In:
Journal of Cardiovascular Pharmacology and Therapeutics, SAGE Publications, Vol. 17, No. 2 ( 2012-06), p. 215-222
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.
Type of Medium:
Online Resource
ISSN:
1074-2484
,
1940-4034
DOI:
10.1177/1074248411419502
Language:
English
Publisher:
SAGE Publications
Publication Date:
2012
detail.hit.zdb_id:
2230155-0
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