title: 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.affiliation: Institute for Biomedical Research, Kaunas University of Medicine, Eiveniu 4, LT-50009 Kaunas-7, Lithuania. sonatai@centras.lt
authors.forename: Sonata
authors.initials: S
authors.lastname: Trumbeckaite
authors.forename: Marius
authors.initials: M
authors.lastname: Kincius
authors.forename: Andrius
authors.initials: A
authors.lastname: Preidis
authors.forename: Monika
authors.initials: M
authors.lastname: Preidiene
authors.forename: Vincentas
authors.initials: V
authors.lastname: Veikutis
authors.forename: Vilmante
authors.initials: V
authors.lastname: Borutaite
authors.forename: Antanas
authors.initials: A
authors.lastname: Gulbinas
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008111:Liver Function Tests; D008763:Methylhydrazines / Q000008:administration & dosage / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D002317:Cardiovascular Agents; D008763:Methylhydrazines; C050147:3-(2,2,2-trimethylhydrazine)propionate