The action mechanism of ranolazine, an antiangina drug, could be at least partly metabolic, including inhibition of fatty acid oxidation and stimulation of glucose utilization in the heart. The purpose of the present work was to investigate if ranolazine affects hepatic carbohydrate metabolism. For this purpose, the hemoglobin-free isolated perfused rat liver was used as the experimental system. Ranolazine increased glycolysis and glycogenolysis and decreased gluconeogenesis. These effects were accompanied by an inhibition of oxygen consumption. The drug also changed the redox state of the NAD+-NADH couple. For the cytosol, increased NADH/NAD+ ratios were observed both under glycolytic conditions as well as under gluconeogenic conditions. For the mitochondria, increased NADH/NAD+ ratios were found in the present work in the absence of exogenous fatty acids in contrast with the previous observation of a decreasing effect when the liver was actively oxidizing exogenous oleate. It seems likely that ranolazine inhibits gluconeogenesis and increases glycolysis in consequence of its inhibitory actions on energy metabolism and fatty acid oxidation and by deviating reducing equivalents in favour of its own biotransformation. This is in line with the earlier postulates that ranolazine diminishes fatty acid oxidation, shifting the energy source from fatty acids to glucose.
References
[1]
Anderson, J.R. and Nawarskas, J.J. (2005) Ranolazine, a Metabolic Modulator for the Treatment of Chronic Stable Angina. Cardiology in Review, 13, 202-210. http://dx.doi.org/10.1097/01.crd.0000161979.62749.e7
[2]
Clarke, B., Spedding, M., Patmore, L. and McCormack, J.G. (1993) Protective Effects of Ranolazine in Guinea-Pig Hearts during Low-Flow Ischaemia and Their Association with Increases in Active Dehydrogenase. British Journal of Pharmacology, 109, 748-750. http://dx.doi.org/10.1111/j.1476-5381.1993.tb13637.x
[3]
Clarke, B., Wyatt, K.M. and McCormack, J.G. (1996) Ranolazine Increases Active Pyruvate Dehydrogenase in Perfused Normoxic Rat Hearts: Evidence for an Indirect Mechanism. Journal of Molecular and Cellular Cardiology, 28, 341-350. http://dx.doi.org/10.1006/jmcc.1996.0032
[4]
McCormack, J.G., Barr, R.L., Wolff, A.A. and Lopaschuk, G.D. (1996) Ranolazine Stimulates Glucose Oxidation in Normoxic, Ischemic and Reperfused Ischemic Rat Hearts. Circulation, 93, 135-142.
http://dx.doi.org/10.1161/01.CIR.93.1.135
[5]
Fragasso, G. (2007) Inhibition of Free Fatty Acids Metabolism as a Therapeutic Target in Patients with Heart Failure. International Journal of Clinical Practice, 61, 603-610. http://dx.doi.org/10.1111/j.1742-1241.2006.01280.x
[6]
Marx, S. and Sweeney, M. (2006) Mechanism of Action of Ranolazine. Archives of Internal Medicine, 166, 1325-1326.
http://dx.doi.org/10.1001/archinte.166.12.1325-b
[7]
Verrier, R.L., Kumar, K., Nieminen, T. and Belardinelli, L. (2013) Mechanisms of Ranolazine’s Dual Protection against Atrial and Ventricular Fibrillation. Eurospace, 15, 317-324. http://dx.doi.org/10.1093/europace/eus380
[8]
Kahlig, K.M., Hirakawa, R., Liu, L., George Jr., A.L., Belardinelli, L. and Rajamani, S. (2014) Ranolazine Reduces Neuronal Excitability by Interacting with Inactivated States of Brain Sodium Channels. Molecular Pharmacology, 85, 162-174. http://dx.doi.org/10.1124/mol.113.088492
[9]
Jerling, M., Huan, B.L., Leung, K., Chu, N., Abdallah, H. and Hussein, Z. (2005) Diltiazem, or Simvastatin during Combined Administration in Healthy Subjects. Studies to Investigate the Pharmacokinetic Interactions between Ranolazine and Keto-Conazole. Journal of Clinical Pharmacology, 45, 422-433.
http://dx.doi.org/10.1177/0091270004273992
[10]
Mito, M.S., Constantin, J., Castro, C.V., Ono, M.K.C. and Bracht, A. (2010) Effects of Ranolazine on Fatty Acid Transformation in the Isolated Perfused Rat Liver. Molecular and Cellular Biochemistry, 345, 35-44.
http://dx.doi.org/10.1007/s11010-010-0557-8
[11]
Williamson, J.R., Browning, E.T. and Scholz, R. (1969) Control Mechanisms of Gluconeogenesis and Ketogenesis. I. Effects of Oleate on Gluconeogenesis in Perfused Rat Liver. Journal of Biological Chemistry, 244, 4607-4616.
