Zebedin Eva, Koenig Xaver, Radenkovic Miroslav, Pankevych Halyna, Todt Hannes, Freissmuth Michael, Hilber Karlheinz
Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Waehringer Strasse 13a, 1090 Vienna, Austria.
Naunyn Schmiedebergs Arch Pharmacol. 2008 Mar;377(1):87-100. doi: 10.1007/s00210-007-0248-5. Epub 2008 Jan 5.
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.
两亲性肽短杆菌肽正在进行治疗囊性纤维化的临床开发。它沉积在细胞膜中并与磷脂酰乙醇胺结合。短杆菌肽可能因此改变生物物理膜特性并扰乱离子通道的功能。如果是这样，在心脏组织中，其应用存在引发心律失常的风险。事实上，在犬类毒理学测试期间的心电图中观察到室性早搏复合波。为了研究短杆菌肽的致心律失常潜力，我们通过全细胞膜片钳技术，在天然细胞中以及使用异源表达系统，研究了其对电压门控hERG钾、钠和钙通道电流的影响；1 nM至0.1 μM的短杆菌肽浴液浓度对这些电流没有任何影响。然而，浓度≥0.3 μM时，所有研究电流的幅度均降低。此外，在短杆菌肽存在下，钠电流快速失活动力学减慢。短杆菌肽浴液浓度进一步升高（≥3.3 μM）会诱导与孔形成一致的泄漏电流。短杆菌肽对离子通道功能的报道效应可能源于膜生物物理特性的变化，而非肽与离子通道蛋白的特异性相互作用。在治疗条件下（即通过吸入给药），短杆菌肽的血浆浓度低于0.5 nM。因此，吸入时，短杆菌肽具有很大的安全边际，极不可能引发心律失常。
