Electrophysiological and Proarrhythmic Effects of Hydroxychloroquine Challenge in Guinea-Pig Hearts,ACS Pharmacology & Translational Science

当前位置： X-MOL 学术 › ACS Pharmacol. Transl. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Electrophysiological and Proarrhythmic Effects of Hydroxychloroquine Challenge in Guinea-Pig Hearts
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-08-30 , DOI: 10.1021/acsptsci.1c00166
Gongxin Wang ₁ , Chieh-Ju Lu ₁ , Andrew W Trafford ₂ , Xiaohui Tian ₃ , Hannali M Flores ₄ , Piotr Maj ₅ , Kevin Zhang ₆ , Yanhong Niu ₇ , Luxi Wang ₁ , Yimei Du ₈ , Xinying Ji ₃ , Yanfang Xu ₉ , Lin Wu ₁₀ , Dan Li ₁₁ , Neil Herring ₁₁ , David Paterson ₁₁ , Christopher L-H Huang _{12,

13} , Henggui Zhang _{4,

13,

14} , Ming Lei _{5,

13} , Guoliang Hao _{1,

11}

Affiliation

Henan SCOPE Research Institute of Electrophysiology Co. Ltd., Kaifeng 475000, China.
Unit of Cardiac Physiology, Institute of Cardiovascular Sciences, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester M13 9PL, U.K.
Department of Pharmacy, Huaihe Hospital and College of Medicine, Henan University, Kaifeng 475000, China.
Biological Physics Group, Department of Physics and Astronomy, The University of Manchester, Manchester M13 9PL, U.K.
Department of Pharmacology, University of Oxford, Oxford OX1 2JD, U.K.
School of Medicine, Imperial College of London, London SW7 2AZ, U.K.
Fuwai Central China Cardiovascular Hospital, Zhengzhou 450003, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Department of Pharmacology, Hebei Medical University, Shijiazhuang City 050017, China.
Department of Cardiology, Peking University First Hospital, Beijing 100034, China.
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 2JD, U.K.
Physiological Laboratory and Department of Biochemistry, University of Cambridge, Cambridge CB2 3EG, U.K.
Key Laboratory of Medical Electrophysiology of the Ministry of Education and Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, China.
Peng Cheng Laboratory, Shenzhen 518066, China.

Hydroxychloroquine (HCQ), clinically established in antimalarial and autoimmune therapy, recently raised cardiac arrhythmogenic concerns when used alone or with azithromycin (HCQ+AZM) in Covid-19. We report complementary, experimental, studies of its electrophysiological effects. In patch clamped HEK293 cells expressing human cardiac ion channels, HCQ inhibited I_Kr and I_K1 at a therapeutic concentrations (IC₅₀s: 10 ± 0.6 and 34 ± 5.0 μM). I_Na and I_CaL showed higher IC₅₀s; I_to and I_Ks were unaffected. AZM slightly inhibited I_Na, I_CaL, I_Ks, and I_Kr, sparing I_K1 and I_to. (HCQ+AZM) inhibited I_Kr and I_K1 (IC₅₀s: 7.7 ± 0.8 and 30.4 ± 3.0 μM), sparing I_Na, I_CaL, and I_to. Molecular induced-fit docking modeling confirmed potential HCQ-hERG but weak AZM-hERG binding. Effects of μM-HCQ were studied in isolated perfused guinea-pig hearts by multielectrode, optical RH237 voltage, and Rhod-2 mapping. These revealed reversibly reduced left atrial and ventricular action potential (AP) conduction velocities increasing their heterogeneities, increased AP durations (APDs), and increased durations and dispersions of intracellular [Ca²⁺] transients, respectively. Hearts also became bradycardic with increased electrocardiographic PR and QRS durations. The (HCQ+AZM) combination accentuated these effects. Contrastingly, (HCQ+AZM) and not HCQ alone disrupted AP propagation, inducing alternans and torsadogenic-like episodes on voltage mapping during forced pacing. O’Hara-Rudy modeling showed that the observed I_Kr and I_K1 effects explained the APD alterations and the consequently prolonged Ca²⁺ transients. The latter might then downregulate I_Na, reducing AP conduction velocity through recently reported I_Na downregulation by cytosolic [Ca²⁺] in a novel scheme for drug action. The findings may thus prompt future investigations of HCQ’s cardiac safety under particular, chronic and acute, clinical situations.

中文翻译：

羟氯喹挑战对豚鼠心脏的电生理和致心律失常作用

羟氯喹 (HCQ) 已在临床上用于抗疟疾和自身免疫治疗，但最近在 Covid-19 中单独使用或与阿奇霉素 (HCQ+AZM) 一起使用时，引起了心律失常的担忧。我们报告了对其电生理效应的补充性实验研究。在表达人心脏离子通道的膜片钳 HEK293 细胞中，HCQ以治疗浓度抑制 I _Kr和 I _{K1 （IC}₅₀ s：10 ± 0.6 和 34 ± 5.0 μM）。I _Na和 I _CaL显示出更高的 IC ₅₀ s；I _to和 I _Ks不受影响。AZM 轻微抑制 I _Na、I _CaL、 I _Ks和 I _Kr，但不影响 I _K1和 I _to。(HCQ+AZM) 抑制 I _Kr和 I _K1 (IC ₅₀ s: 7.7 ± 0.8 和 30.4 ± 3.0 μM)，保留 I _Na、 I _CaL和 I _to。分子诱导拟合对接模型证实了 HCQ-hERG 的潜在结合，但 AZM-hERG 的结合较弱。通过多电极、光学 RH237 电压和 Rhod-2 绘图研究了 μM-HCQ 对离体灌注豚鼠心脏的影响。^{这些结果分别揭示了左心房和心室动作电位 (AP) 传导速度可逆性降低，增加了它们的异质性、AP 持续时间 (APD) 增加以及细胞内 [Ca 2+} ] 瞬变的持续时间和离散度增加。随着心电图 PR 和 QRS 持续时间的增加，心脏也变得心动过缓。(HCQ+AZM) 组合增强了这些效果。相比之下，(HCQ+AZM)而不是单独的HCQ会扰乱AP传播，在强制起搏期间在电压映射上诱导交替和类似扭转的发作。O'Hara-Rudy 模型表明，观察到的 I _Kr和 I _K1效应解释了 APD 变化以及因此延长的 Ca ²⁺瞬变。后者可能会下调 I _Na，通过最近报道的一种新的药物作用方案中胞质 [Ca ^{2+ ] 下调 I}_{Na来降低 AP 传导速度。}因此，这些发现可能会促使未来在特定的慢性和急性临床情况下对 HCQ 的心脏安全性进行研究。

更新日期：2021-10-08

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文