Inhibitory action of E3810 on H+, K+-ATPase and gastric acid secretion in vitro

The inhibitory action of (±)-sodium 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl} methylsulfinyl]-1H-benzimidazole (E3810) on H+, K+-ATPase and gastric acid secretion in vitro was investigated, and it was compared with those of omeprazole (OPZ). E3810 concentration-dependently inhibited the H+, K+-ATPase activity of hog gastric vesicles. Its IC50 was 0.26 μM at pH 6.1. The inhibition was irreversible in nature and reversed by dithiothreitol. The potency of E3810 was 10-times that of omeprazole. Acidification of the intravesicular (luminal) space increased 1000-fold the potency of E3810, indicating that E3810 is a specific inhibitor which binds to the luminal cysteine residue of H+, K+-ATPase. Prolonged incubation of up to 180 min in the absence of thiol reagents of rabbit gastric glands which had been inhibited by a low concentration of E3810 (0.3 and 0.5 μM) time-dependently and completely reversed the inhibition, as determined by aminopyrine uptake, whereas it did not recover the acid secretion in omeprazole-treated glands. These results suggest that the acid-activated E3810 is a potent specific inhibitor of H+, K+-ATPase, and that the duration of the inhibitory action of E3810 is much shorter than that of omeprazole in isolated gastric glands.