Regulatory mechanism of gastric acid secretion and mucosal integrity. An analysis with various gene deficient mice.

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  • OKABE Susumu
    Department of Applied Pharmacology, Kyoto Pharmaceutical University
  • FURUTANI Kazuharu
    Department of Applied Pharmacology, Kyoto Pharmaceutical University
  • MAEDA Kazuhiko
    Department of Applied Pharmacology, Kyoto Pharmaceutical University
  • AIHARA Takeshi
    Department of Applied Pharmacology, Kyoto Pharmaceutical University
  • FUJISHITA Teruaki
    Department of Applied Pharmacology, Kyoto Pharmaceutical University
  • TONAI Shunsuke
    Department of Applied Pharmacology, Kyoto Pharmaceutical University

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  • 薬理学におけるトランスレーショナルリサーチ　　基盤研究から臨床まで　　各種遺伝子改変マウスを用いた胃酸分泌および胃粘膜細胞の恒常性の解明
  • 各種遺伝子改変マウスを用いた胃酸分泌および胃粘膜細胞の恒常性の解明
  • カクシュ イデンシ カイヘン マウス オ モチイタ イサン ブンピ オヨビ イ ネンマク サイボウ ノ コウジョウセイ ノ カイメイ

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Abstract

Mechanisms for gastric acid secretion have been elucidated through invention of new methods and new drugs. Current genetic technology have generated knockout (KO) mice lacking receptors such as CCK2, histamine H2, muscarinic M3 and M1, or enzymes such as histidine decarboxylase (HDC) and H+,K+-ATPase. Here, we review the functional and morphological changes in the gastric mucosa of such KO mice. In M3R-KO mice (intragastric pH 5.9), carbachol, histamine and gastrin stimulated acid secretion like they did in wild-type mice. Carbachol-stimulated acid secretion was significantly inhibited by famotidine and pirenzepine. The serum gastrin level in M3R-KO mice was increased, yet the stomach weight and the gastric mucosa remained unchanged. In H2R-KO mice (intragastric pH 3.0), serum gastrin and mucosal histamine levels significantly increased. Carbachol significantly stimulated acid secretion, yet histamine and gastrin had little or no effect on acid secretion. The stomach wet weight increased with time after birth and the serum albumin level was decreased. In the gastric mucosa with hyperplasia, numerous enlarged cysts and a marked expression of TGF-α were observed, indicating the occurrence of Menetrier's disease like mucosal changes. G/D cell ratio was greatly increased, providing evidence of the increased serum gastrin level. In HDC-KO mice (intragastric pH 4.5), the stomach weight was also increased 6 mo after birth, with no enlarged cysts in the gastric mucosa. Conclusion: The above results indicate that KO mice can be used to yield many important findings that selective antagonists cannot reveal.<br>

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