阿利沙坦酯对自发性高血压大鼠稳定降压及心脏保护作用的研究

Study on the effects of allisartan isoproxil on stabilizing antihypertension and myocardial protection in spontaneous hypertensive rats

目的探讨阿利沙坦酯对自发性高血压大鼠(SHR)稳定降压及心脏保护的作用。方法将20只13周龄雄性SHR采用抽签法随机分成模型组和阿利沙坦酯组,每组10只;另10只同龄雄性Wistar-Kyoto大鼠为对照组。阿利沙坦酯组连续灌胃给药阿利沙坦酯34周,模型组和对照组给予等量蒸馏水。从第16周开始每4周监测1次血压,48周时超声检测室间隔舒张末期厚度(IVSd)、室间隔收缩末期厚度(IVSs)、舒张期左心室后壁厚度(LVPWd)、收缩期左心室后壁厚度(LVPWs)、收缩期左心室内径(LVIDs)、舒张期左心室内径(LVIDd)、射血分数(EF)和左心室质量(LVM),随后处死动物并取材。苏木精-伊红(HE)染色与Masson染色观察大鼠心脏病理改变。实时荧光定量逆转录聚合酶链反应(qPCR)与蛋白免疫印迹技术(Western blot)检测心肌组织中Ⅰ型胶原蛋白(Col-Ⅰ)、Ⅲ型胶原蛋白(Col-Ⅲ)、骨骼肌肌动蛋白α1(ACTA1)和血小板反应蛋白(THBS4)mRNA与蛋白表达水平。结果与对照组相比,模型组大鼠收缩压与舒张压升高(P<0.05);与模型组相比,阿利沙坦酯组大鼠的收缩压与舒张压降低(P<0.05)。与对照组比较,模型组IVSd、IVSs、LVPWd、LVM和LVPWs升高,LVIDd与EF降低(P<0.05);与模型组比较,阿利沙坦酯组IVSd、IVSs、LVPWd、LVM和LVPWs降低,LVIDd、LVIDs与EF升高(P<0.05);与对照组相比,模型组心脏组织心肌纤维紊乱,大量蓝色胶原纤维沉积,Col-Ⅰ、Col-Ⅲ、ACTA1和THBS4的mRNA及蛋白表达水平升高(P<0.05);与模型组相比,阿利沙坦酯组心肌病理改变改善,Col-Ⅰ、Col-Ⅲ、ACTA1和THBS4 m RNA及蛋白表达水平降低(P<0.05)。结论阿利沙坦酯可有效降低SHR血压,减轻高血压所致的心肌纤维化水平,改善心室重构与心功能。

Objective To investigate the effect of allisartan isoproxil on stable antihypertension and cardioprotection in spontaneous hypertensive rats(SHR).Methods Twenty 13-week-old male SHR rats were randomly divided into the model group and the alisartan ester group,with 10 rats in each group.The other 10 male Wistar-Kyoto rats of the same age were used as the control group.The allisartan isoproxil group was administered allisartan isoproxil by gavage continuously for 34 weeks,the model group and the control group were given equal amounts of distilled water.Blood pressure was monitored every four weeks starting at the 16 week.Interventricular septum in diastolem(IVSd),interventricular septum in systole(IVSs),left ventricular posterior wall in diastole(LVPWd),left ventricular posterior wall in systole(LVPWs),end-systolic left ventricular diameter(LVIDs),end-diastole left ventricular diameter(LVIDd),ejection fraction(EF)and left ventricular mass(LVM)were measured by ultrasound at 48 weeks.The animals were then executed and sampled.Hematoxylin-eosin(HE)staining and Masson trichrome staining were used to observe myocardial pathological changes of rat heart.qPCR and Western blot assay were used to detect the mRNA and protein expression of collagen typeⅠ(Col-Ⅰ),collagen typeⅢ(Col-Ⅲ),skeletal muscle actinα1(ACTA1),and platelet response protein(THBS4)in myocardial tissues.Results Compared with the control group,the blood pressure was significantly higher in the model group(P<0.05).Compared with the model group,systolic blood pressure and diastolic blood pressure were significantly lower in the allisartan isoproxil group(P<0.05).Compared with the control group,IVSs,LVPWd,LVM and LVPWs were increased,and LVIDd and EF were decreased in the model group(P<0.05).Compared with the model group,IVSs,IVSd,LVPWd,LVM and LVPWs were decreased,and LVIDd,LVIDs and EF were increased in the allisartan isoproxil group(P<0.05).Compared with the control group,myocardial fibers were disordered,blue collagen fibers were deposited and the mRNA and protein expression levels of Col-Ⅰ,Col-Ⅲ,ACTA1 and THBS4 were increased in the model group.(P<0.05).Compared with the model group,the myocardial pathological changes were improved,the mRNA and protein levels of Col-Ⅰ,Col-Ⅲ,ACTA1 and THBS4 were decreased in the alisartan isoproxil group(P<0.05).Conclusion Allisartan isoproxil can effectively reduce blood pressure in SHR,attenuate the level of myocardial tissue fibrosis due to hypertension,and improve ventricular remodeling and cardiac function.