title: Inhibitors of arachidonate-regulated calcium channel signaling suppress triggered activity induced by the late sodium current.
abstract: Disturbances in myocyte calcium homeostasis are hypothesized to be one cause for cardiac arrhythmia. The full development of this hypothesis requires (i) the identification of all sources of arrhythmogenic calcium and (ii) an understanding of the mechanism(s) through which calcium initiates arrhythmia. To these ends we superfused rat left atria with the late sodium current activator type II Anemonia sulcata toxin (ATXII). This toxin prolonged atrial action potentials, induced early afterdepolarization, and provoked triggered activity. The calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93 (N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulphon-amide) suppressed ATXII triggered activity but its inactive congener KN-92 (2-[N-(4-methoxy benzenesulfonyl)]amino-N-(4-chlorocinnamyl)-N-methylbenzylamine) did not. Neither drug affected normal atrial contractility. Calcium entry via L-type channels or calcium leakage from sarcoplasmic reticulum stores are not critical for this type of ectopy as neither verapamil ((RS)-2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl]-(methyl)amino}-2-prop-2-ylpentanenitrile) nor ryanodine affected ATXII triggered activity. By contrast, inhibitors of the voltage independent arachidonate-regulated calcium (ARC) channel and the store-operated calcium channel specifically suppressed ATXII triggered activity without normalizing action potentials or affecting atrial contractility. Inhibitors of cytosolic calcium-dependent phospholipase A2 also suppressed triggered activity suggesting that this lipase, which generates free arachidonate, plays a key role in ATXII ectopy. Thus, increased left atrial late sodium current appears to activate atrial Orai-linked ARC and store operated calcium channels, and these voltage-independent channels may be unexpected sources for the arrhythmogenic calcium that underlies triggered activity.
authors.affiliation: KOR Therapies, LLC, The University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: kor.cures@gmail.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Wolkowicz
authors.affiliation: The Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Patrick K
authors.initials: PK
authors.lastname: Umeda
authors.affiliation: The Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Oleg F
authors.initials: OF
authors.lastname: Sharifov
authors.affiliation: The Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: C Roger
authors.initials: CR
authors.lastname: White
authors.affiliation: The Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: The Department of Anesthesiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Mahtani
authors.affiliation: The Department of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Urthaler
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000502:physiology; D016275:Atrial Function / Q000187:drug effects*; D001596:Benzylamines / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003064:Cnidarian Venoms / Q000494:pharmacology*; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors; D006325:Heart Atria / Q000187:drug effects*; D064801:Phospholipase A2 Inhibitors / Q000494:pharmacology; D051381:Rats; D012964:Sodium / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D016718:Arachidonic Acid; D001596:Benzylamines; D015220:Calcium Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002316:Cardiotonic Agents; D003064:Cnidarian Venoms; D054513:Group IV Phospholipases A2; D064801:Phospholipase A2 Inhibitors; D012964:Sodium; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C028800:toxin II (Anemonia sulcata); C516391:Pla2g4a protein, rat
keywords: ARC channel; ATXII; Early afterdepolarization; LOE-908; Late sodium current; Orai; SKF-96365; Store operated calcium channel; Triggered activity