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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

M₁ Receptor-Mediated Nitric Oxide-Dependent Relaxation Unmasked in Stomach Fundus from M₃ Receptor Knockout Mice

Eli Lilly and Company, Lilly Research Laboratories, Neuroscience Research, Lilly Corporate Center, Indianapolis, Indiana

Muscarinic receptors can mediate both contractile and relaxant responses in smooth muscle. The stomach fundus from wild-type mice possesses a neuronal M₁ receptor that mediates relaxation to carbamylcholine and (4-hydroxy-2-butynyl)-1-trimethylammonium-3-chlorocarbanilate chloride (McN-A-343) but is masked by M₃ receptor-mediated contraction to both agonists. When the M₃ receptor was deleted, cholinergic-induced relaxation was unmasked. M₁ receptor antagonism with pirenzepine, nitric oxide (NO) synthase inhibition with N-nitro-L-arginine methyl ester hydrochloride, and inhibition of neuronal activation with tetrodotoxin abolished relaxation to McN-A-343 in tissues from M₃ receptor knockout mice, supporting the neuronal localization of an M₁ receptor that activated NO release to effect relaxation. However, the cyclooxygenase inhibitor indomethacin did not affect contraction or relaxation to carbamylcholine in stomach fundus from wild-type or M₃ receptor knockout mice, indicating that cyclooxygenase products played no role in these responses. The neuronal M₁ receptor modulated relaxation induced by carbamylcholine and McN-A-343 but not relaxation induced by electric field stimulation of the stomach fundus. These data support the presence of M₁ receptor-mediated relaxation in the stomach and suggest that when the M₃ receptor is eliminated or blocked, M₁ receptor-mediated gastric relaxation may be enhanced, possibly leading to alterations in gastric emptying and subsequent effects on body weight.

Address correspondence to: Peter W. Stengel, Eli Lilly and Company, Lilly Research Laboratories, Neuroscience Research, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: stengel_peter_w{at}lilly.com

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