Smnd-309 Therapeutic Effect And Mechanism Of Acute Myocardial Ischemia

Background and objective:Coronary heart disease (CHD) is coronary artery disease caused by myocardial ischemic or necrosis, also called Coronary atheroselerot heart disease (CAHD) Acute myocardial infarction is a kind of coronary heart disease. The basic cause of acute myocardial infarction is coronary atherosclerosis, causing severe structure and lumen myocardial blood deficiency, and not fully establish collateral circulation, and on this basis, once the blood supply is decreased sharply or interrupted, further severe acute myocardial ischemia lasting 1 hour above, myocardial infarction. In recent years, with the social lifestyle and diet structure changing, ischaemic heart disease incidence is increasing trend year by year, cardiovascular, cerebrovascular diseases and cancer was considered as the "three killer" threaten human health. Therefore, the study of anti-myocardial ischemic drugs is more and more attentioned in the world. Now traditional anti-myocardial ischemia drugs improve oxygen supply and demand relation through by increased coronary flow, adjusted the supply of oxygen, reduced the myocardial consumption of oxygen, improve metabolism, play protective roles on myocardial infarction injury and have better cardioprotective effect, However, myocardial infarction exist complex causes and pathophysiological change, and the traditional medicines have certain deficiencies. Thus developing new drugs and explore anti-myocardial ischemia mechanism is still an important study. SMND-309, a novel derivate of salvianolic acid B synthesized by Shandong Engineering Research Center For Nature Drug was demonstrated in our former experiments having many pharmacologic actions such as anti-oxidant, anti-apoptotic properties, improving the blood flow ischemic area of heart, extending coronary artery vessel, diminuting the scope of acute myocardial infarction, ameliorating the myocardial dysfunction induced by ischemia-reperfusion, and so on. In the present study, we investigated the cardioprotective effects of SMND-309 on animal models of myocardial infarction and elucidated the possible mechanisms on the basis of biochemical, histopathological and immunohisto-chemical studies.Methods:Myocardial infarction was induced by permanent ligation of the left coronary artery in rats. After ligation, the rats were randomly divided into six groups of 20 animals each:sham group, acute myocardial infarction (AMI) group, SMND-309 treated (5mg/kg, 10mg/kg,20mg/kg) groups, salvianolic acid B treated (10mg/kg). All drugs were administered via tail vein injection just 5 min after coronary occlusion. The sham group received the same volume of physiological saline. Electrocardiogram measurements were performed before coronary occlusion and 5,30,60,120,180 and 240 min after coronary occlusion. LeadⅡECG monitoring was undertaken throughout the experimental duration, and S-T segments elevation in the experimental animals was considered. After 6 hour of the coronary ligation, the blood was taken by abdominal aorta, then the serum was isolated by centrifugalization for the assays of the activity of serum creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and aspertate aminotransferase (AST) and the levels of cardiac troponin T (cTnT) in serum. Hearts were removed rapidly and transected after blood collection. The distal portion of the heart was fixed with 10% formalin for subsequent haematoxylin-eosin (H&E) staining, immunohistochemical staining (Bax and Bcl-2 protein) and terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) positivity. The proximal portion was homogenized, then centrifuged and the supernatant serum samples were collected for the measurement of the content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px). In order to evaluate the effect of SMND-309 on free radical damage induced by myocardial ischemia in AMI rats.Results:The results indicated:(1) SMND-309 (10 and 20 mg/kg respectively) significantly attenuated the elevation in S-T segments with the passage of time in 240 min, compared with the AMI group (p<0.05 or p<0.01). (2) SMND-309 significantly attenuated the increase in CK-MB, LDH, AST and cTnT content compared with the AMI group (p<0.05 or p<0.01). (3) Treatment with SMND-309 (10 and 20 mg/kg respectively) significantly attenuated the pathophysiological changes in the cardiac muscle fibre, Treatment with SMND-309 (10 and 20 mg/kg respectively) significantly reduced the number of apoptosis cells, enhanced Bcl-2 expression, reduced Bax expression and attenuated the ratio of Bcl-2/Bax (p<0.05 or p<0.01), compared with the AMI group (p<0.05 or p<0.01) (4) Treatment with SMND-309 (10 and 20 mg/kg respectively) significantly enhanced the activities of catalase, glutathione peroxidase and superoxide dismutase and inhibited the increase in malondialdehyde contents in AMI rat cardiocytes (p<0.05 or p<0.01). (5) SMND-309 exhibited significantly higher potency compared to salvianolic acid B at the same dose (10 mg/kg).Conclusion:It is concluded that SMND-309 is an effective cardioprotective agent. The antioxidant and anti-apoptotic properties may contribute to the beneficial effects of SMND-309. These findings indicate that SMND-309 may be used as an effective and promising medicine for both prophylaxis and treatment of ischaemic heart disease.