Role of endothelial nitric oxide synthase in aggravation of indomethacin-induced gastric damage in adjuvant arthritic rats.
Role of endothelial nitric oxide synthase in aggravation of indomethacin-induced gastric damage in adjuvant arthritic rats.
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发表时间：
2009-12
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通讯作者：
S. Kato;F. Ohkawa;Y. Ito;K. Amagase;K. Takeuchi
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作者：
S. Kato;F. Ohkawa;Y. Ito;K. Amagase;K. Takeuchi
探讨一氧化氮合酶（NOS）同工酶在吲哚美辛致佐剂性关节炎大鼠胃损伤加重中的作用。注射弗氏完全佐剂2周后给予吲哚美辛，4 h后检查胃损伤情况。吲哚美辛引起正常大鼠胃出血性损伤，关节炎大鼠胃出血性损伤明显加重。L-NAME （NOS的非选择性抑制剂）和氨基胍（iNOS的相对选择性抑制剂）预处理对正常大鼠的溃疡反应没有影响，但对关节炎大鼠的病变加重有剂量依赖性，但氨基胍的作用明显小于L-NAME。1400w（一种选择性iNOS抑制剂）和L-NIO（一种选择性eNOS抑制剂）显著抑制关节炎大鼠溃疡形成反应的增加，而L-NPA（一种选择性nNOS抑制剂）则无明显抑制作用。同时给药1400w和L-NIO几乎完全消除了关节炎大鼠的损伤加重。关节炎大鼠胃黏膜中eNOS和iNOS的表达明显增强，而nNOS的表达不明显。与正常大鼠相比，关节炎大鼠粘膜中非蛋白巯基含量明显降低。谷胱甘肽对关节炎大鼠损伤的加重有明显的预防作用。这些结果表明，除了iNOS外，eNOS衍生的NO介导了关节炎大鼠胃对吲哚美辛的溃疡反应增加。推测eNOS/NO可能对粘膜SH缺乏的关节炎大鼠的胃粘膜产生有害作用。
The role of nitric oxide synthase (NOS) isozymes in the aggravation of indomethacin-induced gastric damage in adjuvant arthritic rats was investigated. Two weeks after injection of Freund's complete adjuvant, the animals were given indomethacin, and the stomach was examined for damage 4 h later. Indomethacin caused hemorrhagic lesions in the normal rat stomach, and these lesions were markedly aggravated in arthritic rats. Pretreatment with L-NAME (a nonselective inhibitor of NOS) and aminoguanidine (a relative selective inhibitor of iNOS) did not affect the ulcerogenic response in normal rats but dose-dependently prevented the aggravation of lesions in arthritic rats, but the effect of aminoguanidine was apparently less than that of L-NAME. The increased ulcerogenic response in arthritic rats was significantly suppressed by 1400 W (a selective inhibitor of iNOS) and L-NIO (a selective inhibitor of eNOS) but not by L-NPA (a selective inhibitor of nNOS). The concurrent administration of 1400 W and L-NIO almost totally abolished the aggravation of damage in arthritic rats. The expressions of eNOS and iNOS but not nNOS in the gastric mucosa were clearly enhanced in arthritic rats. Mucosal levels of non-protein sulfhydryls were significantly lower in arthritic rats than those in normal rats. The aggravation of damage in arthritic rats was significantly prevented by glutathione. These results suggest that the increased ulcerogenic response to indomethacin in arthritic rat stomachs is mediated by NO derived from eNOS in addition to iNOS. It is assumed that eNOS/NO may act harmfully on the gastric mucosa of arthritic rats with mucosal SH deficiency.