MP07-12: Inhibition of smooth muscle contraction in isolated human detrusor tissues by mirabegron requires concentrations out of therapeutic range, and is limited to neurogenic contractions

Ru Huang*, Alexander Tamalunas, Raphaela Waidelich, Frank Strittmatter, Christian G. Stief, Martin Hennenberg, Munich, Germany

Introduction: Mirabegron is available for treatment of storage symptoms in overactive bladder (OAB), caused by spontaneous bladder smooth muscle contractions. Following its introduction, the specificity for ß3-adrenoceptors and the concept of ß3-adrenergic bladder smooth muscle relaxation has been challenged, so that mechanisms underlying the benefits from mirabegron raised questions. Previous in vitro studies using human detrusor tissues adressing effects on cholinergic contractions assessed relaxation of unphysiological, low steady-state precontractions by mirabegron, or used concentrations up to 30 µM, while plasma levels of mirabegron do not exceed 150 nM. However, effects of therapeutic concentrations on full cholinergic contractions, and on non-cholinergic detrusor contractions are unknown. Here, we assessed effects of mirabegron on neurogenic and on full agonist-induced contractions of human detrusor tissues.

Methods: Detrusor tissues were obtained from patients undergoing radical cystectomy. Contractions were induced by electric field stimulation (EFS), and by cumulative concentrations of cholinergic agonists, endothelin-1 and the thromboxane A2 analog U4669 in an organ bath.

Results: EFS-induced contractions of human detrusor tissues were inhibited using 10 µM mirabegron (Emax controls 161% [127-195] of KCl-induced contraction, mirabegron 75% [56-94], p<0.006), but not by 1 µM mirabegron. Inhibition by 10 µM mirabegron was resistant to the ß3-adrenergic antagonist L-748,337 (Emax 135% [63-207] L-748,337 alone, 45% [-7 to 97] L-748,337+mirabegron, p<0.02). Concentration-dependent contractions by carbachol were not inhibited by 1 µM or 10 µM mirabegron. Concentration response curves for methacholine were slightly right-shifted by 10 µM mirabegron, but not by 1 µM mirabegron. Concentration-dependent contractions by endothelin-1 or U46619 were not changed by 10 µM mirabegron. Tolterodine (300 nM) rightshifted concentration response curves for carbachol and methacholine, including increases in EC50 values and unchanged Emax values, and inhibited EFS-induced contractions.

Conclusions: Inhibition of neuogenic contractions in isolated detrusor tissues by mirabegron requires concentrations highly exceeding plasma levels during standard dosing and Ki values for ß3-adrenoceptors. Full phasic contractions by cholinerigc agonists and by non-cholinerigc agonists are not affected by therapeutic concentrations. Improvements of storage symptoms are not attributed to ß3-adrenoceptors in the bladder wall, but rather imparted by spinal or central nervous mechanisms.

Source of Funding: Deutsche Forschungsgemeinschaft; Chinese Scholarship Council