Attenuation of liver normothermic ischemia-reperfusion injury by preservation of mitochondrial functions with S-15176, a potent trimetazidine derivative

Citation
A. Elimadi et al., Attenuation of liver normothermic ischemia-reperfusion injury by preservation of mitochondrial functions with S-15176, a potent trimetazidine derivative, BIOCH PHARM, 62(4), 2001, pp. 509-516
Citations number
34
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
BIOCHEMICAL PHARMACOLOGY
ISSN journal
0006-2952 → ACNP
Volume
62
Issue
4
Year of publication
2001
Pages
509 - 516
Database
ISI
SICI code
0006-2952(20010815)62:4<509:AOLNII>2.0.ZU;2-L
Abstract
We investigated the antiischemic properties of a new compound, S-15176, in an experimental model of rat liver subjected to 120-min normothermic ischem ia followed by 30-min reperfusion. Rats were divided into groups, pretreate d with different doses of S-15176 (1.25, 2.5, 5 and 10 mg/kg/day by intramu scular injection) or solvent alone, and subjected to the ischemia-reperfusi on process. Another group served as the sham-operated controls. Ischemia-re perfusion induced huge alterations of hepatocyte functions, namely, a decre ase in ATP content and bile flow, and membrane leakage of alanine aminotran sferase (ALAT) and aspartate aminotransferase (ASAT). These effects were as sociated with alterations in mitochondrial functions characterized by (1) a decrease in ATP synthesis, (2) a decrease in NAD(P)H levels and mitochondr ial membrane potential, and (3) an increase in mitochondrial swelling refle cting the generation of permeability transition. Pretreatment of rats with S-15176 alleviated these deleterious ischemia-reperfusion effects at both t he cellular and mitochondrial levels in a dose-dependent manner. The protec tion of mitochondrial functions was almost complete at a dosage of 10 mg/kg /day. In addition, in vitro, S-15176 totally abolished the swelling of isol ated mitochondria induced by a calcium overload with an IC50 value of 10 mu M These data demonstrate that S-15176 protects mitochondria against the del eterious effects of ischemia-reperfusion and suggest that this protective e ffect could be related to the inhibition of the mitochondrial permeability transition. (C) 2001 Elsevier Science Inc. All rights reserved.