阿托伐他汀的降血压作用及其机制实验研究

Effect of Atrovastatin on Blood Pressure by Regulating Expression of AT1 Receptor in Spontaneously Hypertension Rats

目的观察阿托伐他汀对自发性高血压大鼠(SHR)血压的影响,并通过其对血管紧张素Ⅱ1型(AT1)受体表达的影响探讨其调节血压的机制。方法将24只16周雄性SHR随机分为4组:SHR对照组,阿托伐他汀50mg剂量组[50mg/(kg.d)],阿托伐他汀10mg剂量组[10mg/(kg.d)],缬沙坦组[20mg/(kg.d)],灌胃给药共6周。在给药前和给药后,每2周采用尾袖法测量大鼠尾动脉收缩压(SBP),化学比色法检测大鼠主动脉活性氧(ROS)浓度;免疫组织化学法和原位杂交法检测AT1受体蛋白和mRNA表达。结果实验前SHR各组SBP无差异,但显著高于WKY组(P<0.01);给药后4,6周,50mg剂量组SBP明显下降(P<0.01),10mg剂量组SBP无明显变化;自给药后2周缬沙坦组SBP逐渐下降(P<0.01)。SHR对照组血清ROS水平显著高于WKY组(P<0.01);用药6周后,50mg剂量组血清ROS水平明显降低(P<0.05)。SHR对照组心肌AT1受体蛋白阳性表达明显高于WKY组(P<0.01),50mg剂量组AT1受体蛋白阳性表达明显减少,平均光密度值显著降低(P<0.01)。SHR对照组AT1受体mRNA表达明显高于WKY组(P<0.01),50mg剂量组AT1受体mRNA表达下调,平均光密度值显著降低(P<0.01)。结论阿托伐他汀可降低SHR的血压,下调SHR心肌细胞AT1受体表达,减少ROS生成,改善血管内皮功能而发挥降低血压的作用。

Objective To investigate the effect of atorvastatin on blood pressure in spontaneously hypertensive rats（SHR） and to explore its potential mechanism via the effects of atorvastatin on expression of angiotensin type 1 （ AT1 ） receptor, Methods Sixteen-week old male SHR（ n = 24） were randomly divided into four groups （ n = 6, each ） ： （ 1 ） SHR control group ; （ 2 ） 50 mg atorvastatln group[50 mg/（kg · d） ] ;（3）10 mg atorvastatin group[ 10 mg/（kg· d） ] ;（4） valsartan group[20 mg/（kg ·d） ]. Systolic blood pressure（SBP） was assessed with the tail-cuff method before and 6 weeks after treatment with atorvastatin, blood samples were taken for the determination of reactive oxygen species（ROS） levels in serum by chemistry, colorimetry. The localization of AT1 receptor protein in myocardium was investigated by immunohistochemistric assays. The level of AT1 receptor mRNA expression was detected by in situ hybridization. Results SBP was significantly decreased in 50 mg atorvastatin group at 4 weeks and 6 weeks（ P 〈0.01 ） and was not influenced in 10 mg atorvastatin group, Serum ROS level in SHR control group was significantly higher than that in WKY group（ P 〈0.01 ）, There was a significantly reduction in serum ROS level in 50 mg atorvastatin group after 6 weeks（ P 〈 0, 05 ）. The expression of AT1 receptor protein in 50 mg atorvastatin group was significantly decreased and average light density value was diminished too（ P 〈 0, 01 ）, The result showed that both the expression of AT1 receptor mRNA and average light density value were diminished in 50 mg atorvastatin group（ P 〈 0, 01 ）. Conclusions Atorvastatin caused a sig- nificant reduction of blood pressure in SHR. It down-regulates AT~ receptor expression of myocardium cell that leads to reduced production of ROS, It is infered that the reduction of blood pressure with atorvastatin be caused by downregulation of AT1 receptor expression and improvement of endothelial dysfunction.