Use-dependent block of cardiac sodium channels by quaternary derivatives of lidocaine

1984 ◽  
Vol 400 (2) ◽  
pp. 121-129 ◽  
Author(s):  
Gary A. Gintant ◽  
Brian F. Hoffman
Toxicon ◽  
2007 ◽  
Vol 49 (2) ◽  
pp. 181-193 ◽  
Author(s):  
Dorothy A. Hanck ◽  
Michael F. Sheets

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Dmytro O Kryshtal ◽  
Daniel J Blackwell ◽  
Christian L Egly ◽  
Abigail N Smith ◽  
Suzanne M Batiste ◽  
...  

Rationale: The class Ic antiarrhythmic drug flecainide prevents ventricular tachyarrhythmia in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease caused by hyperactive cardiac ryanodine receptor (RyR2) calcium (Ca) release. Although flecainide inhibits single RyR2 channels in vitro , reports have claimed that RyR2 inhibition by flecainide is not relevant for its mechanism of antiarrhythmic action and concluded that sodium channel block alone is responsible for flecainide’s efficacy in CPVT. Objective: To determine whether RyR2 block independently contributes to flecainide’s efficacy for suppressing spontaneous sarcoplasmic reticulum (SR) Ca release and for preventing ventricular tachycardia in vivo . Methods and Results: We synthesized N -methyl flecainide analogues (QX-FL and NM-FL) and showed that N -methylation reduces flecainide’s inhibitory potency on RyR2 channels but not on cardiac sodium channels. Antiarrhythmic efficacy was tested utilizing a calsequestrin knockout (Casq2-/-) CPVT mouse model. In membrane-permeabilized Casq2-/- cardiomyocytes — lacking intact sarcolemma and devoid of sodium channel contribution — flecainide, but not its analogues, suppressed RyR2-mediated Ca release at clinically relevant concentrations. In voltage-clamped, intact Casq2-/- cardiomyocytes pretreated with tetrodotoxin (TTX) to inhibit sodium channels and isolate the effect of flecainide on RyR2, flecainide significantly reduced the frequency of spontaneous SR Ca release, while QX-FL and NM-FL did not. In vivo , flecainide effectively suppressed catecholamine-induced ventricular tachyarrhythmias in Casq2-/- mice, whereas NM-FL did not, despite comparable sodium channel block. Conclusions: Flecainide remains an effective inhibitor of RyR2-mediated arrhythmogenic Ca release even when cardiac sodium channels are blocked. In mice with CPVT, sodium channel block alone was not enough to prevent arrhythmias. Hence, RyR2 inhibition by flecainide is critical for its mechanism of antiarrhythmic action.


Medicina ◽  
2018 ◽  
Vol 54 (4) ◽  
pp. 61 ◽  
Author(s):  
Agnieszka Chrustek ◽  
Iga Hołyńska-Iwan ◽  
Inga Dziembowska ◽  
Joanna Bogusiewicz ◽  
Marcin Wróblewski ◽  
...  

Pyrethroids are synthetic derivatives of natural pyrethrins extracted from Chrysanthemum cinerariaefolium. They are 2250 times more toxic to insects than to vertebrates due to insects’ smaller size, lower body temperature and more sensitive sodium channels. In particular, three pyrethroid compounds, namely deltamethrin, permethrin, and alpha-cypermethrin, are commonly used as insecticides and are recommended for in-home insect control because they are considered to be relatively non-toxic to humans in all stages of life. However, recent data show that they are not completely harmless to human health as they may enter the body through skin contact, by inhalation and food or water, and absorption level depending on the type of food. Permethrin seems to have an adverse effect on fertility, the immune system, cardiovascular and hepatic metabolism as well as enzymatic activity. Deltamethrin induces inflammation, nephro- and hepatotoxicity and influences the activity of antioxidant enzymes in tissues. Alpha-cypermethrin may impair immunity and act to increase glucose and lipid levels in blood. The aim of the review is to provide comprehensive information on potential hazards associated to human exposure to deltamethrin, permethrin and alpha-cypermethrin. The results of presented studies prove that the insecticides must be used with great caution.


2019 ◽  
Vol 598 (14) ◽  
pp. 2835-2846 ◽  
Author(s):  
Christopher N. Johnson

ChemInform ◽  
2010 ◽  
Vol 26 (45) ◽  
pp. no-no
Author(s):  
K. G. ESTEP ◽  
K. A. JOSEF ◽  
E. R. BACON ◽  
P. M. CARABATEAS ◽  
S. IV RUMNEY ◽  
...  

Circulation ◽  
2003 ◽  
Vol 107 (25) ◽  
pp. 3216-3222 ◽  
Author(s):  
M. Tateyama ◽  
J. Kurokawa ◽  
C. Terrenoire ◽  
I. Rivolta ◽  
R.S. Kass

2001 ◽  
Vol 134 (6) ◽  
pp. 1195-1206 ◽  
Author(s):  
Cyril Goudet ◽  
Tania Ferrer ◽  
Loipa Galàn ◽  
Adriana Artiles ◽  
Cesar F V Batista ◽  
...  

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