体内外实验研究发现速效救心丸通过抑制L型钙通道CaV1.2电流终止心室颤动

QI Jian-yong; KANG Dong-yuan; YU Juan; ZHANG Min-zhou

doi:10.1007/s11655-022-3623-7

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体内外实验研究发现速效救心丸通过抑制L型钙通道CaV1.2电流终止心室颤动

Original Article | Updated：2023-02-01

- 体内外实验研究发现速效救心丸通过抑制L型钙通道CaV1.2电流终止心室颤动
- Suxiao Jiuxin Pills Prevent Ventricular Fibrillation from Inhibiting L-type Calcium Currents CaV1.2 in vivo and in vitro
- 中国结合医学杂志（英文版） 2023年29卷第2期页码：108-119
- Affiliations：
  
  1.Acute Myocardial Infarction Key Laboratory of Chinese Medicine in Guangzhou, the 2nd Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Province Hospital of Chinese Medicine, Guangzhou (510006), China
  2.Intensive Care Research Team of Traditional Chinese Medicine, the 2nd Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Province Hospital of Chinese Medicine, Guangzhou(510006), China
  3.Animal Center, the 2nd Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Province Hospital of Chinese Medicine, Guangdong Province Academy of Chinese Medicine, Guangzhou (510006), China
- Author bio：
  
  Prof. ZHANG Min-zhou, E-mail:mingzhouzhang8@163.com
- Funds：
  
  the National Natural Science Foundation of Guangdong(2020A1515010777)
- DOI：10.1007/s11655-022-3623-7
  中图分类号：
- 纸质出版日期：2023-02，
  
  网络出版日期：2022-11-03，
  
  录用日期：2022-07-11
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体内外实验研究发现速效救心丸通过抑制L型钙通道CaV1.2电流终止心室颤动[J]. 中国结合医学杂志（英文版）, 2023,29(2):108-119.

QI Jian-yong, KANG Dong-yuan, YU Juan, et al. Suxiao Jiuxin Pills Prevent Ventricular Fibrillation from Inhibiting L-type Calcium Currents CaV1.2 in vivo and in vitro[J]. Chinese Journal of Integrative Medicine, 2023,29(2):108-119.
体内外实验研究发现速效救心丸通过抑制L型钙通道CaV1.2电流终止心室颤动[J]. 中国结合医学杂志（英文版）, 2023,29(2):108-119. DOI： 10.1007/s11655-022-3623-7.

QI Jian-yong, KANG Dong-yuan, YU Juan, et al. Suxiao Jiuxin Pills Prevent Ventricular Fibrillation from Inhibiting L-type Calcium Currents CaV1.2 in vivo and in vitro[J]. Chinese Journal of Integrative Medicine, 2023,29(2):108-119. DOI： 10.1007/s11655-022-3623-7.

摘要

目的:

研究复方中药速效救心丸 (SJP)

是否是一种有效的、预防心室颤动 (VF) 的药物.

方法:

在新西兰兔和C57/BL6J小鼠体内

腹腔注射异丙肾上腺素 (ISO) 结合心电起搏

诱发心室颤动. 膜片钳实验

检测SJP对细胞L型钙通道电流 (CaV1.2) 、电压依赖性钠通道电流 (I

) 、快速型和缓慢型延迟整流钾通道 (I

) 电流的作用. 计算机仿真实验

将SJP对CaV1.2电流影响的实验数据

整合入心室肌细胞动作电位 (AP) 模型和仿真心电图 (pseudo-ECG) 模型中.

结果:

SJP显著降低新西兰兔和C57/BL6J小鼠心室颤动发生的概率和室颤持续时间. 膜片钳实验显示SJP降低了CaV1.2通道的峰值电流幅度

半数有效抑制浓度 (IC

) 为16.9 mg/L. SJP-30 mg/L

-32.8±6.1 pA; 维拉帕米

-16.2±1.8 pA; 对照组

-234.5±16.7 pA

0.01) . CaV1.2通道电流的稳态激活曲线、失活曲线和复活曲线未发生显著变化. 进一步发现

SJP并未显著改变INa、IKr和IKs电流 (SJP与各自对照组相比

0.05) . 计算机仿真实验显示

SJP

减少CaV1.2电流

缩短动作电位时间

从而引起仿真心电图中室颤转变为窦性心律.

结论:

通过体内实验、体外实验、和计算机仿真实验证实

SJP通过抑制L-型钙通道CaV1.2电流

抑制室颤

为速效救心丸临床应用防治心室颤动

提供了实验基础.

Abstract

Objective:

To investigate whether Suxiao Jiuxin Pills (SJP)

a Chinese herbal remedy

is an anti-ventricular fibrillation (VF) agent.

