Effects Of Ramipril On Myocardial Ischemia-Reperfusion Injury In Rats And Its Mechanism

The myocardial ischemia reperfusion injury (MIRI) is a repeated damage when the bloodstream with ischemic myocardial tissue was recoverd, which can induce significant patho-physiological changes in cadiocyte of reperfusion region and local vascular net. Now it is a great development to the clinical medicine, that the acute myocardial infarct patients have been cured by thromboclasis,coronary artery repatency, precutaneous transluminal coronary angioplasty and other heart surgery in the last years. The myocardial tissue get again blood reperfusion due to cardiovascular repatency or reconstructive operation, which can really obtain satisfactory favorable therapeutic efficacy in multitudinous conditions. However, the blood reperfusion will cause myocardial tissue the second injury, even lead to serious arrhythmia. Therefore, it has important clinical meaning to seek safe and active medicine to treat myocardial ischemia reperfusion injury.Angiotensin converting enzyme inhibitors (ACEI) have becomed the first selection active drug in treatment of hypertension and congestive heart failure,but curative effect still was dispute in treatment of acute myocardial infarction. Ramipril, a prodrug, is new generation powerful and long acting ACEI, which hydrolyze and form compt ramiprilat in liver after absorption through gastrointestinal tract. Although clinical indication of Ramipril have enlarged into light or midrange heart failure after acute myocardial infarction, It still not be reported that Ramipril whether or not apply directly treatment of myocardial ischemia-reperfusion injury. We investigated the effects of Ramipril on experimental myocardial ischemia-reperfusion injury in rats and determined the changes of myocardial infarct size, the activity of serum creatine kinase, lactate dehydrogenase and aspartic transaminase, the content of malonydialhyde and the activity of superoxide dismutase and glutathione peroxidase in serum, the levels of plasma thromboxane A2 and protacyclin, and the contents of nitric oxide, endothelin and angiotensionâ…¡in serum. In the same time, we discussed the effect mechanism of Ramipril on antimyocardial ischemia reperfusion injury, which offered experiment foundation for enlargement of clinical indication of Ramipril.1.Methods1.1 Groups and dosages:80 wistar rats (weight 230-260g) were divided randomly into four groups including the sham operation group, the ischemia reperfusion model group, Verapamil group 10mg/kg group and Ramipril 1.0mg/kg group and there are 20 rats in every group. Rats of the sham operation group and ischemia reperfusion model group were given with 0.5% CMC 5ml/kg in intragastric administration. All rats were given drug one time every morning in two days and given again drug one time before built the myocardial ischemia-reperfusion model in the third day morning.1.2 Methods and parameters:After anesthetized with aether, rats were faced upward fixed on the operation table. Open the chest between the left third and fourth rib and the heart was exposed. A 0 nylon suture attached to a fine needle was placed under the left anterior descending coronary artery and a fine emulsoid tube was placed between coronary artery and suture. Then coronary artery was ligated with slipknot immediately. The heart was return into the chest, the blood and gas were squeezed out and the chest was closed swiftly. The time opening the chest is no more than 30 seconds. The sham operation group placed the suture only but not ligate coronary artery. After coronary artery was ligated 30 minutes, rats of each group were opened the chest and exposed the heart again. The nylon suture was undid immediately and the heart was reperfused. After reperfused 120 minutes, rats were anesthetized with pentobarbital sodium(30mg/kg intraperitoneal injection). Blood were collected with aorta abdominalis to determine activities of creatine kinase(CK), lactate dehydrogenase(LDH) and aspartic transaminase(AST) in serum, and the contents of malonydialhyde (MDA), nitric oxide (NO), endothelin (ET) and angiotensinâ…¡(Angâ…¡) and the activities of superoxide dismutase(SOD) and glutathione peroxidase(GSH-Px) in serum, and the levels of prostacyclin(PGI2) and thromboxane A2(TXA2) in plasma. The hearts of rats were taken out and were dyed with N-BT to measure myocardial infarct size (MIS).2. ResultsThe results indicated that in rats treated with ischemia-reperfusion injury, MIS is enlarged obviously; activities of CK, LDH and AST in serum are increased significantly; contents of MDA, ET and Angâ…¡in serum are increased significantly; content of NO and activities of SOD and GSH-Px in serum are decreased significantly; the level of TXA2 is higher, the level of plasma PGI2 and the ratio of PGI2 to TXA2 are both lower in plasma.Compared with ischemia-reperfusion injury group, Ramipril can significantly zoom out MIS, decrease the activities of CK, LDH and AST in serum and the contents of MDA, ET and Angâ…¡in serum, increase the content of NO and activities of SOD and GSH-Px in serum, the level of PGI2 in plasma and the ratio of PGI2 to TXA2, and decrease the level of TXA2in plasma. The results above indicated that Ramipril has the effect of antimyocardial ischemia reperfusion injury.3. Conclusion1) Ramipril can significantly zoom out MIS, decrease the activities of CK, LDH and AST in serum in rats treated with ischemia-reperfusion injury, which indicated that Ramipril has the significant protective effect on myocardial ischemia reperfusion injury.2) Ramipril can significantly decrease the content of MDA and increase activities of SOD and GSH-Px in serum in rats treated with ischemia-reperfusion injury, which indicated that Ramipril bring into full play effect of antimyocardial ischemia reperfusion injury through decreasing accumulation of lipid peroxidation and strengthening clear ability of organism on free radical.3) Ramipril can significantly decrease the level of TXA2 and increase the level of PGI2 in plasma and the ratio of PGI2 to TXA2 in rats treated with ischemia-reperfusion injury, which indicated that Ramipril achieve effect of antimyocardial ischemia reperfusion injury through correcting disequilibrium of the ratio of PGI2 to TXA2.4) Ramipril can significantly decrease the level of ET and Angâ…¡in plasma and increase the content of NO in serum in rats treated with ischemia-reperfusion injury, which indicated that Ramipril can improve coronary flow of ischemia-reperfusion injury and inhibit ventricular and vascular remodeling.To sum up, it may be the synthetic action with many ways that Ramipril reduced myocardial ischemia-reperfusion injury. This study proves the important experimental foundation for effective prevention and cure of myocardial ischemia reperfusion injury in clinic.