Rouget_2014_Pharmacol.Res_80_14

Activation of beta3-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 beta3-adrenoceptor agonists on nerve-evoked bladder contractions. Therefore in the current study, the role of beta3-adrenoceptors in modulating efferent neurotransmission was evaluated. The effects of beta3-adrenoceptor agonism on neurogenic contractions induced by electrical field stimulation (EFS) were compared with effects on contractions induced by exogenous acetylcholine (Ach) and alphabeta-methylene adenosine triphosphate (alphabeta-meATP) in order to determine the site of action. Isoproterenol inhibited EFS-induced neurogenic contractions of human bladder (pD2=6.79; Emax=65%). The effect of isoproterenol was selectively inhibited by the beta3-adrenoceptor antagonist L-748,337 (pKB=7.34). Contractions induced by exogenous Ach (0.5-1muM) were inhibited 25% by isoproterenol (3muM) while contractions to 10Hz in the same strip were inhibited 67%. The selective beta3-adrenoceptor agonist CL-316,243 inhibited EFS-induced neurogenic contractions of rat bladder (pD2=7.83; Emax=65%). The effects of CL-316,243 were inhibited in a concentration dependent manner by L-748,337 (pA2=6.42). Contractions induced by exogenous Ach and alphabeta-meATP were significantly inhibited by CL-316,243, 29% and 40%, respectively. These results demonstrate that the activation of beta3-adrenoceptors inhibits neurogenic contractions of both rat and human urinary bladder. Contractions induced by exogenously applied parasympathetic neurotransmitters are also inhibited by beta3-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 beta3-adrenoceptors may inhibit neurotransmitter release.