Methods:

VF was induced by isoproterenolol (ISO) intraperitoneal injection followed by electrical pacing in mice and rabbits. The effects of SJP on the L-type calcium channel current (CaV1.2)

voltage-dependent sodium channel current (I

)

rapid and slow delayed rectifier potassium channel current (I

and I

respectively) were studied by whole-cell patch-clamp method. Computer simulation was implemented to incorporate the experimental data of SJP effects on the CaV1.2 current into the action potential (AP) and pseudo-electrocardiography (pseudo-ECG) models.

Results:

SJP prevented VF induction and reduced VF durations significantly in mice and rabbits. Patch-clamp experiments revealed that SJP decreased the peak amplitude of the CaV1.2 current with a half maximal concentration (IC

) value of 16.9 mg/L (SJP-30 mg/L

–32.8±6.1 pA; Verapamil

–16.2±1.8 pA;

. control

–234.5±16.7 pA

0.01

respectively). The steady-state activation curve

inactivation curve

and the recovery from inactivation of the CaV1.2 current were not shifted significantly. Specifically

SJP did not altered I

and I

currents significantly (SJP

. control

0.05). Computer simulation showed that SJP-reduced CaV1.2 current shortened the AP duration

transiting VF into sinus rhythm in pseudo-ECG.

Conclusion:

SJP reduced VF via inhibiting the CaV1.2 current with

in vivo

in vitro

and

in silico

studies

which provide experimental basis for SJP anti-VF clinical application.

关键词

速效救心丸心室颤动膜片钳计算机仿真CaV1.2钙通道

Keywords

Suxiao Jiuxin Pillsventricular fibrillationpatch clampsimulationCaV1.2

references

Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, et al. Heart disease and stroke statistics-2022 Update: A report from the American Heart Association. Circulation 2022;145:e153-e639.

Bennett MT, Brown ML, Koehler J, Lexcen DR, Cheng A, Cheung JW. Trends in implantable cardioverter-defibrillator programming practices and its impact on therapies: Insights from a North American Remote Monitoring Registry 2007-2018. Heart Rhythm 2022;19:219-225.

Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781-788.

Duan X, Zhou L, Wu T, Liu G, Qiao J, Wei J, et al. Chinese herbal medicine suxiao jiuxin wan for angina pectoris.Cochrane Database Syst Rev 2008;2008(1):CD004473.

Lu Z, Zhang Y, Zhuang P, Zhang J, Zhou H, Zhang M, et al.Protective effect of Suxiao jiuxin pill, a traditional Chinese medicine, against acute myocardial ischemia in dogs. BMC Complement Altern Med 2015;15:373.

Guo QX, Zhang J, Li YQ, Zhang GF. Study on anti-atherosclerotic effect of Suxiao Jiuxin Pill and its mechanism.Afr J Tradit Complement Altern Med 2013;11:97-102.

Bai XY, Zhang P, Yang Q, Liu XC, Wang J, Tong YL, et al.Suxiao jiuxin pill induces potent relaxation and inhibition on contraction in human artery and the mechanism. Evid Based Complement Alternat Med 2014;2014:956924.

Ren Z, Ma J, Zhang P, Luo A, Zhang S, Kong L, et al. The effect of ligustrazine on L-type calcium current, calcium transient and contractility in rabbit ventricular myocytes. J Ethnopharmacol 2012;144:555-561.

Hall AC, Turcotte CM, Betts BA, Yeung WY, Agyeman AS, Burk LA. Modulation of human GABAA and glycine receptor currents by menthol and related monoterpenoids. Eur J Pharmacol 2004;506:9-16.

Meng L, Wang HB, Deng ZQ, Wang Y, Wu JB, Lai ZY.Activation of Borneol on volume sensitive chloride channels in nasopharyngeal carcinoma cells. Chin Pharmacol Bull (Chin) 2014;30:1671-1676.

Yang HJ, Kong B, Shuai W, Zhang JJ, Huang H. Shensong Yangxin protects against metabolic syndrome-induced ventricular arrhythmias by inhibiting electrical remodeling.Front Pharmacol 2020;11:993.

Tan YF, Yu J, Pan WJ, Qi JY, Zhang MZ. Protective mechanisms of Suxiao Jiuxin Pills on myocardial ischemia-reperfusion injury in vivo and in vitro. Chin J Integr Med 2020;26:583-590.

Schwetz TA, Norring SA, Bennett ES. N-glycans modulate K(v)1.5 gating but have no effect on K(v)1.4 gating. Biochim Biophys Acta 2010;1798:367-375.

Chen FS, Fedida D. On the mechanism by which 4-Aminopyridine occludes quinidine block of the cardiac K+ channel, hKv1.5. J Gen Physiol 1998;111:539-554.

Snyders J, Knoth KM, Roberds SL, Tamkun MM. Time-, voltage-, and state-dependent block by quinidine of a cloned human cardiac potassium channel. Mol Pharmacol 1992;41:322-330.

