Mizoguchi H, Ogawa Y, Kanatsu K, Tanaka A, Kato S, Takeuchi K
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan.
J Gastroenterol Hepatol. 2001 Oct;16(10):1112-9. doi: 10.1046/j.1440-1746.2001.02592.x.
We evaluated the effect of rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid), a novel anti-ulcer drug, on indomethacin-induced small intestinal lesions in rats.
The animals were administered indomethacin (10 mg/kg, s.c.), and they were killed 24 h later. Rebamipide (30-300 mg/kg) was administered p.o. twice, 30 min before, and 6 h after indomethacin.
Indomethacin caused hemorrhagic lesions in the rat small intestine, accompanied by an increase in enterobacterial translocation, inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO) activities, as well as thiobarbituric acid (TBA) reactants, and these changes were significantly prevented by the supplementation with 16,16-dimethyl prostaglandin E2 (dmPGE2; 10 microg/kg, i.v.) or the pretreatment of animals with the antibiotic ampicillin. Treatment of the animals with rebamipide dose-dependently prevented the development of intestinal lesions, and this effect was mimicked by i.v. administration of superoxide dismutase (SOD: 3000 U/kg) + catalase (CAT: 5000 U/kg). The protection by rebamipide was accompanied by a significant suppression of the increase in both MPO and iNOS activities, and a complete inhibition of the increase in TBA reactants, while SOD + CAT significantly inhibited the increase of MPO activity and TBA reactants, but not iNOS activity. The bacterial translocation following indomethacin was also significantly decreased by either rebamipide or SOD + CAT.
These results confirmed the importance of enterobacteria and iNOS/NO in the pathogenesis of indomethacin-induced small intestinal lesions, and suggested that rebamipide prevents the development of these lesions, probably by its radical scavenging action.
我们评估了新型抗溃疡药物瑞巴派特（2-(4-氯苯甲酰氨基)-3-[2(1H)-喹啉酮-4-基]丙酸）对吲哚美辛诱导的大鼠小肠损伤的影响。
给动物皮下注射吲哚美辛（10 mg/kg），24小时后处死。瑞巴派特（30 - 300 mg/kg）经口给药，在吲哚美辛给药前30分钟及给药后6小时各给药一次。
吲哚美辛导致大鼠小肠出现出血性损伤，同时伴有肠细菌移位增加、诱导型一氧化氮合酶（iNOS）和髓过氧化物酶（MPO）活性升高以及硫代巴比妥酸（TBA）反应物增加，补充16,16-二甲基前列腺素E2（dmPGE2；10 μg/kg，静脉注射）或用抗生素氨苄西林对动物进行预处理可显著预防这些变化。用瑞巴派特治疗动物可剂量依赖性地预防肠道损伤的发生，静脉注射超氧化物歧化酶（SOD：3000 U/kg）+过氧化氢酶（CAT：5000 U/kg）可模拟这种作用。瑞巴派特的保护作用伴随着MPO和iNOS活性增加的显著抑制以及TBA反应物增加的完全抑制，而SOD + CAT显著抑制MPO活性和TBA反应物的增加，但不抑制iNOS活性。瑞巴派特或SOD + CAT也可显著降低吲哚美辛后的细菌移位。
这些结果证实了肠细菌和iNOS/NO在吲哚美辛诱导的小肠损伤发病机制中的重要性，并表明瑞巴派特可能通过其自由基清除作用预防这些损伤的发生。
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