Modulation of nerve-evoked contractions by β3-adrenoceptor agonism in human and rat isolated urinary bladder.

Abstract Activation of β 3 -adrenoceptors has been shown to have a direct relaxant effect on urinary bladder smooth muscle from both rats and humans, however there are very few studies investigating the effects of β 3 -adrenoceptor agonists on nerve-evoked bladder contractions. Therefore in the current study, the role of β 3 -adrenoceptors in modulating efferent neurotransmission was evaluated. The effects of β 3 -adrenoceptor agonism on neurogenic contractions induced by electrical field stimulation (EFS) were compared with effects on contractions induced by exogenous acetylcholine (Ach) and αβ-methylene adenosine triphosphate (αβ-meATP) in order to determine the site of action. Isoproterenol inhibited EFS-induced neurogenic contractions of human bladder (p D 2  = 6.79; E max  = 65%). The effect of isoproterenol was selectively inhibited by the β 3 -adrenoceptor antagonist L-748,337 (p K B  = 7.34). Contractions induced by exogenous Ach (0.5–1 μM) were inhibited 25% by isoproterenol (3 μM) while contractions to 10 Hz in the same strip were inhibited 67%. The selective β 3 -adrenoceptor agonist CL-316,243 inhibited EFS-induced neurogenic contractions of rat bladder (p D 2  = 7.83; E max  = 65%). The effects of CL-316,243 were inhibited in a concentration dependent manner by L-748,337 (p A 2  = 6.42). Contractions induced by exogenous Ach and αβ-meATP were significantly inhibited by CL-316,243, 29% and 40%, respectively. These results demonstrate that the activation of β 3 -adrenoceptors inhibits neurogenic contractions of both rat and human urinary bladder. Contractions induced by exogenously applied parasympathetic neurotransmitters are also inhibited by β 3 -agonism however the effect is clearly less than on neurogenic contractions (particularly in human), suggesting that in addition to a direct effect on smooth muscle, activation of prejunctional β 3 -adrenoceptors may inhibit neurotransmitter release.