Effect of the histamine (H2) inhibitor metiamide on histamine-stimulated bile flow in dogs

Abstract

The effects of the histamine H2-receptor inhibitor metiamide on histamine-stimulated canine bile flow and gastric hydrogen ion output were evaluated. Histamine was found to stimulate bile volume in doses comparable to those that stimulated gastric hydrogen ion output; both responses appeared to have the same maximal response dose, 150 mug/kg per h. Metiamide alone did not alter hepatic bile flow. Administration of metiamide, 2 mg/kg per h, along with various doses of histamine demonstrated that the H2-receptor antagonist decreased bile volume and gastric hydrogen ion output from values obtained with histamine administration alone. The D50 of histamine for bile flow was 16.3 mug/kg per h and the D50 for hydrogen ion output was 44.2 mug/kg per h, Kinetic analysis suggests that the decrease in histamine-stimulated hydrogen ion output produced by metiamide is the result of competitive inhibition; the decrease in histamine-stimulated bile volume by metiamide which is different from the hydrogen ion inhibition, suggests noncompetitive inhibition. These data indicate that the mechanism of histamine choleresis is different from the mechanism of histamine-stimulated gastric acid output and that histamine-stimulated bile flow may not be the result of direct hormone-receptor interaction.

Effects of Histamine and Histamine Antagonists on Hepatic Bile Flow in the Conscious Sheep

“…A constant degree of inhibition in the presence of increasing doses of agonist (histamine) strongly suggested that the antagonists (cimetidine and ranitidine) were not competing with the agonist for receptor sites, indicating noncompetitive inhibition. Similar conclusions were drawn by Kaminski et al (1976) using another H2-antagonist, metiamide. The concomitant infusion of diphenhydramine, an HI-antagonist, enhanced the inhibitory action of small doses of either cimetidine or ranitidine.…”

“…The choleretic effect of histamine, although a new finding in the sheep, has been reported previously in the dog (Jones & Grossman, 1969;Kaminski, Ruwart & Jellineck, 1976). Histamine most probably directly stimulated bile flow since gastrectomized dogs (without any secretin release) also responded to histamine.…”

“…Their bile salt data were derived indirectly from electrolyte concentrations. Subsequent work by Kaminski et al (1976) on the dog did not confirm this. Although Kaminski et al did not comment on the site of action of histamine, it could be deduced from their data that histamine probably increased the bile salt-independent component of bile flow.…”

H-2 Histamine Receptors

“…In the same study the amounts of pancreatic and biliary secretion were unaffected by either the cimetidine or the reduced acid load in the duodenum. However, hista mine stimulates bile tlow and this is blocked (noncompetitively) by metia mide (45).…”