Abderemane-Ali F, Findeisen F, Rossen ND, Minor DL Jr. A selectivity filter gate controls voltage-gated calcium channel calcium-dependent Inactivation. Neuron 2019;101:1134-1149.

Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004;119:19-31.

Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci USA 2005;102:8089-8096;

Dilmac N, Hilliard N, Hockerman GH. Molecular determinants of Ca2+ potentiation of diltiazem block and Ca2+-dependent inactivation in the pore region of cav1.2.Mol Pharmacol 2003;64:491-501.

Bennett ES. Effects of channel cytoplasmic regions on the activation mechanisms of cardiac versus skeletal muscle Na(+) channels. Biophys J 1999;77:2999-3009.

Norring SA, Ednie AR, Schwetz TA, Du D, Yang H, Bennett ES. Channel sialic acids limit hERG channel activity during the ventricular action potential. FASEB J 2013;27:622-631.

Cheng H, Zhang Y, Du C, Dempsey CE, Hancox JC.High potency inhibition of hERG potassium channels by the sodium-calcium exchange inhibitor KB-R7943. Br J Pharmacol 2012;165:2260-2273.

Caballero R, Moreno I, González T, Arias C, Valenzuela C, Delpón E, et al. Spironolactone and its main metabolite, canrenoic acid, block human ether-a-go-go-related gene channels. Circulation 2003;107:889-895.

Sun DD, Wang HC, Wang XB, Luo Y, Jin ZX, Li ZC, et al.Tanshinone ⅡA: a new activator of human cardiac KCNQ1/KCNE1 (I(Ks)) potassium channels.Eur J Pharmacol 2008;590:317-321.

Herrington J, Solaro CR, Neely A, Lingle CJ. The suppression of Ca(2+)- and voltage-dependent outward K+ current during mAChR activation in rat adrenal chromaffin cells. J Physiol 1995;485:297-318.

Lovell PV, McCobb DP. Pituitary control of BK potassium channel function and intrinsic firing properties of adrenal chromaffin cells. J Neurosci 2001;21:3429-3442.

Moreno JD, Zhu ZI, Yang PC, Bankston JR, Jeng MT, Kang C, et al. A computational model to predict the effects of class Ⅰ anti-arrhythmic drugs on ventricular rhythms. Sci Transl Med 2011;3:98ra83.

Yang PC, Kurokawa J, Furukawa T, Clancy CE. Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study. PLoS Comput Biol 2010;6:e1000658.

Hool LC. Hypoxia increases the sensitivity of the L-type Ca(2+) current to beta-adrenergic receptor stimulation via a C2 region-containing protein kinase C isoform. Circ Res 2000;87:1164-1171.

Gaur N, Rudy Y, Hool L. Contributions of ion channel currents to ventricular action potential changes and induction of early afterdepolarizations during acute hypoxia.Circ Res 2009;105:1196-1203.

Gima K, Rudy Y. Ionic current basis of electrocardiographic waveforms: a model study. Circ Res 2002;90:889-896.

Elayi CS, Charnigo RJ, Heron PM, Lee BK, Olgin JE.Primary prevention of sudden cardiac death early post-myocardial infarction: root cause analysis for Implantable cardioverter-defibrillator failure and currently available options. Circ Arrhythm Electrophysiol 2017;10:e005194.

Sendfeld F, Selga E, Scornik FS, Pérez GJ, Mills NL, Brugada R. Experimental models of Brugada syndrome. Int J Mol Sci 2019;20:2123.

Sattler SM, Skibsbye L, Linz D, Lubberding AF, Tfelt-Hansen J, Jespersen T. Ventricular arrhythmias in first acute myocardial infarction: epidemiology, mechanisms, and interventions in large animal models. Front Cardiovasc Med 2019;6:158.

Hwang J, Kim TY, Terentyev D, Zhong M, Kabakov AY, Bronk P, et al. Late INa blocker GS967 supresses polymorphic ventricular tachycardia in a transgenic rabbit model of long QT type 2. Circ Arrhythm Electrophysiol 2020;13:e006875.

Schwartz PJ, Ackerman MJ, Antzelevitch C, Bezzina CR, Borggrefe M, Cuneo BF, et al. Inherited cardiac arrhythmias. Nat Rev Dis Primers 2020;6:58.

Glaaser IW, Kass RS, Clancy CE. Mechanisms of genetic arrhythmias: from DNA to ECG. Prog Cardiovasc Dis 2003;46:259-270.

Johnson EK, Springer SJ, Wang W, Dranoff EJ, Zhang Y, Kanter EM, et al. Differentiate expression and remodeling of transient outward potassium currents in human left ventricles. Circ Arrhythm Electrophysiol 2018;11:e005914.

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