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

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)