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Late sodium current and intracellular ionic homeostasis in acute ischemia

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Abstract

Blockade of the late Na+ current (I NaL) protects from ischemia/reperfusion damage; nevertheless, information on changes in I NaL during acute ischemia and their effect on intracellular milieu is missing. I NaL, cytosolic Na+ and Ca2+ activities (Nacyt, Cacyt) were measured in isolated rat ventricular myocytes during 7 min of simulated ischemia (ISC); in all the conditions tested, effects consistently exerted by ranolazine (RAN) and tetrodotoxin (TTX) were interpreted as due to I NaL blockade. The results indicate that I NaL was enhanced during ISC in spite of changes in action potential (AP) contour; I NaL significantly contributed to Nacyt rise, but only marginally to Cacyt rise. The impact of I NaL on Cacyt was markedly enhanced by blockade of the sarcolemmal(s) Na+/Ca2+ exchanger (NCX) and was due to the presence of (Na+-sensitive) Ca2+ efflux through mitochondrial NCX (mNCX). sNCX blockade increased Cacyt and decreased Nacyt, thus indicating that, throughout ISC, sNCX operated in the forward mode, in spite of the substantial Nacyt increment. Thus, a robust Ca2+ source, other than sNCX and including mitochondria, contributed to Cacyt during ISC. Most, but not all, of RAN effects were shared by TTX. (1) The paradigm that attributes Cacyt accumulation during acute ischemia to decrease/reversal of sNCX transport may not be of general applicability; (2) I NaL is enhanced during ISC, when the effect of Nacyt on mitochondrial Ca2+ transport may substantially contribute to I NaL impact on Cacyt; (3) RAN may act mostly, but not exclusively, through I NaL blockade during ISC.

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Acknowledgements

This research was supported by grant from Gilead Inc. (Fremont, CA, US) and FAR 2015 to A. Zaza. We are grateful to Dr. Luiz Belardinelli for providing stimulating discussion throughout the execution of the study and Dr. Luca Sala for contributing to some experiments and providing insightful comments on the manuscript.

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  1. Department of Biotechnologies and Biosciences, University Milano-Bicocca, Piazza della Scienza 2, 20126, Milan, Italy

    Carlotta Ronchi, Eleonora Torre, Riccardo Rizzetto, Joyce Bernardi, Marcella Rocchetti & Antonio Zaza

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  1. Carlotta Ronchi
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  2. Eleonora Torre
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Correspondence to Antonio Zaza.

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All experiment were approved and conducted in accordance with guidelines issued by the Animal Care Committee of the University Milano-Bicocca, in compliance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The manuscript does not contain human data.

Conflict of interest

The study has been partially funded by Gilead, Inc. (Fremont, CA), which is the patent holder for Ranolazine. The authors declare that they have no further conflict of interest.

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Ronchi, C., Torre, E., Rizzetto, R. et al. Late sodium current and intracellular ionic homeostasis in acute ischemia. Basic Res Cardiol 112, 12 (2017). https://doi.org/10.1007/s00395-017-0602-9

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