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

• Published in: Pharmacological reports 2009-09, Vol.61 (5), p.859-869
• Main Authors: Trumbeckaitė, Sonata, Kincius, Marius, Preidis, Andrius, Preidienė, Monika, Veikutis, Vincentas, Borutaitė, Vilmantė, Gulbinas, Antanas
• Format: Article
• Language: English
• Subjects: alanine aminotransferase; Animals; aspartate aminotransferase; Cardiovascular Agents - administration & dosage; Cardiovascular Agents - pharmacology; Dose-Response Relationship, Drug; Drug Safety and Pharmacovigilance; Female; ischemia; Liver - drug effects; Liver - enzymology; Liver - pathology; Liver Function Tests; liver mitochondria; Methylhydrazines - administration & dosage; Methylhydrazines - pharmacology; mildronate; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Mitochondria, Liver - pathology; Pharmacotherapy; Pharmacy; Rats; Rats, Wistar; reperfusion; Reperfusion Injury - physiopathology; Reperfusion Injury - prevention & control
• ISSN: 1734-1140; 2299-5684
• DOI: 10.1016/S1734-1140(09)70142-2

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 (100mg/kg/day or 200mg/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/reperffusion-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, 90min of liver ischemia followed by a 30min reperfusion has a deleterious effect on rat liver mitochondrial function. Mildronate pre-treatment of rats at doses of 100 or 200mg/kg/day for one or two weeks did not prevent ischemia/reperfusion-induced mitochondrial dysfunction and liver injury.