Comparison of electrophysiological and antiarrhythmic effects of vernakalant, ranolazine, and sotalol in canine pulmonary vein sleeve preparations

Sicouri, Serge; Pourrier, Marc; Gibson, John K.; Lynch, Joseph J.; Antzelevitch, Charles

doi:10.1016/j.hrthm.2011.10.021

Cited by 21 publications

(18 citation statements)

References 49 publications

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“…Reduction of late I Na by ranolazine and GS-458967, a selective and potent inhibitor of late I Na , has also been shown to reduce the incidence of DADs in experimental studies of pulmonary vein and superior vena cava sleeves (Sicouri et al 2012a, b, 2013) Blocking late I Na using R 56865, ranolazine, or TTX has been shown to reduce Na + -dependent Ca 2+ loading of cardiac myocytes from normal and failing hearts (Song et al 2006; Undrovinas et al 2010; Sossalla et al 2008; Haigney et al 1994; Fraser et al 2006). These findings implicate increased Na + entry into myocytes via Na + channels as a cause of Na + and Ca 2+ loading of myocytes, and arrhythmogenic DADs, while inhibition of late I Na can be used as a means of reducing occurrences of DADs.…”

Section: Mechanisms Underlying Late Ina-induced Arrhythmogenesismentioning

confidence: 99%

The Role of Late I Na in Development of Cardiac Arrhythmias

Antzelevitch

Nesterenko

Shryock

et al. 2014

Handbook of Experimental Pharmacology

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Late INa is an integral part of the sodium current, which persists long after the fast-inactivating component. The magnitude of the late INa is relatively small in all species and in all types of cardiomyocytes as compared with the amplitude of the fast sodium current, but it contributes significantly to the shape and duration of the action potential. This late component had been shown to increase in several acquired or congenital conditions, including hypoxia, oxidative stress, and heart failure, or due to mutations in SCN5A, which encodes the α-subunit of the sodium channel, as well as in channel-interacting proteins, including multiple β subunits and anchoring proteins. Patients with enhanced late INa exhibit the type-3 long QT syndrome (LQT3) characterized by high propensity for the life-threatening ventricular arrhythmias, such as Torsade de Pointes (TdP), as well as for atrial fibrillation. There are several distinct mechanisms of arrhythmogenesis due to abnormal late INa, including abnormal automaticity, early and delayed afterdepolarization-induced triggered activity, and dramatic increase of ventricular dispersion of repolarization. Many local anesthetic and antiarrhythmic agents have a higher potency to block late INa as compared with fast INa. Several novel compounds, including ranolazine, GS-458967, and F15845, appear to be the most selective inhibitors of cardiac late INa reported to date. Selective inhibition of late INa is expected to be an effective strategy for correcting these acquired and congenital channelopathies.

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Section: Mechanisms Underlying Late Ina-induced Arrhythmogenesismentioning

confidence: 99%

The Role of Late I Na in Development of Cardiac Arrhythmias

Antzelevitch

Nesterenko

Shryock

et al. 2014

Handbook of Experimental Pharmacology

Self Cite

131

122

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“…3B. In the canine pulmonary vein sleeve preparation, drugs with a Na + channel-blocking property such as ranolazine and vernakalant effectively suppressed delayed afterdepolarizations and triggered activities induced by rapid train stimulation in the presence of isoproterenol and highCa 2+ concentrations (31). Furthermore, in the isolated canine pulmonary vein, the angiotensin-converting enzyme inhibitor enarapril or the angiotensin II-receptor blocker losartan also suppressed delayed afterdepolarizations and triggered activities (32), which shows a "direct" antiarrhythmic effect by suppressing triggers responsible for the genesis of atrial fibrillation in addition to their "upstream" effects to reduce atrial structural remodeling.…”

Section: Antiarrhythmic Effects Of Drugs In the Pulmonary Veinmentioning

confidence: 99%

Pulmonary Vein Myocardium as a Possible Pharmacological Target for the Treatment of Atrial Fibrillation

et al. 2014

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Abstract. The pulmonary vein has a unique electrophysiological property showing an autonomic electrical activity, and this phenomenon has been further focused on as a source of triggers of atrial fibrillation. The pulmonary vein cardiomyocytes have shorter action potential duration, less negative resting membrane potential, and smaller maximum upstroke velocity than those in the left atrium, whose underlying cellular mechanisms may generate arrhythmogenic substrates such as abnormal automaticity and triggered activity. In diseased conditions including sustained atrial tachycardia or chronic volume overload, its arrhythmogenic profile can be further modified through abbreviation of action potential duration of the pulmonary vein myocardium, which may become a cause of reentry. Recently, antiarrhythmic effects of various drugs have been extensively investigated in isolated pulmonary vein preparations. The present review article highlights the recent advances in our understanding of electrophysiological and pharmacological profiles of the pulmonary vein.

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“…10,22 This leads to a significant prolongation of action potential duration and QT interval. A prolongation of the repolarization period is frequently associated with increased proarrhythmia risk.…”

Section: Prevention Of Proarrhythmia In Heart Failurementioning

confidence: 99%

“…Studies in atrial sleeve preparations have proven a rather atrialselective effect of vernakalant, 10 which is mainly related to the late Na þ channel (I Na,late ). 11 Inhibition of I Na,late seems to be a promising therapeutic approach for pharmacotherapy of AF, because the I Na,late inhibitor ranolazine has proven to be effective in reduction of AF in experimental 12,13 and clinical 14 studies.…”

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confidence: 99%