基于兔心室楔形组织块模型研究3种中药单体对心肌电生理特性和心脏安全性的影响  

Determination of electrophysiological effects and cardiac safety of three Chinese herb monomers by using the isolated rabbit ventricular wedge model

作　　者：高原[1,2] 宋歌 赵文萍[4] 刘腾先[2] 严干新 唐进法 李彬[1] 曹英杰[1] 崔琳[1] 朱明军[1] GAO Yuan;SONG Ge;ZHAO Wen-ping;LIU Teng-xian;YAN Gan-xin;TANG Jin-fa;LI Bin;CAO Ying-jie;CUI Lin;ZHU Ming-jun(The First Affiliated Hospital of Henan University of Traditional Chinese Medicine,Henan Province Engineering Research Center of Safety Evaluation and Risk Management of Traditional Chinese Medicine,Zhengzhou 450000,China;Lankenau Institute for Medical Research,Pennsylvania 19096,USA;Henan Province Hospital of Traditional Chinese Medicine,Zhengzhou 450000,China;Affiliated Hospital of Heibei University,Baoding 071000,China)

机构地区：[1]河南中医药大学第一附属医院,河南省中药安全评价与风险防控工程研究中心,郑州450000 [2]美国Lankenau医学研究中心,Pennsylvania 19096 [3]河南省中医院,郑州450000 [4]河北大学附属医院,保定071000

出　　处：《中华中医药杂志》2023年第5期2304-2310,共7页China Journal of Traditional Chinese Medicine and Pharmacy

基　　金：国家自然科学基金重点项目(N o.82030120),国家自然科学基金青年科学基金项目(No.81503435);河南省重点研发与推广专项(科技攻关)(No.212102310367);河南省中管局国家中医临床研究基地科研专项(No.2018JDZX058);河南省中医药科学研究专项课题(No.2022ZY2009,No.20-21ZY2097,No.2022ZY1021,No.20-21ZY2109);横向课题(No.XZ2022013)。

摘　　要：目的:应用冠状动脉灌注兔心室楔形组织块模型观察3种常见中药单体对心肌电生理特性和心脏安全性的影响。方法:采用冠状动脉灌注兔右心室楔形组织块模型,对模型施加基础刺激周长(BCL)1 000 ms的基础刺激,稳定1 h后进行实验;实验药物组给予3种中药单体(甘草次酸、小檗碱和青藤碱)各4个给药浓度;对照组给予与溶解3种中药单体各给药浓度相同容积的二甲基亚砜(DMSO);观察对跨壁心电图QRS复合波时程、QT间期、T波峰值至终点的时程(Tp-e)的影响,以及是否引发早期后除极(EAD)和尖端扭转性室速(TdP)。结果:与对照组比较,甘草次酸在2个相对较高浓度时(10、30μmol/L)增宽QRS,且无明显的使用依赖性,同时显著缩短QT,具有INa抑制作用;小檗碱延长QT和Tp-e间期,且呈浓度依赖性,在2个相对高浓度时(10、30μmol/L)诱发心内膜EAD,表现出快速延迟整流钾电流(IKr)抑制作用;青藤碱延长QT间期,且呈浓度依赖性,在2个相对高浓度时(30、100μmol/L)轻度增宽QRS,且表明出较弱的使用依赖性,提示其在较低浓度时抑制IKr,较高浓度时抑制钠电流(INa)。结论:基于冠状动脉灌注兔心室楔形组织块模型,研究药物导致的心电图(ECG)和动作电位(AP)改变,简单有效地评估3种中药单体的浓度依赖性电生理特性和致心律失常潜在风险。Objective:To observe the effects of three common traditional Chinese medicine monomers on myocardial electrophysiological characteristics and cardiac safety by using a coronary artery perfusion rabbit ventricular wedge tissue block model.Methods:Using a coronary artery perfusion rabbit right ventricular wedge tissue block model,a basal stimulus with a basal stimulus circumference(BCL)of 1000 ms was applied to the model and the experiment was performed after 1 h of stabilization;The experimental drug group was given four dosing concentrations of each of the three herbal monomers(glycyrrhizic acid,berberine and cyanophylline);The control group was given dimethyl sulfoxide(DMSO)in the same volume as the dissolved 3 herbal monomers of each administration concentration;Observe the influence on the time course of QRS complex wave,QT interval,T wave peak to terminal time course(Tp-e)of transmural ECG,and whether it induces early afterdepolarization(EAD)and torsades de pointes(TdP).Results:Compared with the control group,glycyrrhetinic acid broadened QRS at 2 relatively high concentrations(10,30µmol/L)without significant use-dependence,while significantly shortening QT and having an INa inhibitory effect;Berberine prolonged QT and Tp-e intervals in a concentration-dependent manner,induced endocardial EAD at two relatively high concentrations(10,30µmol/L),and exhibited rapid delayed rectifier potassium current(IKr)inhibition;Cyanidin prolongs the QT interval in a concentration-dependent manner,mildly widens the QRS at two relatively high concentrations(30,100µmol/L),and showed a weaker use-dependence,suggesting that it inhibits IKr at lower concentrations and sodium current(INa)at higher concentrations.Conclusion:Based on a coronary artery perfusion rabbit ventricular wedge tissue block model,the drug-induced electrocardiogram(ECG)and action potential(AP)alterations are studied to simply and effectively assess the concentration-dependent electrophysiological properties and arrhythmogenic potential risks of the three he

关 键 词：中药单体 兔心室楔形组织块模型 QT间期 QRS TP-E间期 使用依赖性 早期后除极 离子 

分 类 号：R285[医药卫生—中药学]