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Effects of SEA0400 on arrhythmogenicity in a Langendorff-perfused 1-month myocardial infarction rabbit model.

AbstractBACKGROUND:
The effects of SEA0400, a Na(+) /Ca(2+) exchanger (NCX) blocker, on dynamic factors and arrhythmogenic alternans in 1-month myocardial infarction (MI) hearts remain unknown.
METHODS:
Simultaneous voltage and intracellular Ca(2+) (Cai ) optical mapping was performed in 12 rabbit hearts with MI for 1 month and six normal rabbit hearts as control. Western-blot studies were performed in both groups in an additional six hearts for each. Action potential duration (APD) restitution was constructed and arrhythmogenic alternans was induced by dynamic pacing. SEA0400 (0.03, 3 μM) was administered after baseline studies.
RESULTS:
SEA0400 suppressed pacing-induced ventricular premature beats in a concentration-dependent manner. SEA0400 at 0.03 μM steepened APD restitution slopes and enhanced spatially discordant alternans (SDA), which became insignificant at 3 μM. The VF inducibility was seven of nine at baseline, nine of nine at 0.03 μM SEA0400, and five of nine at 3 μM SEA0400 (P = NS). Significant upregulation of NCX in the remote but not periinfarct zone and less degree downregulation of DHP1α in the remote versus periinfarct zone may play a role in enhancing SDA induction by SEA0400 in 1-month MI hearts.
CONCLUSIONS:
In 1-month MI hearts, SEA0400 suppresses pacing-induced ventricular premature beats, but also is proarrhythmic by steepening APD restitution and enhancing SDA via NCX inhibition. Heterogeneous upregulation of NCX and downregulation of DHP1α may contribute to SDA augmentation by SEA0400 in this model. The insignificant effect of SEA0400 on VF inducibility suggests that suppression of both reentry and triggered activity is required to suppress VF induction in this model.
AuthorsChung-Chuan Chou, Po-Cheng Chang, Ming-Shien Wen, Hui-Ling Lee, Yen Chu, Akemichi Baba, Toshio Matsuda, San-Jou Yeh, Delon Wu
JournalPacing and clinical electrophysiology : PACE (Pacing Clin Electrophysiol) Vol. 36 Issue 5 Pg. 596-606 (May 2013) ISSN: 1540-8159 [Electronic] United States
PMID23380010 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2013, The Authors. Journal compilation ©2013 Wiley Periodicals, Inc.
Chemical References
  • Aniline Compounds
  • Anti-Arrhythmia Agents
  • Phenyl Ethers
  • SEA 0400
  • Sodium-Calcium Exchanger
Topics
  • Aniline Compounds (administration & dosage, adverse effects)
  • Animals
  • Anti-Arrhythmia Agents (administration & dosage, adverse effects)
  • Arrhythmias, Cardiac (chemically induced, drug therapy, physiopathology)
  • Heart Rate (drug effects)
  • Myocardial Infarction (complications, drug therapy, physiopathology)
  • Perfusion (methods)
  • Phenyl Ethers (administration & dosage, adverse effects)
  • Rabbits
  • Sodium-Calcium Exchanger (antagonists & inhibitors)
  • Treatment Outcome

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