Late Sodium Current Inhibition Alone with Ranolazine Is Sufficient to Reduce Ischemia- and Cardiac Glycoside-Induced Calcium Overload and Contractile Dysfunction Mediated by Reverse-Mode Sodium/Calcium Exchange

Soliman, Daniel; Wang, Lianguo; Hamming, Kevin S.C.; Yang, Wei; Fatehi, Mohammad; Carter, Christian C.; Clanachan, Alexander S.; Light, Peter E.

doi:10.1124/jpet.112.196949

Cited by 25 publications

(26 citation statements)

References 45 publications

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“…VF results in global cardiac ischemia, and it is demonstrated that cardiac ischemia is associated with increases in the late Na + current and subsequent intracellular Na + overload. 9,12,17,18,20 Compensatory mechanisms are subsequently activated, including Na + -Ca 2+ exchanger reverse mode, 10,11 which can result in Ca 2+ overload in cardiomyocytes. This provides a potential substrate for various cardiac arrhythmias as demonstrated in several previous studies.…”

Section: + Current Blockade and Vf And Refibrillationmentioning

confidence: 99%

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

Azam

Zamiri

Massé³

et al. 2017

Circ: Arrhythmia and Electrophysiology

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Background-After defibrillation of initial ventricular fibrillation (VF), it is crucial to prevent refibrillation to ensure successful resuscitation outcomes. Inability of the late Na + current to inactivate leads to intracellular Ca 2+ dysregulation and arrhythmias. Our aim was to determine the effects of ranolazine and GS-967, inhibitors of the late Na + current, on ventricular refibrillation. Methods and Results-Long-duration VF was induced electrically in Langendorff-perfused rabbit hearts (n=22) and terminated with a defibrillator after 6 minutes. Fibrillating hearts were randomized into 3 groups: treatment with ranolazine, GS-967, or nontreated controls. In the treated groups, hearts were perfused with ranolazine or GS-967 at 2 minutes of VF. In control experiments, perfusion solution was supplemented with isotonic saline in lieu of a drug. Inducibility of refibrillation was assessed after initial long-duration VF by attempting to reinduce VF. Sustained refibrillation was successful in fewer ranolazine-treated (29.17%; P=0.005) or GS-967-treated (45.83%, P=0.035) hearts compared with that in nontreated control hearts (84.85%). In GS-967-treated hearts, significantly more spontaneous termination of initial long-duration VF was observed (66.67%; P=0.01). Ca 2+ transient duration was reduced in ranolazine-treated hearts compared with that in controls (P=0.05) and also Ca 2+ alternans (P=0.03). Conclusions-Late Na + current inhibition during long-duration VF reduces the susceptibility to subsequent refibrillation, partially by mitigating dysregulation of intracellular Ca 2+. These results suggest the potential therapeutic use of ranolazine and GS-967 and call for further testing in cardiac arrest models. (Circ Arrhythm Electrophysiol. 2017;10:e004331.

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Section: + Current Blockade and Vf And Refibrillationmentioning

confidence: 99%

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

Azam

Zamiri

Massé³

et al. 2017

Circ: Arrhythmia and Electrophysiology

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“…RAN, an effective I Na.L inhibitor in therapeutic concentrations (< 10 mΜ), can obviously lower the density of (31). However, in this study, RAN decreased the hypoxia-increased reverse I NCX by inhibiting I Na.L .…”

Section: Discussionmentioning

confidence: 62%

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

Wang

et al. 2014

J Pharmacol Sci

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Abstract. Ranolazine (RAN), a novel antianginal agent, inhibits the increased late sodium current (I Na.L ) under many pathological conditions. In this study, the whole-cell patch-clamp technique was used to explore the effects of RAN on I Na.L and reverse Na + /Ca 2+ exchange current (I NCX ) in rabbit ventricular myocytes during hypoxia. Tetrodotoxin (TTX) at 2 mM or RAN at 9 mM decreased significantly I Na.L and reverse I NCX under normoxia and RAN had no further effects on both currents in the presence of TTX. RAN (3, 6, and 9 mM) attenuated hypoxia-increased I Na.L and reverse I NCX in a concentration-dependent manner. Hypoxia-increased I Na.L and reverse I NCX were inhibited by 2 mM TTX, whereas 9 mM RAN applied sequentially did not further decrease both currents. In another group, after both currents were decreased by 9 mM RAN, 2 mM TTX had no further effects in the presence of Ran. In monophasic action potential (MAP) recording, early after-depolarizations (EADs) were suppressed by RAN (9 mM) during hypoxia. In conclusion, RAN decreased reverse I NCX by inhibiting I Na.L in normoxia, concentration-dependently attenuated the increase of I Na.L , which thereby decreased the reverse I NCX , and obviously relieved EADs during hypoxia.

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“…Ca 2+ is the key regulator of the majority of functions in cardiac myocytes, including metabolism, electric activity, contractility as well as apoptosis [154,169,170,[209][210][211][212]. Elevated cytosolic calcium leads to Ca 2+ overload in sarcoplasmic reticulum resulting in contractile dysfunction and increased risk for arrhythmia [51,[213][214][215][216][217].…”

Section: The Plateau Sodium Current In Heart Diseasesmentioning

confidence: 99%

“…Role of I Na,L in arrhythmogenesis Acquired or inherited increase of INa,L is associated with enhanced risk for cardiac arrhythmia and inhibition of INa,L was demonstrated to prevent or abolish arrhythmic electric activity of the heart [1,3,5,6,41,57,123,214,215]. There are multiple mechanisms INa,L might lead to manifest arrhythmic activity.…”

Section: The Plateau Sodium Current In Heart Diseasesmentioning

confidence: 99%

“…Other activators like ouabaine or Pyrethroids are also used for research purposes but held more 'dirty' [6,121]. Pharmacological suppression of plateau sodium current was shown beneficial to reduce contractile dysfunction and arrhythmic activity in several pathologic model [45,197,214,[242][243][244][245]. Since INa,L is the non-inactivating component of INa,T, it is inhibited by sodium channel blockers including quinidine, mexiletine or local anesthetics like lidocaine.…”

Section: The Plateau Sodium Current In Heart Diseasesmentioning

confidence: 99%

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An Emerging Antiarrhythmic Target: Late Sodium Current

Bányász

Szentandrássy²,

Magyar³

et al. 2014

CPD

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The cardiac late sodium current (INa,L) has been in the focus of research in the last decade. The first reports on the sustained component of voltage activated sodium current dates back to the early seventies, but early observations interpreted this tiny current as a product of a few channels that fail to inactivate having neither physiologic nor pathologic implications. INa,L has emerged recently as a potentially major arrhythmogenic mechanism in various heart diseases attracting the attention of both clinicians and researchers. Research activity on INa,L has exponentially increased since Ranolazine, an FDA-approved antianginal drug was shown to successfully suppress cardiac arrhythmias by inhibiting INa,L. This review aims to conclude a series of papers concerned with physiology and regulation of cardiac late sodium current. Focusing on some recent development of the field we discuss here critical evidences implicating INa,L as a potential target for treating myocardial dysfunction and cardiac arrhythmias.

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Late Sodium Current Inhibition Alone with Ranolazine Is Sufficient to Reduce Ischemia- and Cardiac Glycoside-Induced Calcium Overload and Contractile Dysfunction Mediated by Reverse-Mode Sodium/Calcium Exchange

Abstract: Excessive reverse-mode (RM) sodium/calcium exchanger 1

Cited by 25 publications

References 45 publications

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

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

An Emerging Antiarrhythmic Target: Late Sodium Current

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