title: 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) 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.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. tsuji@medone.med.osaka-u.ac.jp
authors.forename: Shingo
authors.initials: S
authors.lastname: Tsuji
authors.forename: Wei-Hao
authors.initials: WH
authors.lastname: Sun
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tsujii
authors.forename: Naoki
authors.initials: N
authors.lastname: Kawai
authors.forename: Arata
authors.initials: A
authors.lastname: Kimura
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Kakiuchi
authors.forename: Shoichi
authors.initials: S
authors.lastname: Yasumaru
authors.forename: Masato
authors.initials: M
authors.lastname: Komori
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Murata
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Sunao
authors.initials: S
authors.lastname: Kawano
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000818:Animals; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis; D000431:Ethanol / Q000494:pharmacology; D005753:Gastric Mucosa / Q000737:chemistry / Q000187:drug effects* / Q000201:enzymology; D007527:Isoenzymes / Q000032:analysis / Q000096:biosynthesis*; D064747:Lansoprazole; D008297:Male; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use*; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011949:Receptors, Cholecystokinin / Q000502:physiology*; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011949:Receptors, Cholecystokinin; D064747:Lansoprazole; D000431:Ethanol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D009853:Omeprazole