Study On Protective Effects Of Fluvastatin On Myocardial Lesion In Diabetic Rats And Its Mechanisms

Objective :Observation of the Protective effects of Fluvastatin on myocardial injury In diabetic rats and to explore the mechanism of Fluvastatin's effects on myocardiopathy in diabetic rats.Methods: 120 SPF male Sprauge-Dualey(SD) rats were used in the experiment .10 rats were taken as normal control. Diabetic rats were induced by intraperitoneal administration of streptozotocin(STZ) at 65mg/kg. Seven days after STZ administration ,fasting blood glucose(FBG) was monitored ,and hyperglycemia was detected by measuring the glucose content via the tail vein. Rat with plasma glucose greater than 16.7mmol/L was defined as hyperglycemia. The animals were divided into 6 groups Fluvastatin was administered intravenously at the dose of 2,6,18mg/kg /d and 6mg/kg+2units/d weekly to the trea-tment group while the same volume of normal saline was given to the normal control a-nd diabetic model(DM) weekly for 8 consecutive weeks and insulin was subcutaneously d-aily at a dose of 2units/day in the insulin group.Subsequent FBG and body weight mea-surement was performed weekly for 8 weeks.The general condition,food and fluid intake , urine output, behavioral change and mortality of the animals were observed during the e-xperimental period. 24h after the last dose of Fluvastatin administration ,FBG and body weight were checked. Using the BL-420+ Biotech system hemodynamics was monitored in all rats weth respect to ECG, and cardiac function including LVSP, LVEDP, and + dp/dtmax , t-dp /dt after urethane anesthesia .Blood samples were collected from the cervical vein and then centrifuged for measurement of TG,TC,HDL,LDH,CK and the activity of SOD,GSH-PX, MDA and content of Ca2+-ATPase in the myocardy homogenate by modified radio-enzymatic method. Heart index(heart mass/body weight ratio) and ventricular index(left ventricular mass/body weight ratio) were measured, and samples were collected for histological and ultrastructural examination. All results were expressed as mean+SEM and analyzed SPSS 11.5Results:1.Compared with the normal control group,diabetic group showed significantly higher blood glucoe level,weight loss.(P<0.05).In Fluvastatin treated group, the blood glucoe level,weight loss were no significantly difference compared with that in diabetic group.2. Compared with the normal control group,the ECG of diabetic group change si-gnificantly. and cardiac function including LVSP, LVEDP, and + dp/dtmax , t-dp /dt and showed significant difference compared with that in normal control group. In Fluvastatin treated group cardiac function improve significantly difference compared with that in diabetic group(P <0.05,P <0.01).3. Compared with the normal control group ,Heart index(heart mass/body weight ratio) and ventricular index(left ventricular mass/body weight ratio) significantly increased in diabetic group (P <0.05,P <0.01).In Fluvastatin treated group the Heart index and ventricular index was significantly decreased compared with that in diabetic group(P <0.05,P <0.01).4. The myocardial tissues of rats staining by HE,PAS,VG showed:In normal control group, the cardiac muscle fibers had no hypertrophy, caryon of cadiocyte were round and ellipsc, they were in the centre of the cadiocytes, the myocardial mesenchymals had normally structure.The were no PAS positive material could be found in cardiac muscle fibers;the myocardial collagen fibers distributed uniformly. In diabetic group, the cadiocyte were hypertrophy and anachromasis, they were obscure boundary and their caryons were nonuniform. Sometimes even focal necrosis of cadiocytes and inflammatory cells cound be found.. There were many PAS positive materials could be found in cardiac muscle fibers.The myocardial collagen fibers were misdiatribution abnormally and ranked disordered, they connected to nets each other. These changes were seldom seen in Fluvastatin treate-d group. The myocardial ultrastructure of the diabetic group was found swollen,and myofibrils fragmentary. The myocardial myocomma was found to be typically deranged, and part of the transwerse striations disappeared. Mitochondria were swollen and vacuolized. Glycogen granules were seen in the cytoplasm of cardiomyocytes.5. Compared with the normal control group,the TG and TC was higher and the HDL was lower in diabetic group there were significantly(P <0.05,P <0.01)There were significantly differences among the TG, TC of all the treatment (except 2mg/kg group) and in diabetic group(P <0.05,P <0.01).6.Compared with the normal control group,the activitly of SOD,GSH-PX,Ca2+-ATPase significantly decreased while the content of MDA increased in diabetic group (P <0.05,P <0.01). In Fluvastatin treated groups the activitly of SOD,GSH-PX,Ca2+-ATPase significantly increased compared with in diabetic group (P <0.05,P <0.01).7.Compared with the normal control group,the PKC expression significantly increased (P<0.01)in diabetic group. In Fluvastatin treated groups, the PKC expression were significantly decreased(P<0.01,P<0.05)and showed no significantly different compared with those in normal control group (P>0.05)。Conclusion:1.Fluvastatin can protect myocardiopathy in diabetic rats.2.These positive effects were probably may relate with the actions on SOD GSH-PX,Ca2+-ATPase significantly and cutting down the content of MDA and PKC.