TY - JOUR
T1 - The Cardioprotective Effect of Mildronate is Diminished After Co-Treatment With l-Carnitine
AU - Kuka, Janis
AU - Vilskersts, Reinis
AU - Cirule, Helena
AU - Makrecka, Marina
AU - Pugovics, Osvalds
AU - Kalvinsh, Ivars
AU - Dambrova, Maija
AU - Liepinsh, Edgars
N1 - Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The European Social Foundation agreement No. 2009/0147/1DP/1.1.2.1.2/09/IPIA/VIAA/009; The European Regional Development Fund grant No. 2DP/2.1.1.1.0/10/APIA/VIAA/063; the Latvian State Research Program grant No. 2010.10-4/VPP-4.
PY - 2012/6
Y1 - 2012/6
N2 - 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.
AB - 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.
KW - cardioprotection
KW - carnitine palmitoyltransferase I
KW - mildronate
KW - mitochondrial respiration
UR - http://www.scopus.com/inward/record.url?scp=84867190368&partnerID=8YFLogxK
UR - https://journals.sagepub.com/doi/pdf/10.1177/1074248411419502
U2 - 10.1177/1074248411419502
DO - 10.1177/1074248411419502
M3 - Article
C2 - 21903968
AN - SCOPUS:84867190368
SN - 1074-2484
VL - 17
SP - 215
EP - 222
JO - Journal of Cardiovascular Pharmacology and Therapeutics
JF - Journal of Cardiovascular Pharmacology and Therapeutics
IS - 2
ER -