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目的:考察米非司酮对胰岛素抵抗高血压大鼠血管收缩功能的影响。方法:将40只雄性SD大鼠随机分为正常组、模型组、罗格列酮(0.4 mg.kg-1)组、米非司酮低剂量(20 mg.kg-1)组、米非司酮高剂量(40 mg.kg-1)组。除正常组外均予以高脂饮食饲养,8周后,取血样测定各组大鼠空腹胰岛素含量、空腹血糖含量,并计算胰岛素敏感指数及抵抗指数以判断胰岛素抵抗模型是否形成,测定血清皮质酮浓度以考察胰岛素抵抗形成过程中糖皮质激素的变化,测定肾上腺素和去甲肾上腺素浓度以考察交感神经紧张程度,并于实验期间采用套尾法每4周测定1次血压。实验8周末处死大鼠,取出胸主动脉,制备胸主动脉环。用氯化钾预刺激收缩血管环后,分别加入系列浓度的去甲肾上腺素(1×10-9～1×10-5mol.L-1)和血管紧张素Ⅱ(1×10-8、3×10-8、1×10-7、3×10-7和1×10-6mol.L-1),并在地塞米松孵育后再次加入同等系列浓度的去甲肾上腺素。采用生物机能实验系统测定胸主动脉血管的收缩幅度,以氯化钾诱发的最大收缩幅度为100%,将加入去甲肾上腺素或血管紧张素Ⅱ后的血管收缩幅度与氯化钾诱发的最大收缩幅度之间的百分比计为收缩率以反映血管收缩功能。结果:高脂饮食饲养8周可致动物出现高血糖、高胰岛素血症、胰岛素敏感性降低、胰岛素抵抗指数上升,以及血清儿茶酚胺、血清皮质酮水平和血压升高,米非司酮可逆转除皮质酮水平升高以外的上述变化。与正常组相比,模型组大鼠胸主动脉环对去甲肾上腺素及血管紧张素Ⅱ的收缩反应明显增强;与模型组相比,米非司酮高、低剂量组大鼠胸主动脉环对去甲肾上腺素及血管紧张素Ⅱ所致的收缩反应显著降低,用地塞米松孵育后,其对去甲肾上腺素所致的收缩反应与模型组相比无显著变化,但较正常组及未用地塞米松孵育时显著升高。结论:高脂饮食饲养8周可诱导大鼠形成胰岛素抵抗高血压模型并伴有血管收缩功能障碍;米非司酮可改善以上症状,推测其可能通过拮抗糖皮质激素的生物学效应及降低胰岛素抵抗高血压大鼠血管环对血管紧张素Ⅱ的收缩性而发挥作用。
Objective: To investigate the effect of mifepristone on vasoconstrictive function in insulin resistance hypertensive rats. Methods: Forty male SD rats were randomly divided into normal group, model group, rosiglitazone (0.4 mg.kg-1) group, low dose of 20 mg.kg-1 mifepristone group Chlordone high dose (40 mg.kg-1) group. After 8 weeks, fasting insulin and fasting blood glucose were measured in blood of rats in each group. Insulin sensitivity index and resistance index were calculated to determine whether insulin resistance model was formed. Serum corticosterone Concentration in order to investigate the changes of glucocorticoid during the formation of insulin resistance. The levels of epinephrine and norepinephrine were measured to investigate the degree of sympathetic tone. Blood pressure was measured once every 4 weeks during the experiment. Rats were sacrificed on the 8th week of experiment, the thoracic aorta was removed and the thoracic aortic rings were prepared. After preconditioning the contracting vascular rings with potassium chloride, a series of concentrations of norepinephrine (1 × 10-9 ~ 1 × 10-5mol.L-1) and angiotensin Ⅱ (1 × 10-8.3 × 10 -8, 1 × 10 -7, 3 × 10 -7, and 1 × 10 -6 mol·L -1) were added, and an equal series of concentrations of norepinephrine were added after dexamethasone incubation. The contraction of thoracic aorta was measured by the bio-functional experimental system. The maximal contraction induced by potassium chloride was 100%. The amplitude of vasoconstriction induced by adding norepinephrine or angiotensin Ⅱ was the largest Shrinkage as a percentage between the rate of shrinkage to reflect vasoconstrictive function. Results: Hypercholesterolemia, hyperinsulinemia, decreased insulin sensitivity, increased insulin resistance index, and elevated serum catecholamines, serum corticosterone levels and blood pressure were observed in high fat diet for 8 weeks, and mifepristone could be reversed Cortisone levels other than the above changes. Compared with the normal group, the contraction of the thoracic aorta ring of normorelin group and normrepinephrine was significantly increased in the model group. Compared with the model group, the thoracic aorta of the high and low dose mifepristone groups The contractile response of noradrenalin and angiotensin Ⅱ to the ring was significantly reduced. After dexamethasone incubation, the contractile response to norepinephrine did not change significantly compared with the model group, but compared with the normal group and Not significantly increased when incubated with dexamethasone. Conclusion: The high-fat diet can induce the formation of insulin resistant hypertensive rat model with vasoconstriction dysfunction for 8 weeks. Mifepristone can improve the above symptoms, suggesting that it may antagonize the biological effects of glucocorticoid and reduce insulin Resistance to angiotensin Ⅱ in the vascular rings of hypertensive rats play a role.