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

• Published in: Pharmacological research Vol. 80; pp. 14 - 20
• Main Authors: Rouget, Céline, Rekik, Moèz, Camparo, Philippe, Botto, Henry, Rischmann, Pascal, Lluel, Philippe, Palea, Stefano, Westfall, Timothy D.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-02-2014
• Subjects: Acetylcholine - antagonists & inhibitors; Acetylcholine - pharmacology; Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - antagonists & inhibitors; Adenosine Triphosphate - pharmacology; Adrenergic beta-3 Receptor Agonists - pharmacology; Adrenergic beta-3 Receptor Antagonists - pharmacology; Aminophenols - pharmacology; Animals; CL-316,243; Dioxoles - antagonists & inhibitors; Dioxoles - pharmacology; Dose-Response Relationship, Drug; Electric Stimulation; Female; Human urinary bladder; Humans; In Vitro Techniques; Isoproterenol; Isoproterenol - antagonists & inhibitors; Isoproterenol - pharmacology; Male; Muscle Contraction - drug effects; Muscle Contraction - physiology; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Neurogenic contractions; Rat urinary bladder; Rats; Receptors, Adrenergic, beta-3 - physiology; Sulfonamides - pharmacology; Urinary Bladder - drug effects; Urinary Bladder - innervation; Urinary Bladder - physiology; β-Adrenoceptors; OAB; EFS; Human urinary bladder; Rat urinary bladder; Ach; β-Adrenoceptors; Neurogenic contractions; Isoproterenol; CL-316,243; αβ-meATP
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2013.12.006

Activation of β3-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 β3-adrenoceptor agonists on nerve-evoked bladder contractions. Therefore in the current study, the role of β3-adrenoceptors in modulating efferent neurotransmission was evaluated. The effects of β3-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 (pD2=6.79; Emax=65%). The effect of isoproterenol was selectively inhibited by the β3-adrenoceptor antagonist L-748,337 (pKB=7.34). Contractions induced by exogenous Ach (0.5–1μM) were inhibited 25% by isoproterenol (3μM) while contractions to 10Hz in the same strip were inhibited 67%. The selective β3-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 αβ-meATP were significantly inhibited by CL-316,243, 29% and 40%, respectively. These results demonstrate that the activation of β3-adrenoceptors inhibits neurogenic contractions of both rat and human urinary bladder. Contractions induced by exogenously applied parasympathetic neurotransmitters are also inhibited by β3-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 β3-adrenoceptors may inhibit neurotransmitter release.