Contractile responses to alpha(1)-adrenoceptor agonists in isolated human male and female urethra

Objective To investigate the contractile responses mediated through alpha(1 )-adrenoceptors in human urethra and to evaluate the effectiveness Of NS-49 [(R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulphon-anilide hydro chloride], a novel alpha(1)-adrenoceptor agonist, against contraction of th e human urethra. Materials and methods The contractile responses were assessed in 10 male pr ostatic urethrae and six female urethrae. Antagonism was evaluated in the u rethra using phenylephrine. a nonselective alpha(1)-adrenoceptor agonist, c umulatively applied >20 min after applying 0.1 mu mol/L prazosin or 0.1 mu mol/L 5-methylurapidil, a selective alpha(1A)-adrenoceptor antagonist. Agon ism was determined in both male and female urethrae to obtain the concentra tion-response curve for the agonist. Results Phenylephrine caused both male and female urethrae to contract, and showed high potency and efficacy. Prazosin antagonized these contractions with low affinity (apparent pK(B) of 8.30 in male urethrae). 5-Methylurapid il, also antagonized the contractions with low affinity (apparent pK(B) of 7.88 in male urethrae). Noradrenaline and phenylephrine caused both male an d female urethrae to contract, with high potency and efficacy. A novel and selective alpha(1A)-and alpha(1L)-adrenoceptor agonist, NS-49, induced cont ractile responses with high potency and moderate efficacy, whereas methoxam ine induced contractions with low potency and moderate efficacy. Norephedri ne was a very weak contractile agonist. Conclusion In the human urethra, phenylephrine-induced contractions were me diated through alpha(1L)-adrenoceptors and not through alpha(1A)-adrenocept ors, Contractions of the human urethra induced by NS-49 were also mediated mainly through alpha(1L)-adrenoceptors, with high potency and moderate effi cacy. NS-49 may therefore be useful for the treatment of urinary stress inc ontinence, with minimal side-effects because it has subtype selectivity.