Angiotensin Inhibitors In Type 2 Diabetic Rat Heart Injury

Objective:The project aims to study type 2 angiotensin II in diabetic rat hearts, and to explore its mechanism of myocardial injury caused, and the inhibition of angiotensinⅡdiabetes drugs on the role of myocardial injury in a preliminary observation.Methods:Will be a total of 55 male SD rats were divided into two groups, diabetic group fed with high sugar and fat combined with low dose of streptozotocin (40 mg/kg) caused an intraperitoneal injection induced model of type 2 diabetes; the control group fed with normal diet and Intraperitoneal injection of equal amount of citric acid buffer; week after tail vein injection of fasting blood glucose (FBG)(?) 16.7mmo/L, and observed no significant decrease during the glucose in diabetic rats were determined to be successful model. Diabetic group and then subsequently divided into three groups, one group was given normal saline (0.5ml/kg/d), one group was given ramipril solution (1mg/kg/d), one group was given valsartan solution (10mg/kg/d), fed once a day for eight weeks after the detection of cardiac function HR, LVSP,±dp/dtmax and other indicators of various parameters, and then animals were sacrificed, serum and myocardial tissue specimens from tested.Determined by ELISA in serum insulin, serum and myocardium of angiotensinⅡ(AngⅡ), serum creatine kinase (CK-MB), cardiac troponinⅠ(cTnⅠ) levels, myocardial tissue sections with TdT Mediated dUTP nick end labeling (TUNEL) staining and Caspase-3 activity measured reflects myocardial cell apoptosis of myocardial extent of myocardial myeloperoxidase (MPO) levels reflect the degree of inflammatory cell infiltration, myocardial biochemical methods Superoxide dismutase (SOD) content and malondialdehyde (MDA), reflecting the degree of myocardial free radical damage, serum and myocardial tissue content and NO 3-nitrotyrosine levels reflect myocardial peroxynitrite Free radical damage.Results:12 model diabetic ratsBefore modeling fasting blood glucose between the groups (FBG), serum insulin were not significantly different (FBG:diabetic group 5.49±0.14 mmol/L and the control group,5.24±0.13 mmol/L compared p> 0.05; insulin:diabetes 1.15±0.14 ng/ml and the control group 1.11±0.13 ng/ml compared p> 0.05); injection of STZ 1 week, diabetic FBG greater than 16.7mmol/L, and significantly higher than the control group (17.2±1.56 mmol/L and Control group,5.24±0.15 mmol/L compared p<0.01), insulin was significantly higher than the control group (1.78±0.14 ng/ml and the control group 1.11±0.10 ng/ml compared p<0.05); administration of 8 weeks After the blood glucose level diabetes+saline group (20.06±1.37 mmol/L), diabetic+ramipril group (20.5±1.15 mmol/L) diabetes+valsartan group (20.14±0.76 mmol/L) was no significant difference (Posts p> 0.05), and were significantly higher than the control group (5.13±0.13 mmol/L, p<0.01); blood insulin levels diabetic+saline group (2.09±0.28 ng/ml), diabetic+ ramipril group (1.58±0.25ng/ml), diabetes+valsartan group (1.64±0.21 ng/ml) and no significant difference (p> 0.05), diabetic+saline group than in the control group (1.13±0.11 ng/ml) was significantly higher (p＜0.01), Table 1. The results showed:type 2 diabetic rat model is established successfully, angiotensin II inhibitor ramipril and valsartan on blood glucose and blood insulin levels had no significant effect.2 Determination of cardiac functionCompared with the control group, diabetic+saline group dp/dtmax decreased (3704.70±262.29 mmHg/ s and the control group 6417.53±415.75 mmHg/s compared p<0.01), LVSP decreased significantly (97.18±4.26 mmHg with the control group 113.44±2.70 mmHg compared p<0.05),-dp/dtmax significantly decreased (-5845.21±349.36mmHg/s and the control group-2961.75±341.37mmHg/s comparison p <0.01), LVEDP was significantly higher (22.88±2.09 mmHg and 8.66±1.22 mmHg in control group comparison p<0.01); that diabetic rats were lower systolic and diastolic function; and diabetic+saline group, diabetic+ramipril group, diabetic+valsartan group±dp/dtmax were significantly higher (p<0.05), LVEDP was significantly decreased (p<0.01) Table 2, show that:after administration of ramipril and valsartan significantly reduced the diabetes-induced cardiac dysfunction.3 content of plasma and myocardium AngⅡchangesCompared with the control group, diabetic+saline group, the plasma and myocardium AngⅡlevels were significantly elevated (plasma:3.65±0.20 ng/ml and the control group 2.84±0.18 ng/ml compared p<0.01, tissue:713.79±11.69 pg/ml and control group 356.68±9.91 pg/ml compared p<0.01); and diabetic+ saline group, fed diabetic+ramipril group plasma (3.09±0.19ng/ml with the saline group 3.65±0.20 ng/ml compared p<0.05), tissue (424.51±11.98pg/ml with the saline group 713.79±11.69 pg/ml compared p <0.01) AngⅡwere significantly decreased, while the fed group and diabetes+valsartan physiological Saline group in plasma and myocardium AngⅡwas no significant difference in Table 3.4 plasma CK-MB, CTnⅠcontentCompared with the control group, diabetic+saline group, the plasma CK-MB was significantly higher (28.06±1.16 ng/ml, and the control group,12.58±0.73 ng/ml compared p<0.01), cTnⅠconcentration was significantly