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Molecular Pharmacology

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Research ArticleArticle

Preferential Block of Late Sodium Current in the LQT3 ΔKPQ Mutant by the Class IC Antiarrhythmic Flecainide

Toshihisa Nagatomo, Craig T. January and Jonathan C. Makielski
Molecular Pharmacology January 2000, 57 (1) 101-107;
Toshihisa Nagatomo
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Craig T. January
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Jonathan C. Makielski
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Abstract

Flecainide block of Na+ current (INa) was investigated in wild-type (WT) or the long QT syndrome 3 (LQT3) sodium channel α subunit mutation with three amino acids deleted (ΔKPQ) stably transfected into human embryonic kidney 293 cells using whole-cell, patch-clamp recordings. Flecainide (1–300 mM) caused tonic and use-dependent block (UDB) of INa in a concentration-dependent manner. Compared with WT, ΔKPQ INa was more sensitive to flecainide, and flecainide preferentially inhibited late INa (mean current between 20 and 23.5 ms after depolarization) compared with peak INa. The IC50 value of peak and late INa for WT was 127 ± 6 and 44 ± 2 μM (n = 20) and for ΔKPQ was 80 ± 9 and 19 ± 2 μM (n = 31) respectively. UDB of peak INawas greater and developed more slowly during pulse trains for ΔKPQ than for WT. The IC50 value for UDB of peak INafor WT was 29 ± 4 μM (n = 20) and for ΔKPQ was 11 ± 1 μM (n = 26). For ΔKPQ, UDB of late INa was greater than for peak INa. Recovery from block was slower for ΔKPQ than for WT. We conclude that ΔKPQ interacts differently with flecainide than with WT, leading to increased block and slowed recovery, especially for late INa. These data provide insights into mechanisms for flecainide block and provide a rationale at the cellular and molecular level that open channel block may be a useful pharmacological property for treatment of LQT3.

Footnotes

  • Send reprint requests to: Jonathan C. Makielski, M.D., University of Wisconsin Clinics and Hospitals, 600 Highland Ave, H6/349, Madison, WI. E-mail: jcm{at}medicine.wisc.edu

  • ↵1 Current affiliation: Second Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

  • This work was supported by National Institutes of Health Grant HL56441 (JCM) and grants from the University of Wisconsin Cardiovascular Research Center, the Oscar Rennebohm Foundation, and by a travel grant from the Fukuda Memorial Foundation (TN).

  • This work was published previously in abstract form: Nagatomo T, Fan Z, Ye B, January CT, Makielski JC (1996). Effects of flecainide on the long QT sodium channel syndrome. Circulation 96(Suppl):677.

  • Abbreviations:
    LQT
    long QT syndrome
    ΔKPQ
    LQT3 sodium channel α subunit mutation with three amino acids deleted
    INa
    Na+ current
    UDB
    use-dependent block
    WT
    wild-type
    MEM
    minimal essential medium
    • Received June 29, 1999.
    • Accepted October 2, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (1)
Molecular Pharmacology
Vol. 57, Issue 1
1 Jan 2000
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Research ArticleArticle

Preferential Block of Late Sodium Current in the LQT3 ΔKPQ Mutant by the Class IC Antiarrhythmic Flecainide

Toshihisa Nagatomo, Craig T. January and Jonathan C. Makielski
Molecular Pharmacology January 1, 2000, 57 (1) 101-107;

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Research ArticleArticle

Preferential Block of Late Sodium Current in the LQT3 ΔKPQ Mutant by the Class IC Antiarrhythmic Flecainide

Toshihisa Nagatomo, Craig T. January and Jonathan C. Makielski
Molecular Pharmacology January 1, 2000, 57 (1) 101-107;
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