Busca avançada
Ano de início
Entree
(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Mirabegron relaxes urethral smooth muscle by a dual mechanism involving (3)-adrenoceptor activation and (1)-adrenoceptor blockade

Texto completo
Autor(es):
Alexandre, E. C. [1] ; Kiguti, L. R. [2] ; Calmasini, F. B. [1] ; Silva, F. H. [1] ; da Silva, K. P. [2] ; Ferreira, R. [3] ; Ribeiro, C. A. [2] ; Monica, F. Z. [1] ; Pupo, A. S. [2] ; Antunes, E. [1]
Número total de Autores: 10
Afiliação do(s) autor(es):
[1] Univ Campinas UNICAMP, Dept Pharmacol, Campinas, SP - Brazil
[2] Univ Sao Paulo State UNESP, Inst Biosci, Dept Pharmacol, Botucatu, SP - Brazil
[3] Univ Campinas UNICAMP, Fac Med Sci, Hematol & Hemotherapy Ctr, Campinas, SP - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: British Journal of Pharmacology; v. 173, n. 3, p. 415-428, FEB 2016.
Citações Web of Science: 20
Resumo

Linked ArticleThis article is commented on by Michel, M. C., pp. 429-430 of this issue. To view this commentary visit . Background and PurposeMirabegron is the first (3)-adrenoceptor agonist approved for treatment of overactive bladder syndrome. This study aimed to investigate the effects of (3)-adrenoceptor agonist mirabegron in mouse urethra. The possibility that mirabegron also exerts (1)-adrenoceptor antagonism was also tested in rat smooth muscle preparations presenting (1A)- (vas deferens and prostate), (1D)- (aorta) and (1B)-adrenoceptors (spleen). Experimental ApproachFunctional assays were carried out in mouse and rat isolated tissues. Competition assays for the specific binding of {[}H-3]prazosin to membrane preparations of HEK-293 cells expressing each of the human (1)-adrenoceptors, as well as -adrenoceptor mRNA expression and cyclic AMP measurements in mouse urethra, were performed. Key ResultsMirabegron produced concentration-dependent urethral relaxations that were shifted to the right by the selective (3)-adrenoceptor antagonist L-748,337 but unaffected by (1)- and (2)-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 (1)-adrenoceptor agonist phenylephrine. Schild regression analysis revealed that mirabegron behaves as a competitive antagonist of (1)-adrenoceptors in urethra, vas deferens and prostate ((1A)-adrenoceptor, pA(2)5.6) and aorta ((1D)-adrenoceptor, pA(2)5.4) but not in spleen ((1B)-adrenoceptor). The affinities estimated for mirabegron in functional assays were consistent with those estimated in radioligand binding with human recombinant (1A)- and (1D)-adrenoceptors (pK(i)6.0). Conclusion and ImplicationsThe effects of mirabegron in urethral smooth muscle are the result of (3)-adrenoceptor agonism together with (1A) and (1D)-adrenoceptor antagonism. (AU)

Processo FAPESP: 14/02196-2 - Papel do estresse oxidativo e degradação da guanilil ciclase solúvel na disfunção miccional em camundongos obesos resistentes à insulina
Beneficiário:Eduardo Costa Alexandre
Linha de fomento: Bolsas no Brasil - Doutorado
Processo FAPESP: 08/50423-7 - Adrenoceptores alfa-1A, seus ligantes e eficácias colaterais
Beneficiário:André Sampaio Pupo
Linha de fomento: Auxílio à Pesquisa - Regular