Adrenoceptor pharmacology: urogenital applications

Abstract

Although the selective alpha1-adrenoceptor antagonists were initially developed as antihypertensive drugs, and they are still utilized for this indication, the alpha1-adrenoceptor blockers are now used extensively for the symptomatic treatment of benign prostatic hyperplasia (BPH). As a result, a number of new drugs in this class have been specifically developed for use in BPH. The utility of alpha1-adrenoceptor antagonists in BPH derives from the observation, made several decades ago, that the irreversible, alpha1- adrenoceptor selective antagonist phenoxybenzamine, blocked the contractile activity of norepinephrine in isolated strips of rat or human prostate. Following the further subclassification of alpha1-adrenoceptors into the alpha1A-, alpha1B- and alpha1D-adrenoceptor subtypes, the relationship between subtype selectivity and efficacy in BPH has been investigated in the hope of developing more selective drugs for the treatment of this disorder. Molecular characterization of the adrenoceptor population in human prostate clearly shows the alpha1A-adrenoceptor subtype to predominate, and highly selective alpha1A-adrenoceptor antagonists have been identified and investigated in BPH. However, controversy remains as to whether prostatic smooth muscle contraction is mediated by the alpha1A-adrenoceptor, or by another novel alpha1-adrenoceptor subtype (not corresponding to any of the three known recombinant alpha1-adrenoceptors), or both. alpha1-Adrenoceptor agonists have been used clinically for the treatment of stress incontinence, acting to increase urethral tone by contracting urethral smooth muscle. Research efforts are ongoing to identify agents of this class having a selective action on urethral versus vascular smooth muscle, in order to produce a greater effect on the urethra without producing dose-limiting increases in blood pressure. Local administration of vascular smooth muscle relaxants, either alone or in combination, has been used for the treatment of erectile dysfunction. An alpha1-adrenoceptor antagonist is often used as one comportent in such mixtures, which act to relax trabecular smooth muscle. The recent demonstration that a systemically administered drug can produce a sufficiently selective action on cavernosal smooth muscle to allow efficacy without producing limiting systemic side effects has renewed interest in the possibility of systemic administration of alpha1-adrenoceptor antagonists for this indication.