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

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 frequency-response curves and concentration-response curves for different cholinergic and noncholinergic 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 mu M mirabegron, but not using 1 mu M. Inhibition by 10 mu M mirabegron was resistant to the beta(3)-adrenergic antagonist L-748,337. Concentration-dependent contractions by carbachol were not inhibited by 1 mu M or 10 mu M mirabegron. Concentration-response curves for methacholine were slightly right-shifted by 10 mu M, but not 1 mu M 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 neurogenic contractions in isolated detrusor tissues by mirabegron requires concentrations highly exceeding known plasma levels during standard dosing and the known binding constant (K-i values) for beta(3)-adrenoceptors. Full contractions by cholinergic 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 beta(3)-adrenoceptors in the bladder wall itself. SIGNIFICANCE STATEMENT Mirabegron is used for overactive bladder (OAB) treatment, but the underlying mechanisms are unclear, and preclinical and clinical findings are controversial due to limitations in available studies. Our findings suggest that inhibition of detrusor contractions by mirabegron is limited to neurogenic contractions, which requires unphysiologic concentrations and does not involve beta(3)-adrenoceptors. Mechanisms accounting for improvements of OAB by mirabegron are located outside the urinary bladder.

Automated summary

Mirabegron can inhibit neurogenic contractions in the detrusor muscle of the bladder, but it requires concentrations higher than standard dosing levels and does not involve beta(3)-adrenoceptors. Contractions induced by cholinergic agonists, endothelin-1, and U46619 are not affected by therapeutic concentrations of mirabegron. The mechanisms for improvement of overactive bladder symptoms are likely located outside of the urinary bladder.