The Study Of Preventive Effect On Endothelium Impairment By Telmisartan Combined With Atorvastatin In Diabetic Rats

Backgroud and object:AHA has pointed out unequivocally that diabetes mellitus is a cardiovascular disease early since 1999.Many studies have indicated that vascular endothelial cell has already presented both functional and structural dysfunction in the early stage of insulin resistance, and dysfunction of endothelial cell is the early change of atherosclerotic development.The studies in recent years showed that hepatocyte growth factor(HGF) is a protective factor of vascular endothelial cell,local vascular HGF production is decreased in diabetes mellitus,the decrease of HGF might be a trigger of endothelial injury.Telmisartan is an unique angiotensin II receptor blocker(ARB) with selective PPARγ-modulating activity,it can improve insulin resistance and reduce the level of blood glucose.Statins have been used extensively for the treatment of diabetes,but the combination of ARB and statins in the treatment of diabetic endothelial injury and its mechanisms is waiting for being illuminated.In this study,we treated diabetic rats by administration of single telmisartan and the combination of telmisartan and atorvastatin,observed the effects on expression of HGF in aorta and phenotype or function of vascular endothelial cell in order to investigate their potential mechanisms in preventing and curing endothelial injury and to provid experimental proof for searching more effective treatment of diabetic earlier artherosclerosis in clinical work.Methods:Ten of the fifty Male Sprague-Dawley rats were drawn out randomly as normal group,other forty rats were used to establish diabetic animal models.The modeling diabetic rats were randomly divided into diabetes group(n=10),telmisartan group(n=10) and combining treated group(n=9).Telmisartan was administered in dosage of 6.5mg·kg-1·d-1 in telmisartan group,telmisartan plus atorvastatin was administered in dosage of 6.5mg·kg-1·d-1 and 2.5mg.kg-1.d-1 in combining treated group,comparative distilled water was administered in normal group and diabetes group,all were treated for 8 weeks.After treatment with different diet and drug regimens for 8 weeks,Systolic blood pressure was measured,then rats were sacrificed by drawing blood from heart and the blood and aortas were collected,blood glucose(Glu),blood lipids,catalase(CAT),malondialdehyde(MDA)and nitrogen monoxidum(NO)were measured,the expression of HGF in aorta was detected with immunohistochemistry(IHC) and RT-PCR,the appearance of vascular endothelial cell was observed with transmission electron microscope (TEM).Result:(1)compared with normal group,SBP,Glu,TC,TG,LDL and MDA in diabetes group were markedly increased(P﹤0.05),HDL,CAT,NO and expression of HGF protein and HGFmRNA were notably decreased(P﹤0.05),impaired changes of endothelial cell such as swelling,necrosis,amotio in TEM were developed.(2)compared with diabetes group,SBP,Glu,TC,TG,LDL,MDA,the expression of HGF protein and HGFmRNA in telmisartan group and combining treated group were notably decreased(P﹤0.05),HDL,CAT,NO were markedly increased (P﹤0.05),the phenotype of endothelial cell in TEM was improved obviously.(3)compared with telmisartan group,the decrease of TC,TG,LDL,MDA and the increase of HDL,CAT,NO in combining treated group were more significan(tP﹤0.05),there was some decrease in SBP and some increase in the expression of HGF protein and HGFmRNA,but there were no statistical significance(P﹥0.05),the appearance of endothelial cell in TEM was recovered to normal on the whole.Conclusion:The blood pressure , blood glucose and lipids were significantly increased in diabetic rats before treatment.In contrast,HGF in vascular endothelial cell was decreased obviously,accompanied with morphological changes of endothelial cells,such as swelling,necrosis,shedding and the functional impairments.Telmisartan lowered the blood pressure,improved the disorder of blood lipids and oxidative stress , up-regulated the expression of HGF,thus improved the phenotype and function of vascular endothelial cell in diabetic rats.The combined treatment with telmisartan and atorvastatin improved the phenotype and function of vascular endothelial cell better,which may suggests that the combination of telmisartan and statins has synergistic action in preventing endothelial cell damage in diabetic rats.The implication of this combination of ARB and Statins is worth studying further.