Inhibition of mitochondrial carnitine palmitoyltransferase-1 by a trimetazidine derivative, S-15176

The purpose of this study was to investigate the possible effect of the trimetazidine derivative S-15176 on carnitine palmitoyltransferase1 (CPT-1) activity in rat heart and liver mitochondria. S-15176 was compared with the other antianginal agents amiodarone, perhexiline and trimetazidine, which do not show any hemodynamic effects and which are believed to exert their effects by switching the cellular metabolism towards glucose utilization at the expense of lipid metabolism, increasing the yield of oxygen utilization. S-15176 inhibited CPT-1 in vitro and was more effective in heart (IC50 = 16.8 muM) than in liver (50.8 +/- 3.0 muM). In the heart, its was less effective than the physiological inhibitor malonyl-CoA (IC50 = 2.1 muM), but it was more potent than amiodarone (IC50 = 140 muM). Kinetic experiments demonstrated a non-competitive inhibition of CPT-1 by S-15176 indicating that the two compounds did not share the same site of action. CPT-1 inhibition was also obvious ex vivo, in heart and liver tissues, after a 2 week treatment with S-15176. This inhibitory effect may shift heart and liver metabolism from fatty acid to glucose oxidation and contribute to the anti-ischemic effects of the drug. (C) 2001 Academic Press.