title: The cardioprotective effect of mildronate is diminished after co-treatment with L-carnitine.
abstract: Mildronate, an inhibitor of L-carnitine biosynthesis and uptake, is a cardioprotective drug whose mechanism of action is thought to rely on the changes in concentration of L-carnitine in heart tissue. In the present study, we compared the cardioprotective effect of mildronate (100 mg/kg) and a combination of mildronate and L-carnitine (100 + 100 mg/kg) administered for 14 days with respect to the observed changes in l-carnitine level and carnitine palmitoyltransferase I (CPT-I)-dependent fatty acid metabolism in the heart tissues. Concentrations of L-carnitine and its precursor γ-butyrobetaine (GBB) were measured by ultraperformance liquid chromatography with tandem mass spectrometry. In addition, mitochondrial respiration, activity of CPT-I, and expression of CPT-IA/B messenger RNA (mRNA) were measured. Isolated rat hearts were subjected to ischemia-reperfusion injury. Administration of mildronate induced a 69% decrease in L-carnitine concentration and a 6-fold increase in GBB concentration in the heart tissue as well as a 27% decrease in CPT-I-dependent mitochondrial respiration on palmitoyl-coenzyme A. In addition, mildronate treatment induced a significant reduction in infarct size and also diminished the ischemia-induced respiration stimulation by exogenous cytochrome c. Treatment with a combination had no significant impact on L-carnitine concentration, CPT-I-dependent mitochondrial respiration, and infarct size. Our results demonstrated that the mildronate-induced decrease in L-carnitine concentration, concomitant decrease in fatty acid transport, and maintenance of the intactness of outer mitochondrial membrane in heart mitochondria are the key mechanisms of action for the anti-infarction activity of mildronate.
authors: Latvian Institute of Organic Synthesis, Riga, Latvia. janis_kuka@biomed.lu.lv
authors: Janis
authors: J
authors: Kuka
authors: Reinis
authors: R
authors: Vilskersts
authors: Helena
authors: H
authors: Cirule
authors: Marina
authors: M
authors: Makrecka
authors: Osvalds
authors: O
authors: Pugovics
authors: Ivars
authors: I
authors: Kalvinsh
authors: Maija
authors: M
authors: Dambrova
authors: Edgars
authors: E
authors: Liepinsh
mesh_terms: D000818:Animals; D001622:Betaine / Q000031:analogs & derivatives / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002331:Carnitine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002853:Chromatography, Liquid / Q000379:methods; D004347:Drug Interactions; D005227:Fatty Acids / Q000378:metabolism; D008297:Male; D008763:Methylhydrazines / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry / Q000379:methods; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D002317:Cardiovascular Agents; D005227:Fatty Acids; D008763:Methylhydrazines; D014803:Vitamin B Complex; D001622:Betaine; C002889:gamma-butyrobetaine; C050147:3-(2,2,2-trimethylhydrazine)propionate; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine