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Effects of ranolazine on fatty acid transformation in the isolated perfused rat liver

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Abstract

It has been proposed that in the heart, ranolazine shifts the energy source from fatty acids to glucose oxidation by inhibiting fatty acid oxidation. Up to now no mechanism for this inhibition has been proposed. The purpose of this study was to investigate if ranolazine also affects hepatic fatty acid oxidation, with especial emphasis on cell membrane permeation based on the observations that the compound interacts with biological membranes. The isolated perfused rat liver was used, and [1-14C]oleate transport was measured by means of the multiple-indicator dilution technique. Ranolazine inhibited net uptake of [1-14C]-oleate by impairing transport of this fatty acid. The compound also diminished the extra oxygen consumption and ketogenesis driven by oleate and the mitochondrial NADH/NAD+ ratio, but stimulated 14CO2 production. These effects were already significant at 20 μM ranolazine. Ranolazine also inhibited both oxygen consumption and ketogenesis driven by endogenous fatty acids in substrate-free perfused livers. In isolated mitochondria ranolazine inhibited acyl-CoA oxidation and β-hydroxybutyrate or α-ketoglutarate oxidation coupled to ADP phosphorylation. It was concluded that ranolazine inhibits fatty acid uptake and oxidation in the liver by at least two mechanisms: inhibition of cell membrane permeation and by an inhibition of the mitochondrial electron transfer via pyridine nucleotides.

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Acknowledgments

This study was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and from the Programa Nacional de Núcleos de Excelência (PRONEX, Fundação Araucária-CNPq). The authors wish to thank the technical assistance of Celia Akemi Gasparetto.

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Authors and Affiliations

  1. Laboratory of Liver Metabolism, Department of Biochemistry, University of Maringá, Maringá, 87020900, Brazil

    Márcio Shigueaki Mito, Jorgete Constantin, Cristiane Vizioli de Castro, Nair Seiko Yamamoto & Adelar Bracht

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  1. Márcio Shigueaki Mito
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  2. Jorgete Constantin
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  3. Cristiane Vizioli de Castro
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  4. Nair Seiko Yamamoto
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  5. Adelar Bracht
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Correspondence to Adelar Bracht.

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Mito, M.S., Constantin, J., de Castro, C.V. et al. Effects of ranolazine on fatty acid transformation in the isolated perfused rat liver. Mol Cell Biochem 345, 35–44 (2010). https://doi.org/10.1007/s11010-010-0557-8

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  • DOI: https://doi.org/10.1007/s11010-010-0557-8

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