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

Journal of Cardiovascular Pharmacology and Therapeutics

Volumn 17, Issue 2, 2012, Pages 215-222

  Kuka, Janis ^a   Vilskersts, Reinis ^a,b   Cirule, Helena ^a   Makrecka, Marina ^a,b   Pugovics, Osvalds ^a   Kalvinsh, Ivars ^a   Dambrova, Maija ^a,b   Liepinsh, Edgars ^a  

^a LATVIAN INSTITUTE OF ORGANIC SYNTHESIS   (Latvia)

^b RIGA STRADINS UNIVERSITY   (Latvia)

Author keywords

cardioprotection; carnitine palmitoyltransferase I; mildronate; mitochondrial respiration

Indexed keywords

3 (2,2,2 TRIMETHYLHYDRAZINE)PROPIONATE; 3-(2,2,2-TRIMETHYLHYDRAZINE)PROPIONATE; BETAINE; CARDIOVASCULAR AGENT; CARNITINE; CARNITINE PALMITOYLTRANSFERASE; DRUG DERIVATIVE; FATTY ACID; GAMMA BUTYROBETAINE; GAMMA-BUTYROBETAINE; METHYLHYDRAZINE DERIVATIVE; VITAMIN B COMPLEX;

ANIMAL; ARTICLE; COMPARATIVE STUDY; DRUG EFFECT; DRUG INTERACTION; HEART INFARCTION; HEART MITOCHONDRION; LIQUID CHROMATOGRAPHY; MALE; METABOLISM; METHODOLOGY; MITOCHONDRIAL MEMBRANE; PATHOPHYSIOLOGY; RAT; REPERFUSION INJURY; TANDEM MASS SPECTROMETRY; WISTAR RAT;

ANIMALS; BETAINE; CARDIOVASCULAR AGENTS; CARNITINE; CARNITINE O-PALMITOYLTRANSFERASE; CHROMATOGRAPHY, LIQUID; DRUG INTERACTIONS; FATTY ACIDS; MALE; METHYLHYDRAZINES; MITOCHONDRIA, HEART; MITOCHONDRIAL MEMBRANES; MYOCARDIAL INFARCTION; MYOCARDIAL REPERFUSION INJURY; RATS; RATS, WISTAR; TANDEM MASS SPECTROMETRY; VITAMIN B COMPLEX;

EID: 84867190368     PISSN: 10742484     EISSN: 19404034     Source Type: Journal    
DOI: 10.1177/1074248411419502     Document Type: Article

References (34)

