The Selective Cardiac Late Sodium Current Inhibitor GS‐458967 Suppresses Autonomically Triggered Atrial Fibrillation in an Intact Porcine Model

Carneiro, Bárbara Seabra; Bento, S B S Afonso Alves; Bačić, Boris; Nearing, Bruce D.; Rajamani, Sridharan; Belardinelli, Luiz; Verrier, Richard L.

doi:10.1111/jce.12824

Cited by 24 publications

(14 citation statements)

References 30 publications

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“…19 In studies conducted in intact animals, GS-967 reduced ischemia-induced susceptibility to atrial and ventricular arrhythmias and repolarization alternans and heterogeneity. 7,14,20 GS-967 has also been shown to suppress focal arrhythmias in intact rat hearts. 21 …”

Section: Discussionmentioning

confidence: 95%

“…epinephrine infusion to achieve high levels of adrenergic stimulation and to facilitate both the initiation and maintenance of the arrhythmia. 7 The onset of AF was invariably preceded by . TWA a was calculated on the basis of the maximum absolute value of the difference between the A and B modified moving average computed beats from the J point to the end of the T a wave, as described in the formula in the upper panel.…”

Section: Present Studymentioning

confidence: 99%

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Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

et al. 2016

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Section: Discussionmentioning

confidence: 95%

Section: Present Studymentioning

confidence: 99%

Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

et al. 2016

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“…S4). Usedependent block of WT or mutant cardiac sodium channels by GS967 was not examined previously Bonatti et al, 2014;Alves Bento et al, 2015;Burashnikov et al, 2015;Carneiro et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

Use-Dependent Block of Human Cardiac Sodium Channels by GS967

2016

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GS-458967, 6-(4-(Trifluoromethoxy)phenyl)-3-(trifluoromethyl)- [1,2,4]triazolo [4,3-a]pyridine (GS967) is a recently described, novel, sodium channel inhibitor exhibiting potent antiarrhythmic effects in various in vitro and in vivo models. The antiarrhythmic mechanism has been attributed to preferential suppression of late sodium current. However, there has been no reported systematic investigation of the effects of this compound on isolated sodium channels. Here, we examined the effects of GS967 on peak (I NaP ) and late (I NaL ) sodium current recorded from cells that heterologously expressed human cardiac voltage-gated sodium channel, the principle cardiac sodium channel. As previously described, we observed that GS967 exerted tonic block of I NaL (63%) to a significantly greater extent than I NaP (19%). However, GS967 also caused a reduction of I NaP in a frequency-dependent manner, consistent with use-dependent block (UDB). GS967 evoked more potent UDB of I NaP (IC 50 5 0.07 mM) than ranolazine (16 mM) and lidocaine (17 mM). Use-dependent block was best explained by a significant slowing of recovery from fast and slow inactivation with a significant enhancement of slow inactivation in the presence of GS967. Furthermore, GS967 was found to exert these same effects on a prototypical long QT syndrome mutation (delKPQ). An engineered mutation at an interaction site for local anesthetic agents (F1760A) partially attenuated the effect of GS967 on UDB, but had no effect on tonic I NaL block. We conclude that GS967 is a preferential inhibitor of I NaL , but it also exerts previously unreported strong effects on slow inactivation and recovery from inactivation, resulting in substantial UDB that is not entirely dependent on a known interaction site for local anesthetic agents.

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“…The selective and potent late I Na inhibitor GS‐458967 (GS967) has minimal effects on other cardiac ion currents (Belardinelli et al ., ), cardiac contractility (Fernandes et al ., ) and conduction velocity. Antiarrhythmic properties of GS967 were demonstrated in vitro (Belardinelli et al ., ; Sicouri et al ., ) as well as in a number of in vivo ventricular (Belardinelli et al ., ; Bonatti et al ., ; Pezhouman et al ., ; Alves Bento et al ., ) and atrial (Burashnikov et al ., ; Carneiro et al ., ) arrhythmia models but not in the CAVB dog. The use of this canine model would provide additional information relevant for clinical applications due to the comparable cardiac electrophysiology between dogs and humans.…”

Section: Introductionmentioning

confidence: 90%

Selective late sodium current inhibitor GS‐458967 suppresses Torsades de Pointes by mostly affecting perpetuation but not initiation of the arrhythmia

Bossu

Houtman

Meijborg³

et al. 2018

British J Pharmacology

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Background and PurposeEnhanced late sodium current (late I Na) in heart failure and long QT syndrome type 3 is proarrhythmic. This study investigated the antiarrhythmic effect and mode of action of the selective and potent late I Na inhibitor GS‐458967 (GS967) against Torsades de Pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog.Experimental ApproachElectrophysiological and antiarrhythmic effects of GS967 were evaluated in isolated canine ventricular cardiomyocytes and CAVB dogs with dofetilide‐induced early afterdepolarizations (EADs) and TdP, respectively. Mapping of intramural cardiac electrical activity in vivo was conducted to study effects of GS967 on spatial dispersion of repolarization.Key ResultsGS967 (IC50~200nM) significantly shortened repolarization in canine ventricular cardiomyocytes and sinus rhythm (SR) dogs, in a concentration and dose‐dependent manner. In vitro, despite addition of 1μM GS967, dofetilide‐induced EADs remained present in 42% and 35% of cardiomyocytes from SR and CAVB dogs, respectively. Nonetheless, GS967 (787±265nM) completely abolished dofetilide‐induced TdP in CAVB dogs (10/14 after dofetilide to 0/14 dogs after GS967), while single ectopic beats (sEB) persisted in 9 animals. In vivo mapping experiments showed that GS967 significantly reduced spatial dispersion of repolarization: cubic dispersion was significantly decreased from 237±54ms after dofetilide to 123±34ms after GS967.Conclusion and ImplicationsGS967 terminated all dofetilide‐induced TdP without completely suppressing EADs and sEB in vitro and in vivo, respectively. The antiarrhythmic mode of action of GS967, through the reduction of spatial dispersion of repolarization, seems to predominantly impede the perpetuation of arrhythmic events into TdP rather than their initiating trigger.

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The Selective Cardiac Late Sodium Current Inhibitor GS‐458967 Suppresses Autonomically Triggered Atrial Fibrillation in an Intact Porcine Model

Cited by 24 publications

References 30 publications

Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

Use-Dependent Block of Human Cardiac Sodium Channels by GS967

Selective late sodium current inhibitor GS‐458967 suppresses Torsades de Pointes by mostly affecting perpetuation but not initiation of the arrhythmia

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