| The Cardioprotective Effect of Mildronate is Diminished After Co-Treatment With L-Carnitine. | |
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MedLine Citation:
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PMID: 21903968 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
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Authors:
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Janis Kuka; Reinis Vilskersts; Helena Cirule; Marina Makrecka; Osvalds Pugovics; Ivars Kalvinsh; Maija Dambrova; Edgars Liepinsh |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-9-8 |
Journal Detail:
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Title: Journal of cardiovascular pharmacology and therapeutics Volume: - ISSN: 1940-4034 ISO Abbreviation: - Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-9-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9602617 Medline TA: J Cardiovasc Pharmacol Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Latvian Institute of Organic Synthesis, Riga, Latvia. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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