The selective β 3-adrenoceptor agonist
mirabegron, an established alternative to
antimuscarinic therapy for patients with
overactive bladder, induces 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 μM) inhibited specific [N-methyl-3H]
scopolamine methyl chloride 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 higher than those in the submaxillary gland and brain.
Mirabegron induced 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 pEC50 values were 7.06 and 4.97. Based on the receptor binding affinity and pharmacokinetics of
mirabegron,
muscarinic receptor occupancy in the human bladder for 24 hours after the administration of a single oral dose of 50 mg
mirabegron was 37%-76%. The present results demonstrate for the first time that
mirabegron may relax the detrusor smooth muscle not only by β 3-adrenoceptor activation but also
muscarinic receptor blockade. SIGNIFICANCE STATEMENT:
Mirabegron, the first selective β 3-adrenoceptor agonist, represents an alternative to
antimuscarinic agents for management of
overactive bladder (OAB). The present study aimed to clarify whether
mirabegron directly binds to
muscarinic receptors and affects
cholinergic agonist-induced contractions in rat urinary bladder and to predict
muscarinic receptor occupancy in human bladder after
oral administration of
mirabegron. The results demonstrated that
mirabegron therapy for patients with OAB may be due not only to β 3-adrenoceptor activation but also
muscarinic receptor blockade.