二氮嗪预处理对肝硬化大鼠肝脏保护作用.docVIP

二氮嗪预处理对肝硬化大鼠肝脏保护作用 　 作者：史卫海，孙亚伟，徐学忠，戎亚雄，李文美 【摘要】 目的 探讨采用线粒体ATP敏感性钾通道(mitoKATP通道)选择性开放剂二氮嗪(DE)进行预处理能否模拟缺血预处理(IP)对硬化肝脏缺血再灌注损伤的保护作用及其可能的作用机制。方法 雄性肝硬化SD大鼠随机分为5组(每组8只)。IP组以肝缺血5 min作预处理；DE组以静脉注射DE 作为预处理；DE+5-HD组是在DE组基础上再予静注mitoKATP通道选择性阻滞剂5-hydroxydecanoate(5-HD)进行预处理;对照组(C组)以静注等量生理盐水作为预处理;上述4组均在预处理后行肝缺血45 min再灌注60 min;缺血方式均为70%肝脏热缺血。假手术组（S组）仅行开腹，不作任何其他处理。完成预定实验操作后分别取血用于血清谷丙转氨酶(ALT)与乳酸脱氢酶(LDH)检测，切取肝组织用于测定ATP酶活力、湿重/干重(W/D)的测定及观察显微、超微结构变化。结果 C组ALT，LDH，ATP酶及W/D的水平明显高于S组(Plt;0.01)，肝脏的显微及超微结构损伤明显；IP组与DE组的各项肝组织损伤指标均明显好于C组，ATP酶活性低于C组(Plt;0.05及Plt;0.01)；而DE+5-HD组的肝损伤指标均差于DE组，ATP酶活性高于DE组(Plt;0.05及Plt;0.01)。 结论 使用DE进行药物预处理能够模拟出IP效应，对肝硬化大鼠肝脏I/R损伤具有保护作用，其作用可能与下调肝组织ATP酶活性，减少ATP大量分解，使肝组织ATP含量升高，改善肝能量代谢，增加能量储备;改善肝组织微循环，减轻肝脏水肿有关。 【关键词】 缺血预处理；缺血/再灌注；线粒体ATP敏感性钾通道；肝硬化；二氮嗪；大鼠 Abstract Objective To explore whether the pretreatment with diazoxide(DE)—a selective opener of mitochondrial ATP sensitive potassium (mitoKATP) channels can mimic the protective function of ischemic preconditioning (IP) on liver ischemia/reperfusion (I/R) injury in rats with cirrhosis and the probable mechanism. Methods Male SD rats with liver cirrhosis were randomly divided into five groups (n=8 in each group). Pretreatment with hepatic ischemia for 5 min was regarded as IP group； pretreatment with DE 5 mg/kg intravenously injection was regarded as DE group； pretreatment with intravenous injection of a selective mitoKATP channels inhibitor 5-hydroxydecanoate(5-HD) based upon DE group was considered as DE+5-HD group and pretreatment with normal saline in equal volume as a control group（C group）. The four groups mentioned-above were subjected to hepatic ischemia for 45 min after pretreatment, then, 50 minutes reperfusion was performed on them. All of rats were subjected to 70% warm ischemia. The additional fifth group of rats was undergone a sham operation(S group)， in whom only anesthesia and laparotomy were performed without any other measures. Blood and liver tissue were obtained to determine the biochemistry lev