Angiotensin Inhibitors In Type 2 Diabetic Rats Blood Vessel Damage Of Protection

Introduction:Diabetes is the current threat to human health, the important disease in our country, patients with diabetes already accounts for 7% of the crowd, the resulting medical spending accounts for about 17% of total social medical spending, and more than a rapidly rising trend. The main damage from long-term diabetes high sugar and fat cause extensive organ damage and vascular damage, especially with cardiovascular complications, such as diabetic nephropathy, fundus lesions were the most.In recent years studies have shown that diabetes sufferers angiotensinogen leels. AngiotensinⅡ(AngiotensinⅡ, Ang II) is renin-Angiotensin system (RAS) the main effect factors involved in cardiovascular function, the physical adjustment and hypertension, atherosclerosis and myocardial infarction and so on many kinds of cardiovascular disease pathology process, with wide biological activities, such as strong vasoconstriction, stimulating various inflammatory cytokine release occurs in the cell, inducing such effect, oxidative stress is caused by diabetes may be involved in the heart, blood vessels, such as the various organs of kidney damage, if can inhibit its role may reduce diabetes organ damage, exact function and mechanism needs research proof.Objective:1. The establishment of type 2 diabetic rats model, named after the success of the mould maker angiotensinⅡinhibitor drug therapy, monitoring test rat glucose, insulin, serum and vascular tissues angiotensin II level in the change.2. Observation test rats not rely on vascular endothelial dependence and the diastolic function changes, and analysis AngⅡthe function and mechanism. Methods:This study selected healthy weight 120-150g male Wistar rat 64 (bought from shanxi medical university animal experiment center), randomly divided into two groups:normal control group (NC group) 16 and diabetes group (DM group) 48. Feed normal control group standards, diabetics fatty, sugary feed, feeding four weeks later, fasting 10h, diabetes were given (STZ) caused by intraperitoneal injection, type 2 diabetes model; Normal control group gives citric acid buffer liquid injection added.A week after the injection tail venous blood sampling measured fasting plasma glucose (FBG), FBG≥16.7 mmol/L, and without apparent glucose observation period fell a determined for diabetic rats made mould success.Diabetes groups and random into three groups:diabetes+physiological saline groups (DMP group), diabetes+valsartan groups(DMV group) and diabetes+ramipril group (DMR group), each group of 16.4 group rats, continue to the original feed 8 weeks, diabetes+valsartan group to valsartan every day 10 mg/kg stomach once, diabetes+ramipril group to ramipril every day 1 mg/kg stomach once, diabetes+ physiological saline groups to such as saline volume everay day stomach once, weekly measured fasting blood sugar once, monitor blood glucose changes. Then kill animals, to return the serum and the thoracic aorta, renal artery, mesenteric artery to conduct the follow-up observations.The levels of insulin and angiotensinⅡin serum and vascular tissue in the content of angiotensin II were measured by ELISA mesord; Collect the aorta, renal artery, mesenteric artery for vasoconstriction diastolic function vitro reflect vascular injury determination; Measuring vascular nitric oxide (NO) and malondialdehyde (MDA) and superoxide dismutase (SOD) content analysis caused AngⅡsource; the production of free radicals.Measuring myeloperoxidase (MPO) activity analysis AngⅡwhich caused inflammatory cells infiltrating mechanism.Results:1. The establishment of diabetic rats modelBuild mode, every groups rats blood sugar levels are indiscriminate.Give STZ intraperitoneal injection after eight weeks, compared with normal controls rats, three groups of diabetic rats, blood sugar concentration significantly increased (DMP group 19.98+1.41 mmol/L, DMV group 20.05±1.02mmol/L,DMR grpup21.42±1.26mmol/L vs. NC group 5.09±0.25mmol/L, P<0.01), while three group of diabetic rats serum insulin levels and no difference between the normal control group. Type 2 diabetes that building a successful model of rats.2. Diabetic rats