Inhibition of Full Smooth Muscle Contraction in Isolated Human Detrusor Tissues by Mirabegron Is Limited to Off-Target Inhibition of Neurogenic Contractions

Abstract

Mirabegron is used for treatment of storage symptoms in overactive bladder (OAB), caused by spontaneous bladder smooth muscle contractions. However, owing to limitations in available studies using human tissues central questions are still unresolved, including mechanisms underlying improvements by mirabegron and its anticontractile effects in the detrusor. Here, we assessed concentration-dependent mirabegron effects on contractions of human detrusor tissues in frequence-response curves and concentration-response curves for different cholinergic and non-cholinergic agonists. Detrusor tissues were sampled 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 A 2 analog U46619. EFS-induced contractions were inhibited using 10 µM mirabegron, but not using 1 µM. Inhibition by 10 µM mirabegron was resistant to the β 3adrenergic antagonist L-748,337. 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, but not 1 µM mirabegron. Concentration-dependent contractions by endothelin-1 or U46619 were not changed by mirabegron. In contrast, the muscarinic antagonist tolterodine right-shifted concentration response curves for carbachol and methacholine, and inhibited EFS-induced contractions. In conclusion, inhibition of neuogenic contractions in isolated detrusor tissues by mirabegron requires concentrations highly exceeding known plasma levels during standard dosing and the known K i values for β 3 -adrenoceptors. Full contractions by cholinerigc agonists, endothelin-1 and U46619 are not affected by therapeutic concentrations of mirabegron. Improvements of storage symptoms are most likely not imparted by inhibition of β 3 -adrenoceptors in the bladder wall itself.