Center for Pharma-Food Research (CPFR), Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (S.Y., J.C.); Laboratory of Pharmaceutics, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan (M.S., T.O.); and Department of Pharmacology II, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan (K.M., H.W., K.S.)
Center for Pharma-Food Research (CPFR), Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan (S.Y., J.C.); Laboratory of Pharmaceutics, Faculty of Pharma-Science, Teikyo University, Tokyo, Japan (M.S., T.O.); and Department of Pharmacology II, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, Nishinomiya, Japan (K.M., H.W., K.S.).
J Pharmacol Exp Ther. 2021 May;377(2):201-206. doi: 10.1124/jpet.120.000301. Epub 2021 Mar 3.
The selective -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 [-methyl-H]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 pEC 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 -adrenoceptor activation but also muscarinic receptor blockade. SIGNIFICANCE STATEMENT: Mirabegron, the first selective -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 -adrenoceptor activation but also muscarinic receptor blockade.
选择性β肾上腺素受体激动剂米拉贝隆是治疗膀胱过度活动症的抗毒蕈碱药物的替代品，它对受体、转运体和肝酶具有额外的作用。本研究旨在使用放射性配体结合和功能测定法阐明米拉贝隆对大鼠膀胱中毒蕈碱受体的影响。米拉贝隆（0.1-100 μM）以浓度依赖性方式抑制大鼠膀胱和其他组织中[甲基-H]莨菪碱氯化物的特异性结合。在膀胱中的结合亲和力与心脏相似，明显高于颌下腺和大脑。米拉贝隆诱导大鼠离体膀胱中乙酰胆碱诱导收缩的浓度依赖性松弛。使用双位点模型的进一步分析表明，米拉贝隆的高亲和力和低亲和力组分的相对数量分别为 44.5%和 55.5%。各自的 pEC 值分别为 7.06 和 4.97。基于米拉贝隆的受体结合亲和力和药代动力学，口服 50 mg 米拉贝隆单剂量后 24 小时，人膀胱中的毒蕈碱受体占有率为 37%-76%。本研究结果首次表明，米拉贝隆不仅通过β肾上腺素受体激活，而且通过毒蕈碱受体阻断来松弛逼尿肌平滑肌。
米拉贝隆是第一个选择性β肾上腺素受体激动剂，代表了抗毒蕈碱药物治疗膀胱过度活动症（OAB）的替代品。本研究旨在阐明米拉贝隆是否直接与毒蕈碱受体结合，并影响大鼠膀胱中胆碱能激动剂诱导的收缩，并预测米拉贝隆口服后在人膀胱中的毒蕈碱受体占有率。结果表明，米拉贝隆治疗 OAB 患者的作用可能不仅与β肾上腺素受体激活有关，还与毒蕈碱受体阻断有关。
