Crucial role of histamine for regulation of gastric acid secretion ascertained by histidine decarboxylase-knockout mice.
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 H2-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.
Furutani
Kazuharu
K
Department of Applied Pharmacology, Kyoto Pharmaceutical University, Misasagi, Yamashina, Japan.
Aihara
Takeshi
T
Nakamura
Eiji
E
Tanaka
Satoshi
S
Ichikawa
Atsushi
A
Ohtsu
Hiroshi
H
Okabe
Susumu
S
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005755:Gastrins / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology*; D006640:Histidine Decarboxylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D013806:Theophylline / Q000494:pharmacology
D005755:Gastrins; D005576:Colforsin; D006632:Histamine; D002217:Carbachol; D013806:Theophylline; D006640:Histidine Decarboxylase