Hypaconitine-induced QT prolongation mediated through inhibition of KCNH2 (hERG) potassium channels in conscious dogs
Hypaconitine-induced QT prolongation mediated through inhibition of KCNH2 (hERG) potassium channels in conscious dogs
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DOI：
10.1016/j.jep.2015.03.023
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发表时间：
2015-05-26
影响因子：
5.4
通讯作者：
Huang, Lizhen
中科院分区：
文献类型：
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作者：
Xie, Shuilin;Jia, Ying;Huang, Lizhen
民族药理相关性：次乌头碱是乌头属中草药中的主要乌头生物碱之一。这些草药被广泛用于治疗心功能不全和心律失常。然而，乌头碱的毒性和药理活性都是已知的，特别是心脏毒性，包括QT延长，这种毒性的机制尚不清楚。材料和方法：本研究通过给清醒的Beagle犬口服次乌头碱，遥测记录心电图。进行药代动力学研究(6h)以评价QT延长与暴露水平的关系。以稳定表达KCNH2(Herg)基因的HEK293细胞为研究对象，采用手动膜片钳技术检测次乌头碱对KCNH2通道的影响。结果：在清醒犬中，各剂量次乌头碱均可使QTcV(根据Van de Water公式校正的QT间期)延长23%(67ms)以上，且呈剂量依赖性。QTcV最大延长出现在给药后2 h。最大延长百分率与次乌头碱血药浓度呈显著正相关(R2=0.789)。在HEK293细胞的体外实验中，次乌头碱以浓度依赖的方式抑制KCNH_2电流，IC50为8.1nM。结论：次乌头碱抑制KCNH_2钾通道，这种作用可能是清醒犬QT延长的分子机制。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
Ethnopharmacological relevance: Hypaconitine is one of the main aconitum alkaloids in traditional Chinese medicines prepared with herbs from the genus Acotinum. These herbs are widely used for the treatment of cardiac insufficiency and arrhythmias. However, Acotinum alkaloids are known for their toxicity as well as their pharmacological activity, especially cardiotoxicity including QT prolongation, and the mechanism of this toxicity is not clear.Material and methods: In this study, hypaconitine was administered orally to conscious Beagle dogs, and electrocardiograms were recorded by telemetry. Pharmacokinetic studies (6 h) were conducted to evaluate the relationship between QT prolongation and exposure level. HEK293 cells stably transfected with KCNH2 (hERG) cDNA were used to examine the effects of hypaconitine on the KCNH2 channel by using the manual patch clamp technique.Results: In the conscious dogs, all doses of hypaconitine induced QTcV (QT interval corrected according to the Van de Water formula) prolongation by more than 23% (67 ms) of control in a dose-dependent manner. The maximum QTcV prolongation was observed at 2 h after dosing. Maximum prolongation percentages were plotted against plasma concentrations of hypaconitine and showed a strong correlation (R-2=0.789). In the in vitro study in HEK293 cells, hypaconitine inhibited the KCNH2 currents in a concentration-dependent manner with an IC50 of 8.1 nM.Conclusion: These data suggest that hypaconitine inhibits KCNH2 potassium channels and this effect might be the molecular mechanism underlying QT prolongation in conscious dogs. (C) 2015 Elsevier Ireland Ltd. All rights reserved.