201. Muscarinic receptor subtypes and signalling involved in the attenuation of isoprenaline-induced rat urinary bladder relaxation
- Author
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Noach de Haas, Eric L. Stangeland, Tod Steinfeld, Mathai Mammen, Lambertus P. W. Witte, Martin C. Michel, Jayashree Aiyar, Urology, Other Research, and Pharmacology and pharmacotherapeutics
- Subjects
Male ,Relaxation ,medicine.medical_specialty ,Carbachol ,Muscle Relaxation ,Urinary Bladder ,M2 muscarinic receptor ,Stimulation ,Muscarinic Antagonists ,Muscarinic Agonists ,Muscarinic agonist ,THRX-182087 ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Isoprenaline ,Receptors, Adrenergic, beta ,Muscarinic acetylcholine receptor ,medicine ,Animals ,Rats, Wistar ,Receptor ,β-Adrenoceptor ,M3 muscarinic receptor ,030304 developmental biology ,Receptor, Muscarinic M3 ,Pharmacology ,Receptor, Muscarinic M2 ,0303 health sciences ,Chemistry ,Isoproterenol ,Muscarinic acetylcholine receptor M3 ,General Medicine ,Adrenergic beta-Agonists ,Rats ,Muscle relaxation ,Endocrinology ,Original Article ,030217 neurology & neurosurgery ,Signal Transduction ,medicine.drug - 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.
- Published
- 2011
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