Electrophysiologic characterization of the antipsychotic drug sertindole in a rabbit heart model of torsade de pointes: Low torsadogenic potential despite QT prolongation
Electrophysiologic characterization of the antipsychotic drug sertindole in a rabbit heart model of torsade de pointes: Low torsadogenic potential despite QT prolongation
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DOI：
10.1124/jpet.300.1.64
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发表时间：
2002-01-01
影响因子：
3.5
通讯作者：
Haverkamp, W
中科院分区：
文献类型：
--
作者：
Eckardt, L;Breithardt, G;Haverkamp, W
人们越来越担心，延长 QT 间期的抗精神病药物几乎总是会增加患者发生危及生命的尖端扭转型室性心律失常 (VT) 的风险。因此，我们试图比较精神药物舍吲哚的电生理效应，舍吲哚通过抑制延迟整流钾电流（/（Kr））的快速分量来延长心脏复极，但与抗心律失常药物d/-索他洛尔相比，具有较低的扭转致伤潜力。在 18 只 Langendorff 灌注的兔心脏中，索他洛尔（10 μM，n = 8）和舍吲哚（0.5、1.0 和 1.5 μM；n = 10）导致显着且可比较的 QT 延长。在索他洛尔存在的情况下，将钾浓度降低至 1.5 mM 后，房室结阻滞心脏中可重复发生尖端扭转型室速。高剂量舍吲哚 (1.5 μM) 仅在 QRS 延长的情况下引起单形性 VT (n = 4) 和非持续多形性 VT (n = 2)。多个同时发生的心外膜和心内膜单相动作电位以及容积传导心电图显示，在存在 d/-索他洛尔的情况下，T/U 波变宽、早期后除极以及复极离散度增加。与索他洛尔相反，在存在舍吲哚的情况下，QT 和单相动作电位延长与周期长度无关。舍吲哚对跨壁或室间复极离散度没有显着影响。没有发生早期后除极。尽管 QT 延长相当，但舍吲哚并未表现出其他 //(Kr) 阻滞剂（如 d/-索他洛尔）典型的致心律失常特征。舍吲哚和通道之间不同的相互作用模式和/或舍吲哚的额外药理作用，例如其抑制I(Na)的能力和/或其阻断α(1)-受体的能力，可能发挥了作用。
There is growing concern that antipsychotic drugs that prolong the QT interval almost always increase the risk for patients to develop life-threatening ventricular tachyarrhythmias (VTs) of the torsade de pointes type. We therefore sought to compare the electrophysiologic effects of the psychotropic agent sertindole, which prolongs cardiac repolarization by inhibiting the rapid component of the delayed rectifier potassium current (/(Kr)) but has a low torsadogenic potential to the antiarrhythmic agent d/-sotalol. In 18 Langendorff-perfused rabbit hearts, sotalol (10 muM, n = 8) and sertindole (0.5, 1.0, and 1.5 muM; n = 10) led to significant and comparable QT prolongation. In the presence of sotalol, torsade de pointes reproducibly occurred in atrioventricular node-blocked hearts after lowering the potassium concentration to 1.5 mM. High doses of sertindole (1.5 muM) only caused monomorphic VT (n = 4) and nonsustained polymorphic VT (n = 2) in the presence of QRS prolongation. Multiple simultaneous epi- and endocardial monophasic action potentials and a volume-conducted ECG demonstrated widening of the T/U wave, early afterdepolarizations, and increased dispersion of repolarization in the presence of d/-sotalol. In contrast to sotalol, QT and monophasic action potential prolongation were cycle length-independent in the presence of sertindole. Sertindole had no significant effect on transmural or interventricular dispersion of repolarization. Early afterdepolarizations did not occur. Despite comparable QT prolongation, sertindole did not display the proarrhythmic profile typical of other blockers of //(Kr) such as d/-sotalol. It is likely that a different mode of interaction between sertindole and the channel and/or additional pharmacological effects of sertindole, e.g., its ability to inhibit /(Na) and/or its ability to block alpha(1)-receptors, play a role.