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

• Published in: The Journal of pharmacology and experimental therapeutics 2003-02, Vol.304 (2), p.675-682
• Main Authors: Stengel, Peter W., Cohen, Marlene L.
• Format: Article
• Language: English
• Subjects: Animals; Cyclooxygenase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Electric Stimulation - methods; Gastric Fundus - drug effects; Gastric Fundus - physiology; In Vitro Techniques; Male; Mice; Mice, Knockout; Muscarinic Agonists - pharmacology; Muscle Relaxation - drug effects; Muscle Relaxation - physiology; Nitric Oxide - antagonists & inhibitors; Nitric Oxide - physiology; Receptor, Muscarinic M1; Receptor, Muscarinic M3; Receptors, Muscarinic - deficiency; Receptors, Muscarinic - genetics; Receptors, Muscarinic - physiology
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.102.042283

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 with Nω-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.