Omeprazole: Its Influence on Gastric Acid Secretion, Gastrin and ECL Cells

Abstract

The H+,K+-ATPase inhibitor omeprazole is a highly effective gastric antisecretory agent, both in animals and man, with a long duration of action. These properties are shared by a number of recently described histamine H,-receptor antagonists. In life-long oncogenicity studies of these H,-receptor antagonists, as well as with the H+,K+-ATPase inhibitor omeprazole, gastric enterochromaffin-like cell (ECL cell) hyperplasia and carcinoids have been found. The purpose of this paper is to summarize available evidence for the "Gastrin Hypothesis" to explain the development of ECL-cell hyperplasia. The hypothesis may be outlined as follows: 1) Inhibition of gastric acid secretion leads to elevated antral pH and, secondarily, to release of gastrin from the antral gastrin cells into the blood stream. 2) Gastrin causes both general hypertrophy of the oxyntic mucosa and hyperplasia of the ECL cells in the oxyntic mucosa. That this sequence of events occurs not only with omeprazole but also with other effective gastric antisecretory agents has been verified in the rat by giving the H,-receptor antagonist ranitidine as a continuous infusion. Ranitidine caused a hypergastrinemia of a similar magnitude as that seen after omeprazole, provided that the acid secretion was inhibited to a similar degree. At similar gastrin levels, ECL-cell hyperplasia of the same magnitude developed during both ranitidine and omeprazole treatment. Antrectomy prevented the development of ECL-cell hyperplasia during omeprazole treatment, indicating that the hyperplasia was not due to the drug treatment per se, but rather to the hypergastrinemia. Both the hypergastrinemia and the ECL-cell hyperplasia were found to be reversible. Control plasma gastrin levels were reached within a few days of stopping long-term treatment, and the ECL-cell density was back to normal 20 weeks after discontinuing 10 weeks of treatment with highdose omeprazole. We conclude from these studies that the ECL-cell hyperplasia seen in rats after long-term treatment with gastric acid secretion inhibitors is reversible and secondary to the hypergastrinemia, and is not caused by the drugs per se. Furthermore, although the gastrin mechanism for the regulation of the ECL cells seems to be similar in different species, there are quantitative differences with regard to the ECLcell density and possibly also the sensitivity of ECL cells to gastrin.

Effects of Partial Resection of Acid-Secreting Mucosa on Plasma Gastrin and Enterochromaffin-Like Cells in the Rat Stomach

“…From available results, it appears unlikely that either achlorhydria or antisecretagogues per se are responsible for the proliferation of ECL cells. The 'gastrin hy pothesis' postulates that hypergastrinemia (whatever the cause) results in ECL cell hy perplasia and may give rise to the develop ment of gastric ECL cell carcinoids in rats in response to life-long hypergastrinemia [13]. The results of the present study support the 'gastrin hypothesis'; ECL cell hyperplasia has developed 10 weeks after surgery and ECL cell density is correlated to the plasma gastrin levels.…”

“…Since these cells represent the major store of hista mine in the rat stomach, the histamine con centration seems to reflect the number of ECL cells [3]. Under conditions of pharma cological inhibition of acid secretion [3,13], the ECL cell number is well correlated to the gastrin level. Some investigators have ques tioned the hypothesis that gastrin is respon sible for ECL cell hyperplasia after druginduced inhibition of acid secretion [14,20].…”

“…The 'gastrin hypothesis' maintains that the hyperplasia of ECL cells, including the carcinoids that develop in the stomach of rats after life-long treatment with effective antisecretagogues, is a consequence of hypergastrinemia [13]. However, the role of gas trin as the factor stimulating the prolifera tion of the ECL cells during treatment with antisecretagogues has not been generally ac cepted [14], As a result of complete fundectomy, i.e.…”

Lansoprazole and Omeprazole Have Similar Effects on Plasma Gastrin Levels, Enterochromaffin-Like Cells, Gastrin Cells and Somatostatin Cells in the Rat Stomach

“…Based on the results of these studies, it has been con cluded that long-term hypergastrinemia will result in ECL cell hyperplasia in rats and. eventually, in the development of gastric ECL cell carcinoids if the hypergastrinemia is sus tained during most of the life span [8,[14][15][16][17].…”

Effect of 7 Years’ Daily Oral Administration of Omeprazole to Beagle Dogs

“…In the preclinical safety program, to study long-term effects of omeprazole, high doses were given for 1 year to dogs and life-long to rodents [3]. As an early part of this program, the present 7 years' study in dogs was started in order to study possible adverse effects of long-term treatment with omeprazole in a dose resulting in clinically relevant plas ma concentrations and an acid inhibition of about 50%, which was the reduction in acid secretion reported follow ing vagotomy [5], The long-term effects of hypergastrinemia secondary to acid inhibition by high doses of ome prazole have been extensively investigated in the rat [3,[6][7][8], In the present study, the dog was choosen for 7 years of treatment since the lifetime of the rat is maximally 2 1/2 years. In addition to the investigation of clinical and pathological effects, including histopathology of most or gans and tissues at the end of the study, special attention was made to follow the histology of the stomach -the tar get organ for omeprazole.…”