PMID- 24362110
OWN - NLM
STAT- MEDLINE
DCOM- 20141014
LR  - 20140210
IS  - 1879-0712 (Electronic)
IS  - 0014-2999 (Linking)
VI  - 724
DP  - 2014 Feb 5
TI  - Inhibitors of arachidonate-regulated calcium channel signaling suppress triggered 
      activity induced by the late sodium current.
PG  - 92-101
LID - S0014-2999(13)00948-5 [pii]
LID - 10.1016/j.ejphar.2013.12.020 [doi]
AB  - 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.
CI  - Copyright (c) 2013 Elsevier B.V. All rights reserved.
FAU - Wolkowicz, Paul
AU  - Wolkowicz P
AD  - KOR Therapies, LLC, The University of Alabama at Birmingham, Birmingham, AL 
      35294, USA. Electronic address: kor.cures@gmail.com.
FAU - Umeda, Patrick K
AU  - Umeda PK
AD  - The Department of Medicine, The University of Alabama at Birmingham, Birmingham, 
      AL 35294, USA.
FAU - Sharifov, Oleg F
AU  - Sharifov OF
AD  - The Department of Medicine, The University of Alabama at Birmingham, Birmingham, 
      AL 35294, USA.
FAU - White, C Roger
AU  - White CR
AD  - The Department of Medicine, The University of Alabama at Birmingham, Birmingham, 
      AL 35294, USA.
FAU - Huang, Jian
AU  - Huang J
AD  - The Department of Medicine, The University of Alabama at Birmingham, Birmingham, 
      AL 35294, USA.
FAU - Mahtani, Harry
AU  - Mahtani H
AD  - The Department of Anesthesiology, The University of Alabama at Birmingham, 
      Birmingham, AL 35294, USA.
FAU - Urthaler, Ferdinand
AU  - Urthaler F
AD  - The Department of Medicine, The University of Alabama at Birmingham, Birmingham, 
      AL 35294, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131219
PL  - Netherlands
TA  - Eur J Pharmacol
JT  - European journal of pharmacology
JID - 1254354
RN  - 0 (Benzylamines)
RN  - 0 (Calcium Channels)
RN  - 0 (Cardiotonic Agents)
RN  - 0 (Cnidarian Venoms)
RN  - 0 (Phospholipase A2 Inhibitors)
RN  - 0 (Sulfonamides)
RN  - 139298-40-1 (KN 93)
RN  - 27YG812J1I (Arachidonic Acid)
RN  - 60748-45-0 (toxin II (Anemonia sulcata))
RN  - 9NEZ333N27 (Sodium)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - EC 3.1.1.4 (Group IV Phospholipases A2)
RN  - EC 3.1.1.4 (Pla2g4a protein, rat)
SB  - IM
MH  - Animals
MH  - Arachidonic Acid/physiology
MH  - Atrial Function/*drug effects
MH  - Benzylamines/pharmacology
MH  - Calcium Channels/*physiology
MH  - Calcium Signaling
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & 
      inhibitors/metabolism
MH  - Cardiotonic Agents/*pharmacology
MH  - Cnidarian Venoms/*pharmacology
MH  - Group IV Phospholipases A2/antagonists & inhibitors
MH  - Heart Atria/*drug effects
MH  - Phospholipase A2 Inhibitors/pharmacology
MH  - Rats
MH  - Sodium/*physiology
MH  - Sulfonamides/pharmacology
OTO - NOTNLM
OT  - ARC channel
OT  - ATXII
OT  - Early afterdepolarization
OT  - LOE-908
OT  - Late sodium current
OT  - Orai
OT  - SKF-96365
OT  - Store operated calcium channel
OT  - Triggered activity
EDAT- 2013/12/24 06:00
MHDA- 2014/10/15 06:00
CRDT- 2013/12/24 06:00
PHST- 2013/05/20 00:00 [received]
PHST- 2013/12/11 00:00 [revised]
PHST- 2013/12/12 00:00 [accepted]
PHST- 2013/12/24 06:00 [entrez]
PHST- 2013/12/24 06:00 [pubmed]
PHST- 2014/10/15 06:00 [medline]
AID - S0014-2999(13)00948-5 [pii]
AID - 10.1016/j.ejphar.2013.12.020 [doi]
PST - ppublish
SO  - Eur J Pharmacol. 2014 Feb 5;724:92-101. doi: 10.1016/j.ejphar.2013.12.020. Epub 
      2013 Dec 19.