Effects of Ranolazine on Carbohydrate Metabolism in the Isolated Perfused Rat Liver

Abstract

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.