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Home / Equine Research Bank / Heart Rhythm / Pharmacologic inhibition of small-conductance calcium-activa...
Heart rhythm2014; 12(4); 825-835; doi: 10.1016/j.hrthm.2014.12.028

Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses.

Abstract: Small-conductance calcium-activated potassium (SK) channels have been found to play an important role in atrial repolarization and atrial fibrillation (AF). Objective: The purpose of this study was to investigate the existence and functional role of SK channels in the equine heart. Methods: Cardiac biopsies were analyzed to investigate the expression level of the most prominent cardiac ion channels, with special focus on SK channels, in the equine heart. Subcellular distribution of SK isoform 2 (SK2) was assessed by immunohistochemistry and confocal microscopy. The electrophysiologic and anti-AF effects of the relative selective SK channel inhibitor NS8593 (5 mg/kg IV) were evaluated in anesthetized horses, focusing on the potential of NS8593 to terminate acute pacing-induced AF, drug-induced changes in atrial effective refractory period, AF duration and vulnerability, and ventricular depolarization and repolarization times. Results: Analysis revealed equivalent mRNA transcript levels of the 3 SK channel isoforms in atria compared to ventricles. Immunohistochemistry and confocal microscopy displayed a widespread distribution of SK2 in both atrial and ventricular cardiomyocytes. NS8593 terminated all induced AF episodes (duration ≥15 minutes), caused pronounced prolongation of atrial effective refractory period, and reduced AF duration and vulnerability. QRS duration and QTc interval were not affected by treatment. Conclusions: SK channels are widely distributed in atrial and ventricular cardiomyocytes and contribute to atrial repolarization. Inhibition by NS8593 terminates pacing-induced AF of short duration and decreases AF duration and vulnerability without affecting ventricular conduction and repolarization. Thus, inhibition by NS8593 demonstrates clear atrial antiarrhythmic properties in healthy horses.
Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
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Publication Date: 2014-12-24 PubMed ID: 25542425DOI: 10.1016/j.hrthm.2014.12.028Google Scholar: Lookup
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  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The researchers conducted a study on horses to understand the functional role of Small-Conductance Calcium-Activated Potassium (SK) channels in the equine heart since these have been shown to play a key role in arrhythmias. Specific drug inhibition of these channels by NS8593 demonstrated anti-arrhythmic effect on the atrial heart tissues, but didn’t affect ventricular conduction and repolarization.

Research Methodology

  • The study began with the investigation of SK channels in the equine heart through analysis of cardiac biopsies. The primary aim was to understand the degree of expression of major cardiac ion channels in the horse’s heart, with a special focus on SK channels.
  • The subcellular distribution of SK isoform 2 (SK2) was evaluated using immunohistochemistry and confocal microscopy techniques.
  • The researchers applied the selective SK channel inhibitor NS8593 on anesthetized horses to assess its electrophysiological and anti-AF effects. They specifically focused on NS8593’s capacity to end the acute pacing-induced AF, discern the changes it causes in the atrial effective refractory period, AF length and susceptibility, plus ventricular depolarization and repolarization durations.

Research Findings

  • The researchers found that the SK isoforms were expressed equally in both the atria and ventricles. Further, they noticed that the SK2 was dispersed comprehensively in both atrial and ventricular cardiomyocytes.
  • The use of NS8593 yielded positive results as it managed to terminate all the initiated AF incidences. Notably, it extended the atrial effective refractory period considerably, and lowered the length and vulnerability of AF.
  • Important to note is that the QRS duration and QTc interval remained unaffected after treatment with NS8593.

Conclusion

  • The results suggested that SK channels are ubiquitous in both the atrial and ventricular cardiomyocytes and play an important role in atrial repolarization.
  • The use of NS8593, an inhibitor of the SK channels, demonstrated clear antiarrhythmic properties, ending pacing-induced AF of short duration and decreasing AF duration and susceptibility, all without affecting ventricular conduction and repolarization.
  • This breakthrough could potentially be applied in equine medicine to treat cardiac arrhythmias, but these findings might also have broader implications for understanding and treating human heart diseases. Nevertheless, further studies would be necessary.

Cite This Article

APA
Haugaard MM, Hesselkilde EZ, Pehrson S, Carstensen H, Flethøj M, Præstegaard KF, Sørensen US, Diness JG, Grunnet M, Buhl R, Jespersen T. (2014). Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses. Heart Rhythm, 12(4), 825-835. https://doi.org/10.1016/j.hrthm.2014.12.028

Publication

Heart rhythm
ISSN: 1556-3871
NlmUniqueID: 101200317
Country: United States
Language: English
Volume: 12
Issue: 4
Pages: 825-835
PII: S1547-5271(14)01546-X

Researcher Affiliations

Haugaard, Maria Mathilde
  • Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Electronic address: mmha@sund.ku.dk.
Hesselkilde, Eva Zander
  • Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Pehrson, Steen
  • Department of Cardiology, The Heart Centre, Copenhagen University Hospital, Taastrup, Denmark.
Carstensen, Helena
  • Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Flethøj, Mette
  • Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Præstegaard, Kirstine Færgemand
  • Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Sørensen, Ulrik Svane
  • Acesion Pharma, Copenhagen, Denmark.
Diness, Jonas Goldin
  • Acesion Pharma, Copenhagen, Denmark.
Grunnet, Morten
  • Acesion Pharma, Copenhagen, Denmark.
Buhl, Rikke
  • Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jespersen, Thomas
  • Danish National Foundation Research Centre in Arrhythmias (DARC) and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

MeSH Terms

  • 1-Naphthylamine / analogs & derivatives
  • 1-Naphthylamine / pharmacology
  • Animals
  • Anti-Arrhythmia Agents / pharmacology
  • Atrial Fibrillation / drug therapy
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / pathology
  • Disease Models, Animal
  • Electrophysiologic Techniques, Cardiac
  • Heart Atria / metabolism
  • Heart Atria / pathology
  • Horses
  • Immunohistochemistry
  • Microscopy, Confocal
  • Models, Anatomic
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Small-Conductance Calcium-Activated Potassium Channels / antagonists & inhibitors
  • Small-Conductance Calcium-Activated Potassium Channels / physiology
  • Treatment Outcome

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This article has been cited 49 times.
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