higher (2.02±0.09 ng/ml, and the control group 0.78±0.05 ng/ml compared p＜0.01); and diabetic+saline group, gavage ramipril group (CK-MB 15.67±1.10 ng/ml, cTnl 1.79±0.05 ng/ml), valsartan gavage group (CK-MB 16.05±0.85 ng/ml, cTnⅠ1.66±0.09 ng/ml) Ck-Mb, and cTnⅠwere significantly decreased, indicating that diabetes caused significant myocardial Cell structure damage, the release of cell contents, and ramipril and valsartan reduced the structural damage caused by diabetes, heart, shown in Table 4.5, apoptosis is increased in diabetic rats, perfusion group than in the apoptosis of normal saline irrigation to reduce5.1 T U N E L detectionCompared with the control group, diabetic+saline group increased the proportion of TUNEL positive cells (0.36±0.03%, and 0.04±0.02% in control group comparison p<0.01); and diabetic+saline group, Ramipril Fed group (0.13±0.02%), valsartan gavage group (0.11±0.02%) TUNEL-positive cells was significantly reduced, suggesting that diabetes can cause cardiomyocyte apoptosis, and ramipril and valsartan reduced diabetic Cardiomyocyte apoptosis, shown in Table 5.5.2 Caspase-3 activity was measured myocardialCompared with the control group, diabetic+saline group Caspase-3 activity in myocardial tissue was significantly higher (0.83±0.07 nmol/h/mg, with the control group 0.13±0.01 nmol/h/mg comparison p <0.01); and diabetes+saline group, gavage ramipril group (0.66±0.04nmol/h/mg) and valsartan gavage group (0.64±0.05nmol/h/mg) myocardial Caspase-3 activity was significantly decreased Table 5 also proved ramipril and valsartan reduced the diabetes-induced myocardial apoptosis level.6, MPO content in myocardial tissueCompared with the control group, diabetic+saline group was significantly higher myocardial tissue MPO (0.186±0.004 U/g, and the control group,0.016±0.002 U/g compared p<0.01); and diabetic+saline group Ramipril fed group (0.126±0.005 U/g), valsartan fed group (0.119±0.003 U/g) MPO was significantly reduced, see Table 6, show that diabetes causes myocardial infiltration of inflammatory cells Increase, while reducing the ramipril and valsartan in rats with diabetes induced by the degree of myocardial cell infiltration.7, NO generation in plasma and myocardium and myocardial 3-Determination of nitrotyrosine 7.1 Determination of plasma and myocardial NOCompared with the control group, diabetic+saline group, the plasma, myocardial NO content decreased significantly (plasma:36.93±2.10 umol/L, and the control group,58.32±2.41 umol/L comparison p<0.01, tissue:0.82±0.09 umol/g, and the control group,1.93±0.06 umol/g comparison p<0.01); and diabetic+ saline group, gavage ramipril group (serum:45.43±2.38 umol/L, tissue:1.45±0.04 umol/g), valsartan gavage group (serum:47.54±2.90 umol/L, tissue:1.56±0.06umol/g) NO were significantly increased. Table 7.7.2 myocardial peroxynitrite radical (ONOO-) product of 3-Determination of nitrotyrosineCompared with the control group, diabetic+saline group myocardial tissue of 3-nitrotyrosine was significantly higher (0.944±0.078 ng/mg pro, and the control group,0.325±0.032 ng/mg pro comparison p <0.01); Compared with diabetic+saline group, gavage ramipril group (0.494±0.044 ng/mg pro), valsartan fed group (0.547±0.061 ng/mg pro) 3-nitrotyrosine was significantly Reduced, see Table 7, show that diabetes caused a myocardial production of nitrite free radical damage, and ramipril and valsartan reduced the diabetes-induced myocardial nitrite free radical injury.8 myocardial MDA content and SOD activity determination8.1 Determination of myocardial MDACompared with the control group, diabetic+saline group was significantly higher myocardial tissue MDA (3.03±0.10 ng/mg, with the control group 1.62±0.12 ng/mg comparison p<0.01); and diabetic+saline group Ramipril fed group (2.68±0.15 ng/mg), valsartan fed group (2.49±0.08 ng/mg) MDA content was decreased. Table 8.8.2 Determination of myocardial SODCompared with the control group, diabetic+saline group was significantly reduced myocardial SOD (98.50±7.97 U/mg, with the control group 193.92±11.70 U/mg comparison p<0.01); and diabetic+saline group, Stomach ramipril group (134.76±9.14 U/mg), valsartan intragastric group (151.09±4.25 U/mg) SOD were significantly increased. Table 8.The results showed that the diabetic rat heart cells to accelerate lipid peroxidation, scavenging oxygen free radicals decreased significantly, given after administration of ramipril and valsartan significantly inhibited the lipid peroxidation caused by diabetes, injury, protection Endogenous free radical scavenging mechanism.Conclusion:Type 2 diabetes can cause the activation of angiotensin system and angiotensinⅡincreased, elevated angiotensinⅡby increasing free radicals, reducing the endogenous scavenging oxygen free radicals, increased inflammatory Cell infiltration and cardiomyocyte apoptosis pathway induced structural damage, heart dysfunction; inhibition of AngⅡgeneration drugs such as angiotensin-converting enzyme inhibitor ramipril and the angiotensin receptor blocker valsartan may be blood vessels against diabetes AngiotensinⅡdamage, and mitigate the extent of myocardial injury in diabetes, protect the heart, this protection independent of its effect on blood glucose.