Crucial role of histamine for regulation of gastric acid secretion ascertained by histidine decarboxylase-knockout mice

Kazuharu Furutani, Takeshi Aihara, Eiji Nakamura, Satoshi Tanaka, Atsushi Ichikawa, Hiroshi Ohtsu, Susumu Okabe

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Histidine decarboxylase (HDC) represents the sole enzyme that produces histamine in the body. The present work investigated the role of endogenous histamine in carbachol- and gastrin-induced gastric acid secretion with HDC-knockout (HDC-/-) mice. Acid secretion was measured in either mice subjected to acute fistula production under urethane anesthesia or conscious mice that had previously undergone pylorus ligation. In wild-type mice, carbachol and gastrin significantly stimulated acid secretion, increasing gastric mucosal histamine. In contrast, in HDC-/- mice, carbachol and gastrin had little impact when either delivered alone or together. Nonetheless, the two agents achieved a synergistic effect when delivered together with exogenous histamine, stimulating acid secretion in HDC -/- mice. Such synergism was abolished by the histamine H 2-receptor antagonist famotidine. cAMP involvement in acid secretion was also examined with theophylline, a phosphodiesterase inhibitor, and forskolin, an adenylate cyclase activator. In wild-type mice, theophylline significantly increased acid secretion, enhancing carbachol- and gastrin-stimulated acid secretion. In contrast, in HDC-/- mice, theophylline failed to exert an effect on basal acid secretion, as well as carbachol- and gastrin-stimulated acid secretion. Although forskolin interacted with carbachol, allowing acid secretion in HDC-/- mice, similar results were not achieved with gastrin. Such results suggest that 1) histamine is essential for carbachol- and gastrin-stimulated gastric acid secretion in mice; and 2) histamine-induced cAMP production contributes to the in vivo response to carbachol or gastrin.

Original languageEnglish
Pages (from-to)331-338
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
Publication statusPublished - Oct 1 2003
Externally publishedYes


ASJC Scopus subject areas

  • Pharmacology

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