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This study was performed to determine the relationship between net ion fluxes across the rat gastric mucosa and gastric mucosal damage after gastric ischemia and after intravenous administration of acetylsalicylic acid, and to determine the effect of cimetidine on these parameters. Gastric mucosal blood, albumin, and fluid loss that occurred after gastric ischemia was not associated with an increase in net H+ flux from mucosa to serosa. A significant increase in net Na+ and K+ flux from serosa to mucosa occurred. In the presence of cimetidine (150 mg/kg X h, i.v.), which reduced gastric damage, net H+ flux increased significantly, whereas there was an inhibition of Na+ and K+ fluxes. Acetylsalicylic acid-induced gastric hemorrhage preceded an increase in net H+ flux from serosa to mucosa, although net Na+ and K+ fluxes were unaffected. Cimetidine (150 mg/kg X h, i.v.) potentiated gastric hemorrhage and this was associated with an increase in net K+ flux from serosa to mucosa. These studies demonstrate that overt damage to the rat gastric mucosa can occur without changes in net ion fluxes across the gastric mucosa.

The present study has been made in anesthetized rats to characterize conditions of exposure to acid and extent of ischemia which determine the development of gastric hemorrhage. Gastric hemorrhage occurred in rats subjected to shock during exposure of the gastric lumen to acid after the reinfusion of withdrawn blood. When the acid concentration was constant, bleeding was dependent on the degree of shock. When hemorrhage shock was constant, bleeding from the stomach appeared pH dependent, although this did not quite achieve statistical significance. Cimetidine 2 x 10(-6) mol kg-1 min-1 (30 mg kg-1 hr-1) and 1 x 10(-5) mol kg-1 min-1 (150 mg kg-1 hr-1) significantly reduced gastric hemorrhage whether given prophylactically before gastric injury or therapeutically after completion of gastric injury. Because protection can be demonstrated against an injury involving exogenous acid and after the injury has been established, it is probable that the effectiveness of cimetidine in these studies is independent of its antisecretory effects.

The concept of two classes of histamine receptor, H1 and H2, is introduced and the chemical derivation of histamine H2-receptor antagonists is outlined briefly. Starting from the structure of histamine, chemical modification led eventually to burimamide, the first described histamine H2-receptor antagonist. Further stepwise modifications ultimately afforded metiamide and cimetidine. In vitro studies show that cimetidine is a specific competitive histamine H2-receptor antagonist. In vivo, it is a potent inhibitor of histamine-stimulated gastric acid secretion in rats and dogs after both intravenous and oral administration. It is equally potent as an inhibitor of pentagastrin-stimulated secretion. The evidence suggests that cimetidine inhibits gastric acid secretion through blockade of histamine H2-receptors in the gastric mucosa. Cimetidine has been shown to have low acute toxicity. Repeated dose studies of up to 24 months in rats and up to 12 months in dogs have been carried out and the results are presented and discussed. There is no known toxic effect which would limit the usefulness of cimetidine in man.