吡哆胺和替米沙坦对自发性高血压大鼠氧化应激水平的影响

摘要

Objective To investigate the effects and the mechanism of telmisartan and pyridoxamine on oxidative stress in spontaneously hypertensive rats(SHR).Methods SHRs(male,20 weeks of age) were randomly divided into four groups (n＝ 12 for each):hypertension control (HC) group (2 ml of distilled water),telmisartan group[T,6 mg/(kg · d)],pyridoxamine group[P,200 mg/(kg · d)]and combined group(TP,6 mg/kg telmisartan and 200 mg/kg pyridoxamine per day).Treatments were continued for 16 weeks.The normal control group included 13 WKY rats and received gastric lavage with distilled water.SBP of tail artery was measured during the intervention ervey 2 weeks.The levels of AGEs,SOD and MDA were measured by ELISA,xanthine oxidase and thiobarbituric acid methods after the intervention.Expressiones of NF-κBp65,ERK1 and ERK2 in renal tissue were detected by immunohistochemistry.Expression of RAGE in the renal cortex was investigated by Western blot.Results SOD activity was decreased in the HC group.The levels of AGEs,MDA,RAGE and the activations of NF-κBp65 and ERK1/2 were increased in the HC group (t＝4.53,5.52,2.93,al1 P＜0.05).After the 16 weeks' intervention,SOD activity was elevated in T,P and TP groups compared to that in HC group (P＜0.05).The positive expressiones of NF-κBp65,ERK1 and ERK2 were significantly reduced in T,P and TP groups compared to those in HC group (F＝20.13、148.82、18.70,all P＜0.05).All the positive expressiones of NF-κBp65,ERK 1and ERK2 were lowest in the TP group versus T and P groups (t ＝ 3.58、2.84,P ＜ 0.05).Conclusions Telmisartan and pyridoxamine can alleviate the oxidative stress in spontaneously hypertensive rats,which may result from the blocking effect of Ang Ⅱ,the reduction of AGEs-RAGE and inhibiting the signal pathways of ROS,NF-κBp65 and ROS-ERK1/2.%目的 观察单用及联用替米沙坦和吡哆胺对自发性高血压大鼠(SHR)肾脏氧化应激的影响,并探讨其作用机制.方法 20周龄雄性SHR大鼠随机分为4组(每组12只):高血压组(蒸馏水)、替米沙坦组(每天6 mg/kg)、吡哆胺组(每天200 mg/kg)、联合组(每天替米沙坦6 mg/kg+吡哆胺200 mg/kg),连续灌胃给药16周.WKY大鼠为正常对照组,每天蒸馏水2 ml灌胃.监测大鼠尾动脉收缩压变化,测定糖基化终末产物(AGEs)(酶联免疫吸附试验法)、超氧化物歧化酶(黄嘌呤氧化酶法)、丙二醛(硫代巴地妥酸法),免疫组化法检测肾组织核转录因子(NF)-κBp65、细胞外调节蛋白激酶(ERK)1及ERK2,Western blot检测肾组织RAGE表达.结果 高血压组血清SOD活力降低,血清AGEs、MDA增高,肾组织MDA、RAGE含量增高,肾组织NF-κBp65、ERK1和ERK2阳性表达水平增高(t＝4.53、5.52、2.93,均P＜0.05).替米沙坦、吡哆胺干预16周后,血清SOD活力升高,血清及肾皮质的MDA含量明显降低(t＝2.43、2.73,P＜0.05).单用及联用组的肾组织NF-κBp65、ERK1和ERK2阳性表达低于高血压组(F＝ 20.13、148.82、18.70,P＜0.05),其中联合组的表达水平较单用组更低(t＝3.58、2.84,P＜0.05).结论 替米沙坦及吡哆胺均可改善自发性高血压大鼠的氧化应激水平,可能与降低体内AGEs-RAGE水平有关,二者联用抑制ROS、NF-κBp65、ROS-ERK1/2信号通路具有协同效应.