THE ALPHA(1)-ADRENERGIC RECEPTOR THAT MEDIATES SMOOTH-MUSCLE CONTRACTION IN HUMAN PROSTATE HAS THE PHARMACOLOGICAL PROPERTIES OF THE CLONEDHUMAN ALPHA(1C) SUBTYPE

Molecular cloning studies have revealed the existence of three subtype s of al-adrenergic receptors. However, the link between any individual subtype and its functional role in the body has remained elusive. In an effort to bridge the gap between molecular biology and pathophysiol ogy, we have chosen a model smooth muscle system, the human prostate, and investigated the role of alpha(1) subtypes in this tissue. To dete rmine which alpha(1)-adrenergic receptor subtype mediates the contract ile response of the human prostate, we first studied the pharmacologic al properties of three cloned human alpha(1) subtypes (alpha(1a/d), al pha(1b), and alpha(1c)) Prazosin, terazosin, doxazosin, alfuzosin, and abanoquil showed no selectivity for the human alpha(1) subtypes. WB-4 101 and 5-methylurapidil showed a rank order of potency of alpha(1c) > alpha(1a/d) much greater than alpha(1b). Indoramin and (+)-niguldipin e were selective for the alpha(1c)-adrenergic receptor, with at least 10-fold lower affinity at either alpha(1a/d) or alpha(1b) subtypes SK& F104856 was found to be 6-fold more potent at the alpha(1a/d) receptor subtype than at alpha(1b)- or alpha(1c)-adrenergic receptors. We next determined the potency of these antagonists to inhibit the phenylephr ine-induced contraction of human prostatic tissue in vitro. The potenc ies of indoramin, 5-methylurapidil, and SK&F104856 to inhibit the cont ractile response and to displace [H-3]prazosin from the cloned human a lpha(1c) subtype were similar. Our data suggest that the alpha(1) rece ptor that mediates the contraction of human prostate smooth muscle has the pharmacological properties of the cloned human alpha(1c)-adrenerg ic receptor. The findings of the present study suggest that selective alpha(1c)-adrenergic receptor antagonists may be clinically more effic acious and better tolerated agents for the treatment of symptomatic be nign prostatic hyperplasia.