et al, 1994;Marshall et al, 1995). The resulting tone is believed to contribute substantially to the urinary out¯ow obstruction observed in patients with BPH (Furuya et al, 1982), with the remaining obstruction being attributable to increased prostate mass.…”

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

“…Homma et al [24] performed a post hoc analysis of the data from a randomized, double-blind, placebocontrolled clinical trial of silodosin in Japan and found that ejaculation disorder caused by selective α1A-blockers was associated with very large improvements in the lower urinary tract symptoms. The silodosin subgroup with ejaculation failure experienced a greater reduction in the total IPSS than the silodosin subgroup without ejaculation impairmentand the placebo subgroup (211.8 vs. 27.2 vs. 25.3, respectively).…”