Impaired gastric secretion and lack of trophic responses to hypergastrinemia in M3 muscarinic receptor knockout mice.
OBJECTIVE
The physiologic significance of the M(3) muscarinic receptor is unclear due to an absence of specific ligand. In the present study, M(3) receptor knockout (KO) mice were used to elucidate the role of M(3) receptors in gastric acid secretion and gastric mucosal integrity.


METHODS
M(3) 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 M(3) 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 approximately 30% acid output in M(3) 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 M(3) KO mice.


CONCLUSIONS
The present study shows that M(3) 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.
Aihara
Takeshi
T
Departmentof Applied Pharmacology, Kyoto Pharmaceutical University, Yamashina, Japan.
Fujishita
Teruaki
T
Kanatani
Keiko
K
Furutani
Kazuharu
K
Nakamura
Eiji
E
Taketo
Makoto M
MM
Matsui
Minoru
M
Chen
Duan
D
Okabe
Susumu
S
D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D004759:Enterochromaffin Cells / Q000378:metabolism; D005260:Female; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology; D005755:Gastrins / Q000097:blood*; D006632:Histamine / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043587:Receptor, Muscarinic M3 / Q000502:physiology*
D005755:Gastrins; D043587:Receptor, Muscarinic M3; D001569:Benzodiazepines; C087260:YM 022; D006632:Histamine; D002118:Calcium