Involvement of beta(3)-adrenoceptors in mouse urinary bladder function: role in detrusor muscle relaxation and micturition reflex.
beta(3)-adrenoceptor activation produces relaxation of human urinary bladder smooth muscle (detrusor). Therefore, beta(3)-adrenoceptor agonism is being investigated as a new therapeutic strategy for the treatment of overactive bladder. The aim of the current study was to identify the functional presence of beta(3)-adrenoceptors in mouse isolated urinary bladder using the selective beta(3)-adrenoceptor agonist CL316,243 and antagonists SR59230A and L748,337. The effects of CL316,243 on basal tone, spontaneous activity and electrical field stimulation (EFS)-induced contractions were investigated using in vitro techniques, while the in vivo effects of intravenously administered CL316,243 on the micturition reflex were investigated using cystometry. CL316,243 decreased basal tone (pEC(50)=6.4+/-0.4) as well as spontaneous activity (53+/-7% at 3 microM) and inhibited EFS-induced contractions (pEC(50)=7.0+/-0.2) of the detrusor muscle. The beta(3)-adrenoceptor antagonist SR59230A (1 microM) significantly inhibited the relaxing effects of CL316,243 on basal tone and neurogenic contractions (pA(2)=7.0 and 7.2, respectively). Another beta(3)-adrenoceptor antagonist L748,337 (1-10 microM) significantly blocked the CL316,243-evoked inhibition of neurogenic contractions in a concentration-dependent manner (pK(B)=6.8), while the selective beta(2)-adrenoceptor antagonist ICI118,551(30 nM) had no effect. In anesthetized mice, CL316,243 (0.03 and 0.1 mg/kg, i.v.) significantly increased bladder capacity and threshold pressure without a modification of bladder compliance. Moreover, it induced a significant decrease in the amplitude of both micturition and non-voiding contractions. Based on the current results obtained using the beta(3)-adrenoceptor agonist CL316,243 (as well as various beta-adrenoceptor antagonists), functional beta(3)-adrenoceptors appear to be present in mouse urinary bladder.
Deba
Aurore
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UROsphere, Faculté des Sciences Pharmaceutiques, 35 Chemin des Maraîchers, Toulouse Cedex 09, France.
Palea
Stefano
S
Rouget
Celine
C
Westfall
Timothy D
TD
Lluel
Philippe
P
D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D004149:Dioxoles / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D009126:Muscle Relaxation / Q000187:drug effects; D009132:Muscles / Q000187:drug effects / Q000294:innervation / Q000378:metabolism / Q000502:physiology*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014554:Urination / Q000187:drug effects
D058667:Adrenergic beta-3 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004149:Dioxoles; D022702:Receptors, Adrenergic, beta-3; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate