The novel β3-adrenoceptor agonist mirabegron reduces carbachol-induced contractile activity in detrusor tissue from patients with bladder outflow obstruction with or without detrusor overactivity

Abstract

β(3)-Adrenoceptors are major players in detrusor relaxation and have been suggested as a new putative target for the treatment of overactive bladder syndrome. We determined the effects of mirabegron (YM178), a novel β(3)-adrenoceptor agonist, on carbachol-induced tone in isolated human detrusor preparations from patients with bladder outflow obstruction (BOO) with and without detrusor overactivity (DO), and from patients with normal bladder function. We compared the effects to those of isoprenaline, a non-selective β-adrenoceptor agonist. Detrusor specimens were obtained from patients with benign prostatic hyperplasia undergoing cystoscopy and from patients undergoing radical prostatectomy/cystectomy (in total 33 donors). Detrusor contractility was evaluated by organ bath studies and strips were incubated with carbachol (1μM) to induce and enhance tension. Both mirabegron and isoprenaline reduced carbachol-induced tone in tissues from all groups. Isoprenaline decreased tension with higher potency than mirabegron in normal, BOO and BOO+DO detrusor strips with pIC(50) values of 7.49 ± 0.16 vs. 6.23 ± 0.26 (P=0.0002), 6.89 ± 0.34 vs. 6.04 ± 0.31 (P=0.01), and 6.57 ± 0.20 vs. 5.41 ± 0.08 (P<0.0001, n=4), respectively. The maximal relaxant effect of isoprenaline and mirabegron in the normal, BOO and BOO+DO detrusor was 37.7 ± 14.4% and 36.1 ± 23.3%, 14.4 ± 12.2% vs. 33.4 ± 21.0% and 18.3 ± 10.0% vs. 28.3 ± 12.2% (n=4, P>0.05), respectively. Mirabegron and isoprenaline reduced carbachol-induced tone in both normal bladders and obstructed bladder with and without DO. Isoprenaline had higher potency than mirabegron, but the efficacy of mirabegron effect was the same as that of isoprenaline.