Abstract

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. M₁receptor antagonism with pirenzepine, nitric oxide (NO) synthase inhibition withN^ω-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.