Mirabegron relaxes urethral smooth muscle by a dual mechanism involving β3-adrenoceptor activation and α1-adrenoceptor blockade

dc.contributorUniversidade Estadual Paulista (UNESP)
dc.creatorAlexandre, E. C.
dc.creatorKiguti, L. R.
dc.creatorCalmasini, F. B.
dc.creatorSilva, F. H.
dc.creatorSilva, K. P. da
dc.creatorFerreira, R.
dc.creatorRibeiro, C. A.
dc.creatorMónica, F. Z.
dc.creatorPupo, A. S.
dc.creatorAntunes, E.
dc.date2015-12-07T15:32:45Z
dc.date2016-10-25T21:23:01Z
dc.date2015-12-07T15:32:45Z
dc.date2016-10-25T21:23:01Z
dc.date2015
dc.date.accessioned2017-04-06T09:28:30Z
dc.date.available2017-04-06T09:28:30Z
dc.identifierBritish Journal of Pharmacology, 2015.
dc.identifier1476-5381
dc.identifierhttp://hdl.handle.net/11449/131221
dc.identifierhttp://acervodigital.unesp.br/handle/11449/131221
dc.identifier10.1111/bph.13367
dc.identifier0000-0002-7984-5908
dc.identifier26493129
dc.identifierhttp://dx.doi.org/10.1111/bph.13367
dc.identifier.urihttp://repositorioslatinoamericanos.uchile.cl/handle/2250/941761
dc.descriptionMirabegron is the first β3-adrenoceptor (AR) agonist approved for treatment of overactive bladder syndrome (OAB). This study aimed to investigate the effects of β3-adrenoceptor (AR) agonist mirabegron in mouse urethra. The possibility that mirabegron exerts α1-AR antagonism was also tested in rat smooth muscle preparations presenting α1A- (vas deferens and prostate), α1D- (aorta) and α1B-AR (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-ARs, as well as β-AR mRNA expression and cyclic AMP measurements in mouse urethra were performed. Mirabegron produced concentration-dependent urethral relaxations that were right shifted by the selective β3-AR antagonist L 748,337, but unaffected by β1- and β2-AR antagonists (atenolol and ICI 118,551, respectively). Mirabegron-induced relaxations were enhanced by the phosphodiesterase-4 inhibitor rolipram, and this agonist stimulated cAMP synthesis. Mirabegron also produced rightward shifts in urethral contractions induced by the α1-AR agonist phenylephrine. Schild regression analysis revealed that mirabegron behaves as a competitive antagonist of α1-AR in urethra, vas deferens and prostate (α1A-AR, pA2  ≅ 5.6) and aorta (α1D-AR, pA2  ≅ 5.4), but not in spleen (α1B-AR). The affinities estimated for mirabegron in functional assays were consistent with those estimated in radioligand binding with human recombinant α1A- and α1D-ARs (pKi ≅ 6.0). The effects of mirabegron in urethral smooth muscle are the result of β3-AR agonism together with α1A / α1D-AR antagonism.
dc.languageeng
dc.publisherWiley Online Library
dc.relationBritish Journal of Pharmacology
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.subjectCyclic amp
dc.subjectISoprenaline
dc.subjectLower urinary tract symptoms
dc.subjectMirabegron
dc.subjectOveractive bladder syndrome
dc.subjectRolipram
dc.subjectΑ1-adrenoceptors
dc.subjectΒ3-adrenoceptor
dc.titleMirabegron relaxes urethral smooth muscle by a dual mechanism involving β3-adrenoceptor activation and α1-adrenoceptor blockade
dc.typeOtro


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