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

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 ofmore » 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. - Highlights: • We study effects of anticonvulsant retigabine on the heart's electrical properties. • Retigabine does not modulate cardiac ion channels in therapeutic concentrations. • The activity of sympathetic ganglionic neurons is inhibited by retigabine. • Ganglionic block may generate QT interval prolongation and cardiac arrhythmias.« less

Authors:
; ; ; ; ; ; ; ;
Publication Date:
OSTI Identifier:
22722906
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 329; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTICONVULSANTS; AUTONOMIC NERVOUS SYSTEM; CONCENTRATION RATIO; ECOLOGICAL CONCENTRATION; ELECTRICAL PROPERTIES; GUINEA PIGS; HEART; INHIBITION; IONS; MODULATION; NERVE CELLS; POTENTIALS; STEM CELLS

Citation Formats

Rubi, Lena, Kovar, Michael, Zebedin-Brandl, Eva, Koenig, Xaver, Dominguez-Rodriguez, Manuel, Todt, Hannes, Kubista, Helmut, Boehm, Stefan, and Hilber, Karlheinz. Modulation of the heart's electrical properties by the anticonvulsant drug retigabine. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.06.018.
Rubi, Lena, Kovar, Michael, Zebedin-Brandl, Eva, Koenig, Xaver, Dominguez-Rodriguez, Manuel, Todt, Hannes, Kubista, Helmut, Boehm, Stefan, & Hilber, Karlheinz. Modulation of the heart's electrical properties by the anticonvulsant drug retigabine. United States. doi:10.1016/J.TAAP.2017.06.018.
Rubi, Lena, Kovar, Michael, Zebedin-Brandl, Eva, Koenig, Xaver, Dominguez-Rodriguez, Manuel, Todt, Hannes, Kubista, Helmut, Boehm, Stefan, and Hilber, Karlheinz. Tue . "Modulation of the heart's electrical properties by the anticonvulsant drug retigabine". United States. doi:10.1016/J.TAAP.2017.06.018.
@article{osti_22722906,
title = {Modulation of the heart's electrical properties by the anticonvulsant drug retigabine},
author = {Rubi, Lena and Kovar, Michael and Zebedin-Brandl, Eva and Koenig, Xaver and Dominguez-Rodriguez, Manuel and Todt, Hannes and Kubista, Helmut and Boehm, Stefan and Hilber, Karlheinz},
abstractNote = {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. - Highlights: • We study effects of anticonvulsant retigabine on the heart's electrical properties. • Retigabine does not modulate cardiac ion channels in therapeutic concentrations. • The activity of sympathetic ganglionic neurons is inhibited by retigabine. • Ganglionic block may generate QT interval prolongation and cardiac arrhythmias.},
doi = {10.1016/J.TAAP.2017.06.018},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 329,
place = {United States},
year = {2017},
month = {8}
}