[12]
Veiga, R.P., Silva, M.H.R.A., Teodoro, G.R., Yamamoto, N.S., Constantin, J. and Bracht, A. (2008) Metabolic Fluxes in the Liver of Rats Bearing the Walker-256 Tumour: Influence of the Circulating Levels of Substrates and Fatty Acids. Cell Biochemistry and Function, 26, 51-63. http://dx.doi.org/10.1002/cbf.1398
[13]
Soboll, S., Scholz, R. and Heldt, H.W. (1978) Subcellular Metabolite Concentrations. Dependence of Mitochondrial and Cytosolic ATP Systems on the Metabolic State of Perfused Rat Liver. European Journal of Biochemistry, 87, 377-390. http://dx.doi.org/10.1111/j.1432-1033.1978.tb12387.x
[14]
Sugden, M.C., Ball, A.J., Ilk, V. and Williamson, D.H. (1980) Stimulation of [1-14C]oleate Oxidation to 14CO2 in Isolated Rat Hepatocytes by Vasopressin: Effects of Ca2+. FEBS Letters, 116, 37-40.
http://dx.doi.org/10.1016/0014-5793(80)80523-0
[15]
Scholz, R. and Bücher, T. (1965) Hemoglobin-Free Perfusion of Rat Liver. In: Chance, B., Estabrook, R.W. and Williamson, J.R., Eds., Control of Energy Metabolism, Academic Press, New York, 393-414.
http://dx.doi.org/10.1016/B978-1-4832-3161-7.50048-3
[16]
Bracht, A., Ishii-Iwamoto, E.L. and Kelmer-Bracht, A.M. (2003) O estudo do metabolismo no fígado em perfusao. In: Bracht, A. and Ishii-Iwamoto, E.L., Eds., Métodos de Laboratório em Bioquímica, Editora Manole, Sao Paulo, 275- 289.
Clark, L.C. (1956) Monitoring and Control of Blood O2 Tension. Transactions of the American Society of Artificial Internal Organs, 2, 41-49.
[19]
Bazotte, R.B., Constantin, J., Hell, N.S. and Bracht, A. (1990) Hepatic Metabolism of Meal-Fed Rats: Studies in Vivo and in the Isolated Perfused Liver. Physiology & Behavior, 48, 247-253.
http://dx.doi.org/10.1016/0031-9384(90)90308-Q
[20]
Thurman, R.G. and Scholz, R. (1977) Interaction of Glycolysis and Respiration in Perfused Liver. Changes in Oxygen Uptake Following the Addition of Ethanol. European Journal of Biochemistry, 75, 13-21.
http://dx.doi.org/10.1111/j.1432-1033.1977.tb11499.x
[21]
Kimmig, R., Mauch, T.J. and Scholz, R. (1983) Actions of Glucagon on Flux Rates in Perfused Rat Liver. 2. Relationship between Inhibition of Glycolysis and Stimulation of Respiration by Glucagon. European Journal of Biochemistry, 136, 617-620. http://dx.doi.org/10.1111/j.1432-1033.1983.tb07785.x
[22]
Sies, H. (1982) Nicotinamide Nucleotide Compartmentation. In: Sies, H., Ed., Metabolic Compartmentation, Academic Press, New York, 205-231.
[23]
Gasparin, F.R.S., Salgueiro-Pagadigorria, C.L., Bracht, L., Ishii-Iwamoto, E.L., Bracht, A. and Constantin, J. (2003) Action of Quercetin on Glycogen Catabolism in the Rat Liver. Xenobiotica, 33, 587-602.
http://dx.doi.org/10.1080/0049825031000089100
[24]
Pereira, S.R.C., Darronqui, E., Constantin, J., Silva, M.H.R.A., Yamamoto, N.S. and Bracht, A. (2004) The Urea Cycle and Related Pathways in the Liver of Walker-256 Tumor-Bearing Rats. Biochimica et Biophysica Acta, 1688, 187-196.
http://dx.doi.org/10.1016/j.bbadis.2003.12.001
[25]
Pivato, L.S., Constantin, R.P., Ishii-Iwamoto, E.L., Kelmer-Bracht, A.M., Yamamoto, N.S., Constantin, J. and Bracht, A. (2006) Metabolic Effects of Carbenoxolone in the Rat Liver. Journal of Biochemical and Molecular Toxicology, 20, 230-240. http://dx.doi.org/10.1002/jbt.20139
[26]
Acco, A., Comar, J.F. and Bracht, A. (2004) Metabolic Effects of Propofol in the Isolated Perfused Rat Liver. Basic & Clinical Pharmacology & Toxicology, 95, 166-174. http://dx.doi.org/10.1111/j.1742-7843.2004.pto950404.x
[27]
Wyatt, K.M., Skene, C., Veitch, K., Hue, L. and McCormack, J.G. (1995) The Antianginal Ranolazine Is a Weak Inhibitor of the Respiratory Complex I, but with Greater Potency in Broken or Uncoupled than in Coupled Mitochondria. Biochemical Pharmacology, 50, 1599-1606. http://dx.doi.org/10.1016/0006-2952(95)02042-X
[28]
Scholz, A., Hansen, W. and Thurman, R.G. (1973) Interaction of Mixed-Function Oxidation with Biosynthetic Processes. 1. Inhibition of Gluconeogenesis by Aminopyrine in Perfused Rat Liver. European Journal of Biochemistry, 38, 64-72. http://dx.doi.org/10.1111/j.1432-1033.1973.tb03034.x
[29]
Orrenius, S. and Sies, H. (1982) Compartmentation of Detoxification Reactions. In: Sies, H., Ed., Metabolic Compartmentation, Academic Press, New York, 485-520.
