Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments.

Starmer, C. Frank; Lastra, Anselmo; Nesterenko, Vladislav V.; Grant, Augustus O.

doi:10.1161/01.cir.84.3.1364

Cited by 121 publications

(72 citation statements)

References 42 publications

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“…1,39 -41 Computer models support the hypothesis that proarrhythmic mechanisms of Na ϩ channel blockade are associated with the reduction of Na ϩ channel availability. 42 In our study, flecainide potentiated the delay of recovery from inactivation caused by IsoK ( Figure 4B). Studies in the intact EBZ preparation have shown this synergistic effect of flecainide on conduction abnormalities of this arrhythmic substrate.…”

Section: Discussionsupporting

confidence: 61%

Oxidative Mediated Lipid Peroxidation Recapitulates Proarrhythmic Effects on Cardiac Sodium Channels

Fukuda

Davies

Nakajima

et al. 2005

Circulation Research

118

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Abstract-Sudden cardiac death attributable to ventricular tachycardia/fibrillation (VF) remains a catastrophic outcome of myocardial ischemia and infarction. At the same time, conventional antagonist drugs targeting ion channels have yielded poor survival benefits. Although pharmacological and genetic models suggest an association between sodium (Na ϩ ) channel loss-of-function and sudden cardiac death, molecular mechanisms have not been identified that convincingly link ischemia to Na ϩ channel dysfunction and ventricular arrhythmias. Because ischemia can evoke the generation of reactive oxygen species, we explored the effect of oxidative stress on Na ϩ channel function. We show here that oxidative stress reduces Na ϩ channel availability. Both the general oxidant tert-butyl-hydroperoxide and a specific, highly reactive product of the isoprostane pathway of lipid peroxidation, E 2 -isoketal, potentiate inactivation of cardiac Na ϩ channels in human embryonic kidney (HEK)-293 cells and cultured atrial (HL-1) myocytes. Furthermore, E 2 -isoketals were generated in the epicardial border zone of the canine healing infarct, an arrhythmogenic focus where Na ϩ channels exhibit similar inactivation defects. In addition, we show synergistic functional effects of flecainide, a proarrhythmic Na ϩ channel blocker, and oxidative stress. These data suggest Na ϩ channel dysfunction evoked by lipid peroxidation is a candidate mechanism for ischemia-related conduction abnormalities and arrhythmias.

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Section: Discussionsupporting

confidence: 61%

Oxidative Mediated Lipid Peroxidation Recapitulates Proarrhythmic Effects on Cardiac Sodium Channels

Fukuda

Davies

Nakajima

et al. 2005

Circulation Research

118

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“…4,31,32,33 Hille,34 in his modulated receptor hypothesis explains the shift of inactivation in presence of use-dependent block of sodium currents during repetitive pulses. 35,36,37 The hypothesis predicted that the open and inactivated states of voltage gated Na channels have higher affinities toward LA drugs than that of the resting state.…”

Section: Kinetics Of Drug Bindingmentioning

confidence: 99%

Probing kinetic drug binding mechanism in voltage-gated sodium ion channel: open state versus inactive state blockers

Pal

Gangopadhyay

2015

Channels

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The kinetics and nonequilibrium thermodynamics of open state and inactive state drug binding mechanisms have been studied here using different voltage protocols in sodium ion channel. We have found that for constant voltage protocol, open state block is more efficient in blocking ionic current than inactive state block. Kinetic effect comes through peak current for mexiletine as an open state blocker and in the tail part for lidocaine as an inactive state blocker. Although the inactivation of sodium channel is a free energy driven process, however, the two different kinds of drug affect the inactivation process in a different way as seen from thermodynamic analysis. In presence of open state drug block, the process initially for a long time remains entropy driven and then becomes free energy driven. However in presence of inactive state block, the process remains entirely entropy driven until the equilibrium is attained. For oscillating voltage protocol, the inactive state blocking is more efficient in damping the oscillation of ionic current. From the pulse train analysis it is found that inactive state blocking is less effective in restoring normal repolarisation and blocks peak ionic current. Pulse train protocol also shows that all the inactive states behave differently as one inactive state responds instantly to the test pulse in an opposite manner from the other two states.

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“…The latter is known to facilitate reentry arrhythmias. 20 Finally, because not all cardiac APDs are identical, it is important that many potassium channels be open at the end of the action potential and early during diastole. This not only clamps the membrane potential closer to the potassium equilibrium potential but also reduces the tissue impedance, rendering activation due to current flow between cells at different potentials less likely.…”

Section: Mechanismsmentioning

confidence: 99%

Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic

2001

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Background-Prolongation of action potential duration (APD) is considered a major antiarrhythmic mechanism (class III), but paradoxically, it frequently is also proarrhythmic (torsade de pointes). Methods and Results-The cardiac electrophysiological effects of 702 chemicals (class III or HERG channel block) were studied in 1071 rabbit Langendorff-perfused hearts. Temporal instability of APD, triangulation (duration of phase 3 repolarization), reverse use-dependence, and induction of ectopic beats were measured. Instability, triangulation, and reverse use-dependence were found to be important determinants of proarrhythmia. Agents that lengthened the APD by Ͼ50 ms, with induction of instability, triangulation, and reverse use-dependence (nϭ59), induced proarrhythmia (primarily polymorphic ventricular tachycardia); in their absence (nϭ19), the same prolongation of APD induced no proarrhythmia but significant antiarrhythmia (PϽ0.001). Shortening of APD, when accompanied by instability and triangulation, was also markedly proarrhythmic (primarily monomorphic ventricular tachycardia). In experiments in which instability and triangulation were present, proarrhythmia declined with prolongation of APD, but this effect was not large enough to become antiarrhythmic. Only with agents without instability did prolongation of APD become antiarrhythmic. For 20 selected compounds, it was shown that instability of APD and triangulation observed in vitro were strong predictors of in vivo proarrhythmia (torsade de pointes). Conclusions-Lengthening of APD without instability or triangulation is not proarrhythmic but rather antiarrhythmic.

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Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments.

Cited by 121 publications

References 42 publications

Oxidative Mediated Lipid Peroxidation Recapitulates Proarrhythmic Effects on Cardiac Sodium Channels

Oxidative Mediated Lipid Peroxidation Recapitulates Proarrhythmic Effects on Cardiac Sodium Channels

Probing kinetic drug binding mechanism in voltage-gated sodium ion channel: open state versus inactive state blockers

Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic

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