罗格列酮对胰岛素抵抗大鼠主动脉内皮功能的影响及其机制的研究

Effects and Mechanisms of Rosiglitazone on Aortic Endothelium-Dependent Vasodilation in Insulin-Resistance Rats

目的：观察罗格列酮对胰岛素抵抗大鼠主动脉内皮依赖性血管舒张和一氧化氮（NO）含量、内皮型一氧化氮合酶（eNOS）、磷脂酰肌醇-3激酶及蛋白激酶B表达的影响。方法：4～6周龄雄性SD大鼠予高糖高脂喂养8周，建立胰岛素抵抗模型，分为对照组和治疗组，每组各15只，治疗组用罗格列酮[3mg／（kg·d）]干预8周，另取15只正常大鼠为正常组。实验终止时用葡萄糖输注率评价胰岛素抵抗，观察大鼠离体主动脉对乙酰胆碱依赖性血管舒张反应，Griess重氮化反应法检测主动脉NO含量，逆转录聚合酶链反应方法检测磷脂酰肌醇-3激酶、蛋白激酶B和eNOS mRNA表达，电镜观察主动脉超微结构。结果：对照组葡萄糖输注率、主动脉内皮依赖性舒张功能、NO浓度、磷脂酰肌醇-3激酶、蛋白激酶B、eNOS mRNA表达较正常组均显著降低（P〈0.01），治疗组上述指标均显著升高（P〈0.01）。透射电镜检查可见对照组主动脉内皮细胞和内皮下结构的病理改变，治疗组胸主动脉超微结构接近正常。结论：胰岛素抵抗大鼠存在内皮依赖性舒张功能紊乱和主动脉NO浓度、磷脂酰肌醇-3激酶、蛋白激酶B、eNOS mRNA表达下降，用罗格列酮治疗可改善其内皮功能，增强NO产生和磷脂酰肌醇-3激酶、蛋白激酶B、eNOS mRNA表达。

Objective：To study the effects of rosiglitazone on aortic endothelium-dependent vasodilation, nitric oxide（NO） production, expression of endothelial nitric oxide synthase（ eNOS）, phosphatidylinositol 3-kinase（PI3K） and protein kinase B （PKB） in rats with insulin-resistance（IR）. Methods： Insulin resistance（IR） rat model was established in 4- 6 week-old male SD rats by high glucose and high fat feed for 6 weeks, IR rat were randomly divided into control group and rosiglitazone-treated group. Rosiglitazone-treated rats were given rosiglitazone 3 rag/（ kg · d） for 8 weeks, other 15 normal rats were as normal control group. Insulin-resistance was evaluated by glucose infusion rate of euglycemic hyperinsulinemic clamp technique at the end of trial. Achtylcholine-induced vasodilation response in isolated aortic rings were observed and aortic NO concentration were measured using Griess Reaction. Expression of eNOS-, P13K-, and PKB mRNA of aorta were assayed by RT-PCR meatheds. Uhrastructure of aorta were measured by electron microscopy. Results： Glucose infusion rate, endothelium-dependent vasodilation, NO concentration and the expression of eNOS-,PI3K-, PKB mRNA in isolated aortic rings decreased significantly in IR control group compared with in normal control group（ P 〈 0. 01 ）. While those indexs in Rosiglitazone-treated group increased significantly （ P 〈 0. 01 ）. Pathologic changes of aortic ultrastructure can be found in IR control group while the ultrastrueture of aorta in Rosiglitazone-treated group was nearly normal. Conclusion：There are endothelium-dependent vasodilation dysfunction in rats with IR. NO concentration, PI3K-, PKB-, and eNOS mRNA expression of aorta also decrease in those rats. Treatment with rosiglitazon can improve endothelial function, increase aortic NO production and PI3K-, PKB-,and eNOS mRNA expression in IR rats.