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Molecular Pharmacology

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Research ArticleArticle

Use-Dependent Block of Human Cardiac Sodium Channels by GS967

Franck Potet, Carlos G. Vanoye and Alfred L. George Jr.
Molecular Pharmacology July 2016, 90 (1) 52-60; DOI: https://doi.org/10.1124/mol.116.103358
Franck Potet
Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Carlos G. Vanoye
Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Alfred L. George Jr.
Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois
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Abstract

GS-458967, 6-(4-(Trifluoromethoxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (GS967) is a recently described, novel, sodium channel inhibitor exhibiting potent antiarrhythmic effects in various in vitro and in vivo models. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current. However, there has been no reported systematic investigation of the effects of this compound on isolated sodium channels. Here, we examined the effects of GS967 on peak (INaP) and late (INaL) sodium current recorded from cells that heterologously expressed human cardiac voltage-gated sodium channel, the principle cardiac sodium channel. As previously described, we observed that GS967 exerted tonic block of INaL (63%) to a significantly greater extent than INaP (19%). However, GS967 also caused a reduction of INaP in a frequency-dependent manner, consistent with use-dependent block (UDB). GS967 evoked more potent UDB of INaP (IC50 = 0.07 µM) than ranolazine (16 µM) and lidocaine (17 µM). Use-dependent block was best explained by a significant slowing of recovery from fast and slow inactivation with a significant enhancement of slow inactivation in the presence of GS967. Furthermore, GS967 was found to exert these same effects on a prototypical long QT syndrome mutation (delKPQ). An engineered mutation at an interaction site for local anesthetic agents (F1760A) partially attenuated the effect of GS967 on UDB, but had no effect on tonic INaL block. We conclude that GS967 is a preferential inhibitor of INaL, but it also exerts previously unreported strong effects on slow inactivation and recovery from inactivation, resulting in substantial UDB that is not entirely dependent on a known interaction site for local anesthetic agents.

Footnotes

    • Received January 11, 2016.
    • Accepted April 29, 2016.
  • This work was supported by a Scientist Development Grant [11SDG5330006] from the American Heart Association (F.P.) and a research grant from Gilead Sciences, Inc.

  • This work was partially supported by a research grant from Gilead Sciences, Inc.

  • dx.doi.org/10.1124/mol.116.103358.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 90 (1)
Molecular Pharmacology
Vol. 90, Issue 1
1 Jul 2016
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Research ArticleArticle

GS967 Block of Human Cardiac Sodium Channels

Franck Potet, Carlos G. Vanoye and Alfred L. George
Molecular Pharmacology July 1, 2016, 90 (1) 52-60; DOI: https://doi.org/10.1124/mol.116.103358

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Research ArticleArticle

GS967 Block of Human Cardiac Sodium Channels

Franck Potet, Carlos G. Vanoye and Alfred L. George
Molecular Pharmacology July 1, 2016, 90 (1) 52-60; DOI: https://doi.org/10.1124/mol.116.103358
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