Pathogenic Importance of Intestinal Hypermotility in NSAID-Induced Small Intestinal Damage in Rats
Pathogenic Importance of Intestinal Hypermotility in NSAID-Induced Small Intestinal Damage in Rats
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DOI：
10.1159/000064419
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发表时间：
2002-10
期刊：
影响因子：
3.2
通讯作者：
K. Takeuchi;Tohu Miyazawa;A. Tanaka;S. Kato;T. Kunikata
中科院分区：
文献类型：
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作者：
K. Takeuchi;Tohu Miyazawa;A. Tanaka;S. Kato;T. Kunikata
背景/目的：非甾体类抗炎药（NSAID）如吲哚美辛会对小肠产生损伤，这是一种主要的不良反应。我们研究了各种非甾体抗炎药对肠蠕动的影响，并研究了在大鼠对吲哚美辛的肠溃疡反应中蠕动变化的致病重要性。研究方法：未禁食的动物皮下给予各种NSAID（吲哚美辛10 mg/kg、双氯芬酸40 mg/kg、氟比洛芬20 mg/kg、萘普生40 mg/kg），在吲哚美辛的情况下，24 h后在小肠中检查以下参数：病变评分、肠杆菌和髓过氧化物酶（MPO）的数量以及诱导型一氧化氮（iNOS）活性。在麻醉下使用气囊监测肠蠕动作为腔内压力记录。结果如下：所有检测的NSAID均降低了粘膜PGE 2水平，并在小肠中产生出血性病变，伴有肠道运动亢进。作为NSAID的代表，吲哚美辛还在肠损伤发生之前增加肠细菌侵袭和MPO以及iNOS活性的程度，并且观察到运动过度反应早于由该药剂引起的任何其他事件的发生。吲哚美辛引起的肠道病变可通过补充dmPGE 2、用氨苄青霉素抑制细菌侵入或用氨基胍抑制iNOS活性来预防，而仅通过dmPGE 2来预防高运动性反应。此外，观察到的dmPGE 2的效果都模仿阿托品时，肠运动亢进抑制这种代理。结论：这些结果表明，肠道运动过度的致病重要性，在肠道溃疡反应的NSAID大鼠，并表明，这一事件是至关重要的发生下PG缺乏的肠细菌入侵，其次是各种炎症变化和粘膜损伤。这项研究还表明，解痉药对NSAID诱导的肠道病变有保护作用。
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. Methods: 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. Results: All NSAIDs tested decreased mucosal PGE2 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 dmPGE2, inhibition of bacterial invasion with ampicillin or inhibition of iNOS activity with aminoguanidine, while the hypermotility response was prevented by dmPGE2 only. In addition, the observed effects of dmPGE2 were all mimicked by atropine when the intestinal hypermotility was suppressed by this agent. Conclusion: 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.