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Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine

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Abstract

Budipine is a non-dopaminergic antiparkinsonian drug causing acquired forms of Long QT syndrome (aLQTS). As a consequence, the manufacturer has restricted the use of budipine in patients who exhibit additional risk factors for the development of “Torsades-de-Pointes” tachycardias (TdP). The molecular basis of this serious side effect has not been elucidated yet.

Human ether-a-go-go related gene (HERG) channel block being the main cause of drug induced QT prolongation, we investigated the effect of budipine on the rapid component of the delayed-rectifier potassium current (IK(r)) in guinea pig cardiomyocytes and on HERG potassium channels heterologously expressed in Xenopus oocytes.

In guinea pig cardiomyocytes, budipine (10 μM) inhibited IK(r) by 86% but was without any effect on calcium currents. In Xenopus oocytes, HERG potassium channels were blocked by budipine with an IC50 of 10.2 μM. Onset of block was fast and block was only slowly and incompletely reversible upon washout.

Budipine blocked HERG channels in the open and inactivated state, but not in the closed states. The half-maximal activation voltage was slightly shifted towards more negative potentials. Steady-state inactivation of HERG was also influenced by budipine. Budipine block was neither voltage- nor frequency-dependent.

In HERG channel mutants Y652A and F656A, drug affinity was reduced dramatically. Therefore, these two aromatic residues in the channel pore are likely to form a main part of the binding site for budipine.

In summary, this is the first study that provides a molecular basis for the budipine-associated aLQTS observed in clinical practice. Furthermore, these findings underline the importance of the aromatic residues Y652 and F656 in the binding of lipophilic drugs to HERG channels.

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Abbreviations

IK(r) :

The rapid component of the delayed-rectifier potassium current

HERG:

Human ether-a-go-go related gene

aLQTS:

Acquired Long QT syndrome

TdP:

Torsade-de-Pointes tachycardia

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Acknowledgements

This work was supported by a grant of the Deutsche Forschungsgemeinschaft Ki 663/1-1 to Dr. Kiehn and KA 1714/1-1 to Dr. Karle. Data presented here are part of the thesis of E. Scholz. E. Zitron was supported by the German National Merit Scholarship Foundation. The skilful assistance of Klara Gueth and Ramona Bloehs is gratefully acknowledged.

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Authors and Affiliations

  1. 3rd Department of Internal Medicine (Cardiology), University of Heidelberg Medical School, Bergheimerstrasse 58, 69115, Heidelberg, Germany

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

  2. 7th Department of Internal Medicine (Sports Medicine), University of Heidelberg Medical School, Bergheimerstrasse 58, 69115, Heidelberg, Germany

    Simon Peth

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

    Volker A. W. Kreye

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  1. Eberhard P. Scholz
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  2. Edgar Zitron
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  3. Claudia Kiesecker
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  9. Volker A. W. Kreye
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  11. Hugo A. Katus
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  12. Johann Kiehn
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Correspondence to Christoph A. Karle.

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E.P. Scholz and E. Zitron contributed equally to this work

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Scholz, E.P., Zitron, E., Kiesecker, C. et al. Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine. Naunyn-Schmiedeberg's Arch Pharmacol 368, 404–414 (2003). https://doi.org/10.1007/s00210-003-0805-5

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