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Zebedin E, Koenig X, Radenkovic M, et al. Effects of duramycin on cardiac voltage-gated ion channels. Naunyn Schmiedebergs Arch Pharmacol. 2008;377(1):87-100doi: 10.1007/s00210-007-0248-5.
Zebedin, E., Koenig, X., Radenkovic, M., Pankevych, H., Todt, H., Freissmuth, M., & Hilber, K. (2008). Effects of duramycin on cardiac voltage-gated ion channels. Naunyn-Schmiedeberg's archives of pharmacology, 377(1), 87-100. https://doi.org/10.1007/s00210-007-0248-5
Zebedin, Eva, et al. "Effects of duramycin on cardiac voltage-gated ion channels." Naunyn-Schmiedeberg's archives of pharmacology vol. 377,1 (2008): 87-100. doi: https://doi.org/10.1007/s00210-007-0248-5
Zebedin E, Koenig X, Radenkovic M, Pankevych H, Todt H, Freissmuth M, Hilber K. Effects of duramycin on cardiac voltage-gated ion channels. Naunyn Schmiedebergs Arch Pharmacol. 2008 Mar;377(1):87-100. doi: 10.1007/s00210-007-0248-5. Epub 2008 Jan 05. PMID: 18176799.
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Naunyn Schmiedebergs Arch Pharmacol. 2008 Mar;377(1):87-100. doi: 10.1007/s00210-007-0248-5. Epub 2008 Jan 05.

Effects of duramycin on cardiac voltage-gated ion channels.

Naunyn-Schmiedeberg's archives of pharmacology

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

Affiliations

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

PMID: 18176799 DOI: 10.1007/s00210-007-0248-5

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 microM did not generate any effects on these currents. Concentrations >or=0.3 microM, 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 (>or=3.3 microM) 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.

References

  1. Circ Res. 1992 Nov;71(5):1231-41 - PubMed
  2. Annu Rev Physiol. 1979;41:413-24 - PubMed
  3. Trends Pharmacol Sci. 2001 May;22(5):240-6 - PubMed
  4. J Mol Cell Cardiol. 1991 Feb;23 Suppl 1:11-22 - PubMed
  5. Chest. 2004 Jan;125(1):143-9 - PubMed
  6. Am J Physiol. 1990 Sep;259(3 Pt 1):C450-4 - PubMed
  7. J Pharmacol Exp Ther. 1991 Dec;259(3):1050-8 - PubMed
  8. Br J Pharmacol. 2007 Aug;151(8):1368-76 - PubMed
  9. J Physiol. 1994 Sep 1;479 ( Pt 2):265-79 - PubMed
  10. J Mol Cell Cardiol. 1996 Apr;28(4):743-53 - PubMed
  11. Biochem Pharmacol. 1991 Oct 24;42(10 ):2027-35 - PubMed
  12. Eur J Biochem. 1993 Sep 1;216(2):419-28 - PubMed
  13. Circ Res. 1983 May;52(5):543-56 - PubMed
  14. Arch Biochem Biophys. 1990 Aug 1;280(2):405-11 - PubMed
  15. Biochim Biophys Acta. 1992 Jun 11;1107(1):179-85 - PubMed
  16. Cardiovasc Drugs Ther. 1993 Aug;7 Suppl 3:575-84 - PubMed
  17. Pflugers Arch. 1989 Oct;415(1):124-6 - PubMed
  18. Am J Physiol. 1992 Aug;263(2 Pt 2):H410-7 - PubMed
  19. Cell Biochem Biophys. 2003;38(2):161-90 - PubMed
  20. J Pharmacol Toxicol Methods. 2004 Sep-Oct;50(2):93-101 - PubMed
  21. N Engl J Med. 1988 Aug 4;319(5):257-62 - PubMed
  22. Xenobiotica. 2003 Feb;33(2):197-210 - PubMed
  23. Curr Opin Cardiol. 2007 Jan;22(1):39-43 - PubMed
  24. Membr Biochem. 1993 Apr-Jun;10 (2):107-18 - PubMed
  25. Am J Cardiol. 1987 Apr 30;59(11):10E-18E - PubMed
  26. Biophys J. 2007 Sep 1;93(5):1608-19 - PubMed
  27. Chest. 2007 May;131(5):1461-6 - PubMed
  28. Am J Physiol Cell Physiol. 2004 Aug;287(2):C270-80 - PubMed
  29. Brain Res. 1996 Jan 15;706(2):343-6 - PubMed
  30. Pflugers Arch. 1992 Jan;420(1):94-100 - PubMed
  31. Naunyn Schmiedebergs Arch Pharmacol. 2000 Dec;362(6):453-79 - PubMed
  32. Eur Heart J. 1989 Sep;10 Suppl E:73-80 - PubMed
  33. Biochemistry. 1985 Aug 13;24(17):4645-50 - PubMed
  34. J Mol Cell Cardiol. 1991 Feb;23 Suppl 1:23-30 - PubMed
  35. Circ Res. 1981 Jul;49(1):1-15 - PubMed
  36. Ann Intern Med. 1990 Nov 1;113(9):671-6 - PubMed
  37. Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H439-50 - PubMed
  38. Lancet. 2003 Feb 22;361(9358):681-9 - PubMed
  39. Am J Cardiol. 1985 Jan 25;55(3):89B-101B - PubMed
  40. J Am Coll Cardiol. 1987 Jan;9(1):163-8 - PubMed

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