| INTRODUCTIONCardiovascular disease is the first killer for modern humans. According to statistics in 2005, there are 17.5 million people worldwide died of cardiovascular disease, accounting for 30% percent of the total number of deaths ,which contained about 7.6 million people died of coronary heart disease, 5.7 million died of stroke. Therefore cardiovascular disease prevention and treatment has become the focus of medical work. Cardiovascular disease caused by AMI that was induced by coronary artery stenosis such as myocardial ischemia angina, myocardial infarction and other diseases (ie coronary heart disease) take its high percentage. Therefore to improve the symptom of AMI caused by organic coronary stenosis seems particularly important in the treatment of coronary heart disease.The key to cure Myocardial Ischemia is major to make the supply and consumption of oxygen balanced, and its therapy can be divided into two categories. One is to reduce myocardial oxygen consumption; the other is to improve coronary blood flow.Traditional anti-AMI durg include Angiotensin-Converting inhibitors,β- adrenergic blockers, calcium channel blockers, nitrates, statins, metabolic regulation drugs, antithrombotic drugs etc.More and more research have shown that myocardial ischemia is mainly metabolic diseases. With the development of further study and awareness for myocardial ischemia metabolic process, a new concept was raised to treat ischemic heart disease that is to regulate myocardial energy metabolism and improve mitochondrial energy metabolism. The treatment of ischemic cardiomyopathy should be applied not only to improve the homodynamic drugs, but also to improve the abnormal metabolic status of myocardial ischemia, optimize myocardial energy metabolism pathway.Cardiac muscle mainly depend on fatty acids and carbohydrates as energy material. In aerobic conditions, 60%-90% percent of the ATP that normal adult cardiac energy metabolism needed come from the free fatty acid oxidation,and 10% ~ 40% comes from glucose metabolism. Compared with glucose, fatty acid metabolism consume more around 10% ~ 15% oxygen to produce the same amount of ATP. It was found that when coronary blood flow decreased 30% ~ 60% percent, fatty acids is still major energy material(60% ~ 80%) that need consume a lot of oxygen i more free as a, resulting the shortage of the ATP level and myocardial energy.When myocardial oxygen supply is reduced, lactic acid generated by anaerobic glycolysis and ketones produced for the reason of accumulation of fatty acids is increased, which have a toxic effect on cardiac muscle. A variety of factors eventually lead to ischemic myocardial cell damage or even death, sparking diseases such as angina or myocardial infarction.Therefore, to reduce toxic effects of ketone on the myocardium and improve myocardial energy become a good method in the treatment of myocardial ischemia.To reduce the consumption of oxygen caused by myocardial ischemia is particularly important under the hypoxia status and therefore, reducing fatty acids metabolism while increasing glucose metabolism can effectively use the same oxygen to produce more ATP in the status of myocardial ischemia .TMZ plays more important role in the myocardial high-energy phosphate metabolism in the treatment of angina compared with other anti-angina pectoris drugs , inhibiting free fatty acid metabolism, increasing glucose metabolism, which increase ATP generation under the maximum in the case of using the same oxygen, thereby increasing myocardial energy in hypoxia environment and protect the ischemic myocardial cells in some degree. However,a lot of fatty acids cumulate simultaneously when TMZ increased aerobic glucose oxidation and inhibit the aerobic oxidation of fatty acids. Accumulation of fatty acids in the hypoxic environment generated a large number of harmful substances such as ketones, which have toxic effects on cardiac cells.It is important to reduce toxic effects of ketones for myocardium caused by accumulation of fatty acids in the hypoxic environment . Levocarnitine's main function is to promote lipid metabolism. As a long-chain fatty acyl-carrier, Levocarnitine carry long-chain fatty acids from the outside of mitochondrial membrane to the inside so as to completeβ-oxidation.Therefore toxic effect of ketones due to fatty acids accumulation on the myocardium in the ischemia and hypoxia environment is reduced and the rate of ATP formation is accelerated.In view of complementary roles of TMZ and L-carnitine in the treatment of myocardial ischemia, this research's object is to evaluate the anti-AMI effect of its combination namely compound TMZ on acute myocardial ischemia in animal models. METHODSExperiment 1: Effect of monotherapy and combination on AMI in SD ratsExperiment was performed in 6 week-old male SD rats. In the first step, 200 rats were randomly divided into 2 parts, each part were randomly divided into 5 groups. One part: control group, TMZ groups(1mg/kg, 3mg/kg, 6mg/kg; 9mg/kg), the other part: control group, L-carnitine groups(100mg/kg, 300mg/kg, 600mg/kg; 900mg/kg),n=20 in each group.The drugs were injected via abdominal cavity 30 min before LAD occlusion with above-mentioned methods. Four hours later, the rat was killed and the heart was harvested to measure the infarct size. In the second step, 200 male SD rats were randomly divided into 6 groups: control group, combination (3+100, 3+300, 3+600, 1+300 and 6+300 mg/kg) ,n=10 in each group.The drugs were injected via abdominal cavity 30 min before LAD occlusion with above-mentioned methods. Four hours later, the rat was killed and the heart was harvested to measure the infarct size.Experiment 2: Effect of monotherapy and combination on AMI in SD ratsIn the first step, 80 male SD rats were randomly divided into 4 groups: control group, combination(low dose group 0.3 +60 mg/kg; middle dose group,1+200 mg/kg; high dose group, 3+600 mg/kg) ,n=20 in each group.,The drugs were injected via abdominal cavity 30 min before LAD occlusion with above-mentioned methods. Four hours later, the rat was killed and the heart was harvested to measure the infarct size.Experiment 3: Effect of combination on AMI in anesthetized beagle dogsExperiment was performed in anesthetized dog. 36 beagle dogs were randomly divided into 6 groups : control group, combination groups (0.1+20; 0.3 +60; 1+200; 3+600 mg/kg) and positive control(0.127ml/kg), n=6 in each group. Drugs were injected via femoral vein 30 Min before LAD occlusion. Then surface and epicardial electrogram were recorded with above-mentioned methods before and after administration. Three hours after LAD occlusion, 5 ml blood was drew off from RV and the dog was killed and the heart was harvested to measure the infarct size. After blood was centrifuged , the serum was seprarated and the LDH and CK of serum was tested.Experiment 4: The effect of combination on blood pressure, heart rate , ventricular function, blood flow of coronary artery , cardiac output and myocardial oxygen consumption in normal anesthetized beagle dogsExperiment was performed in anesthetized dogs . Thirty animals were randomly divided into 5 groups: control group, 3 combination groups (0.3 +60; 1+200; 3+600 mg/kg) and positive control(0.127ml/kg) , n=6 in each group. Drugs were injected via femoral vein after stabilization for 30 min. The blood pressure, heart rate ,ventricular function ,blood flow of coronary artery , cardiac output and myocardial oxygen consumption were measured with above-mentioned methods before and after administration.CONCLUSIONThe combination composed of TMZ and L-carnitine(1: 200) has satisfactory protective effects on AMI both in rats and dogs.
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