褪黑激素抑制心室肌细胞晚钠电流增大所诱发的心律失常  

Melatonin inhibits arrhythmias induced by increased late sodium currents in ventricular myocytes

作　　者：文杰 刘汗峰 杨岩岩 张泽夫 罗岸涛[1] 曹珍珍 马季骅[1,2] WEN Jie;LIU Han-feng;YANG Yan-yan;ZHANG Ze-fu;LUO An-tao;CAO Zhen-zhen;MA Ji-hua(Medical College of Wuhan University of Science and Technology,Wuhan 430070,China;College of Life Science and Health,Wuhan University of Science and Technology,Wuhan 430070,China)

机构地区：[1]武汉科技大学医学院,湖北武汉430070 [2]武汉科技大学生命科学与健康学院,湖北武汉430070

出　　处：《药学学报》2024年第1期143-151,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81670302)。

摘　　要：褪黑激素(melatonin,Mel)已有研究表明其具有心脏保护作用,但对离子通道作用尚不清楚。本实验探究了Mel对小鼠心室肌细胞晚钠电流(late-sodium current,I_(Na.L))的抑制作用、在器官水平上的抗心律失常作用及其机制。采用膜片钳技术全细胞模式记录离子电流和动作电位(action potential,AP),利用多通道采集分析系统同步记录小鼠心电图(electrocardiogram,ECG)和单相动作电位(monophasic action potential,MAP)。结果显示,Mel抑制瞬时钠电流(transient-sodium current,I_(Na.T))和特异性I_(Na.L)开放剂2 nmol·L^(-1)海葵毒素II(anemone toxins II,ATX II)诱导增大的I_(Na.L),其IC_(50)值分别为686.615和7.37μmol·L^(-1),且Mel不影响L型钙电流(L-type calcium current,I_(Ca.L))、瞬时外向钾电流(transient outward current,I_(to))和AP。此外,16μmol·L^(-1)Mel可缩短ATX II延长的动作电位时程(action potential duration,APD),并消除了由ATX II诱导的早发后除极(early afterdepolarizations,EADs)。在Langendorff灌流的小鼠心脏上,16μmol·L^(-1)Mel显著降低了室速(ventricular tachycardia,VT)和室颤(ventricular fibrillation,VF)的发生率。综上所述,Mel主要通过阻断I_(Na.L)发挥抗心律失常作用,为Mel的临床新应用提供了重要的理论基础。本研究动物福利和实验过程均遵循武汉科技大学实验动物伦理委员会的规定(批准号:2023130)。Melatonin(Mel)has been shown to have cardioprotective effects,but its action on ion channels is unclear.In this experiment,we investigated the inhibitory effect of Mel on late sodium currents(I_(Na.L))in mouse ventricular myocytes and the anti-arrhythmic effect at the organ level as well as its mechanism.The whole-cell patch clamp technique was applied to record the ionic currents and action potential(AP)in mouse ventricular myocytes while the electrocardiogram(ECG)and monophasic action potential(MAP)were recorded simultaneously in mouse hearts using a multichannel acquisition and analysis system.The results demonstrated that the half maximal inhibitory concentration(IC_(50))values of Mel on transient sodium current(I_(Na.T))and specific I_(Na.L)opener 2 nmol·L^(-1)sea anemone toxins II(ATX II)increased I_(Na.L)were 686.615 and 7.37μmol·L^(-1),respectively.Mel did not affect L-type calcium current(I_(Ca.L)),transient outward current(I_(to)),and AP.In addition,16μmol·L^(-1)Mel shortened ATX II-prolonged action potential duration(APD),suppressed ATX II-induced early afterdepolarizations(EADs),and significantly reduced the incidence of ventricular tachycardia(VT)and ventricular fibrillation(VF)in Langendorff-perfused mouse hearts.In conclusion,Mel exerted its antiarrhythmic effects principally by blocking I_(Na.L),thus providing a significant theoretical basis for new clinical applications of Mel.Animal welfare and experimental process are in accordance with the regulations of the Experimental Animal Ethics Committee of Wuhan University of Science and Technology(2023130).

关 键 词：褪黑激素 晚钠电流 动作电位 心律失常 膜片钳 

分 类 号：R966[医药卫生—药理学]