The Cardioprotective Effect of Mildronate is Diminished After Co-Treatment With l-Carnitine

 

From:

Janis Kuka, Dr Pharm1⇓

1. Reinis Vilskersts, Dr Pharm1,2
2. Helena Cirule, MSc1
3. Marina Makrecka, MSc1,2
4. Osvalds Pugovics, Dr Chem1
5. Ivars Kalvinsh, Dr Chem1
6. Maija Dambrova, Dr Pharm1,2
7. Edgars Liepinsh, Dr Pharm1

1. ¹Latvian Institute of Organic Synthesis, Riga, Latvia
2. ²Rigas Stradins University, Riga, Latvia

1. Janis Kuka, Latvian Institute of Organic Synthesis, Aizkraukles Str. 21, Riga LV-1006, Latvia Email: janis_kuka@biomed.lu.lv

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.