Inhibition of nitric oxide synthase reduces renal ischemia/reperfusion injury
Inhibition of nitric oxide synthase reduces renal ischemia/reperfusion injury
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DOI：
10.1016/j.jss.2005.06.019
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发表时间：
2005-12-01
影响因子：
2.2
通讯作者：
Schulak, JA
中科院分区：
文献类型：
--
作者：
Mark, LA;Robinson, AV;Schulak, JA
背景资料。诱导型一氧化氮合酶(INOS)产生的一氧化氮(NO)在肾缺血/再灌注(I/R)损伤中的作用尚不清楚。在本研究中，我们研究了诱导型一氧化氮合酶和一氧化氮在L肾损伤大鼠模型中的作用。此外，还评价了iNOS抑制对肾功能的影响。SD大鼠行左肾缺血和对侧肾切除45min后，行不同时间的再灌流和肾功能分析[血肌酐、钠排泄分数(FENA)、肌酐清除率(CrCl)、血浆和尿液NO水平]。此外，还评价了高选择性iNOS抑制剂1400W的治疗效果。肾功能障碍在再灌流后48h达到高峰，免疫组织化学染色显示iNOS在再灌流后3h的血管和48h的肾小管中均有表达。与对照组相比，治疗组的肾功能显著改善[肌酸酐分别为1.1vs.1.9 mg/dl(P<；0.05)和CrCl0.54vs.0.31ml/min(P<；0.05)]。此外，FENA降低了50%，血浆NO水平显著降低(32.7vs45.7MU/L，P<；0.01)，肾小管内硝基酪氨酸沉积减少。这些数据支持iNOS和NO参与肾I/R损伤发病机制的假设，并提示iNOS抑制剂的使用可能是一种有价值的治疗策略，在肾脏I/R可能普遍存在的临床情况下。(C)2005 Elsevier Inc.保留所有权利。
Background. The role of nitric oxide (NO) production because of inducible nitric oxide synthase (iNOS) in the pathogenesis of renal ischemia/reperfusion (I/R) injury is unclear. In this study the roles of both iNOS and NO were characterized in a rat model of renal L/R injury. In addition, the effect of iNOS inhibition on renal function was evaluated.Methods. Sprague-Dawley rats underwent 45 min of left renal ischemia and contralateral nephrectomy followed by various periods of reperfusion and renal function analysis [plasma creatinine, fractional excretion of sodium (FENa), creatinine clearance (CrCl), and measurement of plasma and urine NO levels]. In addition, the effect of treatment with 1400W, a highly selective iNOS inhibitor, was evaluated.Results. Renal dysfunction peaked at 48 h after reperfusion and immunohistochemistry studies revealed iNOS expression in the vasculature (3 h) and renal tubules (48 h) after reperfusion. Renal function improved significantly in treated animals compared to controls [creatinine of 1.1 v. 1.9 mg/dl (P < 0.05) and CrCl of 0.54 v. 0.31 ml/min (P < 0.05), respectively]. In addition, FENa was decreased by 50%, plasma NO levels were significantly lower (32.7 v. 45.7 mu mol/L, P < 0.01), and deposition of nitrotyosine in the tubules of treated rats was less than in control animals.Conclusions. These data support the hypothesis that iNOS and NO are involved in the pathogenesis of renal I/R injury and suggests that use of iNOS inhibitors may be a valuable therapeutic strategy clinical situations where renal I/R may be prevalent. (c) 2005 Elsevier Inc. All rights reserved.