Omeprazole, SCH 28080 and doxepin differ in their characteristics to inhibit H+/K+-ATPase driven proton accumulation by parietal cell membrane vesicles.

The effects of omeprazole, SCH 28080 and doxepin were studied on H+/K+-ATPase mediated H+ accumulation in parietal cell membrane vesicles. Omeprazole had no effect on the initial rate of H+ accumulation and the initial steady state concentration of H+; an inhibition was found after the vesicles were acidified. This inhibition was counteracted by the SH reducing agent dithioerythritol. SCH 28080 inhibited the initial rate of H+ accumulation and the steady state H+ concentration. The inhibitory effect of SCH 28080 was counteracted by KCl. Doxepin (3-100 microM) reduced the initial steady state H+ concentration. Doxepin concentrations lower than 0.5 microM had no such effect but dissipated the proton gradient after the vesicles were fully acidified. This doxepin effect was partially counteracted by KCl and was also obtained in vesicles in which the pump reaction was stopped by EDTA. These data show that (i) omeprazole is an acid-activated compound which interferes with SH groups of the H+/K+-ATPase localized inside the vesicles; (ii) SCH 28080 interferes with the K+ site of the H+/K+-ATPase; and (iii) doxepin interacts by a K+ antagonistic activity at the H+/K+-ATPase site and in addition by intravesicular neutralization and/or a protonophoric mechanism with the process of H+ formation.