HUMAN GASTRIC-MUCOSAL ADENYLATE-CYCLASE - ACTIVATION BY HISTAMINE-H2-RECEPTOR STIMULATION AND INHIBITION BY CIMETIDINE INVITRO AND IN PEPTIC-ULCER PATIENTS

Biopsy specimens of human fundic mucosa from 96 subjects were assayed for adenylate cyclase activity to characterize specificity of the histamine receptor with selective agonists and antagonists in vitro, and to study the effect of cimetidine therapy. Histamine and the selective histamine H2-receptor agonist dimaprit were almost equally potent throughout the concentration-response curve (10-7-10-3 mol/l); maximal stimulation was obtained with concentrations of 10-4-10-3 mol/l, and half maximal stimulation with about 10-5 mol/l. The selective H1-receptor agonist PEA 10-5 and 10-3 mol/l failed to stimulate adenylate cyclase. Mepyramine 10-6 mol/l, a selective H1-receptor antagonist, and cimetidine 10-6 mol/l, a selective H2-receptor antagonist, did not affect basal adenylate cyclase activity. Histamine-stimulated adenylate cyclase was inhibited in a concentration dependent manner by cimetidine 10-7 and 10-5 mol/l, but not by the same concentrations of mepyramine. Almost identical basal adenylate cyclase activities of about 150 pmol cAMP/mg protein/20 min were found in gastric mucosal biopsies from controls and from peptic ulcer patients, whether or not treated with cimetidine. Histamine 10-5 mol/l doubled adenylate cyclase activity in the controls and the untreated ulcer group, but was completely ineffective in specimens from the cimetidine-treated peptic ulcer patients. The data underline the concept that the effects of histamine on acid secretion and on adenylate cyclase activity are linked together and that the therapeutic effect of cimetidine in ulcer treatment is related to histamine H2-receptor blockade followed by inhibition of adenylate cyclase. © 1979 Springer-Verlag.