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 A2 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 3-adrenergic 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 neurogenic contractions in isolated detrusor tissues by
mirabegron requires concentrations highly exceeding known plasma levels during standard dosing and the known binding constant (Ki values) for β 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 β 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 β 3-adrenoceptors. Mechanisms accounting for improvements of OAB by
mirabegron are located outside the urinary bladder.