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目的:研究CPU86017及其旋光异构体对L-甲状腺素致大鼠心肌病异常的calcineurin和NFκB基因改变,并比较CPU86017及其旋光异构体对它们的作用。方法:大鼠随机分成7组,每日给予L-甲状腺素(0.2 mg.kg-1,sc)共10 d造成心肌病模型,CPU86017及其旋光异构体(SR、SS、RS、RR)(4 mg.kg-1,sc)在d 6连续给药5 d。动物处死后测定心脏指数,取大鼠心脏测定心肌组织中氧化应激指标,NO和iNOS的活力,大鼠左心室心肌Calci-neurin、NF-κB的基因表达由半定量逆转录酶PCR方法测定。结果:L-甲状腺素致大鼠心肌病模型组心肌明显肥大,氧化应激增强,NO含量减少,iNOS活力增强,Calcineurin和NF-κB基因表达上调。给予CPU86017及其旋光异构体能不同程度地改善心肌中NO含量及iNOS活力,减轻氧化应激,可以下调这些基因的表达,其中SR比其它旋光异构体疗效好。结论:Calcineurin和NF-κB可能对L-甲状腺素所致大鼠心肌病中细胞内钙调节起着重要的作用,CPU86017及其旋光异构体SR对L-甲状腺素所致大鼠心肌病具有保护作用,该作用与抑制心肌Calci-neurin、NF-κB基因的表达、抑制NOS及抗氧化有关。
OBJECTIVE: To study the changes of calcineurin and NFκB gene in rat cardiomyopathy induced by L-thyroxine induced by CPU86017 and its optical isomers, and to compare their effects on CPU86017 and its optical isomers. Methods: The rats were randomly divided into 7 groups: cardiomyopathy model, CPU86017 and its optical isomers (SR, SS, RS, RR) were induced by L-thyroxine (0.2 mg.kg- (4 mg.kg-1, sc) were dosed continuously for 5 d at d 6. The cardiac index was measured after sacrifice. The myocardial oxidative stress index, the activity of NO and iNOS, the expression of Calci-neurin and NF-κB in left ventricular myocardium of rats were determined by semi-quantitative reverse transcriptase polymerase chain reaction . Results: The myocardial hypertrophy induced by L-thyroxine in rats with cardiomyopathy significantly increased the oxidative stress, decreased the NO content, increased the iNOS activity and up-regulated the expression of Calcineurin and NF-κB. Given that CPU86017 and its optical isomers can improve NO content and iNOS activity in myocardium to a certain extent and reduce oxidative stress, they can down-regulate the expression of these genes. SR has better curative effect than other optical isomers. Conclusion: Calcineurin and NF-κB may play an important role in intracellular calcium regulation in L-thyroxine-induced cardiomyopathy. CPU86017 and its optical isomer SR have the inhibitory effects on L-thyroxine-induced cardiomyopathy This effect is related to inhibiting the expression of Calci-neurin and NF-κB in myocardium, inhibiting NOS and anti-oxidation.