Atypical tetracyclic antidepressant maprotiline is an antagonist at cardiac hERG potassium channels
Atypical tetracyclic antidepressant maprotiline is an antagonist at cardiac hERG potassium channels
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DOI：
10.1007/s00210-006-0068-z
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发表时间：
2006-06-01
影响因子：
3.6
通讯作者：
Karle, Christoph A.
中科院分区：
文献类型：
--
作者：
Kiesecker, Claudia;Alter, Markus;Karle, Christoph A.
马普替林是一种具有非典型四环结构的抗抑郁化合物，由于其有利的副作用特征而广泛用于老年患者。然而，也有报道与马普替林和其电生理特性的体外研究相关的心律失常。因此，我们表征了马普替林对心脏hERG通道的影响。hERG通道在HEK细胞和爪蟾卵母细胞表达系统中表达。使用全细胞膜片钳和双微电极电压钳测量电流。马普替林抑制hERG电流，在HEK细胞中的IC 50为8.2 μ mol/l，在爪蟾卵母细胞中的IC 50为29.2 μ mol/l。起效相当缓慢，需要几分钟。未观察到效应洗脱。马普替林在开放和失活状态下阻断hERG通道，但在关闭状态下不阻断。在突变型hERG通道Y 652 A和F656 A中，该效应显著减弱（hERG-F656 A）或完全消除（hERG-Y 652 A）。马普替林不影响hERG电流激活和失活的电压依赖性。在正电位下，hERG失活加速。马普替林对hERG电流的影响具有电压依赖性，在更正的电位下显著降低。马普替林对hERG的阻滞作用不具有频率依赖性。马普替林是心脏hERG钾通道的拮抗剂，其优选接近推定的孔结合位点Y 652/17656。尽管马普替林与hERG通道的亲和力较低，但应适当监测其在有获得性长QT综合征风险因素的患者中的使用。
Maprotiline is an antidepressant compound with an atypical tetracyclic structure that is widely used in elderly patients due to its favourable side-effect profile. However, there have been reports of proarrhythmia associated with maprotiline and in vitro studies of its electrophysiological properties have been lacking. Therefore, we characterised the effects of maprotiline on cardiac hERG channels. hERG channels were expressed in HEK cells and in the Xenopus oocyte expression system. Currents were measured using a whole-cell patch clamp and a two-microelectrode voltage-clamp. Maprotiline inhibited hERG currents with an IC50 of 8.2 mu mol/l in HEK cells and 29.2 mu mol/l in Xenopus oocytes. Onset of the effect was rather slow and took several minutes. No wash-out of effect was observed. Maprotiline blocked hERG channels in the open and inactivated states, but not in the closed states. In mutant hERG channels Y652A and F656A, the effect was markedly attenuated (hERG-F656A) or completely abolished (hERG-Y652A). Voltage dependence of hERG current activation and inactivation was not affected by maprotiline. hERG inactivation was accelerated at positive potentials. The effect of maprotiline on hERG currents was voltage-dependent with a marked reduction at a more positive potential. hERG blockade by maprotiline was not frequency-dependent. Maprotiline is an antagonist of cardiac hERG potassium channels that preferably accesses the putative pore binding site Y652/17656. Although the affinity of,maprotiline to hERG channels is low, its use in patients with risk factors for acquired long QT syndrome should be monitored appropriately.