Potential mechanisms of interaction among secretagogues

Abstract

We have considered three possible explanations for the ability of cimetidine to inhibit basal gastric acid secretion as well as acid secretion stimulated by histamine, gastrin, and cholinergic agents. Two of these explanations cannot account for existing experimental observations. The possibility that cimetidine is a noncompetitive inhibitor of gastric acid secretion can be excluded because cimetidine has been shown to be a competitive antagonist of the action of histamine on gastric acid secretion as well as other functions. The hypothesis that histamine is the final common mediator of acid secretion cannot account for these findings: (1) anticholinergic agents inhibit the action of gastrin and histamine on acid secretion, and (2) gastrin as well as acetylcholine potentiate the action of histamine on acid secretion. In contrast, all of the existing experimental observations can be explained by the hypothesis that cimetidine inhibits the direct action of histamine on acid secretion and inhibits the potentiating action of histamine on acid secretion stimulated by gastrin or acetylcholine. We have also examined potentiating interactions between pairs of pancreatic secretagogues and have shown how an anticholingergic agent can appear to inhibit the action of noncholinergic secretagogues by virtue of its ability to abolish the potentiating interaction between the secretagogue and a cholinergic agent. Finally, we have illustrated how the pattern of the response to two agents which potentiate each other may reflect characteristics of the response mechanism rather than the quantitative features of the interaction between the two agents.