The Antianginal Drug Trimetazidine Shifts Cardiac Energy Metabolism From Fatty Acid Oxidation to Glucose Oxidation by Inhibiting Mitochondrial Long-Chain 3-Ketoacyl Coenzyme A Thiolase

摘要: Trimetazidine is a clinically effective antianginal agent that has no negative inotropic or vasodilator properties. Although it thought to have direct cytoprotective actions on the myocardium, mechanism(s) by which this occurs as yet undefined. In study, we determined what effects trimetazidine both fatty acid and glucose metabolism in isolated working rat hearts activities of various enzymes involved oxidation. Hearts were perfused with Krebs-Henseleit solution containing 100 microU/mL insulin, 3% albumin, 5 mmol/L glucose, acids different chain lengths. Both appropriately radiolabeled either (3)H (14)C for measurement glycolysis, oxidation, had effect myocardial oxygen consumption cardiac work under any aerobic perfusion condition used. 0.4 palmitate, decreased rate palmitate oxidation from 488+/-24 408+/-15 nmol x g dry weight(-1) minute(-1) (P<0.05), whereas increased rates 1889+/-119 2378+/-166 (P<0.05). subjected low-flow ischemia, resulted 210% increase rates. ischemic hearts, glycolytic unaltered trimetazidine. The accompanied 37% active form pyruvate dehydrogenase, rate-limiting enzyme No was observed dehydrogenase when substituted 0.8 octanoate 1.6 butyrate, suggesting directly inhibits long-chain This reduction significant decrease activity isoform last beta-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase (IC(50) 75 nmol/L). contrast, concentrations excess 10 micromol/L needed inhibit medium- short-chain forms CoA thiolase, respectively. Previous studies shown inhibition stimulation can protect heart. Therefore, our data suggest may occur because an activity, results