Nicorandil ameliorates ischaemia-reperfusion injury in the rat kidney
Nicorandil ameliorates ischaemia-reperfusion injury in the rat kidney
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DOI：
10.1111/j.1476-5381.2011.01231.x
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发表时间：
2011-05-01
影响因子：
7.3
通讯作者：
Satoh, Keisuke
中科院分区：
文献类型：
--
作者：
Shimizu, Shogo;Saito, Motoaki;Satoh, Keisuke
背景与PURPOSENicordil是一种ATP敏感性钾(K-ATP)通道开放剂和一氧化氮供体，用于治疗心绞痛和急性心力衰竭。本实验观察了两种K-ATP通道开放剂尼可地尔和克罗卡林对大鼠肾脏缺血再灌注(I-R)损伤的影响。实验采用8周龄雄性SD大鼠肾切除，随机分为6组：对照组，左肾缺血30min再灌流24小时组，I-R+尼可地尔3 mg或10 mg中心点kg~(-1)ip组，I-R+克罗卡林100或300µg中心点kg~(-1)ip组。再灌注后用血肌酐(Scr)、尿白蛋白/肌酐比值(ACr)和尿β2-微球蛋白(β2-MG)评价肾功能。用Western印迹法检测K-ATP通道亚型的水平。肾组织切片4-羟基-2-壬烯醛和8-羟基-2‘-脱氧鸟苷染色。KEY结果肾I-R引起SCr、ACR和β2-MG水平显著高于对照组。K-ATP通道开放剂治疗降低了由I-R引起的尿β2-MG水平。K(IR)6.1和K(IR)6.2通道均有表达。I-R组K(IR)6.2通道表达低于对照组，经K-ATP通道开放剂处理后恢复正常。组织学上观察到严重的急性肾小管损伤，K-ATP通道开放剂可剂量依赖性地改善这种损伤。结论SATP敏感的钾通道开放剂对I-R损伤后的近端小管损伤有保护作用。尼可地尔可能是治疗肾部分切除或肾移植患者的一种强大的附加成分。
BACKGROUND AND PURPOSENicorandil, an ATP-sensitive potassium (K-ATP) channel opener and nitric oxide donor, is used in the treatment of angina and acute heart failure. Here we investigated the effects of two K-ATP channel openers, nicorandil and cromakalim on ischaemia reperfusion (I-R) injury in the kidney.EXPERIMENTAL APPROACHRight nephrectomy was performed in 8-week-old male Sprague-Dawley rats and they were then divided into six groups: control group; I-R, including 30 min of left renal ischaemia followed by 24 h of reperfusion; I-R groups plus nicorandil 3 or 10 mg center dot kg-1 i.p.; and I-R groups plus cromakalim 100 or 300 mu g center dot kg-1 i.p. After reperfusion, renal function was estimated by serum creatinine (SCr), urinary albumin : creatinine ratio (ACR) and urinary beta 2-microglobulin (beta 2-MG). Levels of K-ATP channel subtypes were investigated by Western blot. Kidney sections were stained for 4-hydroxy-2-nonenal and 8-hydroxy-2'-deoxyguanosine.KEY RESULTSRenal I-R induced significant increases in SCr, ACR and beta 2-MG levels compared with the control animals. Treatment with K-ATP channel openers reduced urinary beta 2-MG levels, raised by I-R. Both K(IR)6.1 and K(IR)6.2 channels were expressed. Expression of K(IR)6.2 channels in the I-R group was lower than in the control group, which was restored to normal by treatment with K-ATP channel openers. Histologically, severe acute tubular damage was observed in the I-R kidney and this damage was ameliorated by K-ATP channel openers, dose-dependently.CONCLUSIONS AND IMPLICATIONSATP-sensitive potassium channel openers protected against proximal tubule damage after I-R injury. Nicorandil could represent a powerful additional component in the treatment of patients undergoing partial nephrectomy or renal transplantation.