Mirabegron induces relaxant effects via cAMP signaling-dependent and -independent pathways in detrusor smooth muscle.

Objective We previously found that mirabegron exerts a relaxant effect in the presence of the beta(3)-adrenoceptor antagonist SR58894A during carbachol-induced contraction in human and pig detrusor. The aim of this study was to explore the possible mechanism underlying the relaxant effects of mirabegron using detrusor smooth muscle. Methods Human tissue was obtained from urinary bladders of patients undergoing radical cystectomy at Kyushu University and Harasanshin Hospital. Pig tissue was obtained from an abattoir. Tension force (organ bath experiments) was measured in intact or permeabilised (alpha-toxin or beta-escin) detrusor smooth muscle strips. The contribution of cAMP-dependent signaling and the inhibition of Ca2+ sensitization to the relaxant effects of mirabegron were characterized using 1 mu M SR58894A, 100 mu M SQ22536 (an adenylyl cyclase inhibitor), 10 mu M H-89 (a protein kinase [PK] A inhibitor), 10 mu M Y-27632 (a selective Rho kinase inhibitor), and 10 mu M GF-109203X (a selective PKC inhibitor). Results 30 mu M Mirabegron impaired carbachol (0.03-1 mu M)-induced contraction in human detrusor smooth muscle. SR58894A only partially attenuated the relaxant effects of mirabegron in human and pig detrusor strips precontracted with 1 mu M carbachol. In alpha-toxin-permeabilized detrusor strips, tension force at 1 mu M [Ca2+](i) was decreased by mirabegron in a concentration-dependent manner. The relaxant effect of mirabegron was only slightly attenuated by H-89 and not significantly affected by SQ22536. Y-27632 potentiated the relaxation response to mirabegron, but attenuated responses to cAMP; GF-109203X had little effect. Mirabegron but not cAMP had a notable relaxant effect in the pig detrusor smooth muscle permeabilized with beta-escin. Conclusions Mirabegron-induced relaxation of pig and human detrusor smooth muscle occurs via both a beta(3)-adrenoceptor/cAMP-dependent and -independent pathway.