Takeuchi Koji, Miyazawa Tohu, Tanaka Akiko, Kato Shinichi, Kunikata Tomonori
Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto, Japan.
Digestion. 2002;66(1):30-41. doi: 10.1159/000064419.
BACKGROUND/AIM: Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin produce damage in the small intestine as a major adverse reaction. We examined the effect of various NSAIDs on intestinal motility and investigated the pathogenic importance of motility changes in the intestinal ulcerogenic response to indomethacin in rats.
Animals without fasting were given various NSAIDs (indomethacin 10 mg/kg, diclofenac 40 mg/kg, flurbiprofen 20 mg/kg, naproxen 40 mg/kg) s.c., and in the case of indomethacin, the following parameters were examined in the small intestine 24 h later; the lesion score, the number of enterobacteria and myeloperoxidase (MPO) as well as inducible nitric oxide (iNOS) activity. Intestinal motility was monitored as intraluminal pressure recordings using a balloon under anesthesia.
All NSAIDs tested decreased mucosal PGE(2) levels and produced hemorrhagic lesions in the small intestine, accompanied by intestinal hypermotility. As representative of NSAIDs, indomethacin also increased the extent of enterobacterial invasion and MPO as well as iNOS activity before the occurrence of intestinal damage, and the hypermotility response was observed earlier than the onset of any other event caused by this agent. The intestinal lesions induced by indomethacin were prevented by either supplementation with dmPGE(2), inhibition of bacterial invasion with ampicillin or inhibition of iNOS activity with aminoguanidine, while the hypermotility response was prevented by dmPGE(2) only. In addition, the observed effects of dmPGE(2) were all mimicked by atropine when the intestinal hypermotility was suppressed by this agent.
These results suggest the pathogenic importance of intestinal hypermotility in the intestinal ulcerogenic response to NSAIDs in rats and show that this event is critical for the occurrence of enterobacterial invasion under PG deficiency, followed by various inflammatory changes and damage in the mucosa. This study also suggests that the antispasmodic drug is protective against NSAID-induced intestinal lesions.
背景/目的：吲哚美辛等非甾体抗炎药（NSAIDs）会对小肠造成损伤，这是其主要的不良反应。我们研究了各种NSAIDs对肠道运动的影响，并探讨了运动变化在大鼠对吲哚美辛致肠道溃疡反应中的致病重要性。
对未禁食的动物皮下注射各种NSAIDs（吲哚美辛10mg/kg、双氯芬酸40mg/kg、氟比洛芬20mg/kg、萘普生40mg/kg），对于吲哚美辛，24小时后在小肠检测以下参数；损伤评分、肠杆菌数量、髓过氧化物酶（MPO）以及诱导型一氧化氮合酶（iNOS）活性。在麻醉状态下，使用气囊通过记录肠腔内压力来监测肠道运动。
所有测试的NSAIDs均降低了黏膜前列腺素E2（PGE2）水平，并在小肠产生出血性损伤，同时伴有肠道运动亢进。作为NSAIDs的代表，吲哚美辛在肠道损伤发生前还增加了肠杆菌侵袭程度、MPO以及iNOS活性，并且运动亢进反应比该药物引起的任何其他事件出现得更早。吲哚美辛诱导的肠道损伤可通过补充二甲基前列腺素E2（dmPGE2）、用氨苄西林抑制细菌侵袭或用氨基胍抑制iNOS活性来预防，而运动亢进反应仅可通过dmPGE2预防。此外，当用阿托品抑制肠道运动亢进时，dmPGE2观察到的所有效应均被阿托品模拟。
这些结果表明肠道运动亢进在大鼠对NSAIDs的肠道溃疡反应中具有致病重要性，并表明该事件对于在前列腺素缺乏情况下肠杆菌侵袭的发生至关重要，随后会发生各种炎症变化和黏膜损伤。本研究还表明抗痉挛药物对NSAIDs诱导的肠道损伤具有保护作用。
