title: Modulation of nerve-evoked contractions by β3-adrenoceptor agonism in human and rat isolated urinary bladder.
abstract: 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.
authors.affiliation: UROsphere, Faculté des Sciences Pharmaceutiques, 35 chemin des Maraîchers, 31062 Toulouse Cedex 09, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Rouget
authors.affiliation: UROsphere, Faculté des Sciences Pharmaceutiques, 35 chemin des Maraîchers, 31062 Toulouse Cedex 09, France.
authors.forename: Moèz
authors.initials: M
authors.lastname: Rekik
authors.affiliation: Foch Hospital, Anatomy and Cytopathology Department, 92151 Suresnes Cedex, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Camparo
authors.affiliation: Foch Hospital, Urology Department, 92151 Suresnes Cedex, France.
authors.forename: Henry
authors.initials: H
authors.lastname: Botto
authors.affiliation: Rangueil Hospital, Urology Department, 31059 Toulouse Cedex 9, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Rischmann
authors.affiliation: UROsphere, Faculté des Sciences Pharmaceutiques, 35 chemin des Maraîchers, 31062 Toulouse Cedex 09, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lluel
authors.affiliation: UROsphere, Faculté des Sciences Pharmaceutiques, 35 chemin des Maraîchers, 31062 Toulouse Cedex 09, France.
authors.forename: Stefano
authors.initials: S
authors.lastname: Palea
authors.affiliation: UROsphere, Faculté des Sciences Pharmaceutiques, 35 chemin des Maraîchers, 31062 Toulouse Cedex 09, France. Electronic address: timothy.westfall@urosphere.com.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Westfall
mesh_terms: D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D058673:Adrenergic beta-3 Receptor Antagonists / Q000494:pharmacology; D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D004149:Dioxoles / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D022702:Receptors, Adrenergic, beta-3 / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation* / Q000502:physiology
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D000627:Aminophenols; D004149:Dioxoles; C120576:L 748,337; D022702:Receptors, Adrenergic, beta-3; D013449:Sulfonamides; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D000255:Adenosine Triphosphate; D007545:Isoproterenol; D000109:Acetylcholine; C002630:alpha,beta-methyleneadenosine 5'-triphosphate
keywords: CL-316,243; Human urinary bladder; Isoproterenol; Neurogenic contractions; Rat urinary bladder; β-Adrenoceptors