1. Stephens FB Constantin-Teodosiu D Greenhaff PL. New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. J Physiol. 2007; 581(pt 2):431-444.
2. Zammit VA Ramsay RR Bonomini M Arduini A. Carnitine, mitochondrial function and therapy. Adv Drug Deliv Rev. 2009; 61(14):1353-1362.
3. Dambrova M Liepinsh E Kalvinsh I. Mildronate: cardioprotective action through carnitine-lowering effect. Trends Cardiovasc Med. 2002; 12(6):275-279.
4. Simkhovich BZ Shutenko ZV, Meirena DV, et al. 3-(2,2,2-Trimethylhydrazinium)propionate (THP)—a novel gamma-butyrobetaine hydroxylase inhibitor with cardioprotective properties. Biochem Pharmacol. 1988; 37(2):195-202.
5. Spaniol M Brooks H Auer L, et al. Development and characterization of an animal model of carnitine deficiency. Eur J Biochem. 2001; 268(6):1876-1887.
6. Liepinsh E Vilskersts R Skapare E, et al. Mildronate decreases carnitine availability and upregulates glucose uptake and related gene expression in the mouse heart. Life Sci. 2008; 83(17-18):613-619.
7. Liepinsh E Vilskersts R Loca D, et al. Mildronate, an inhibitor of carnitine biosynthesis, induces an increase in gamma-butyrobetaine contents and cardioprotection in isolated rat heart infarction. J Cardiovasc Pharmacol. 2006; 48(6):314-319.
8. Sesti C Simkhovich BZ Kalvinsh I Kloner RA. Mildronate, a novel fatty acid oxidation inhibitor and antianginal agent, reduces myocardial infarct size without affecting hemodynamics. J Cardiovasc Pharmacol. 2006; 47(3):493-499.
9. Liepinsh E Vilskersts R Zvejniece L, et al. Protective effects of mildronate in an experimental model of type 2 diabetes in Goto-Kakizaki rats. Br J Pharmacol. 2009; 157(8):1549-1556.
10. Vilskersts R Liepinsh E Mateuszuk L, et al. Mildronate, a regulator of energy metabolism, reduces atherosclerosis in apoE/LDLR-'/-' mice. Pharmacology. 2009; 83(5):287-293.
11. Vilskersts R Kuka J Svalbe B, et al. Administration of l-carnitine and mildronate improves endothelial function and decreases mortality in hypertensive Dahl rats. Pharmacol Rep. 2011;63(3):752-762.
12. Jogl G Hsiao YS Tong L. Structure and function of carnitine acyltransferases. Ann N Y Acad Sci. 2004; 1033: 17-29.
13. Toleikis A Trumbeckaite S Majiene D. Cytochrome C effect on respiration of heart mitochondria: influence of various factors. Biosci Rep. 2005; 25(5-6):387-397.
14. Dambrova M Cirule H Svalbe B, et al. Effect of inhibiting carnitine biosynthesis on male rat sexual performance. Physiol Behav. 2008; 95(3):341-347.
15. Yu XC Wu S Wang GY, et al. Cardiac effects of the extract and active components of radix stephaniae tetrandrae. II. Myocardial infarct, arrhythmias, coronary arterial flow and heart rate in the isolated perfused rat heart. Life Sci. 2001; 68(25):2863-2872.
16. Liepinsh E Kuka J Svalbe B, et al. Effects of long-term mildronate treatment on cardiac and liver functions in rats. Basic Clin Pharmacol Toxicol. 2009; 105(6):387-394.
17. Gray S Wang B Orihuela Y, et al. Regulation of gluconeogenesis by Krüppel-like factor 15. Cell Metab. 2007; 5(4):305-312.
18. Wilcke M Hultenby K Alexson SE. Novel peroxisomal populations in subcellular fractions from rat liver. Implications for peroxisome structure and biogenesis. J Biol Chem. 1995; 270(12):6949-6958.
19. Jaudzems K Kuka J Gutsaits A, et al. Inhibition of carnitine acetyltransferase by mildronate, a regulator of energy metabolism. J Enzyme Inhib Med Chem. 2009; 24(6):1269-1275.
20. Baliutyte G Baniene R Trumbeckaite S Borutaite V Toleikis A. Effects of Ginkgo biloba extract on heart and liver mitochondrial functions: mechanism(s) of action. J Bioenerg Biomembr. 2010; 42(2):165-172.
21. Srere PA Brazil H Gonen L. The citrate condensing enzyme of pigeon breast muscle and moth flight muscle. Acta Chem Scand. 1963; 17(suppl 1):S129-S134.
22. Yamaguchi R Andreyev A Murphy AN Perkins GA Ellisman MH Newmeyer DD. Mitochondria frozen with trehalose retain a number of biological functions and preserve outer membrane integrity. Cell Death Differ. 2007; 14(3):616-624.
23. Bernatoniene J Majiene D Peciura R, et al. The effect of Ginkgo biloba extract on mitochondrial oxidative phosphorylation in the normal and ischemic rat heart. Phytother Res. 2011; 25(7): 1054-1060.
24. Asaka N Muranaka Y Kirimoto T Miyake H. Cardioprotective profile of MET-88, an inhibitor of carnitine synthesis, and insulin during hypoxia in isolated perfused rat hearts. Fundam Clin Pharmacol. 1998; 12(2):158-163.
25. Hayashi Y Ishida H Hoshiai M, et al. MET-88, a gamma-butyrobetaine hydroxylase inhibitor, improves cardiac SR Ca2+ uptake activity in rats with congestive heart failure following myocardial infarction. Mol Cell Biochem. 2000; 209(1-2):39-46.
26. Rebouche CJ Mack DL, Edmonson PF. l-Carnitine dissimilation in the gastrointestinal tract of the rat. Biochemistry. 1984; 23(26):6422-6426.
27. Degrace P Demizieux L Gresti J, et al. Fatty acid oxidation and related gene expression in heart depleted of carnitine by mildronate treatment in the rat. Mol Cell Biochem. 2004; 258(1-2):171-182.
28. Degrace P Demizieux L Du ZY, et al. Regulation of lipid flux between liver and adipose tissue during transient hepatic steatosis in carnitine depleted rats. J Biol Chem. 2007; 282(29):20816-20826.
29. Dyck JR Hopkins TA Bonnet S, et al. Absence of malonyl coenzyme A decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury. Circulation. 2006; 114(16):1721-1728.
30. Wang W Lopaschuk GD. Metabolic therapy for the treatment of ischemic heart disease: reality and expectations. Expert Rev Cardiovasc Ther. 2007; 5(6):1123-1134.
31. Stanley WC Morgan EE Huang H, et al. Malonyl-CoA decarboxylase inhibition suppresses fatty acid oxidation and reduces lactate production during demand-induced ischemia. Am J Physiol Heart Circ Physiol. 2005; 289(6):H2304-H2309.
32. Ussher JR Lopaschuk GD. Targeting malonyl CoA inhibition of mitochondrial fatty acid uptake as an approach to treat cardiac ischemia/reperfusion. Basic Res Cardiol. 2009; 104(2):203-210.
33. Longo N Amat di San Filippo C Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet. 2006; 142C(2):77-85.
34. Liepinsh E Konrade I Skapare E, et al. Mildronate treatment alters γ-butyrobetaine and l-carnitine concentrations in healthy volunteers. J Pharm Pharmacol. 2011;63(9):1195-1201.