angiotensinⅡlevel changesIn rats, to return before death, collect blood essels determination serum levels of angiotensinⅡcompared with normal control group, found that diabetic + physiological saline groups, serum angiotensinⅡcontent significantly increased (3.58±0.31 ng/ml vs.2.80±0.23 ng/ml, P<0.01), also in vascular tissue also found that, compared with the normal control group diabetes +physiological saline group of vascular tissue angiotensinⅡwas obviously higher (DMP group 635.28±10.28 pg/ml vs NC group232.21±8.35 pg/ml, P<0.01), shows that diabetes cause angiotensin system activation,AngⅡgenerate increased significantly. Give angiotensin converting enzyme inhibitor ramipril, and diabetes+physiological saline group compared, diabetes+ramipril group of serum and blood essels angiotensinⅡwere significantly reduced (serum:3.12±0.18ng/ml vs.3.58±0.31 ng/ml,P<0.01,blood essels:398.03±13.26pg/ml vs 635.28+10.28pg/ml, P<0.01).While diabetes+valsartan group of angiotensinⅡcontent and brine no obvious difference (serum group 3.54±0.15 ng/ml, blood essels 589.51±10.35 pg/ml).3. Diabetic rats endothelial function damage3.1 Endothelial vitro diastolic blood dependence reaction3.1.1 The thoracic aorta endothelial function changeCompared with the normal control group, diabetes+physiological saline group,chest aortic ring acetylcholine induction of endothelial dependence were significantly lower diastolic reaction,expression is Emax reduce(44.51±2.70% vs.87.01±1.03%,P<0.01),EC50 increased (161.60±13.59nmol/L vs.91.52±1.19 nmol/L,P<0.01).Treatment 8w by Valsartan and ramipril, significantly improve the diabetic rats the thoracic aorta ring of endothelial dependence,and compared with diabetes+physiological saline group,Emax increased significantly (80.12±1.29%,78.56±1.05% vs.44.51±2.70%,P<0.01), EC50dropped (109.10±14.20 nmol/L,115.37±15.14 nmol/L vs.161.60±13.59 nmol/L, P<0.01).3.1.2 Renal artery endothelial function changeCompared with the normal control group, diabetes+physiological saline group, renal artery ring acetylcholine induction of endothelial dependence were significantly lower diastolic reaction, expression is Emax reduce (58.71±2.63%vs.96.54+3.04%, P<0.01),EC50 increased (145.62+17.53nmol/L vs.80.39±7.21nmol/L,P<0.01).Treatment 8w by Valsartan and ramipril, significantly improve the diabetic rats the renal artery ring of endothelial dependence, and compared with diabetes+physiological saline group,Emax increased significantly (80.69±1.52%,80.53+2.35% vs.58.71+2.63%, P<0.01), EC50 dropped (98.51+10.82 nmol/L,106.31+15.26 nmol/L vs.145.62+17.53 nmol/L, P<0.01).3.1.3 The mesenteric artery endothelial function changesCompared with the normal control group, diabetes+physiological saline group, mesenteric artery ring acetylcholine induction of endothelial dependence were significantly lower diastolic reaction, expression is Emax reduce (57.94+1.93%vs.95.62+3.72%,P<0.01),EC50 increased (142.73+20.41nmol/L vs.85.46+4.38nmol/L,P<0.01).Treatment 8w by Valsartan and ramipril, significantly improve the diabetic rats the mesenteric artery ring of endothelial dependence,and compared with diabetes+physiological saline group, Emax increased significantly (85.36+2.71%,80.32+1.26% vs.57.94+1.93%, P<0.01), EC50 dropped (100.13+7.58 nmol/L,110.03+12.14 nmol/L vs.142.73+20.41 nmol/L, P<0.01).3.2 Vitro vascular in-endothelial dependence diastolic reaction3.2.1 The thoracic aorta ringsCompared with the normal control group,in diabetes+physiological saline rats, chest aortic rings induced on the sodium nitroprusside(SNP) in-endothelial dependence diastolic reaction, expression is no significant changes,Emax and EC50 without difference. Treatment 8w by Valsartan and ramipril,in every diabetic rats group thoracic aorta ring, the in-endothelial dependence diastolic reaction no significant differences.3.2.2 Renal artery ringsCompared with the normal control group,in diabetes+physiological saline rats, chest aortic rings induced on the sodium nitroprusside(SNP) in-endothelial dependence diastolic reaction, expression is no significant changes,Emax and EC50 without difference Treatment 8w by Valsartan and ramipril, in every diabetic rats group thoracic aorta ring, the in-endothelial dependence