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. © 2011 The Author(s).