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

Abstract

We investigated the antiischemic properties of a new compound, S-15176, in an experimental model of rat liver subjected to 120-min normothermic ischemia followed by 30-min reperfusion. Rats were divided into groups, pretreated with different doses of S-15176 (1.25, 2.5, 5 and 10 mg/kg/day by intramuscular injection) or solvent alone, and subjected to the ischemia--reperfusion process. Another group served as the sham-operated controls. Ischemia--reperfusion induced huge alterations of hepatocyte functions, namely, a decrease in ATP content and bile flow, and membrane leakage of alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT). These effects were associated with alterations in mitochondrial functions characterized by (1) a decrease in ATP synthesis, (2) a decrease in NAD(P)H levels and mitochondrial membrane potential, and (3) an increase in mitochondrial swelling reflecting the generation of permeability transition. Pretreatment of rats with S-15176 alleviated these deleterious ischemia--reperfusion effects at both the cellular and mitochondrial levels in a dose-dependent manner. The protection 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 isolated mitochondria induced by a calcium overload with an IC(50) value of 10 microM. These data demonstrate that S-15176 protects mitochondria against the deleterious effects of ischemia-reperfusion and suggest that this protective effect could be related to the inhibition of the mitochondrial permeability transition.

• Authors: A Elimadi, R Sapena, A Settaf, H Le Louet, J Tillement, D Morin
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 62 Issue 4 Pg. 509-16 (Aug 15 2001) ISSN: 0006-2952 [Print] England
• PMID: 11448461 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Piperazines
• Protective Agents
• S 15176
• NADP
• Adenosine Triphosphate

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Antioxidants (pharmacology, therapeutic use)
• Bile Ducts (drug effects, physiology)
• Cell Membrane (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Hepatocytes (drug effects, metabolism)
• Ischemia (pathology, prevention & control)
• Liver Diseases (pathology, prevention & control)
• Liver Function Tests
• Male
• Membrane Potentials (drug effects)
• Mitochondria, Liver (drug effects, physiology)
• Mitochondrial Swelling (drug effects)
• NADP (metabolism)
• Piperazines (pharmacology, therapeutic use)
• Protective Agents (pharmacology, therapeutic use)
• Rats
• Rats, Wistar
• Reperfusion Injury (pathology, prevention & control)