摘要
目的研究奥美沙坦酯对急性心肌梗死(acute myocardial infarction,AMI)大鼠的内皮功能和细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)/cAMP反应元件结合蛋白(cAMP response element binding protein,CREB)信号通路的干预。方法将40只大鼠随机分为AMI组、奥美沙坦酯低剂量(olmesartan medoxomil low dose,OML)组、奥美沙坦酯高剂量(olmesartan medoxomil high dose,OMH)组和假手术(Sham)组,干预2周后处死,检测血压,血NO、AngⅡ含量,NOS活性,离体胸主动脉条片舒缩功能,MI面积及梗死区心肌中ERK、CREB mRNA表达水平。结果与Sham组比较,AMI组血清NO含量、NOS活性降低,胸主动脉内皮依赖性舒张(endothelium-dependent diastole,EDD)功能减退,血浆AngⅡ含量升高,伴心肌组织ERK、CREB mRNA表达增加,差异有显著性。经奥美沙坦酯干预后,血清NO含量、NOS活性升高达Sham组水平,胸主动脉EDD显著改善,同时呈剂量依赖性升高血浆AngⅡ含量,缩小MI面积,降低ERK、CREB mRNA表达,而各组血压并无明显差异。结论奥美沙坦酯在不影响血压的前提下显著改善AMI后内皮功能紊乱(Endothelial dysfunction,ED),缩小MI面积,并可呈剂量依赖性降低AMI大鼠心肌ERK、CREB mRNA表达。
Objective To study the interventional effects of olmesartan medoxomil （OM） on vascular endothelial function and expressions of ERK/CREB signaling pathway in rats with acute myocardial infarction （AMI）. Methods Totally 24 rats were randomized equally into AMI group, low dose OM treatment group （OML） and high dose treatment group （OMH）. After AMI rat model was established by ligating the left anterior descending branch of coronary artery. Another 7 rat who received sham operation served as sham group. In 24 h after operation, the rats from OML group were given an intragastrie injection of 1 mg/kg OM once per day, and those of OMH group 3 mg/kg. AMI group only received a treatment of latent solvent at same volume. Two weeks after the interventionall rats were sacrificed after blood pressure was measured, and then levels of blood NO and Ang Ⅱ, activities of NOS, endothelial vasomotor effects of isolated thoracic aorta strips, myocardial infaretual area and the expressions of ERK mRNA and CREB mRNA in infarctual myocardium were detected and measured. Results Compared with those in the sham group, levels of serum NO and activities of NOS in AMI group were much lower, NO in sham and AMI group were 55.69± 10.40 and 24.46 ±3.95 μmol/L respectively, and NOS were 23. 80±5.36 and 10. 92 ± 5.96 U/ml, respectively. Endothelium-dependent diastole （EDD） was decreased markedly, （6.15 ± 0. 03） ×10 ^-8 vs （4.45 × 0.21 ） × 10^-7 moL/L in sham and AMI groups. While the levels of plasma Ang Ⅱ in AMI group （281.14 ± 84.90 pg/ml） were distinctly higher than in sham group （181.39 ± 32.70 pg/ml） , accompanied with higher mRNA expressions of ERK1 （0.51 ± 0.09 vs 1.23 ±0.22） and CREB （0.40±0.19 vs 1, 15 ±0.30） in infarctual rnvocardium. All of the above differences were significant. After the treatment of OM, levels of serum NO and activities of NOS were obviously higher and almost reached the similar levels as those in sham group. NO was 43.44± 14.17 and 46.73 ± 11.30 μmol/L in OML and OMH group, respectively, while NOS were 16.21 ± 5.42 and 18.69 ± 6.73 U/ml. Additionally EDD in isolated aortic strips improved greatly, they were （2.65 ±0.12） × 10^-7 and （1.66 ± 1.00） × 10^-7 mol/L. OM not only increased the plasma Ang Ⅱ （344.55 ±76.74 and 511.14 ± 146.65 pg/ml respectively） , but also decreased the size of myocardial infarction and the mRNA expressions of ERK1 （1.02 ±0.18 and 0.79 ±0.13 ） and CREB （0.90±0.18 and 0.65 ±0. 16） in infarctual myocardium in a dose-dependant manner. However, blood pressure in all groups was not affected. Conclusion OM can greatly improve the disordered endothelial function developing post-AMI, decrease the size of myocardial infarction and down-regulate the mRNA expressions of ERK and CREB in myocardium of infarctual zone in a dose-dependent manner. And all of the above protective effects of OM are independent on blood pressure lowering.
出处
《第三军医大学学报》
CAS
CSCD
北大核心
2009年第14期1362-1366,共5页
Journal of Third Military Medical University
