Trimetazidine counteracts the hepatic injury associated with ischemia-reperfusion by preserving mitochondrial function.
Recent studies suggest a crucial role played by mitochondria in the pathogenesis of ischemia-reperfusion injury. This study was conducted to clarify the role of trimetazidine, a cellular anti-ischemic agent, on mitochondria isolated from rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into groups, pretreated with different doses of trimetazidine (5, 10 and 20 mg/kg/day) or saline and subjected to the ischemia-reperfusion process; another group served as the sham-operated controls. Alanine aminotransferase and aspartate aminotransferase activities and hepatocyte ATP content, bile flow and mitochondrial functions were assessed. Ischemia-reperfusion caused membrane leakage from hepatocytes and a decrease in ATP content and in bile flow. These effects were well correlated with alterations 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 manner. It is concluded that trimetazidine at an optimal dosage of 10 mg/kg/day protects mitochondria against the deleterious effects of ischemia-reperfusion. This protective effect appears to be the key factor through which this drug exerts its cytoprotective activity.
Elimadi
A
A
Département de Pharmacologie, IM3, Faculté de Médecine de Paris XII, France. elimadi@univ-paris12.fr
Settaf
A
A
Morin
D
D
Sapena
R
R
Lamchouri
F
F
Cherrah
Y
Y
Tillement
J P
JP
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D007511:Ischemia / Q000378:metabolism*; D008099:Liver / Q000098:blood supply* / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D009243:NAD / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D015427:Reperfusion Injury / Q000378:metabolism*; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; D009243:NAD; D000255:Adenosine Triphosphate; D014292:Trimetazidine