Effects of duramycin on cardiac voltage-gated ion channels.
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.
Zebedin
Eva
E
Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Waehringer Strasse 13a, 1090 Vienna, Austria.
Koenig
Xaver
X
Radenkovic
Miroslav
M
Pankevych
Halyna
H
Todt
Hannes
H
Freissmuth
Michael
M
Hilber
Karlheinz
K
D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D001430:Bacteriocins / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D015220:Calcium Channels / Q000378:metabolism*; D045744:Cell Line, Tumor; D003550:Cystic Fibrosis / Q000188:drug therapy; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use; D015222:Sodium Channels / Q000378:metabolism*; D014162:Transfection
D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D015220:Calcium Channels; D051638:Ether-A-Go-Go Potassium Channels; D010455:Peptides; D015222:Sodium Channels; C040522:duramycin