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Tetrodotoxin-sensitive α-subunits of voltage-gated sodium channels are relevant for inhibition of cardiac sodium currents by local anesthetics

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Abstract

The sodium channel α-subunit (Nav) Nav1.5 is regarded as the most prevalent cardiac sodium channel required for generation of action potentials in cardiomyocytes. Accordingly, Nav1.5 seems to be the main target molecule for local anesthetic (LA)-induced cardiotoxicity. However, recent reports demonstrated functional expression of several “neuronal” Nav’s in cardiomyocytes being involved in cardiac contractility and rhythmogenesis. In this study, we examined the relevance of neuronal tetrodotoxin (TTX)-sensitive Nav’s for inhibition of cardiac sodium channels by the cardiotoxic LAs ropivacaine and bupivacaine. Effects of LAs on recombinant Nav1.2, 1.3, 1.4, and 1.5 expressed in human embryonic kidney cell line 293 (HEK-293) cells, and on sodium currents in murine, cardiomyocytes were investigated by whole-cell patch clamp recordings. Expression analyses were performed by reverse transcription PCR (RT-PCR). Cultured cardiomyocytes from neonatal mice express messenger RNA (mRNA) for Nav1.2, 1.3, 1.5, 1.8, and 1.9 and generate TTX-sensitive sodium currents. Tonic and use-dependent block of sodium currents in cardiomyocytes by ropivacaine and bupivacaine were enhanced by 200 nM TTX. Inhibition of recombinant Nav1.5 channels was similar to that of TTX-resistant currents in cardiomyocytes but stronger as compared to inhibition of total sodium current in cardiomyocytes. Recombinant Nav1.2, 1.3, 1.4, and 1.5 channels displayed significant differences in regard to use-dependent block by ropivacaine. Finally, bupivacaine blocked sodium currents in cardiomyocytes as well as recombinant Nav1.5 currents significantly stronger in comparison to ropivacaine. Our data demonstrate for the first time that cardiac TTX-sensitive sodium channels are relevant for inhibition of cardiac sodium currents by LAs.

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Acknowledgments

The authors gratefully acknowledge the assistance of Heike Bürger (Anesthesiology, Hannover) for excellent assistance and Andreas Niesel (Neurology, Hannover) for excellent technical support. This study was supported by internal funding of the Department of Anesthesiology and Intensive Care, Hannover Medical School, Hannover. Work in the laboratory of A.K. was funded by a grant from the German Research Foundation (DFG) for the Cluster of Excellence from Regenerative Biology to Reconstructive Therapy (REBIRTH) at Hannover Medical School.

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Authors and Affiliations

  1. Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany

    C. Stoetzer, T. Doll, T. Stueber, C. Herzog, F. Echtermeyer & A. Leffler

  2. Institute of Molecular Biology, Hannover Medical School, Hannover, Germany

    F. Greulich, C. Rudat & A. Kispert

  3. Department of Neurology, Hannover Medical School, Hannover, Germany

    F. Wegner

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  1. C. Stoetzer
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  2. T. Doll
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  3. T. Stueber
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  6. F. Greulich
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  9. F. Wegner
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  10. A. Leffler
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Correspondence to C. Stoetzer.

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C. Stoetzer and T. Doll equally contributing authors

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Stoetzer, C., Doll, T., Stueber, T. et al. Tetrodotoxin-sensitive α-subunits of voltage-gated sodium channels are relevant for inhibition of cardiac sodium currents by local anesthetics. Naunyn-Schmiedeberg's Arch Pharmacol 389, 625–636 (2016). https://doi.org/10.1007/s00210-016-1231-9

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  • DOI: https://doi.org/10.1007/s00210-016-1231-9

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