中国药物警戒 ›› 2025, Vol. 22 ›› Issue (7): 763-770.
DOI: 10.19803/j.1672-8629.20250140

• 基础与临床研究 • 上一篇    下一篇

次乌头碱对hERG通道的调控及其心脏毒性效应

邓宝怡1, 李彦凝1, 周柳1,2, 张国壮1, 曹春雨1, 李春1, 赵春晖1, 杨依霏1, 刘婷1#, 张海静1,*   

  1. 1中国中医科学院中药研究所中药安全评价中心,北京 100029;
    2天津中医药大学中药学院,天津 301617
  • 收稿日期:2025-03-07 出版日期:2025-07-15 发布日期:2025-07-17
  • 通讯作者: *张海静,女,博士,副研究员,中药药理与毒理。E-mail: hjzhang@icmm.ac.cn #为共同通信作者。
  • 作者简介:邓宝怡,女,在读硕士,中药药理与毒理。
  • 基金资助:
    国家重点研发计划（2023YFC3504000）; 中国中医科学院基本科研业务费（ZZ15-YQ-037）

Regulation of hERG Channels by Hypaconitine and Its Cardiotoxicity

DENG Baoyi1, LI Yanning1, ZHOU Liu1,2, ZHANG Guozhuang1, CAO Chunyu1, LI Chun1, ZHAO Chunhui1, YANG Yifei1, LIU Ting1#, ZHANG Haijing1,*   

  1. 1The Center for Safety Evaluation of Chinese Medicines, Institute of Chinese Material Medica, China Academy of Chinese Medical Sciences, Beijing 100029, China;
    2School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
  • Received:2025-03-07 Online:2025-07-15 Published:2025-07-17

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摘要： 目的 探讨次乌头碱对心脏传导功能及hERG通道的影响,揭示其在心脏毒性中的潜在机制。方法 采用Lange-ndorff离体心脏灌流技术结合电标测技术,检测离体心脏传导功能的变化;采用全细胞膜片钳技术,检测次乌头碱对hERG通道电流的影响;利用蛋白质免疫印迹实验测定蛋白表达。结果 电标测实验表明,次乌头碱存在剂量依赖性心脏毒性。浓度超25 nmol·L-1时,显著扰乱心脏传导功能,出现传导方向改变、心率加快、传导时间延长及传导速度下降;浓度达100~150 nmol·L-1时,可诱发心室颤动。此外,25 nmol·L-1次乌头碱灌流15 min后,可致QTc间期延长。膜片钳实验结果显示,次乌头碱对hERG通道的半数抑制浓度（IC50）为34.34 μmol·L-1。蛋白质免疫印迹实验进一步发现,200 μmol·L-1次乌头碱能显著降低成熟hERG蛋白（相对分子质量155 000）的表达水平,同时抑制PKA的磷酸化水平。结论 次乌头碱对hERG通道的作用并非其引发豚鼠心脏传导功能紊乱的核心因素。

关键词: 次乌头碱, 心脏标测, hERG通道, hERG蛋白表达, 蛋白激酶A（PKA）, 豚鼠

Abstract: Objective To investigate the effects of hypaconitine on cardiac conduction function and hERG channels, and to elucidate the potential mechanisms underlying cardiotoxicity. Methods Langendorff isolated heart perfusion combined with electrical mapping technology was used to assess changes in cardiac conduction function. Whole-cell patch-clamp techniques were employed to evaluate the effects of hypaconitine on hERG channel currents in hERG-HEK293 cells. Western blot analysis was performed to examine the expression levels of the proteins. Results Electrical mapping experiments revealed that hypaconitine exhibited significant dose-dependent cardiotoxicity. Concentrations above 25 nmol·L-1 disrupted cardiac conduction function, characterized by altered conduction direction, increased heart rate, prolonged conduction time, and reduced conduction velocity. At concentrations of 100 to 150 nmol·L-1,ventricular fibrillation could be induced. Moreover, a 15-min perfusion with 25 nmol·L-1 hypaconitine prolonged the QTc interval. Patch-clamp experiments showed that the half-maximal inhibitory concentration (IC50) of hypaconitine on hERG channels was 34.34 μmol·L-1. Western blot analysis demonstrated that 200 μmol·L-1 hypaconitine significantly decreased the expressions of mature hERG protein (relative molecular mass: 155 000) and inhibited the phosphorylation of PKA. Conclusion The effect of hypaconitine on hERG channels is not the leading contributor to cardiac conduction dysfunction in guinea pigs.

Key words: Hypaconitine, Cardiac Mapping, hERG Channel, hERG Protein Expression, Protein Kinase A (PKA), Guinea Pig

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