Effects of ischemia-reperfusion and pretreatment with mildronate on rat liver mitochondrial function.

Abstract

Mildronate (3-(2,2,2-trimethylhydrazinium) propionate), which is mostly used in cardiological practice and is considered an anti-ischemic drug, was designed to inhibit carnitine biosynthesis in order to prevent accumulation of cytotoxic intermediate products of fatty acid beta-oxidation. Recently it was shown that the mitochondrial respiratory chain may also be a target for mildronate action. In this study, we aimed to investigate whether mildronate can protect the liver against a 90-min normothermic ischemia/30-min reperfusion-induced mitochondrial dysfunction. Rats were pre-treated for one or two weeks with mildronate (100 mg/kg/day or 200 mg/kg/day) or Ringer solution and subjected to ischemia/reperfusion.We found that ischemia/reperfusion caused a decrease in mitochondrial State 3 respiration rate and in the respiratory control index (RCI), and an increase in State 2 respiration rate with succinate, glutamate + malate and palmitoyl-L-carnitine + malate. One or two weeks of pre-treatment of rats with different doses of mildronate did not reduce the ischemia/reperfusion-induced decrease in the State 3 respiration rate or RCI; however, a one week pre-treatment slightly diminished the increase in the State 2 respiration rate with glutamate + malate substrates. The leakage of the liver enzymes, aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase, was similar in both the untreated and pre-treated with mildronate groups. No steatotic livers were observed in any experimental groups after mildronate pre-treatment. In conclusion, 90 min of liver ischemia followed by a 30 min reperfusion has a deleterious effect on rat liver mitochondrial function. Mildronate pre-treatment of rats at doses of 100 or 200 mg/kg/day for one or two weeks did not prevent ischemia/reperfusion-induced mitochondrial dysfunction and liver injury.

• Authors: Sonata Trumbeckaite, Marius Kincius, Andrius Preidis, Monika Preidiene, Vincentas Veikutis, Vilmante Borutaite, Antanas Gulbinas
• Journal: Pharmacological reports : PR (Pharmacol Rep) 2009 Sep-Oct Vol. 61 Issue 5 Pg. 859-69 ISSN: 2299-5684 [Electronic] Switzerland
• PMID: 19904009 (Publication Type: Journal Article)

Chemical References

• Cardiovascular Agents
• Methylhydrazines
• 3-(2,2,2-trimethylhydrazine)propionate

Topics

• Animals
• Cardiovascular Agents (administration & dosage, pharmacology)
• Dose-Response Relationship, Drug
• Female
• Liver (drug effects, enzymology, pathology)
• Liver Function Tests
• Methylhydrazines (administration & dosage, pharmacology)
• Mitochondria, Liver (drug effects, metabolism, pathology)
• Rats
• Rats, Wistar
• Reperfusion Injury (physiopathology, prevention & control)