Wenxin Keli Suppresses Ventricular Triggered Arrhythmias via Selective Inhibition of Late Sodium Current

2013 ◽  
Vol 36 (6) ◽  
pp. 732-740 ◽  
Author(s):  
XIAOLIN XUE ◽  
DONGLIN GUO ◽  
HONGMEI SUN ◽  
DAN WANG ◽  
JIANA LI ◽  
...  
Keyword(s):  
Sodium Current ◽  
Selective Inhibition ◽  
Late Sodium Current ◽  
Triggered Arrhythmias

Selective Inhibition of the Late Sodium Current has No Adverse Effect on Electrophysiological or Contractile Function of the Normal Heart

2014 ◽  
Vol 63 (6) ◽  
pp. 512-519 ◽  
Author(s):  
Sarah Fernandes ◽  
Kirsten Hoyer ◽  
Gongxin Liu ◽  
Wei-Qun Wang ◽  
Arvinder K. Dhalla ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Contractile Function ◽  
Sodium Current ◽  
Selective Inhibition ◽  
Normal Heart ◽  
Late Sodium Current

Abstract 14019: Electrophysiological Effects of the Late Sodium Current Inhibitor GS967 in Scn5a -1798insD Mouse and Human SCN5A -1795insD iPSC-derived Cardiomyocytes

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Vincent Portero ◽  
Maaike Hoekstra ◽  
Arie O Verkerk ◽  
Isabella Mengarelli ◽  
Richard P Davis ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Sodium Current ◽  
Selective Inhibition ◽  
Overlap Syndrome ◽  
Cardiac Conduction ◽  
Resting Membrane Potential ◽  
Late Sodium Current ◽  
Ventricular Activation ◽  
Induced Pluripotent ◽  
Electrophysiological Effects

Background and Aim: Selective inhibition of cardiac late sodium current (I Na,L ) is an emerging target in the treatment of ventricular arrhythmias. The electrophysiological effects of GS967, a potent I Na,L inhibitor, were investigated in an overlap syndrome model of both gain and loss of sodium channel function, comprising cardiomyocytes derived from human SCN5A -1795insD induced pluripotent stem cells (iPSC-CMs) and mice carrying the homologous mutation Scn5a -1798insD. Methods and Results: On patch-clamp analysis, isolated mouse Scn5a -1798insD cardiomyocytes and human SCN5A -1795insD iPSC-CMs showed decreased peak I Na and action potential (AP) upstroke velocity (Vmax) and increased I Na,L and AP duration at 90% repolarization (APD 90 ) as compared to wild-type. GS967 (50-300 nM) significantly decreased APD 90 in mouse Scn5a -1798insD cardiomyocytes by 8±2% (mean±SEM) at 50 nM (n=7), 13±3% at 100 nM (n=11) and 20±5% at 300 nM (n=6) (all p <0.01 vs. control), without affecting Vmax. GS967 (300 nM) selectively inhibited I NaL in mouse Scn5a -1798insD cardiomyocytes (GS967-sensitive current of 0.7±0.1 pA/pF, n=6), but had no effect on peak I Na . Furthermore, GS967 (100 nM) suppressed fast (5 Hz) pacing-induced afterpotentials and triggered activity. In human SCN5A -1795insD iPSC-CMs (n=6), GS967 (300 nM) significantly reduced APD 90 without affecting the resting membrane potential or Vmax. In Langendorff-perfused, isolated mouse Scn5a -1798insD hearts (n=5), GS967 (300 nM) had no effect on ventricular activation time or conduction velocity (as assessed by epicardial mapping). Conclusion: Selective inhibition of I NaL by GS967 attenuated AP prolongation and prevented pro-arrhythmic activity in mouse Scn5a -1798insD cardiomyocytes and human SCN5A-1795insD iPSC-CMs, thus suppressing the gain-of-function features of this overlap syndrome mutation. Importantly, these beneficial actions of GS967 occurred in the absence of deleterious effects on sodium channel availability or cardiac conduction, despite a pre-existing decrease in peak I Na . Thus, selective inhibition of I Na,L constitutes a promising pharmacological treatment of cardiac channelopathies associated with enhanced I NaL , even in overlap syndromes whereby peak I Na is decreased.

