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 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.