title: Inhibitory mechanism of BRL37344 on muscarinic receptor-mediated contractions of the rat urinary bladder smooth muscle.
abstract: We examined the inhibitory mechanism of BRL37344, a beta-adrenoceptor agonist that is considered to be specific to beta(3)-subtype, on muscarinic receptor-mediated contraction of the rat urinary bladder smooth muscle. BRL37344 produced apparently biphasic concentration-relaxation curves in the urinary bladder smooth muscle contracted with carbachol (0.6 microM). The first and second phases had estimated p D(2) (-logEC(50)) values of 7.80+/-0.34 and 4.62+/-0.18, respectively ( n=6). The first component of the BRL37344 concentration-response curve was not affected by propranolol (1 microM), whereas it was inhibited by higher concentrations of the drug (10 microM or 30 microM). The second component was completely resistant to propranolol. On the other hand, BRL37344 produced monophasic concentration-relaxation of 30 mM KCl-precontracted urinary bladder smooth muscle with a p D(2) value of 8.34+/-0.18 ( n=6). Pretreatment of the urinary bladder smooth muscles with BRL37344 (30, 100 and 300 microM) significantly ( P<0.05) shifted the concentration-response curves for carbachol-induced contractions. In radioligand binding experiments, BRL37344 concentration-dependently displaced the specific binding of [(3)H] N-methyl scopolamine to muscarinic receptors on rat urinary bladder smooth muscle membranes. Additionally, BRL37344 inhibited [(3)H] N-methyl scopolamine binding to cloned human muscarinic receptors (M(1)-M(5)) expressed in Chinese hamster ovary cells. These results suggest that BRL37344 attenuates muscarinic receptor-mediated contractions through prevention of the agonists binding to their receptors, in addition to stimulation of beta(3)-adrenoceptors, in rat urinary bladder.
authors.affiliation: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kubota
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakahara
authors.forename: Motonari
authors.initials: M
authors.lastname: Yunoki
authors.forename: Akiko
authors.initials: A
authors.lastname: Mitani
authors.forename: Takeshi
authors.initials: T
authors.lastname: Maruko
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Kunio
authors.initials: K
authors.lastname: Ishii
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D011433:Propranolol / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013997:Time Factors; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D018679:Cholinergic Agonists; D004983:Ethanolamines; D022702:Receptors, Adrenergic, beta-3; D011976:Receptors, Muscarinic; C057368:BRL 37344; D002217:Carbachol; D011433:Propranolol