The mechanism of action of omeprazole--a survey of its inhibitory actions in vitro.

In order to study the mechanism of inhibition of gastric acid secretion by omeprazole, its action was investigated in several different in vitro preparations. In preparations from isolated gastric mucosa, isolated rabbit gastric glands and isolated parietal cells, omeprazole was found to inhibit both basal and stimulated acid secretion. These effects were seen irrespective of whether acid formation was stimulated by histamine or by db-cAMP. The inhibitory pattern of omeprazole was found to be of a non-competitive nature against db-cAMP stimulation. Furthermore, in isolated glands, omeprazole was found to inhibit stimulation induced by high medium K+ and low Na+ concentrations. The basal membrane of the intact gland preparation was made permeable to molecules of large size by the use of digitonin, and acid secretion was subsequently initiated by the addition of exogenous ATP. Even under these conditions, omeprazole was found to be inhibitory, with an IC50-value comparable to that of intact glands. SCN- was found to mimic the action of omeprazole in that it counteracted both basal and stimulated acid secretion in the test models described above. In contrast, cimetidine was found to inhibit only histamine stimulation, consonant with its H2-receptor-blocking properties. In the gastric gland preparation, changes in oxygen consumption is closely related to changes in acid formation. When oxygen consumption and acid formation were measured in parallel under histamine stimulation, another benzimidazole, timoprazole (H 83/69) (structurally related to omeprazole), was found to inhibit both parameters. However, under non-stimulated conditions, timoprazole was found to have only a minor effect on the oxygen consumption. The isolated H+K+ATPase preparation was used in order to investigate the effects of omeprazole at the "proton pump level". This enzyme was found to be inhibited by omeprazole in a pH-dependent manner. Under neutral or slightly alkaline conditions, slight inhibition occurred. When the pH of the incubation media was progressively decreased, the inhibitory activity of omeprazole was augmented. Several reactions of the H+K+ATPase enzyme cycle were investigated, i.e., K+-stimulated ATPase- and pNPPase- activities and formation of phosphoenzyme. All three of these reactions were inhibited. The results presented are in agreement with the hypothesis that omeprazole inhibits gastric acid secretion by blocking the gastric H+K+ATPase.