Milberg Peter, Ramtin Shahram, Mönnig Gerold, Osada Nani, Wasmer Kristina, Breithardt Günter, Haverkamp Wilhelm, Eckardt Lars
Hospital of the Westfälische Wilhelms-University, Department of Cardiology and Angiology and Institute for Arteriosclerosis Research, Münster, Germany.
J Cardiovasc Pharmacol. 2004 Sep;44(3):278-86. doi: 10.1097/01.fjc.0000129581.81508.78.
The mechanisms for the different proarrhythmic potential of antiarrhythmic drugs in the presence of comparable QT prolongation are not completely understood. The reasons for the lower proarrhythmic potential of amiodarone as compared with other class-III antiarrhythmic drugs such as sotalol, a fact that has been well established for years, is insufficiently known. Therefore, the aim of our study was to assess the different electrophysiologic effects of amiodarone and sotalol in a previously developed experimental model of proarrhythmia. In eight male rabbits, amiodarone (280-340 mg/d) was fed over a period of six weeks. Hearts were excised and retrogradely perfused. Up to eight simultaneous epi- and endocardial monophasic action potentials (MAP) were recorded. Results were compared with sotalol-treated (10-50-100 microM) hearts (n = 13). Amiodarone and sotalol (50 microM and 100 microM) led to a significant increase in QT interval (mean increase: amiodarone: 31 +/- 6 ms; sotalol: 41 +/- 4 ms and 61 +/- 9 ms) and MAP-duration (mean increase-MAP90: amiodarone: 20 +/- 5 ms; sotalol: 17 +/- 5 ms and 25 +/- 8 ms) (P < 0.01). In bradycardic (AV-blocked) hearts, MAP-recordings demonstrated reverse-use dependence and a significant increase in dispersion of repolarization (MAP90) in the presence of sotalol (P < 0.01), but not in amiodarone-treated hearts (10%; p = ns). Sotalol led to early afterdepolarizations (EAD) and torsade de pointes (TdP) after lowering of potassium concentration (6 of 13 hearts). In amiodarone-treated, hypokalemic hearts, no EAD or TdP occurred. Sotalol changed the MAP configuration to a triangular pattern (ratio-MAP90/50: 1.52 as compared with 1.36 at baseline) whereas amiodarone caused a rectangular pattern of MAP prolongation (ratio-MAP90/50: 1.36). In conclusion, these results show no direct correlation between the occurrence of TdP and the degree of QT prolongation. Several factors including reverse-use dependence, dispersion of repolarization, and the propensity to induce early afterdepolarizations but also differences in the action potential configuration may help to understand proarrhythmic side effects of drugs.
在QT间期延长程度相当的情况下，抗心律失常药物不同的促心律失常潜力机制尚未完全明确。与其他III类抗心律失常药物如索他洛尔相比，胺碘酮促心律失常潜力较低，这一事实多年来已得到充分证实，但其原因仍知之甚少。因此，我们研究的目的是在先前建立的促心律失常实验模型中评估胺碘酮和索他洛尔不同的电生理效应。在8只雄性兔子中，连续6周喂食胺碘酮（280 - 340 mg/d）。取出心脏并进行逆行灌注。同时记录多达8个心外膜和心内膜单相动作电位（MAP）。将结果与索他洛尔治疗组（10 - 50 - 100 microM）的心脏（n = 13）进行比较。胺碘酮和索他洛尔（50 microM和100 microM）导致QT间期显著延长（平均增加：胺碘酮：31±6 ms；索他洛尔：41±4 ms和61±9 ms）以及MAP时程延长（平均增加 - MAP90：胺碘酮：20±5 ms；索他洛尔：17±5 ms和25±8 ms）（P < 0.01）。在心动过缓（房室传导阻滞）的心脏中，MAP记录显示索他洛尔存在时具有反向使用依赖性且复极离散度（MAP90）显著增加（P < 0.01），而胺碘酮治疗的心脏中未出现（10%；p = 无显著性差异）。降低钾浓度后，索他洛尔导致早期后除极（EAD）和尖端扭转型室速（TdP）（13只心脏中有6只）。在胺碘酮治疗的低钾血症心脏中，未出现EAD或TdP。索他洛尔将MAP形态改变为三角形模式（MAP90/50比值：1.52，而基线时为1.36），而胺碘酮导致MAP延长呈矩形模式（MAP90/50比值：1.36）。总之，这些结果表明TdP的发生与QT间期延长程度之间无直接相关性。包括反向使用依赖性、复极离散度、诱发早期后除极的倾向以及动作电位形态差异等几个因素可能有助于理解药物的促心律失常副作用。
