title: Muscarinic receptor subtypes and signalling involved in the attenuation of isoprenaline-induced rat urinary bladder relaxation.
abstract: β-Adrenoceptors are important mediators of smooth muscle relaxation in the urinary bladder, but the concomitant presence of a muscarinic agonist, e.g., carbachol, can attenuate relaxation responses by reducing potency and/or efficacy of β-adrenoceptor agonists such as isoprenaline. Therefore, the present study was designed to explore the subtypes and signalling pathways of muscarinic receptors involved in the attenuation of isoprenaline-induced isolated rat detrusor preparations using novel subtype-selective receptor ligands. In radioligand binding studies, we characterized BZI to be a M(3)-sparing muscarinic agonist, providing selective M(2) stimulation in rat bladder, and THRX-182087 as a highly M(2)-selective antagonist. The use of BZI and of THRX-182087 in the presence of carbachol enabled experimental conditions with a selective stimulation of only M(2) or M(3) receptors, respectively. Confirming previous findings, carbachol attenuated isoprenaline-induced detrusor relaxation. M(2)-selective stimulation partly mimicked this attenuation, indicating that both M(2) and M(3) receptors are involved. During M(3)-selective stimulation, the attenuation of isoprenaline responses was reduced by the phospholipase C inhibitor U 73,122 but not by the protein kinase C inhibitor chelerythrine. We conclude that both M(2) and M(3) receptors contribute to attenuation of β-adrenoceptor-mediated relaxation of rat urinary bladder; the signal transduction pathway involved in the M(3) component of this attenuation differs from that mediating direct contractile effects of M(3) receptors.
authors.affiliation: Depts. of Pharmacology and Pharmacotherapy and of Urology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Lambertus P W
authors.initials: LP
authors.lastname: Witte
authors.forename: Noach
authors.initials: N
authors.lastname: de Haas
authors.forename: Mathai
authors.initials: M
authors.lastname: Mammen
authors.forename: Eric L
authors.initials: EL
authors.lastname: Stangeland
authors.forename: Tod
authors.initials: T
authors.lastname: Steinfeld
authors.forename: Jayashree
authors.initials: J
authors.lastname: Aiyar
authors.forename: Martin C
authors.initials: MC
authors.lastname: Michel
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2 / Q000187:drug effects* / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000187:drug effects* / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011943:Receptors, Adrenergic, beta; D002217:Carbachol; D007545:Isoproterenol