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Neuronal Na + Channels as a Novel Cardiac Antiarrhythmic Target
Author(s) -
Radwanski Przemyslaw,
Brunello Lucia,
Knollmann Björn,
Gyorke Sandor
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.1025.13
Subject(s) - catecholaminergic polymorphic ventricular tachycardia , medicine , cardiology , myocyte , patch clamp , channel blocker , ryanodine receptor 2 , electrophysiology , chemistry , pharmacology , endocrinology , ryanodine receptor , receptor , calcium
Background Certain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with diastolic Ca 2+ release (DCR) from the sarcoplasmic reticulum. Surprisingly, CPVT patients often respond to treatment with Na + channel blockers. However, the relationship between Na + influx and disturbances in Ca 2+ handling immediately preceding arrhythmias in CPVT remains elusive. Methods Confocal microscopy and patch‐clamp recordings ofventricular myocytes isolated from CPVT mouse model with genetic ablation of cardiac calsequestrinwere used to assess Ca 2+ handling and Na + current density during various pharmacological interventions, while surface electrocardiograms were performed during catecholamine challenge. Results A subpopulation of Na + channels (neuronal‐ and not cardiac‐type Na + channels) colocalize with RyR2. Disruption of the cross‐talk between these by neuronal Na + channel blockade abolished persistent Na + current and reduced DCR in cells ( Fig a ).Such reduction of DCR on cellular level translated in decreased arrhythmias in vivo ( Fig b ). On the other hand, augmentation of the neuronal Na + channel activity with β‐Pompilidotoxin (β‐PMTX) increased DCR and caused frequent arrhythmias. Conclusion These data suggest that neuronal Na + channels can potentially serve as an antiarrhythmic target. As current antiarrhythmic drugs are all cardiac‐type Na + channel blockers, this is a major conceptual shift in cellular arrhythmogenesis.