Possible involvement of muscarinic receptor blockade in mirabegron therapy for patients with overactive bladder

A selective b3-adrenoceptor agonist, mirabegron, an established alternative to antimuscarinic therapy for patients with overactive bladder (OAB), has been shown to induce additional effects against receptors, transporters, and hepatic enzymes. The present study aimed to elucidate the effects of mirabegron on muscarinic receptors in the rat bladder using radioligand binding and functional assays. Mirabegron (0.1-100 mM) inhibited specific [N-methyl-3H]scopolamine chloride ([3H]NMS) binding in the bladder and other tissues of rats in a concentration-dependent manner. Binding affinity in the bladder was similar to that in the heart, and significantly lower than those in the submaxillary gland and brain. Mirabegron exerted the concentration-dependent relaxation of carbachol-induced contractions in the rat isolated bladder. Further analyses using a two-site model revealed that the relative quantities of high and low affinity components for mirabegron were 44.5 and 55.5%, respectively. Respective EC50 were 87.3 nM and 10.7 mM. Muscarinic receptor occupancy in the human bladder estimated from the receptor binding affinity and pharmacokinetics of mirabegron was 37-76% until 24 h after the single oral administration of 50 mg mirabegron. The present study is the first to demonstrate that mirabegron may relax the detrusor smooth muscle not only by b3-adrenoceptor activation, but also muscarinic receptor blockade. Significance Statement Mirabegron, the first selective b3-adrenoceptor agonist, represents an alternative to antimuscarinic agent for management of overactive bladder (OAB). The present study aimed to clarify whether or not mirabegron binds directly muscarinic receptors and affects cholinergic agonist-induced contractions in rat urinary bladder, and to predict muscarinic receptor occupancy in human bladder following oral mirabegron. It has been demonstrated for the first time that mirabegron therapy for patients with OAB may result from not only b3-adrenoceptor activation, but also antagonizing muscarinic receptors.