Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, are IKr blockers with proarrhythmic effects in vitro and in vivo
Dehydroevodiamine and hortiamine, alkaloids from the traditional Chinese herbal drug Evodia rutaecarpa, are IKr blockers with proarrhythmic effects in vitro and in vivo
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DOI：
10.1016/j.phrs.2018.02.024
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发表时间：
2018-05-01
影响因子：
9.3
通讯作者：
Hering, Steffen
中科院分区：
文献类型：
--
作者：
Baburin, Igor;Varkevisser, Rosanne;Hering, Steffen
吴茱萸是一种应用广泛的中药。发现吴茱萸提取物抑制hERG通道。本研究的目的是鉴定吴茱萸提取物中的hERG抑制剂，并研究其潜在的预防作用。通过高效液相色谱-微量分离和随后的人胚肾细胞膜片钳研究，鉴定了吴茱萸提取物中的脱氢吴茱萸碱（DHE）和hortiamine作为I-Kr（快速延迟整流电流）抑制剂。DHE和hortiamine抑制IKr，IC（50）分别为253.2 +/- 26.3 nM和144.8 +/- 35.1 nM。在狗心室肌细胞中，DHE剂量依赖性地延长动作电位时程（APD）。在0.01、0.1、1和10 μ M DHE后，分别有14、67、100和67%的细胞出现早期后去极化（埃兹）。在8只麻醉家兔和8只慢性房室传导阻滞（cAVB）犬上观察了DHE的预防作用。在家兔中，DHE使QT间期显著延长12 +/- 10%（0.05 mg/kg/5 min）和60 +/- 26%（0.5 mg/kg/5 min），并在2只家兔中诱导尖端扭转型心律失常（TdP，0.5 mg/kg/5 min）。在cAVB犬中，0.33mg/kg/5 min DHE使QT间期延长48.10%（P < 0.05*），2/4的犬出现TdP。较高剂量未诱导TdP。在人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）中，吴茱萸、DHE和hortiamine的甲醇提取物剂量依赖性地延长APD。在3 μ M DHE和hortiamine诱导埃兹。hERG抑制在亚微摩尔浓度，APD延长和埃兹在hiPSC-CM和剂量依赖性的促肾上腺皮质激素作用的DHE在微摩尔血浆浓度在cAVB狗应该增加认识广泛使用的吴茱萸提取物的促肾上腺皮质激素作用。(C)2018作者爱思唯尔有限公司出版
Evodiae fructus is a widely used herbal drug in traditional Chinese medicine. Evodia extract was found to inhibit hERG channels. The aim of the current study was to identify hERG inhibitors in Evodia extract and to investigate their potential proarrhythmic effects. Dehydroevodiamine (DHE) and hortiamine were identified as I-Kr (rapid delayed rectifier current) inhibitors in Evodia extract by HPLC-microfractionation and subsequent patch clamp studies on human embryonic kidney cells. DHE and hortiamine inhibited IKr with IC(50)s of 253.2 +/- 26.3 nM and 144.8 +/- 35.1 nM, respectively. In dog ventricular cardiomyocytes, DHE dose-dependently prolonged the action potential duration (APD). Early afterdepolarizations (EADs) were seen in 14, 67, 100, and 67% of cells after 0.01, 0.1, 1 and 10 mu M DHE, respectively. The proarrhythmic potential of DHE was evaluated in 8 anesthetized rabbits and in 8 chronic atrioventricular block (cAVB) dogs. In rabbits, DHE increased the QT interval significantly by 12 +/- 10% (0.05 mg/kg/5 min) and 60 +/- 26% (0.5 mg/kg/5 min), and induced Torsade de Pointes arrhythmias (TdP, 0.5 mg/kg/5 min) in 2 rabbits. In cAVB dogs, 0.33 mg/kg/5 min DHE increased QT duration by 48 10% (P < 0.05*) and induced TdP in 2/4 dogs. A higher dose did not induce TdP. In human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), methanolic extracts of Evodia, DHE and hortiamine dose-dependently prolonged APD. At 3 mu M DHE and hortiamine induced EADs.hERG inhibition at submicromolar concentrations, APD prolongation and EADs in hiPSC-CMs and dose dependent proarrhythmic effects of DHE at micromolar plasma concentrations in cAVB dogs should increase awareness regarding proarrhythmic effects of widely used Evodia extracts. (C) 2018 The Authors. Published by Elsevier Ltd.