title: In vitro and in vivo pharmacological profile of the selective β3-adrenoceptor agonist mirabegron in rats.
abstract: To investigate the pharmacological properties of mirabegron in in vitro and in vivo, the effects on cAMP accumulation in Chinese hamster ovary (CHO) cells expressing rat β-adrenoceptors, the relaxant activity in isolated rat bladder smooth muscle, and the voiding effects in cerebral infarcted rats were evaluated. Mirabegron increased cAMP accumulation with EC(50) value and intrinsic activity of 19 nmol/L and 1.0, respectively, in CHO cells expressing rat β(3)-adrenoceptors. The EC(50) values and the intrinsic activities of mirabegron were 610 nmol/L and 0.6 for rat β(1)-adrenoceptors and were sumless and 0.1 for β(2)-adrenoceptors, respectively. Mirabegron showed concentration-dependent relaxant and full agonistic effects in rat bladder strips under passive tension with EC(50) value of 290 nmol/L. The concentration-response curve of mirabegron was affected neither by the β(1)-adrenoceptor selective antagonist CGP-20712A nor by the β(2)-adrenoceptor selective antagonist ICI-118,551. In in vivo studies with cerebral infarcted rats, a significant decrease in the volume voided per micturition compared with sham-operated rats was observed. Mirabegron dose-dependently increased the volume voided per micturition. In conclusion, we have extended the selectivity profile of mirabegron to rats and demonstrated that it is effective via stimulation of β(3)-adrenoceptors in a rat cerebral infarction model of detrusor overactivity.
authors.affiliation: Applied Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc, 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. toshiki.hatanaka@astellas.com
authors.forename: Toshiki
authors.initials: T
authors.lastname: Hatanaka
authors.forename: Masashi
authors.initials: M
authors.lastname: Ukai
authors.forename: Mai
authors.initials: M
authors.lastname: Watanabe
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Someya
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Ohtake
authors.forename: Masanori
authors.initials: M
authors.lastname: Suzuki
authors.forename: Koji
authors.initials: K
authors.lastname: Ueshima
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.forename: Masao
authors.initials: M
authors.lastname: Sasamata
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D058667:Adrenergic beta-3 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016466:CHO Cells; D002544:Cerebral Infarction / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014162:Transfection; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D022702:Receptors, Adrenergic, beta-3; D013844:Thiazoles; D000242:Cyclic AMP; C520025:mirabegron