title: Mechanisms underlying atrial-selective block of sodium channels by Wenxin Keli: Experimental and theoretical analysis.
abstract: BACKGROUND
  Atrial-selective inhibition of cardiac sodium channel current (INa) and INa-dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation. The present study was designed to examine the basis for the atrial-selective actions of Wenxin Keli.
  
  
  METHODS
  Whole cell INa was recorded at room temperature in canine atrial and ventricular myocytes. Trains of 40 pulses were elicited over a range of pulse durations and interpulse intervals to determine tonic and use-dependent block. A Markovian model for INa that incorporates interaction of Wenxin Keli with different states of the channel was developed to examine the basis for atrial selectivity of the drug.
  
  
  RESULTS
  Our data indicate that Wenxin Keli does not bind significantly to either closed or open states of the sodium channel, but binds very rapidly to the inactivated state of the channel and dissociates rapidly from the closed state. Action potentials recorded from atrial and ventricular preparations in the presence of 5g/L Wenxin Keli were introduced into the computer model in current clamp mode to simulate the effects on maximum upstroke velocity (Vmax). The model predicted much greater inhibition of Vmax in atrial vs. ventricular cells at rapid stimulation rates.
  
  
  CONCLUSIONS
  Our findings suggest that atrial selectivity of Wenxin Keli to block INa is due to more negative steady-state inactivation, less negative resting membrane potential, and shorter diastolic intervals in atrial vs. ventricular cells at rapid activation rates. These actions of Wenxin Keli account for its relatively safe and effective suppression of atrial fibrillation.
authors.affiliation: Masonic Medical Research Laboratory, Utica, NY, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.affiliation: Masonic Medical Research Laboratory, Utica, NY, United States.
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martínez
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA, United States.
authors.forename: Alexander
authors.initials: A
authors.lastname: Burashnikov
authors.affiliation: Masonic Medical Research Laboratory, Utica, NY, United States.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Panama
authors.affiliation: Masonic Medical Research Laboratory, Utica, NY, United States.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Cordeiro
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA, United States. Electronic address: cantzelevitch@gmail.com.
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D057809:HEK293 Cells; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000502:physiology*
chemical_list: D004365:Drugs, Chinese Herbal; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C532373:wenxin keli
keywords: Antiarrhythmic drugs; Arrhythmias; Atria; Electrophysiology; Pharmacology; Ventricles
references.citation: Evid Based Complement Alternat Med. 2013;2013:572078
references.pmid: 24319478
references.citation: J Cardiovasc Pharmacol. 2011 Jul;58(1):49-55
references.pmid: 21753258
references.citation: Europace. 2011 Feb;13(2):161-73
references.pmid: 21138930
references.citation: Mol Med Rep. 2013 Feb;7(2):519-24
references.pmid: 23174802
references.citation: J Cardiovasc Electrophysiol. 2003 Oct;14(10 Suppl):S133-9
references.pmid: 14760915
references.citation: J Am Coll Cardiol. 2010 Oct 5;56(15):1216-24
references.pmid: 20883928
references.citation: Evid Based Complement Alternat Med. 2013;2013:245958
references.pmid: 24368925
references.citation: J Atr Fibrillation. 2008;1(2):98-107
references.pmid: 21057583
references.citation: J Cardiovasc Electrophysiol. 2009 Jul;20(7):796-802
references.pmid: 19298570
references.citation: J Pharmacol Exp Ther. 2012 Jan;340(1):161-8
references.pmid: 22005044
references.citation: Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1615-24
references.pmid: 21821780
references.citation: Europace. 2011 Aug;13(8):1148-56
references.pmid: 21561900
references.citation: Eur J Pharmacol. 2011 Jul 15;662(1-3):31-9
references.pmid: 21550338
references.citation: J Cardiovasc Pharmacol. 2010 Jul;56(1):80-90
references.pmid: 20386458
references.citation: Circ Res. 1989 Nov;65(5):1247-62
references.pmid: 2553292
references.citation: Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1606-14
references.pmid: 21821778
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 2011 Apr;383(4):347-56
references.pmid: 21279331
references.citation: J Physiol. 2007 Jul 15;582(Pt 2):675-93
references.pmid: 17478540
references.citation: Heart Rhythm. 2013 Jul;10(7):1054-62
references.pmid: 23499631
references.citation: Heart Rhythm. 2012 Jan;9(1):125-31
references.pmid: 21884675
references.citation: Circ Arrhythm Electrophysiol. 2010 Feb;3(1):88-95
references.pmid: 19952329
references.citation: Expert Opin Emerg Drugs. 2009 Jun;14(2):233-49
references.pmid: 19466903
references.citation: J Gen Physiol. 1983 May;81(5):613-42
references.pmid: 6306139
references.citation: Pacing Clin Electrophysiol. 2013 Jun;36(6):732-40
references.pmid: 23438075
references.citation: Heart Rhythm. 2011 Aug;8(8):1281-90
references.pmid: 21421082
references.citation: Circulation. 2007 Oct 9;116(15):1647-52
references.pmid: 17804441
references.citation: J Thorac Dis. 2015 Feb;7(2):185-92
references.pmid: 25713735
references.citation: Evid Based Complement Alternat Med. 2015;2015:101904
references.pmid: 26074982
references.citation: Circ Arrhythm Electrophysiol. 2015 Oct;8(5):1048-56
references.pmid: 26226999
references.citation: J Cardiovasc Electrophysiol. 2004 Dec;15(12):1444-50
references.pmid: 15610294
references.citation: Ann N Y Acad Sci. 2008 Mar;1123:105-12
references.pmid: 18375582
references.citation: Circ Arrhythm Electrophysiol. 2012 Apr;5(2):400-8
references.pmid: 22322366
references.citation: J Mol Cell Cardiol. 2002 Sep;34(9):1185-94
references.pmid: 12392892
references.citation: J Clin Pharmacol. 2009 Mar;49(3):312-22
references.pmid: 19129422
references.citation: Am J Cardiol. 2003 Mar 20;91(6A):15D-26D
references.pmid: 12670638
references.citation: J Cardiovasc Pharmacol. 2008 Aug;52(2):121-8
references.pmid: 18670368
references.citation: Evid Based Complement Alternat Med. 2014;2014:242589
references.pmid: 24868236
references.citation: Circulation. 2007 Sep 25;116(13):1449-57
references.pmid: 17785620