Influence of Na+ and Li+ ions on the kinetics of sodium channel block by tetrodotoxin and saxitoxin

1991 ◽  
Vol 419 (6) ◽  
pp. 588-595 ◽  
Author(s):  
G. Hansen ◽  
W. Ulbricht
Keyword(s):  
Sodium Channel ◽  
Channel Block ◽  
Kinetics Of

The sodium channel  -subunit SCN3b modulates the kinetics of SCN5a and is expressed heterogeneously in sheep heart

2001 ◽  
Vol 537 (3) ◽  
pp. 693-700 ◽  
Author(s):  
A. I Fahmi ◽  
M. Patel ◽  
E. B Stevens ◽  
A. L Fowden ◽  
J. E. John ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Kinetics Of

Abstract 15420: Resolving a Controversy: Inhibition of Cardiac Ryanodine Receptors is the Principal Mechanism of Antiarrhythmic Action of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Dmytro O Kryshtal ◽  
Daniel J Blackwell ◽  
Christian L Egly ◽  
Abigail N Smith ◽  
Suzanne M Batiste ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Antiarrhythmic Action ◽  
Channel Block ◽  
Principal Mechanism ◽  
Cardiac Sodium Channels

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.

Open channel block of human heart hKv1.5 by the beta-subunit hKv beta 1.2

1997 ◽  
Vol 272 (6) ◽  
pp. H2932-H2941 ◽  
Author(s):  
M. De Biasi ◽  
Z. Wang ◽  
E. Accili ◽  
B. Wible ◽  
D. Fedida
Keyword(s):  
Human Heart ◽  
Open Channel ◽  
Beta Subunit ◽  
Beta Subunits ◽  
Channel Block ◽  
Open Channel Block ◽  
Pharmacological Characterization ◽  
Kinetics Of ◽  
K Currents

Voltage-gated K+ currents in human heart are likely to derive from multisubunit complexes of pore-forming alpha-subunits with one or more auxiliary beta-subunits. We recently cloned a novel beta-subunit from human atrium, hKv beta 1.2 (K. Majumder, M. De Biasi, Z. Wang, and B. A. Wible. FEBS Lett. 361: 13-16, 1995), and showed that it interacts with channels in the Kv1 family. Here we characterize the interaction of hKv beta 1.2 with hKv1.5 in terms of a two-closed-state and one-open-state open channel block model. After coexpression in Xenopus oocytes, hKv1.5 currents were reduced in the presence of hKv beta 1.2, and at positive potentials an inactivation process was introduced. Deactivation kinetics of hKv1.5 were slowed, and there was an increased steepness with a -14-mV hyperpolarizing shift in the midpoint of steady-state activation. The model was able to predict all the above features of the interaction of hKv1.5 and hKv beta 1.2 as a result of rapid open channel block of activated channels. Understanding the mechanism of hKv beta 1.2 action on heart K+ channels will further aid the development of the functional and pharmacological characterization of native cardiac K+ currents.

scholarly journals Atrial-selective sodium channel block for the treatment of atrial fibrillation

2009 ◽  
Vol 14 (2) ◽  
pp. 233-249 ◽  
Author(s):  
Alexander Burashnikov ◽  
Charles Antzelevitch
Keyword(s):  
Atrial Fibrillation ◽  
Sodium Channel ◽  
Channel Block

scholarly journals Detection of Paralytic Shellfish Poison by Rapid Cell Bioassay: Antagonism of Voltage-Gated Sodium Channel Active Toxins in vitro

2003 ◽  
Vol 86 (3) ◽  
pp. 540-543 ◽  
Author(s):  
Ronald L Manger ◽  
Linda S Leja ◽  
Sue Y Lee ◽  
James M Hungerford ◽  
Mary Ann Kirkpatrick ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Mouse Bioassay ◽  
Marine Toxins ◽  
Prolonged Incubation ◽  
Paralytic Shellfish Poison ◽  
Paralytic Shellfish ◽  
Channel Blocking ◽  
In Vitro Effects ◽  
Kinetics Of

Abstract Although cytotoxicity assays provide several advantages over mouse bioassays, sodium channel-blocking marine toxins, such as those associated with paralytic shellfish poison (PSP), require prolonged incubation periods of 24–48 h. This is in marked contrast to in vitro detection of sodium channel-enhancing marine toxins such as ciguatoxins or brevetoxins which can be accomplished in as few as 4–6 h. We developed a modified PSP cell bioassay that is as rapid as in vitro methods for sodium channel-enhancing toxins. The cell bioassay is based on a saxitoxin-dependent antagonism of the rapid in vitro effects of brevetoxin or ciguatoxin. Comparative analysis of naturally incurred PSP residues by both antagonism cell bioassay and the mouse bioassay demonstrated significant correlation. The simplicity, sensitivity, and enhanced kinetics of the new antagonism cell bioassay format provide the basis for development of a practical alternative to conventional mouse testing for PSP.

scholarly journals RYR2 Channel Inhibition Is the Principal Mechanism 0f Flecainide Action in CPVT

2020 ◽  
Author(s):  
Dmytro O Kryshtal ◽  
Daniel Blackwell ◽  
Christian Egly ◽  
Abigail N Smith ◽  
Suzanne M Batiste ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Antiarrhythmic Action ◽  
Channel Block ◽  
Principal Mechanism ◽  
Channel Inhibition ◽  
Ryr2 Channel ◽  
Cardiac Sodium Channels

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-methylated flecainide analogues (QX-FL and NM-FL) and showed that N-methylation reduces flecainide's inhibitory potency on RyR2 channels incorporated into artificial lipid bilayers. N-Methylation did not alter flecainide's inhibitory activity on human cardiac sodium channels expressed in HEK293T cells. 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 had no significant effect on arrhythmia burden, 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 did not prevent ventricular tachycardia. Hence, RyR2 channel inhibition likely constitutes the principal mechanism of antiarrhythmic action of flecainide in CPVT.

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