The Effect And Mechanism Of Prevention And Treatment Of Metoprolol On Vascular Aging In Spontaneously Hypertensive Rats

Background Hypertension is one of the most common cardiovascular diseases in China,which the incidence is as high as 34.9%.Vascular aging is the target organ damage of hypertension,which is closely related to the occurrence and development of cardiovascular and cerebrovascular diseases such as clinical acute myocardial infarction,stroke,peripheral vascular disease,aneurysm,hypertension,cognitive dysfunction and Alzheimer’s disease.Angiotensin converting enzyme inhibitors,beta blockers,calcium channel blockers and diuretics are the antihypertensive drugs recommended in the current hypertension treatment guidelines,However,the different effects of different drugs on vascular aging,the protective advantage of metoprolol against vascular aging and its exact mechanism remains unclear.Objective To investigate the effect of metoprolol on the prevention and treatment of vascular aging in spontaneously hypertensive rats and its potential mechanism.Methods Twenty-four Three-month-old male spontaneously hypertensive rats are randomly divided into observation group(group A),nifedipine group(group B),nifedipine +metoprolol group(group C)and metoprolol group(group D),treated with dietary starch,nifedipine sustained-release tablets 60 mg,nifedipine sustained-release tablets 40 mg+metoprolol sustained-release tablets 75 mg and metoprolol sustained-release tablets 150 mg,respectively.The blood pressure,heart rate of the rats are dynamically observed during nine months of normal diet.Femoral artery strip are taken from rats under anesthesia for examination.The morphological characteristics of femoral artery are observed by HE staining.The vasomotor function of isolated femoral artery is tested by circumferential perfusion.The molecules expression levels of p53,p21,CHOP and XBP1 are detected by immunofluorescence histological staining and real-time quantitative polymerase chain reaction.Results(1)Through dynamic monitoring of blood pressure and heart rate of spontaneously hypertensive rats,comparing with group A,systolic blood pressure decreased by 30%,diastolic blood pressure decreased by 20% and heart rate decreased by 8.8%,36%and 41% in groups B,C and D,respectively.(2)In group A,the boundary between the intima and the media of the femoral artery is not clear,and there is uneven thickening.Compared with group A,the thickness and cross-sectional area of the intima and media in groups B,C and D are significantly reduced,which the group D is the most obvious.(3)The femoral artery ring tension of rats in each group is measured by circumferential perfusion experiment and it is find that the function of the femoral artery in group A is significantly impaired.Compared with group A,the systolic and diastolic functions of femoral artery in group B,C and D are significantly improved after drug intervention,which the group D is the most obvious after metoprolol treatment.(4)Immunofluorescence histological staining and real-time quantitative polymerase chain reaction are used to detect the expression of age-related molecules in the femoral artery wall.we find that compared with group A,the expression levels of m RNA and protein of age-related genes p53 and p21 are significantly down-regulated in groups B,C and D;Compared with group B and C,the expression levels of p53,p21 m RNA and protein in group D are dramatically reduced.(5)Immunofluorescence histological staining and real-time quantitative polymerase chain reaction are used to detect the expression of endoplasmic reticulum stress related molecules in the femoral artery wall.we find that compared with group A,the m RNA and protein expression levels of endoplasmic reticulum stress related genes,CHOP and XBP1,are significantly down-regulated in groups B,C and D;Compared with groups B and C,the expression levels of CHOP and XBP1 m RNA and protein in group D are significantly decline.Conclusion Spontaneously hypertensive rats arteries have the characteristics of aging.The vasomotor function of the femoral artery is disordered in the spontaneously hypertensive rats,the intima and medial layer of the femoral artery are thickened under the microscope,and the expression of endoplasmic reticulum stress related genes are significantly up-regulated in the femoral artery.The vascular aging is significantly inhibited by treatment of metoprolol in spontaneously hypertensive rats,the mechanism may be related to inhibition of endoplasmic reticulum stress in endothelial cells and smooth muscle cells.