Effect Of Metformin On Functional Recovery Of Isolated Rat Heart In The Presence Of Different Levels Of Fatty Acid

Objective: The biguanide metformin is an effective hypoglycaemic drug that has been widely used for the treatment of type 2 diabetes for more then 50 years. The glucose-lowering effect results from increased glucose utilization and decreased endogenous glucose release due to decreased gluconeogenesis. So many clinical studies have reported that metformin reduces cardiovascular end points of type 2 diabetic subjects by actions that cannot solely be attributed to glucose-lowering effects. A large number of studies have show that metformin in nondiabetic rats play a significantly protective effect of the heart, significantly improve the ability of anti-myocardial ischemia/reperfusion injury, reduse decline of cardiac systolic function after ischemia/reperfusion, significantly decrease the infarct size after ischemia/reperfusion. Further research suggests that its mechanism may be related to metformin can activate the key enzyme of the myocardial energy metabolism pathway-AMPK (AMP-activated protein kinase, AMPK). Activation of AMPK, both beneficial and harmful , the mechanism of benefit is the increase in ATP generation and increased NO release, etc, and the mechanism of the harmful is increase the rate of oxidation of fatty acids, but high rates of fatty acid oxidation can dramatically inhibit glucose oxidation rates .firstly, This leads to a decrease in both cardiac function and efficiency; And then, this results in a continued low rate of glucose oxidation, an uncoupling from glycolysis, which made the cells acidosis. This role of activation of AMPK is dependent on the circulating free fatty acid levels. This study was designed to investigate under different levels of fatty acids, the affect and mechanisms of metformin on the acute cardiac ischemia/ reperfusion injury in rats, and the function of AMPK, and know deeply how to use the metformin reasonable after cardiac ischemia/reperfusion. Methods: Male Sprague-Dawlay (SD) rats with 66 (about 200g) were randomly divided into two groups: blank control group (6) and treatment group (60). Treatment group was divided into administration of metformin alone at the time of reperfusion group (6), metformin + AMPK inhibitor(compound C) group (6), low-fatty acid group (6), low fatty acid + compound C group (6), low-fatty acid + metformin group (6), low fatty acid + metformin + compound C group (6), high-fatty acid group (6), high fatty acids + compound C group (6), high-fatty acid + metformin group (6), high fatty acid + metformin + compound C group (6),.。After anesthesia, thoracotomy, use of Langendorff isolated perfused heart to give a balanced (20min), ischemia (30min/reperfusion (60min) treatment, with eight power-lab Introduction physiological recording device to observe and record changes in heart function (including heart rate, left ventricular developed pressure LVDP, the largest rate increase + LVdp/dt, the largest decline in pulse rate -LVdp/dt flow and irrigation). Blank control group, metformin alone group were given ordinary liquid K-H perfusion(11 mmol/L glucose), acute low-fatty acid group dissolved in K-H solution with low concentration of fatty acids (0.2 mmol/L palmitic acid) perfusion, acute high-fat group K-H solution given the high concentration of dissolved fatty acids (1.2 mmol/L palmitic acid) perfusion. All the treatment groups with AMPK blocker, give the AMPK antagonist compound C( 20umol/L) and low-dose metformin (50umol/L) at reperfusion for 20 minutes.Results: Compared to the blank control group, after ischemia/reperfusion performed injury, the low-fatty acid group and low-fatty acid + metformin group of rats performed the left ventricular developed pressure (LVDP) resumed more(P<0.05),eapecially the low-fatty acid + metformin group of rats, resumed more than the low-fatty acid group. The high-fatty acid group and the high-fatty acid group of rats performed more injury than the blank group(P<0.05), especially the high-fatty acid + metformin group of rats recover worse(P<0.05). Under different level of fatty acids, compound C could ameliorate or weaken the left ventricular developed pressure (LVDP). Conclusion: Under not used of fatty acids, glucose is the only energy source , acute metformin therapy enhanced the ability of anti-myocardial ischemia/reperfusion injury of nondiabetic male SD rats and have heart protective effect. At low conditions, the protective effect of increased, and high fatty acids conditions, the performed harmful effects. AMPK antagonist compound C can be reduced or offset by low or high fatty acids performed beneficial and harmful. At low or high fatty acids conditions, metformin through changes AMPK activity, and changer of myocardial glucose utilization and fatty acid relative, and performed beneficial or harmful.