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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Neuronally Released Acetylcholine Acts on the M₂ Muscarinic Receptor to Oppose the Relaxant Effect of Isoproterenol on Cholinergic Contractions in Mouse Urinary Bladder

Department of Pharmacology, School of Medicine, University of California, Irvine, California (F.J.E., S.A., K.J.P., G.J.P., M.S.S., J.A.T.); and Division of Neuronal Network, the Institute of Medical Science, University of Tokyo, Tokyo, Japan (M.M.)

We investigated whether M₂ muscarinic receptor activation opposes isoproterenol-induced relaxation in mouse urinary bladder and whether endogenous acetylcholine acts through a similar M₂ mechanism. When measured in urinary bladder from M₃ receptor knockout mice, the muscarinic agonist oxotremorine-M elicited only very weak contractions. In the presence of ,-methylene ATP (30 µM) and isoproterenol (1 µM), however, oxotremorine-M elicited a robust contractile response. This response was completely absent in bladder from M₂/M₃ double knockout mice, indicating that activation of the M₂ receptor inhibits the relaxant effect of isoproterenol on the contraction to ,-methylene ATP. Similar results were obtained when prostaglandin F₂ (5 µM) was used as the contractile agent but not when serotonin was used. Electrical field stimulation of the urinary bladder from wild-type mouse elicited contractions that were inhibited 20% by atropine and 40% by desensitization with ,-methylene ATP. When measured in the presence of ,-methylene ATP to desensitize the purinergic component of contraction, isoproterenol exhibited moderately greater relaxant activity in field-stimulated bladder from the M₂ knockout mouse compared with that observed in wild-type bladder. This differential relaxant effect of isoproterenol was greatly increased in the presence of physostigmine. In contrast, no differential effects were noted for isoproterenol in similar experiments on bladders from M₃ knockout and M₂/M₃ double knockout mice in the presence of physostigmine. Our results suggest that neuronally released acetylcholine acts on the M₂ muscarinic receptor to inhibit the relaxant effect of isoproterenol on the minor, cholinergic component of contraction in the field-stimulated mouse urinary bladder.

Address correspondence to: Dr. Frederick J. Ehlert, Department of Pharmacology, University of California, Irvine, CA 92697-4625. E-mail: fjehlert{at}uci.edu

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