ROLE OF HISTAMINE(2) RECEPTOR IN INCREASED EXPRESSION OF RAT GASTRIC H-K+-ATPASE ALPHA-SUBUNIT INDUCED BY OMEPRAZOLE()

Omeprazole is a specific inhibitor in vivo of the functioning gastric acid pump, the H+-K+-adenosinetriphosphatase (ATPase), in the secretor y canaliculus of the parietal cell. It has been shown previously that omeprazole in rats led to an increase in the mRNA for the alpha-subuni t of the H+-K+-ATPase. Omeprazole causes a marked increase in circulat ing gastrin in this species, which in turn stimulates release of hista mine from the enterochromaffin-like cell. The possible role of this pa thway was investigated by the in vivo administration of famotidine, a potent H-2 receptor antagonist. A single intraperitoneal dose of famot idine, 200 mg/kg, produced a transient hypergastrinemia peaking at 3 h and normalizing at 12 h, inhibition of secretion that lasted for 12 h , but no change in the level of the alpha-subunit mRNA or of beta-acti n mRNA. In contrast, a single dose of omeprazole, 100 mg/kg, inhibited acid secretion and produced hypergastrinemia, peaking at 12 h, both e ffects lasting for the 24-h observation period. Omeprazole elevated th e alpha-subunit mRNA transiently by more than threefold at 3 h, with n ormal levels being restored at 24 h. The administration of famotidine 1 h after omeprazole did not change the effects of omeprazole on acid secretion but elevated the gastrin levels further. There was now no el evation of the alpha-subunit mRNA for the first 6 h, but a small incre ase at 12 h and a further increase to approximately 2.5-fold at 24 h. Hence the acute effect of omeprazole on alpha-subunit mRNA transcripti on appears to require activation of the H-2 receptor on the parietal c ell, probably resulting from the histamine release induced by hypergas trinemia.