右美托咪定对布比卡因中毒大鼠心肌细胞线粒体损伤的保护

Protective effects of Dexmedetomidine on the mitochondrial damage of cardiomyocytes in Bupivacaine-induced rats

目的探讨右美托咪定(Dex)是否通过AMPK/SIRT1/PGC-1α信号通路调节布比卡因(BPV)中毒大鼠心肌细胞线粒体的能量代谢和氧化应激。方法将40只大鼠随机均分为空白对照组、模型组及Dex 30、60 min组。空白对照组经静脉持续泵入0.9%生理盐水3 mL·kg^-1·min^-1,20 min后处死;模型组大鼠经静脉持续泵入0.5%BPV 2 mg·kg^-1·min^-1,直至出现心律失常后处死;Dex 30、60 min组大鼠经静脉持续泵入0.5%BPV 2 mg·kg^-1·min^-1,至出现心律失常后,分别持续静脉泵入3μg·kg^-1·h^-1Dex 30、60 min后处死。检测大鼠线粒体Na^+-K^+-ATP酶、Ca+-Mg+-ATP酶、乳酸盐脱氢酶(LDH)、活性氧(ROS)的活性,超氧化物歧化酶(SOD)、丙二醛(MDA)含量及AMPK、SIRT1、PGC-1αmRNA和蛋白表达的变化。结果Dex可使大鼠心肌细胞线粒体中Ca^2+-Mg^2+-ATP酶、Na^+-K^+-ATP酶及SOD的活性显著升高,LDH活性及MDA、ROS的水平显著降低,改善线粒体形态结构;同时可上调AMPK、SIRT1和PGC-1αmRNA和蛋白的表达。结论Dex可减轻BPV的心脏毒性,可能是通过调控AMPK/SIRT1/PGC-1α信号通路来改善线粒体的能量代谢和减轻氧化应激来保护BPV中毒大鼠的心肌线粒体。

OBJECTIVE To explore whether Dexmedetomidine(Dex)regulates mitochondrial energy metabolism and oxidative stress in cardiomyocytes of Bupivacaine(BPV)-induced rats through AMPK/SIRT1/PGC-1αsignaling pathway.METHODS Forty healthy rats were randomly divided into blank control group,model group,Dex 30 min group and Dex 60 min group.The rats in the blank control group were continuously pumped with 0.9%normal saline 3 mL·kg^-1·min^-1,and sacrificed 20 minutes later.The rats in the model group were continuously intravenously infused with 0.5%BPV 2 mg·kg^-1·min^-1,and they were sacrificed until arrhythmia occurred.The rats in Dex 30 min group and Dex 60 min group were continuously intravenously pumped with 0.5%BPV 2 mg·kg^-1·min^-1 until arrhythmia occurred,and then 3μg·kg^-1·h^-1 Dex were continuously intravenously pumped for 30 min and 60 min,respectively.Then the rats were killed.The changes of mitochondrial Na^+-K^+-ATPase,Ca^2+-Mg^2+-ATPase,LDH activity,ROS activity,SOD and MDA content and the expression of AMPK,SIRT1 and PGC-1αmRNA and protein were detected.RESULTS Dex can significantly increase the activity of Ca^2+-Mg^2+-ATPase,Na^+-K^+-ATPase and SOD in mitochondria of rat cardiomyocytes,and significantly decrease LDH activity,MDA and ROS levels,and improve mitochondrial morphology.At the same time,Dex can up-regulate the expression of AMPK,SIRT1 and PGC-1αmRNA and protein.CONCLUSION Dex alleviates cardiotoxicity of BPV,possibly by modulating mitochondrial energy metabolism and mitigating oxidative stress by modulating AMPK/SIRT1/PGC-1αsignaling pathway to protect myocardial mitochondria in BPV-induced rats.