Role of histamine2 receptor in increased expression of rat gastric H(+)-K(+)-ATPase alpha-subunit induced by omeprazole

Abstract

Omeprazole is a specific inhibitor in vivo of the functioning gastric acid pump, the H(+)-K(+)-adenosinetriphosphatase (ATPase), in the secretory canaliculus of the parietal cell. It has been shown previously that omeprazole in rats led to an increase in the mRNA for the alpha-subunit of the H(+)-K(+)-ATPase. Omeprazole causes a marked increase in circulating gastrin in this species, which in turn stimulates release of histamine from the enterochromaffin-like cell. The possible role of this pathway was investigated by the in vivo administration of famotidine, a potent H2 receptor antagonist. A single intraperitoneal dose of famotidine, 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-actin mRNA. In contrast, a single dose of omeprazole, 100 mg/kg, inhibited acid secretion and produced hypergastrinemia, peaking at 12 h, both effects lasting for the 24-h observation period. Omeprazole elevated the alpha-subunit mRNA transiently by more than threefold at 3 h, with normal 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 elevation of the alpha-subunit mRNA for the first 6 h, but a small increase at 12 h and a further increase to approximately 2.5-fold at 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Review article: the pharmacological inhibition of gastric acid secretion—tolerance and rebound

“…There is also some experimental evidence that potent acid suppression may upregulate the H + , K + -ATPase. 37 However, this effect seems to be mediated via the histamine H 2 -receptor, 37 supporting the hypothesis outlined above. Moreover, other studies indicate that H + , K + -ATPase mRNA does not change during dosing with proton pump inhibitors for longer periods of time.…”

“…If acid suppressive treatment has been given for a long period of time, it is possible that an increased parietal cell mass 34,35 or an upregulated H + , K + -ATPase activity 37 could partially explain post-treatment rebound acid hypersecretion. The animal studies described above indicate that this is not the case, 37, 38 although we presently lack experimental studies in humans addressing this question.…”

The effects of rabeprazole on parietal cells and enterochromaffin-like cells in rats: a comparison with omeprazole

“…[30][31][32] Based on earlier reports, one of the pathways that stimulates ATPase gene expression is as follows: gastrinAEgastrin/CCK-B receptor of ECL cellsAE histidine decarboxylase gene activationAEhistamineAE H 2 receptor of parietal cellsAEcAMP/intracellular calcium concentration ([Ca 2ϩ ]i) AEH ϩ , K ϩ -ATPase gene activation, and morphological activation (stimulation). [27][28][29] The present study demonstrated that the histamine content of the fundic mucosa was higher with omeprazole treatment than with rabeprazole treatment. In addition, the increase in H ϩ , K ϩ -ATPase mRNA was markedly greater with omeprazole treatment than with rabeprazole treatment, and the difference was significant at a dose of 100mg/kg.…”

“…27 Thus, the elevation of histamine, not gastrin, is the most significant factor promoting an increase in ATPase gene expression and the transformation of parietal cells to a more stimulated state. 27,28 Our previous experiments have also demonstrated that the morphological activation of parietal cells induced by hypergastrinemia, and the subsequent increase of H ϩ , K ϩ -ATPase synthesis by these cells, are mediated by an increase in histidine decarboxylase gene expression in ECL cells that is stimulated through the gastrin/cholecystokinin (CCK)-B receptor. 29 Miyazaki et al 30 have suggested that the massive urinary excretion of histamine caused by treatment with rabeprazole reflects the gastrin-induced mobilization of gastric histamine, and that neither rabeprazole itself nor rabeprazole-induced luminal pH elevation directly promotes the mobilization of oxyntic mucosal histamine.…”

Effects of omeprazole and pirenzepine on enterochromaffin-like cells and parietal cells in rat stomach

“…In rat parietal cells, the hypergastrinemia induced by multiple doses of omeprazole causes a significant increase in H ϩ -K ϩ -adenosine triphosphatase (ATPase) gene expression 9 and in the number of morphologically fully stimulated parietal cells, in which the proton pump protein has moved into the apical membrane. 10 In the rabbit, blocking H ϩ -K ϩ -ATPase by omeprazole enhances the degradation and macrophage-mediated elimination of parietal cells, and also causes an increase in parietal cell production.…”