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Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action

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Abstract

Ajmaline is a class Ia anti-arrhythmic drug used in several European countries and Japan as first-line treatment for ventricular tachyarrhythmia. Ajmaline has been reported to induce cardiac output (QT) prolongation and to inhibit cardiac potassium currents in guinea pig cardiomyocytes. In order to elucidate the molecular basis of these effects, we examined effects of ajmaline on human ether a-go-go related gene HERG potassium channels. Electrophysiological experiments were performed with human embryonic kidney (HEK) cells (whole-cell patch clamp) and Xenopus oocytes (double-electrode voltage clamp) expressing wild-type and mutant HERG channels. Ajmaline blocked HERG currents with an IC50 of 1.0 μmol/l in HEK cells and 42.3 μmol/l in Xenopus oocytes. The onset of block was fast and reached steady-state conditions after 180 s. The inhibitory effect was completely reversible upon wash-out. In HERG mutant channels Y652A and F656A lacking aromatic residues in the S6 domain, the inhibitory effect of ajmaline was completely abolished. Ajmaline induced a small shift in HERG current half-maximal activation voltage towards more negative potentials. Ajmaline did not markedly affect HERG inactivation. Inhibitory effects were not voltage-dependent. Ajmaline block exhibited positive frequency dependence. Ajmaline blocked HERG channels in the open, but not in the closed states. Binding of ajmaline to inactivated HERG channels may also be possible. In inactivation-deficient HERG S620T channels, the sensitivity to ajmaline was markedly reduced. The IC50 of HERG channel blockade in HEK cells lies within the range of unbound therapeutic plasma concentrations of ajmaline. Therefore, inhibitory effects on HERG channels may contribute to both the high anti-arrhythmic efficacy of ajmaline and to its pro-arrhythmic potential.

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Acknowledgements

This work was supported by grants from the Deutsche Forschungsgemeinschaft Ki 663/1-1 to Dr Kiehn and Ka 1714/1-1 to Dr Karle, and by grants from the Novartis-Foundation, from the University of Heidelberg (“AIP+F”) and from the Foundation Cardiology 2000 (Forssman-Scholarship) to Dr Thomas. E. Zitron was supported by the German National Academic Foundation. Data presented here are part of the thesis of C. Kiesecker.

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Authors and Affiliations

  1. Department of Cardiology, University of Heidelberg Medical School, Bergheimerstrasse 58, 69115, Heidelberg, Germany

    Claudia Kiesecker, Edgar Zitron, Sonja Lück, Ramona Bloehs, Eberhard P. Scholz, Sven Kathöfer, Dierk Thomas, Hugo A. Katus, Wolfgang Schoels, Christoph A. Karle & Johann Kiehn

  2. Department of Physiology and Pathophysiology, University of Heidelberg Medical School, Bergheimerstrasse 58, 69115, Heidelberg, Germany

    Volker A. W. Kreye

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  1. Claudia Kiesecker
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  2. Edgar Zitron
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  5. Eberhard P. Scholz
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Correspondence to Christoph A. Karle.

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Kiesecker, C., Zitron, E., Lück, S. et al. Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action. Naunyn-Schmiedeberg's Arch Pharmacol 370, 423–435 (2004). https://doi.org/10.1007/s00210-004-0976-8

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  • DOI: https://doi.org/10.1007/s00210-004-0976-8

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