17β-雌二醇对去卵巢胰岛素抵抗大鼠主动脉舒缩功能损伤的保护作用

17β-estradiol protects against injury of aortic relaxation and contraction in ovariectomized rats with insulin resistance induced by fructose

为观察17β-雌二醇(17beta-estradiol,17β-E2)对去卵巢胰岛素抵抗(insulin resistance,IR)大鼠主动脉结构和舒缩功能的 影响及其可能机制,成年雌性Sprague-Dawley大鼠卵巢切除后,高果糖喂养8周诱导IR,同时给予生理剂量的17β-E2(30 μg／kg),每天皮下注射一次,并检测IR相关指标。大鼠胸主动脉石蜡切片,HE染色,图像分析系统测定其结构。采用 血管环灌流法,观察各组大鼠胸主动脉环对新福林(L-phenylephrine,PE)的收缩反应和对ACh、硝普钠(sodium nitroprusside, SNP)的舒张反应以及一氧化氮合酶(nitric oxide synthase,NOS)抑制剂N-硝基-L-精氨酸甲脂(N-nitrl-L-arginine methyl ester,L- NAME)对卵巢切除+果糖喂养+17β-E2组大鼠胸主动脉Ach的舒张反应的影响;检测各组大鼠一氧化氮(nitric oxide,NO) 含量。结果显示:(1)17β-E2能防止高果糖诱导的去卵巢IR大鼠收缩压升高、高胰岛素血症和胰岛素敏感性下降:(2)各 组大鼠胸丰动脉的结构无显著性差异;(3)卵巢切除+果糖喂养组大鼠与卵巢切除组或果糖喂养组相比,血清NO显著降低, 胸主动脉对PE的收缩反应显著增强,对ACh的舒张反应显著降低,17β-E2能逆转上述改变,L-NAME可部分阻断17β-E2 的这种作用;(4)各组大鼠胸主动脉对SNP的舒张反应和去内皮后对PE的收缩反应均无显著差异。以上结果表明,17β-E2能 抑制高果糖诱导的去卵巢IP大鼠血管舒缩功能的紊乱,其机制一方向可能是部分通过血管内皮细胞NOS途径促进N0的释放, 保护内皮细胞;另一方面可能是通过降低血压,血清胰岛素水平,改善IR所致。

The purpose of the present study was to investigate the effect of 17β-estradiol （17β-E2） on the structure and relaxation and contraction activity of thoracic aortas in ovariectomized rats with insulin resistance induced by fructose. Ovariectomized mature female Sprague-Dawley rats were fed with high fructose diet for 8 weeks to induce insulin resistance. Physiological dose of 17β-E2 （30 μg/kg） was injected subcutaneously every day for 8 weeks. Systolic blood pressure （SBP） was measured by use of tail-cuff. Serum nitric oxide （NO）, estradiol （E2）, fasting blood sugar （FBS） and fasting serum insulin （FSI） were measured respectively in each group. The insulin sensitive index （ISI） was calculated. The thoracic aortas were fixed in formalin, sliced and HE dyed. The structure of thoracic aortas, lumen breadth, media thickness, media thickness/lumen breadth ratio and media cross-section area were measured. The contraction response of thoracic aorta rings induced by L-phenylephrine （PE） and the relaxation response of thoracic aorta rings induced by ACh and sodium nitroprusside （SNP） were measured. To explore the mechanism, nitric oxide synthase （NOS） inhibitor N-nitro-L-arginine methyl ester （L-NAME） was used. The results obtained are as follows： （1） 17β-E2 protected against the effect of high fructose diet, which caused an increase in SBP, hyperinsulinemia and a decrease in ISI in ovariectomized rats. （2） The structure of thoracic aortas had no significant difference among the groups. （3） Compared with the ovariectomized group （OVX） or fructose fed group （F）, serum nitric oxide was significantly reduced, the contraction response of thoracic aorta rings to PE was enhanced and the relaxation response to ACh was depressed significantly in ovariectomized＋fructose fed group （OVX＋F）. The effect of high fructose was reversed by 17β-E2. After pretreatment with L-NAME, the effect of 17β-E2, which enhanced the relaxation response of thoracic aorta rings to ACh in ovariectomized＋fructose＋17β-E2 group （OVX＋F＋E2）, was partly blocked. （4） The relaxation response of thoracic aorta rings to SNP had no significant difference among the groups. （5） The contraction response of thoracic aorta rings without endothelium to PE had no significant difference among the groups. These findings suggest that 17β-E2 may provide protection against the effect of high fructose diet, which causes hypertension, dysfunction of endothelial cells and insulin resistance. The mechanism of this effect of 17β-E2 could be partly associated with the increase of NO by NOS pathway, or associated with the decrease in the level of systolic blood pressure and serum insulin, and the improvement of insulin resistance.