scholarly journals Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts

Heart Rhythm ◽  
2014 ◽  
Vol 11 (3) ◽  
pp. 492-501 ◽  
Author(s):  
Arash Pezhouman ◽  
Sepideh Madahian ◽  
Hayk Stepanyan ◽  
Hayk Ghukasyan ◽  
Zhilin Qu ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Sodium Current ◽  
Selective Inhibition ◽  
Late Sodium Current ◽  
Rat Hearts ◽  
Ventricular Tachycardia And Fibrillation

scholarly journals Ranolazine Attenuates the Enhanced Reverse Na+-Ca2+ Exchange Current via Inhibiting Hypoxia-Increased Late Sodium Current in Ventricular Myocytes

2014 ◽  
Vol 124 (3) ◽  
pp. 365-373 ◽  
Author(s):  
Xiao-Jing Wang ◽  
Lei-Lei Wang ◽  
Chen Fu ◽  
Pei-Hua Zhang ◽  
Ying Wu ◽  
...  
Keyword(s):  
Ventricular Myocytes ◽  
Sodium Current ◽  
Exchange Current ◽  
Late Sodium Current

Late Sodium Current is a Novel Target for Amiodarone: Studies in Failing Human Myocardium

2001 ◽  
Vol 33 (5) ◽  
pp. 923-932 ◽  
Author(s):  
Victor A Maltsev ◽  
Hani N Sabbah ◽  
Albertas I Undrovinas
Keyword(s):  
Sodium Current ◽  
Human Myocardium ◽  
Late Sodium Current ◽  
Novel Target

Larger late sodium current density as well as greater sensitivities to ATX II and ranolazine in rabbit left atrial than left ventricular myocytes

2014 ◽  
Vol 306 (3) ◽  
pp. H455-H461 ◽  
Author(s):  
Antao Luo ◽  
Jihua Ma ◽  
Yejia Song ◽  
Chunping Qian ◽  
Ying Wu ◽  
...  
Keyword(s):  
Left Atrial ◽  
Ventricular Myocytes ◽  
Sodium Current ◽  
Left Ventricular ◽  
Atrial Myocytes ◽  
Open Probability ◽  
Late Sodium Current ◽  
Ventricular Cells ◽  
Open Time ◽  
Hill Slope

An increase of cardiac late sodium current ( INa.L) is arrhythmogenic in atrial and ventricular tissues, but the densities of INa.L and thus the potential relative contributions of this current to sodium ion (Na+) influx and arrhythmogenesis in atria and ventricles are unclear. In this study, whole-cell and cell-attached patch-clamp techniques were used to measure INa.L in rabbit left atrial and ventricular myocytes under identical conditions. The density of INa.L was 67% greater in left atrial (0.50 ± 0.09 pA/pF, n = 20) than in left ventricular cells (0.30 ± 0.07 pA/pF, n = 27, P < 0.01) when elicited by step pulses from −120 to −20 mV at a rate of 0.2 Hz. Similar results were obtained using step pulses from −90 to −20 mV. Anemone toxin II (ATX II) increased INa.L with an EC50 value of 14 ± 2 nM and a Hill slope of 1.4 ± 0.1 ( n = 9) in atrial myocytes and with an EC50 of 21 ± 5 nM and a Hill slope of 1.2 ± 0.1 ( n = 12) in ventricular myocytes. Na+ channel open probability (but not mean open time) was greater in atrial than in ventricular cells in the absence and presence of ATX II. The INa.L inhibitor ranolazine (3, 6, and 9 μM) reduced INa.L more in atrial than ventricular myocytes in the presence of 40 nM ATX II. In summary, rabbit left atrial myocytes have a greater density of INa.L and higher sensitivities to ATX II and ranolazine than rabbit left ventricular myocytes.

scholarly journals LATE SODIUM CURRENT INHIBITOR RANOLAZINE REDUCED SUSCEPTIBILITY TO RE-FIBRILLATIONS FOLLOWING LONG DURATION VF

2015 ◽  
Vol 31 (10) ◽  
pp. S190-S191
Author(s):  
M.A. Azam ◽  
N. Zamiri ◽  
S. Masse ◽  
M. Kusha ◽  
P.F. Lai ◽  
...  
Keyword(s):  
Sodium Current ◽  
Late Sodium Current ◽  
Long Duration
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