Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: Fast phase 3 repolarization prevents early afterdepolarizations and Torsade de Pointes
Divergent proarrhythmic potential of macrolide antibiotics despite similar QT prolongation: Fast phase 3 repolarization prevents early afterdepolarizations and Torsade de Pointes
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DOI：
10.1124/jpet.102.037911
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发表时间：
2002-10-01
影响因子：
3.5
通讯作者：
Haverkamp, W
中科院分区：
文献类型：
--
作者：
Milberg, P;Eckardt, L;Haverkamp, W
已知大环内酯类抗生素在体表心电图QT间期延长相当的情况下具有不同的促心律失常潜力。由于QT间期延长的程度已被用作心脏毒性的替代指标，我们的目的是研究不同的电生理效应的大环内酯类抗生素红霉素，克拉霉素，阿奇霉素在先前开发的实验模型的致心律失常。在37只Langendorff灌注兔心脏中，红霉素（150-300 μ M，n = 13）、克拉霉素（150-300 μ M，n = 13）和阿奇霉素（150-300 μ M，n = 11）导致QT间期和单相动作电位（MAP）时程相似的延长。在心动过缓（房室阻滞）的心脏，8个同时记录的epi和endoembryonic MAP表现出增加的复极分散在所有三种抗生素的存在下。红霉素和克拉霉素导致钾浓度降低后的早期后除极（埃兹）和尖端扭转型室性心动过速（TdP）。在阿奇霉素的存在下，没有EAD或TdP发生。红霉素和克拉霉素使MAP构型改变为三角形，而阿奇霉素引起MAP延长的矩形模式。在另外13个心脏中，在先前用300 μ M红霉素治疗并抑制红霉素引起的TdP后，给予150 μ M阿奇霉素。总之，大环内酯类抗生素导致类似的复极延长，但表现出不同的促心律失常潜力（红霉素>克拉霉素>阿奇霉素）。在阿奇霉素的存在下，EAD和TdP都不会发生。这种效应可能与动作电位延长的矩形模式有关，而红霉素和克拉霉素引起三角形动作电位延长并诱导TdP。
Macrolide antibiotics are known to have a different proarrhythmic potential in the presence of comparable QT prolongation in the surface ECG. Because the extent of QT prolongation has been used as a surrogate marker for cardiotoxicity, we aimed to study the different electrophysiological effects of the macrolide antibiotics erythromycin, clarithromycin, and azithromycin in a previously developed experimental model of proarrhythmia. In 37 Langendorff-perfused rabbit hearts, erythromycin (150-300 muM, n = 13) clarithromycin (150-300 muM, n = 13), and azithromycin (150-300 muM, n = 11) led to similar increases in QT interval and monophasic action potential (MAP) duration. In bradycardic (atrioventricular-blocked) hearts, eight simultaneously recorded epi- and endocardial MAPs demonstrated increased dispersion of repolarization in the presence of all three antibiotics. Erythromycin and clarithromycin led to early afterdepolarizations (EADs) and torsade de pointes (TdP) after lowering of potassium concentration. In the presence of azithromycin, no EAD or TdP occurred. Erythromycin and clarithromycin changed the MAP configuration to a triangular pattern, whereas azithromycin caused a rectangular pattern of MAP prolongation. In 13 additional hearts, 150 muM azithromycin was administered after previous treatment with 300 muM erythromycin and suppressed TdP provoked by erythromycin. In conclusion, macrolide antibiotics lead to similar prolongation of repolarization but show a different proarrhythmic potential (erythromycin > clarithromycin > azithromycin). In the presence of azithromycin, neither EAD nor TdP occur. This effect may be related to a rectangular pattern of action potential prolongation, whereas erythromycin and clarithromycin cause triangular action potential prolongation and induce TdP.