Contractile responses to α 1 ‐adrenoceptor agonists in isolated human male and female urethra

Objective To investigate the contractile responses mediated through α 1 ‐adrenoceptors in human urethra and to evaluate the effectiveness of NS‐49 [(R)‐(–)‐3′‐(2‐amino‐1‐hydroxyethyl)‐4′‐fluoromethanesulphonanilide hydrochloride], a novel α 1 ‐adrenoceptor agonist, against contraction of the human urethra. Materials and methods The contractile responses were assessed in 10 male prostatic urethrae and six female urethrae. Antagonism was evaluated in the urethra using phenylephrine, a nonselective α 1 ‐adrenoceptor agonist, cumulatively applied > 20 min after applying 0.1 μmol/L prazosin or 0.1 μmol/L 5‐methylurapidil, a selective α 1A ‐adrenoceptor antagonist. Agonism was determined in both male and female urethrae to obtain the concentration‐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‐Methylurapidil, also antagonized the contractions with low affinity (apparent pK B of 7.88 in male urethrae). Noradrenaline and phenylephrine caused both male and female urethrae to contract, with high potency and efficacy. A novel and selective α 1A ‐and α 1L ‐adrenoceptor agonist, NS‐49, induced contractile responses with high potency and moderate efficacy, whereas methoxamine induced contractions with low potency and moderate efficacy. Norephedrine was a very weak contractile agonist. Conclusion In the human urethra, phenylephrine‐induced contractions were mediated through α 1L ‐adrenoceptors and not through α 1A ‐adrenoceptors. Contractions of the human urethra induced by NS‐49 were also mediated mainly through α 1L ‐adrenoceptors, with high potency and moderate efficacy. NS‐49 may therefore be useful for the treatment of urinary stress incontinence, with minimal side‐effects because it has subtype selectivity.