Vol. 303, Issue 3, 1301-1308, December 2002

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

Shingo Tsuji, Wei-Hao Sun, Masahiko Tsujii, Naoki Kawai, Arata Kimura, Yoshimi Kakiuchi, Shoichi Yasumaru, Masato Komori, Hiroaki Murata, Yutaka Sasaki, Sunao Kawano and Masatsugu Hori

Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Osaka, Japan (S.T., W.-H.S., M.T., N.K., A.K., Y.K., S.Y., M.K., H.M., Y.S., M.H.); and Department of Clinical Laboratory Science, Osaka University Faculty of Medicine, Suita, Japan (S.K.)

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) E₂ 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 PGE₂ 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 PGE₂ and reduced gastric damage caused by ethanol. Concomitant administration of AG-041R abolished the lansoprazole-induced COX-2 expression, and increased mucosal PGE₂ and mucosal protection. A specific COX-2 inhibitor blocked the lansoprazole-induced increase in mucosal PGE₂ 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.