Tsuji Shingo, Sun Wei-Hao, Tsujii Masahiko, Kawai Naoki, Kimura Arata, Kakiuchi Yoshimi, Yasumaru Shoichi, Komori Masato, Murata Hiroaki, Sasaki Yutaka, Kawano Sunao, Hori Masatsugu
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
J Pharmacol Exp Ther. 2002 Dec;303(3):1301-8. doi: 10.1124/jpet.102.035204.
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.
质子泵抑制剂（PPIs）是一类具有胃抑酸和黏膜保护作用的抗溃疡药物。PPI诱导胃黏膜保护的机制尚不清楚。本研究旨在探讨兰索拉唑诱导大鼠胃黏膜保护的机制。给大鼠分别单独给予0.5、5和50mg/kg/天的兰索拉唑，或同时给予兰索拉唑（50mg/kg/天）和一种特异性胃泌素受体拮抗剂3R-1-（2,2-二乙氧基乙基）-（（4-甲基苯基）氨基甲酰甲基）-3-（（4-甲基苯基）脲基吲哚啉-2-酮）（AG-041R）（3、10和30mg/kg/天），持续14天。检测血清胃泌素浓度。采用蛋白质免疫印迹法和免疫组织化学染色法分析胃黏膜中环氧化酶（COX-1和COX-2）的表达。另一组大鼠用于检测：1）胃黏膜中前列腺素（PG）E2的水平；2）药物对无水乙醇所致胃损伤的影响；3）COX-2特异性抑制剂对胃黏膜中PGE2的影响以及兰索拉唑提供的黏膜保护作用。兰索拉唑剂量依赖性地增加血清胃泌素浓度，并增强COX-2的黏膜表达，但不影响COX-1的表达。兰索拉唑增加胃黏膜PGE2水平，并减轻乙醇所致的胃损伤。同时给予AG-041R可消除兰索拉唑诱导的COX-2表达，并增加黏膜PGE2水平和黏膜保护作用。一种特异性COX-2抑制剂可阻断兰索拉唑诱导的黏膜PGE2增加和黏膜保护作用。内源性胃泌素激活胃泌素受体在兰索拉唑对大鼠胃COX-2上调和黏膜保护作用中起关键作用。
