Lansoprazole Induces Mucosal Protection through Gastrin Receptor-Dependent Up-Regulation of Cyclooxygenase-2 in Rats

Abstract

Proton pump inhibitors (PPIs) are antiulcer agents that have both gastric antisecretory and mucosal protective actions. The mechanisms of PPI-induced gastric mucosal protection are not known. The present study was designed to examine the mechanism for lansoprazole-induced gastric mucosal protection in rats. Rats were given 0.5, 5, and 50 mg/kg/day lansoprazole alone or both lansoprazole (50 mg/kg/day) and a specific gastrin receptor antagonist 3R-1-(2,2-diethoxyethyl)-((4-methylphenyl)amino-carbonyl methyl)-3-((4-methylphenyl)ureidoindoline-2-one) (AG-041R) (3, 10, and 30 mg/kg/day) for 14 days. Serum gastrin concentrations were measured. The expression of cyclooxygenases (COX-1 and COX-2) in the gastric mucosa was analyzed using Western blotting and immunohistochemical staining. Another series of rats was used to examine the 1) levels of prostaglandin (PG) E 2 in gastric mucosa, 2) influences of the drugs on gastric damage caused by absolute ethanol, and 3) effects of a COX-2-specific inhibitor on PGE 2 in the gastric mucosa and the mucosal protection afforded by lansoprazole. Lansoprazole dose dependently increased the serum gastrin concentration and enhanced the mucosal expression of COX-2 but not that of COX-1. Lansoprazole increased gastric mucosal PGE 2 and reduced gastric damage caused by ethanol. Concomitant administration of AG-041R abolished the lansoprazole-induced COX-2 expression, and increased mucosal PGE 2 and mucosal protection. A specific COX-2 inhibitor blocked the lansoprazole-induced increase in mucosal PGE 2 and mucosal protection. Activation of gastrin receptors by endogenous gastrin has a pivotal role in the effects of lansoprazole on COX-2 up-regulation and mucosal protection in the rat stomach.

Effects of lansoprazole on the expression of VEGF and cellular proliferation in a rat model of acetic acid-induced gastric ulcer

“…In addition, in an experimental model of gastric mucosal injury-related ulceration produced using 0.6 N HCl or absolute ethanol, neither marked inhibition of acid secretion nor alkaline reflux-related increase in the gastric pH ameliorated the mucosal injury. On the other hand, PPI administration attenuated such injury, because these drugs not only inhibit gastric acid secretion, but also exert cytoprotective effects [6,7].…”

Lansoprazole Raises Somatostatin, Calcitonin Gene-Related Peptide, and Substance P Levels in Healthy Human Plasma

“…24,25) There are reports that the drug might promote bicarbonate secretion, 24) or increase cyclooxygenase-2 and prostaglandin (PG) E 2 levels. 25) Recently, there have been many reports that capsaicin-sensitive afferent nerves are related to improved mucosal blood flow. Stimulation of the nervea causes the release of CGRP and substance P from nerve endings.…”

Folic Acid Supplementation Ameliorates Inflammation and Apoptosis in Ethanol-Induced Gastric Ulceration in Rats

“…Omeprazole has been extensively used to treat various ailments regarding gastric acid secretion [34]. Besides the anti-secretory effect of omeprazole in acid dependent ulcer models, it is well known to have mucosal protective effect [35], and the healing rates among patients suffering peptic ulcer are mainly due to its gastric mucosa protective effect, associated with the ability to suppress gastric juice acidity [36].…”