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Rubi L, Kovar M, Zebedin-Brandl E, et al. Modulation of the heart's electrical properties by the anticonvulsant drug retigabine. Toxicol Appl Pharmacol. 2017;329:309-317doi: 10.1016/j.taap.2017.06.018.
Rubi, L., Kovar, M., Zebedin-Brandl, E., Koenig, X., Dominguez-Rodriguez, M., Todt, H., Kubista, H., Boehm, S., & Hilber, K. (2017). Modulation of the heart's electrical properties by the anticonvulsant drug retigabine. Toxicology and applied pharmacology, 329309-317. https://doi.org/10.1016/j.taap.2017.06.018
Rubi, Lena, et al. "Modulation of the heart's electrical properties by the anticonvulsant drug retigabine." Toxicology and applied pharmacology vol. 329 (2017): 309-317. doi: https://doi.org/10.1016/j.taap.2017.06.018
Rubi L, Kovar M, Zebedin-Brandl E, Koenig X, Dominguez-Rodriguez M, Todt H, Kubista H, Boehm S, Hilber K. Modulation of the heart's electrical properties by the anticonvulsant drug retigabine. Toxicol Appl Pharmacol. 2017 Aug 15;329:309-317. doi: 10.1016/j.taap.2017.06.018. Epub 2017 Jun 20. PMID: 28641963; PMCID: PMC6420109.
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Toxicol Appl Pharmacol. 2017 Aug 15;329:309-317. doi: 10.1016/j.taap.2017.06.018. Epub 2017 Jun 20.

Modulation of the heart's electrical properties by the anticonvulsant drug retigabine.

Toxicology and applied pharmacology

Lena Rubi, Michael Kovar, Eva Zebedin-Brandl, Xaver Koenig, Manuel Dominguez-Rodriguez, Hannes Todt, Helmut Kubista, Stefan Boehm, Karlheinz Hilber

Affiliations

  1. Center for Physiology and Pharmacology, Department of Neurophysiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
  2. Center for Physiology and Pharmacology, Department of Neurophysiology and Pharmacology, Medical University of Vienna, Vienna, Austria. Electronic address: [email protected].
  3. Center for Physiology and Pharmacology, Department of Neurophysiology and Pharmacology, Medical University of Vienna, Vienna, Austria. Electronic address: [email protected].

PMID: 28641963 PMCID: PMC6420109 DOI: 10.1016/j.taap.2017.06.018

Abstract

Retigabine, currently used as antiepileptic drug, has a wide range of potential medical uses. Administration of the drug in patients can lead to QT interval prolongation in the electrocardiogram and to cardiac arrhythmias in rare cases. This suggests that the drug may perturb the electrical properties of the heart, and the underlying mechanisms were investigated here. Effects of retigabine on currents through human cardiac ion channels, heterologously expressed in tsA-201 cells, were studied in whole-cell patch-clamp experiments. In addition, the drug's impact on the cardiac action potential was tested. This was done using ventricular cardiomyocytes isolated from Langendorff-perfused guinea pig hearts and cardiomyocytes derived from human induced pluripotent stem cells. Further, to unravel potential indirect effects of retigabine on the heart which might involve the autonomic nervous system, membrane potential and noradrenaline release from sympathetic ganglionic neurons were measured in the absence and presence of the drug. Retigabine significantly inhibited currents through hKv11.1 potassium, hNav1.5 sodium, as well as hCav1.2 calcium channels, but only in supra-therapeutic concentrations. In a similar concentration range, the drug shortened the action potential in both guinea pig and human cardiomyocytes. Therapeutic concentrations of retigabine, on the other hand, were sufficient to inhibit the activity of sympathetic ganglionic neurons. We conclude that retigabine- induced QT interval prolongation, and the reported cases of cardiac arrhythmias after application of the drug in a typical daily dose range, cannot be explained by a direct modulatory effect on cardiac ion channels. They are rather mediated by indirect actions at the level of the autonomic nervous system.

Copyright © 2017. Published by Elsevier Inc.

Keywords: Cardiac arrhythmia; Cardiomyocytes; Ion channels; QT interval; Retigabine; Sympathetic ganglionic neurons

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