右美托咪定预处理对大鼠心肌缺血再灌注损伤的影响及其机制

Effect of dexmedetomidine pretreatment on MIRI in rats and its mechanism

目的观察右美托咪定(Dex)预处理对大鼠心肌缺血再灌注损伤(MIRI)的影响,并探讨其机制是否与氧化应激及Epac1/Rap1信号通路有关。方法SD大鼠随机分为假手术组、模型组、Dex组、抑制剂组各8只。Dex组在建模前30 min腹腔注射Dex,抑制剂组在建模前30 min及25 min时分别腹腔注射Epac1拮抗剂ESI09及Dex,假手术组、模型组在建模前30 min腹腔注射相同剂量的生理盐水。除假手术组外,各组均通过结扎左冠状动脉建立MIRI模型,假手术组心脏仅穿线而不结扎左冠状动脉。采用苏木精—伊红(HE)染色观察各组心肌组织病理学变化,ELISA法检测大鼠血清心肌损伤标志物肌酸激酶同工酶(CK-MB)、乳酸脱氢酶(LDH)及氧化应激指标丙二醛(MDA)、超氧化物歧化酶(SOD),Western blotting法检测大鼠心肌组织Epac1/Rap1信号通路相关蛋白Epac1、Rap1。结果假手术组心肌纤维排列整齐、边缘清晰,未见心肌纤维断裂和细胞间质肿胀;模型组心肌纤维出现断裂,排列紊乱、边界模糊,有明显中性粒细胞浸润,细胞间质肿胀明显;Dex组与抑制剂组心肌纤维断裂、中性粒细胞浸润减少、间质肿胀均减轻。血清CK-MB、LDH模型组>Dex组>抑制剂组>假手术组;血清MDA模型组>Dex组>抑制剂组>假手术组,血清SOD假手术组>抑制剂组>Dex组>模型组;心肌组织Epac1、Rap1蛋白表达模型组>Dex组>抑制剂组>假手术组(P均<0.05)。结论Dex预处理对大鼠MIRI具有抑制作用,其机制可能与激活Epac1/Rap1信号通路减轻心肌组织氧化应激有关。

Objective To investigate the protective effect of dexmedetomidine(Dex)pretreatment on myocardial ischemia-reperfusion injury(MIRI)rats and to explore whether its mechanism was related to oxidative stress and Epac1/Rap1 signaling pathway.Methods SD rats were randomly divided into the sham operation group,model group,Dex group and inhibitor group,with 8 rats in each.Rats in the Dex group were intraperitoneally injected with dexmedetomidine 30 min before modeling.In the inhibitor group,Epac1 antagonists ESI09 and Dex were intraperitoneally injected 30 min and 25 min before modeling.Rats in the sham operation group and model group were intraperitoneally injected with the same dose of normal saline 30 min before modeling.Except the sham operation group,MIRI models were established by li⁃gation of the left coronary artery in other groups.In the sham operation group,the heart was only threaded without ligation of the left coronary artery.Hematoxylin-eosin(HE)staining was used to observe the pathological changes of myocardial tis⁃sues.ELISA was used to detect creatine kinase-MB(CK-MB),lactate dehydrogenase(LDH),malondialdehyde(MDA)and superoxide dismutase(SOD).The expression levels of Epac1 and Rap1 signaling pathway-related proteins in the rat myocardial tissues were detected by Western blotting.Results In the sham operation group,the myocardial fibers were arranged neatly,the edges were clear,and there was no myocardial fiber rupture and intercellular swelling;in the model group,the myocardial fibers showed rupture,disordered arrangement,fuzzy boundary,obvious neutrophil infiltration,and obvious intercellular swelling;in the Dex group and inhibitor group,myocardial fiber rupture,neutrophil infiltration and interstitial swelling were reduced.Serum CK-MB was as follows:LDH model group>Dex group>inhibitor group>sham operation group,the serum MDA was in the following order:model group>Dex group>inhibitor group>sham opera⁃tion group,serum SOD was as follows:sham operation group>inhibitor group>Dex group>model group,and the expres⁃sion levels of Epac1 and Rap1 proteins in the myocardial tissues were as follows:model group>Dex group>inhibitor group>sham operation group(all P<0.05).Conclusion Dex preconditioning has a protective effect on myocardial I/R injury rats,and the mechanism may be related to activating Epac1/Rap1 signaling pathway to reduce oxidative stress in the myocardial tissues.