TRIMETAZIDINE COUNTERACTS THE HEPATIC-INJURY ASSOCIATED WITH ISCHEMIA-REPERFUSION BY PRESERVING MITOCHONDRIAL-FUNCTION

Recent studies suggest a crucial role played by mitochondria in the pa thogenesis of ischemia-reperfusion injury. This study was conducted to clarify the role of trimetazidine, a cellular antiischemic agent, on mitochondria isolated from rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into group s, pretreated with different doses of trimetazidine (5, 10 and 20 mg/k g/day) or saline and subjected to the ischemia-reperfusion process; an other group served as the sham-operated controls. Alanine aminotransfe rase and aspartate aminotransferase activities and hepatocyte ATP cont ent, bile flow and mitochondrial functions were assessed. Ischemia-rep erfusion caused membrane leakage from hepatocytes and a decrease in AT P content and in bile flow. These effects were well correlated with al terations in mitochondrial function. namely, decrease in ATP synthesis , NAD(P)H level and mitochondrial membrane potential and generation of mitochondrial permeability transition. The pretreatment of rats with trimetazidine prevented these ischemia-reperfusion deleterious effects at both the cellular and mitochondrial level in a dose-dependent mann er. It is concluded that trimetazidine at an optimal dosage of 10 mg/k g/day protects mitochondria against the deleterious effects of ischemi a-reperfusion. This protective effect appears to be the key factor thr ough which this drug exerts its cytoprotective activity.