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Type: Artigo de periódico
Title: Mirabegron Relaxes Urethral Smooth Muscle By A Dual Mechanism Involving β3 -adrenoceptor Activation And α1 -adrenoceptor Blockade.
Author: Alexandre, E C
Kiguti, L R
Calmasini, F B
Silva, F H
da Silva, K P
Ferreira, R
Ribeiro, C A
Mónica, F Z
Pupo, A S
Antunes, E
Abstract: This article is commented on by Michel, M. C., pp. 429-430 of this issue. To view this commentary visit Mirabegron is the first β3 -adrenoceptor agonist approved for treatment of overactive bladder syndrome. This study aimed to investigate the effects of β3 -adrenoceptor agonist mirabegron in mouse urethra. The possibility that mirabegron also exerts α1 -adrenoceptor antagonism was also tested in rat smooth muscle preparations presenting α1A - (vas deferens and prostate), α1D - (aorta) and α1B -adrenoceptors (spleen). Functional assays were carried out in mouse and rat isolated tissues. Competition assays for the specific binding of [(3) H]prazosin to membrane preparations of HEK-293 cells expressing each of the human α1 -adrenoceptors, as well as β-adrenoceptor mRNA expression and cyclic AMP measurements in mouse urethra, were performed. Mirabegron produced concentration-dependent urethral relaxations that were shifted to the right by the selective β3 -adrenoceptor antagonist L-748,337 but unaffected by β1 - and β2 -adrenoceptor antagonists (atenolol and ICI-118,551 respectively). Mirabegron-induced relaxations were enhanced by the PDE4 inhibitor rolipram, and the agonist stimulated cAMP synthesis. Mirabegron also produced rightward shifts in urethral contractions induced by the α1 -adrenoceptor agonist phenylephrine. Schild regression analysis revealed that mirabegron behaves as a competitive antagonist of α1 -adrenoceptors in urethra, vas deferens and prostate (α1A -adrenoceptor, pA2  ≅ 5.6) and aorta (α1D -adrenoceptor, pA2  ≅ 5.4) but not in spleen (α1B -adrenoceptor). The affinities estimated for mirabegron in functional assays were consistent with those estimated in radioligand binding with human recombinant α1A - and α1D -adrenoceptors (pKi  ≅ 6.0). The effects of mirabegron in urethral smooth muscle are the result of β3 -adrenoceptor agonism together with α1A and α1D -adrenoceptor antagonism.
Citation: British Journal Of Pharmacology. v. 173, n. 3, p. 415-428, 2016-Feb.
Rights: fechado
Identifier DOI: 10.1111/bph.13367
Date Issue: 2016
Appears in Collections:Unicamp - Artigos e Outros Documentos

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