Impaired Gastric Secretion and Lack of Trophic Responses to Hypergastrinemia in M3 Muscarinic Receptor Knockout Mice

Takeshi Aihara, Teruaki Fujishita, Keiko Kanatani, Kazuharu Furutani, Eiji Nakamura, Makoto M. Taketo, Minoru Matsui, Duan Chen, Susumu Okabe

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1774-1784
Number of pages11
JournalGastroenterology
Volume125
Issue number6
DOIs
StatePublished - Jan 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Gastroenterology

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    Aihara, T., Fujishita, T., Kanatani, K., Furutani, K., Nakamura, E., Taketo, M. M., Matsui, M., Chen, D., & Okabe, S. (2003). Impaired Gastric Secretion and Lack of Trophic Responses to Hypergastrinemia in M3 Muscarinic Receptor Knockout Mice. Gastroenterology, 125(6), 1774-1784. https://doi.org/10.1053/j.gastro.2003.09.018