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Effects of duramycin on cardiac voltage-gated ion channels

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Abstract

The amphipathic peptide duramycin is in clinical development for the treatment of cystic fibrosis. It is deposited in cellular membranes where it binds to phosphatidylethanolamine. Duramycin may thereby change the biophysical membrane properties and perturb the function of ion channels. If so, in heart tissue, its application carries the risk to elicit cardiac arrhythmias. In fact, premature ventricular complexes were observed in the electrocardiogram during toxicological testing in dogs. To study the arrhythmogenic potential of duramycin, we investigated its effects on currents through voltage-gated hERG potassium, sodium, and calcium channels in native cells, and using a heterologous expression system, by means of the whole-cell patch clamp technique; duramycin bath concentrations between 1 nM and 0.1 μM did not generate any effects on these currents. Concentrations ≥0.3 μM, however, reduced the amplitudes of all investigated currents. Moreover, sodium current fast inactivation kinetics was slowed in the presence of duramycin. A further rise in duramycin bath concentration (≥3.3 μM) induced a leak current consistent with pore formation. The reported effects of duramycin on ion channel function are likely to arise from a change in the biophysical properties of the membrane rather than from a specific interaction of the peptide with ion channel proteins. Under therapeutic conditions (i.e., administration via inhalation), duramycin plasma concentrations are below 0.5 nM. Thus, upon inhalation, duramycin has a large safety margin and is highly unlikely to elicit arrhythmias.

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Acknowledgements

Financial support was provided by a grant from AOP Austrian Orphan Pharmaceuticals AG; M.R. was supported by a Lise-Meitner fellowship M989-B09 of the FWF (Austrian Science Fund). We are grateful to Martina Molin for the excellent technical assistance; we thank Michael C. Sanguinetti (University of Utah) for kindly providing the plasmid-encoding hERG.

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Authors and Affiliations

  1. Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Waehringer Strasse 13a, 1090, Vienna, Austria

    Eva Zebedin, Xaver Koenig, Miroslav Radenkovic, Halyna Pankevych, Hannes Todt, Michael Freissmuth & Karlheinz Hilber

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  1. Eva Zebedin
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  2. Xaver Koenig
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  3. Miroslav Radenkovic
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  7. Karlheinz Hilber
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Correspondence to Karlheinz Hilber.

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Eva Zebedin, and Xaver Koenig contributed equally.

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Zebedin, E., Koenig, X., Radenkovic, M. et al. Effects of duramycin on cardiac voltage-gated ion channels. Naunyn-Schmied Arch Pharmacol 377, 87–100 (2008). https://doi.org/10.1007/s00210-007-0248-5

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  • DOI: https://doi.org/10.1007/s00210-007-0248-5

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