Inhibition of cardiac HERG potassium channels by the atypical antidepressant trazodone
Inhibition of cardiac HERG potassium channels by the atypical antidepressant trazodone
复制标题
DOI：
10.1007/s00210-004-0952-3
复制
发表时间：
2004-07
期刊：
影响因子：
--
通讯作者：
E. Zitron;Claudia Kiesecker;E. Scholz;Sonja Lück;Ramona Bloehs;S. Kathöfer;Dierk Thomas;J. Kiehn;V. Kreye;H. Katus;W. Schoels;C. Karle
中科院分区：
文献类型：
--
作者：
E. Zitron;Claudia Kiesecker;E. Scholz;Sonja Lück;Ramona Bloehs;S. Kathöfer;Dierk Thomas;J. Kiehn;V. Kreye;H. Katus;W. Schoels;C. Karle
曲唑酮是一种非典型抗抑郁药，常用于治疗情感障碍。曾多次报告与该药物相关的心律失常，并对曲唑酮的心脏安全性提出了担忧。然而，与HERG通道的相互作用作为心脏副作用的主要因素迄今尚未研究。因此，我们研究了曲唑酮对人胚肾（HEK）细胞和异种卵母细胞表达的HERG钾通道的影响。曲唑酮以剂量依赖性方式抑制HERG电流，在HEK细胞中的IC 50为2.9 μM，在异种卵母细胞中为13.2 μM。详细分析了HERG阻断的电生理特性。在HERG通道突变体Y652A和F656A中，在S6结构域中缺少芳香族残基，曲唑酮的亲和力显著降低。曲唑酮加速HERG电流的失活，而不显著影响激活。阻滞是电压依赖性的，在正膜电位下阻滞略有减少。未观察到阻滞的频率依赖性。曲唑酮对HERG通道的阻断具有状态依赖性。通道在激活和失活状态下受到影响，但在关闭状态下不受影响。总之，非典型抗抑郁药曲唑酮在体内可能相关的浓度下阻断心脏HERG通道，特别是在过量时。
Trazodone is an atypical antidepressant that is commonly used in the treatment of affective disorders. There have repeatedly been reports of cardiac arrhythmia associated with this drug and concerns have been raised regarding the cardiac safety of trazodone. However, interaction with HERG channels as a main factor of cardiac side effects has not been studied to date. Therefore, we investigated the effect of trazodone on HERG potassium channels expressed in human embryonic kidney (HEK) cells and inXenopusoocytes. Trazodone inhibited HERG currents in a dose-dependent manner with an IC50of 2.9 μM in HEK cells and 13.2 μM inXenopusoocytes. The electrophysiological properties of HERG blockade were analysed in detail. In HERG channel mutants Y652A and F656A lacking aromatic residues in the S6 domain, the affinity of trazodone was reduced profoundly. Trazodone accelerated inactivation of HERG currents without markedly affecting activation. Blockade was voltage dependent with a small reduction of block at positive membrane potentials. Frequency dependence of block was not observed. Trazodone block of HERG channels was state dependent. Channels were affected in the activated and inactivated states, but not in the closed states. In summary, the atypical antidepressant trazodone blocks cardiac HERG channels at concentrations that are probably relevant in vivo, particularly in overdosage.