右美托咪定拮抗阿霉素小鼠心脏毒性的效果及其机制

Effect and Mechanism of Dexmedetomidine in Antagonizing Adriamycin-induced Cardiotoxicity in Mice

目的探讨右美托咪定拮抗阿霉素对小鼠心脏毒性的效果及作用机制。方法100只清洁级雄性昆明种小鼠随机分为对照组(C组)和实验组(D组)各50只,每组又各分5个亚组,均一次性腹腔注射不同剂量阿霉素。C组每天腹腔注射0.9%氯化钠注射液0.005 mL·g^(-1),D组每天腹腔注射右美托咪定30μg·kg^(-1),共10 d。记录小鼠死亡数量,采用Probit法计算阿霉素致小鼠死亡的半数致死量(median lethal dose,LD50)及95%可信区间(95%CI)。注射0.9%氯化钠/右美托咪定10 d后处死存活小鼠,电镜及光镜下观察小鼠心肌细胞组织学改变,免疫组化法测定小鼠心肌细胞bax和bcl-2蛋白表达情况。结果C组阿霉素对昆明种小鼠腹腔给药的LD50为21.17 mg·kg^(-1)(95%CI:18.12~24.74 mg·kg^(-1)),D组LD50为29.18 mg·kg^(-1)(95%CI:24.90~34.18 mg·kg^(-1)),D组LD50显著高于C组(U=15.5,P=0.002)。C组心肌细胞线粒体结构损伤较D组严重,且可见自噬小体。与C组比较,D组bax表达显著降低(χ2=25.90,P=0.000),2组bcl-2表达比较差异无统计学意义(P>0.05)。结论右美托咪定可明显提高阿霉素致小鼠死亡的LD50,提高小鼠生存率,其机制可能与右美托咪定降低心肌细胞线粒体损伤、抑制bax蛋白表达有关。

Objective To explore the effect and mechanism of dexmedetomidine(DEX)in antagonizing adriamycin-induced cardiotoxicity in mice.Methods A total of 100 clean male Kunming mice were randomly divided into control group(Group C)and experimental group(Group D)with 50 mice each group,and each group was divided into 5 subgroups,all of which were intraperitoneally injected with different doses of adriamycin at one time.In group C,0.005 mL·g^(-1)of 0.9%sodium chloride injection was intraperitoneally injected every day for 10 days,and in group D,30μg·kg^(-1)of dexmedetomidine was intraperitoneally injected every day for 10 days.The number of dead mice was recorded,and the median lethal dose(LD50)and 95%confidence interval(95%CI)of mice who died of adriamycin were calculated by Probit method.After 10 days of injection of 0.9%sodium chloride/dexmedetomidine,the surviving mice were killed.The histological changes of mice cardiomyocytes were observed under electron microscope and light microscope,and the expression of bax and bcl-2 protein in mice cardiomyocytes was determined by immunohistochemistry.Results The LD50of adriamycin administered intraperitoneally to Kunming mice in group C was 21.17 mg·kg^(-1)(95%CI:18.12~24.74 mg·kg^(-1)),and that of group D was 29.18 mg·kg^(-1)(95%CI:24.90~34.18 mg·kg^(-1)).The LD50of group D was significantly higher than that of group C(U=15.5,P=0.002).Mitochondrial structure damage of myocardial cells in group C was more serious than that in group D,and autophagy bodies were found.Compared with group C,the expression of bax in group D was significantly reduced(χ^(2)=25.90,P=0.000),and there was no significant difference in the expression of bcl-2 between the two groups(P>0.05).Conclusion Dextrmedetomidine can significantly increase the LD50of adriamycin-induced death in mice,and improve the survival rate of mice.The mechanism may be related to the reduction of myocardial mitochondrial damage and inhibition of bax protein expression by dexmedetomidine.