diastolic reaction no significant differences.3.2.3 Mesenteric artery ringsCompared with the normal control group,in diabetes+physiological saline rats, chest aortic rings induced on the sodium nitroprusside(SNP) in-endothelial dependence diastolic reaction, expression is no significant changes,Emax and EC50 without difference. Treatment 8w by Valsartan and ramipril, in every diabetic rats group thoracic aorta ring, the in-endothelial dependence diastolic reaction no significant differences.4. Diabetic rats blood vessel damage biochemical changes4.1 diabetic rats serum and blood essels nitric oxide (NO) content changesRats started raising before, each group serum NO content is, NO significant difference (P>0.05). Injection STZ measured after 8 weekend, the serum NO content respectively is (NC group 35.57+3.23μmol/L, DMP group 16.38±1.85μmol/L, DMV group 25.27±2.36μmol/L,DMR group 28.65+1.62μmol/L). Eight weekend, NC group was obviously higher than that of serum NO DMP group, DMV group, DMR rats (P<0.01); DMV group, DMR group two drug rats, serum NO content is DMP group increase, significant difference (P<0.01), and between the two groups is NO significant differences.Compared with normal controls rats, the concent of organization NO in diabetes+physiological saline rats,was obviously lower (0.26+0.04μmol/mg vs.0.98+0.06μmol/mg,P<0.01), in diabetes+valsartan group and diabetes+ramipril rats, the thoracic aorta organization NO content increased significantly with diabetes+physiological saline groups (0.67 +0.03μmol/mg,0.60+0.01μmol/mg,0.69+0.01μmol/mg vs.0.26+0.04μmol/mg,P<0.01), but compared with normal control group had NO significant differences.4.2 Diabetic rats blood essels malondialdehyde (MDA)content changesAccording to the mensuration, compared with normal control group, the thoracic aorta organization MDA content significantly higher (3.14+0.24μmol/mg vs.1.15+0.21μmol/mg, P<0.01).Treatment 8w by Valsartan and ramipril, compared with diabetes+physiological saline, the thoracic aorta organization MDA content decreased obviously (1.72+0.78 umol/1,1.68+ 0.53μmol/mg,1.78+0.25μmol/mg vs.3.14+0.24μmol/mg,P<0.01) in diabetes+valsartan group and diabetes+ramipril rats.4.3 Diabetic rats blood essels and super oxide of enzyme guhya (SOD) content changesAccording to the mensuration, compared with normal control group, the thoracic aorta organization SOD activity significantly reduced (76.91+15.81U/mg vs.173.81+10.82 U/mg, P<0.01)in diabetes+physiological saline groups. Treatment 8w by Valsartan and ramipril, compared with diabetes+physiological saline, the thoracic aorta organization SOD activity increased significantly (138.83±11.16U/mg,140.13±10.68U/mg,140.32±9.73U/mg vs.76.91±15.81 U/mg, P<0.01) in diabetes+valsartan group and diabetes+ramipril rats.4.4 Diabetic rats vascular tissues myeloperoxidase (MPO) activity of change.Compared with the normal control group,the concent of MPO in diabetes+physiological saline groups the thoracic aorta was obviously increased (0.165±0.05U/g vs.0.012±0.03U/g, P<0.01); Treatment 8w by Valsartan and ramipril, compared with diabetes+physiological saline, the thoracic aorta organization MPO activity droped significantly (0.123+0.02 U/g,0.128+ 0.04U/g vs.0.165+0.05 U/g,P<0.01).Conclusion:1. Type 2 diabetic rats caused a serum and build mode vascular tissue level of angiotensinⅡsignificantly increased; Ramipril irrigation stomach can cause serum and vascular tissues angiotensinⅡ, the fall in the levels of valerian sand filling in Tampa stomach angiotensinⅡlevel not significantly influenced. Ramipril and valerian sand filling in Tampa stomach diabetic rats blood glucose and blood insulin levels without obvious change.2. Type 2 diabetic rats caused endothelial rely on blood vessels diastolic function significantly reduce, not endothelial dependence no significant changes diastolic reaction; Valerian sand to Tampa and ramipril 8 weeks of irrigation, considerably reduced stomach treatment, diabetes causes vasodilation function obstacle, its mechanism and ramipril and valerian sand jotham inhibit angiotensin II mediated endothelial radical injury and inflammatory cells infiltrating are concerned, and has nothing to do with the blood sugar level changes.