β受体阻滞剂对自发性高血压大鼠血管老化的影响

Effects ofβ-blockers on vascular aging in spontaneously hypertensive rats

[目的]探讨β受体阻滞剂在自发性高血压大鼠(SHR)血管老化中的防治作用及其潜在机制。[方法]将24只3月龄雄性SHR随机分为安慰剂组、硝苯地平组、硝苯地平+美托洛尔组、美托洛尔组,分别以食用淀粉、硝苯地平缓释片60 mg、硝苯地平缓释片40 mg+美托洛尔缓释片75 mg、美托洛尔缓释片150 mg灌胃治疗,普通饲料喂养9个月,动态观察大鼠血压、心率及一般情况。HE染色观察大鼠股动脉形态学特征,离体股动脉血管环灌流实验检测血管舒缩功能,免疫荧光组织学染色和实时聚合酶链反应(RT-PCR)测定衰老相关基因p53、p21及内质网应激相关基因CHOP、XBP1的表达。[结果]与安慰剂组相比,硝苯地平组、硝苯地平+美托洛尔组、美托洛尔组收缩压下降约30%,舒张压下降约20%,心率分别下降了9%、36%、41%(均P<0.01)。与安慰剂组相比,硝苯地平组、硝苯地平+美托洛尔组、美托洛尔组舒缩功能显著改善,内膜中膜厚度分别下降了24%、14%、37%(均P<0.01);与硝苯地平组、硝苯地平+美托洛尔组相比,美托洛尔组舒缩功能显著改善,内膜中膜厚度分别下降了18%、27%(均P<0.01)。与安慰剂组相比,硝苯地平组p53蛋白、p53 mRNA、p21蛋白、p21 mRNA、CHOP蛋白、CHOP mRNA、XBP1蛋白、XBP1 mRNA的表达水平分别下降了35%(P<0.01)、23%(P<0.05)、25%(P<0.01)、3%(P>0.05)、51%(P<0.01)、24%(P>0.05)、21%(P<0.01)、23%(P>0.05),硝苯地平+美托洛尔组分别下降了36%(P<0.01)、42%(P<0.01)、4%(P>0.05)、24%(P<0.05)、32%(P<0.01)、44%(P<0.05)、13%(P<0.01)、42%(P<0.05),美托洛尔组分别下降了47%(P<0.01)、43%(P<0.01)、42%(P<0.01)、49%(P<0.01)、78%(P<0.01)、56%(P<0.01)、32%(P<0.01)、81%(P<0.01)。与硝苯地平组、硝苯地平+美托洛尔组相比,美托洛尔组进一步抑制衰老和内质网应激相关基因的表达。[结论]SHR的动脉存在明显老化,β受体阻断剂在抑制SHR血管老化方面优于钙通道阻断剂,且高剂量β受体阻断剂改善血管老化程度优于联合用药,其机制可能与抑制内质网应激有关。

Aim To explore the preventive effect and potential mechanism ofβ-blockers in vascular aging of spontaneously hypertensive rat(SHR).Methods 24 three-month-old male spontaneously hypertensive rats were randomly divided into placebo group,nifedipine group,nifedipine+metoprolol group and metoprolol group,treated with edible starch,60 mg nifedipine sustained-release tablets,40 mg nifedipine sustained-release tablets+75 mg metoprolol sustainedrelease tablets and 150 mg metoprolol sustained-release tablets,respectively.The rats fed with common diets for 9 months,and the blood pressure,heart rate and other general condition of the rats were dynamically measured.HE staining was used to observe the morphological characteristics of femoral aorta in rats.The vasomotor function of isolated femoral artery was tested by circumferential perfusion,immunofluorescence histological staining and real-time polymerase chain reaction(RT-PCR)were used to determine the expression of aging related genes p53 and p21,as well as endoplasmic reticulum stress related genes CHOP and XBP1.Results Compared with placebo group,systolic blood pressure decreased by about 30%,diastolic blood pressure decreased by about 20%,and heart rate decreased by 9%,36%and 41%(all P<0.01)in nifedipine group,nifedipine+metoprolol group and metoprolol group,respectively.Compared with placebo group,the systolic and diastolic functions of nifedipine group,nifedipine+metoprolol group and metoprolol group were significantly improved and the intima-media thickness decreased by 24%,14%and 37%(all P<0.01),respectively.Compared with nifedipine group and nifedipine+metoprolol group,the systolic and diastolic functions of metoprolol group were significantly improved and the intima-media thickness decreased by 18%and 27%(all P<0.01),respectively.Compared with the placebo group,the expression levels of p53 protein,p53 mRNA,p21 protein,p21 mRNA,CHOP protein,CHOP mRNA,XBP1 protein and XBP1 mRNA in nifedipine group decreased by 35%(P<0.01),23%(P<0.05),25%(P<0.01),3%(P>0.05),51%(P<0.01),24%(P>0.05),21%(P<0.01)and 23%(P>0.05),the nifedipine+metoprolol group decreased by 36%(P<0.01),42%(P<0.01),4%(P>0.05),24%(P<0.05),32%(P<0.01),44%(P<0.05),13%(P<0.01)and 42%(P<0.05),the metoprolol group decreased by 47%(P<0.01),43%(P<0.01),42%(P<0.01),49%(P<0.01),78%(P<0.01),56%(P<0.01),32%(P<0.01)and 81%(P<0.01).Compared with nifedipine group and nifedipine+metoprolol group,metoprolol group further inhibited the expression of genes related to aging and endoplasmic reticulum stress.Conclusions The arteries of spontaneously hypertensive rats show significant aging.β-blockers are better than calcium channel blockers in inhibiting vascular aging of spontaneously hypertensive rats,and at high dosesβ-blockers improve the degree of vascular aging better than combination therapy,and their mechanism may be related to the inhibition of endoplasmic reticulum stress.