Background & Aims: The physiologic significance of the M3 muscarinic receptor is unclear due to an absence of specific ligand. In the present study, M3 receptor knock-out (KO) mice were used to elucidate the role of M3 receptors in gastric acid secretion and gastric mucosal integrity. Methods: M3 KO versus wild-type mice aged 1 month to 2 years were included. Gastric acid secretion was assessed by both direct intragastric pH measurement and pylorus ligation. Serum gastrin and gastric mucosal histamine levels were determined by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. Morphologic analysis was performed by both immunohistochemistry and transmission electron microscopy. Results: Fasted M3 KO mice exhibited higher intragastric pH, lower acid output after pylorus ligation, a lower proportion of active parietal cells, and higher serum gastrin levels than fasted wild-type mice. Acid secretion in response to carbachol, histamine, gastrin 17, and 2-deoxy-D-glucose was impaired in the mutant mice. Although carbachol was still able to cause ∼30% acid output in M3 KO mice, the acid secretion was inhibited by pirenzepine or famotidine. Despite remarkable hypergastrinemia in M 3 KO mice, there were no trophic responses in the oxyntic mucosa with respect to the mucosal thickness, proliferation rate, and numbers of parietal and enterochromaffin-like cells. Cholecystokinin type 2 receptor antagonist YM022 was without the effect in M3 KO mice. Conclusions: The present study shows that M3 receptors are essential for basal acid secretion, a fully acid secretory response to histamine and gastrin, and the trophic responses of oxyntic mucosa to gastrin.
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