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

Maria Mathilde Haugaard; Eva Zander Hesselkilde; Steen Michael Pehrson; Helena Carstensen; Mette Flethøj Madsen; Kirstine Færgemand Præstegaard; Ulrik Svane Sørensen; Jonas Goldin Diness; Morten Grunnet; Rikke Buhl; Thomas Jespersen

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

Maria Mathilde Haugaard, Eva Zander Hesselkilde, Steen Michael Pehrson, Helena Carstensen, Mette Flethøj Madsen, Kirstine Færgemand Præstegaard, Ulrik Svane Sørensen, Jonas Goldin Diness, Morten Grunnet, Rikke Buhl, Thomas Jespersen

44 Citations (Scopus)

Abstract

BACKGROUND: 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.

CONCLUSION: 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.

Original language	English
Journal	Heart rhythm : the official journal of the Heart Rhythm Society
Volume	12
Issue number	4
Pages (from-to)	825-835
Number of pages	11
ISSN	1547-5271
DOIs	https://doi.org/10.1016/j.hrthm.2014.12.028
Publication status	Published - 1 Apr 2015

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10.1016/j.hrthm.2014.12.028

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Haugaard, M. M., Hesselkilde, E. Z., Pehrson, S. M., Carstensen, H., Madsen, M. F., Præstegaard, K. F., Sørensen, U. S., Diness, J. G., Grunnet, M., Buhl, R., & Jespersen, T. (2015). Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses. Heart rhythm : the official journal of the Heart Rhythm Society, 12(4), 825-835. https://doi.org/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. / Haugaard, Maria Mathilde; Hesselkilde, Eva Zander; Pehrson, Steen Michael et al.

In: Heart rhythm : the official journal of the Heart Rhythm Society, Vol. 12, No. 4, 01.04.2015, p. 825-835.

Research output: Contribution to journal › Journal article › Research › peer-review

Haugaard, MM, Hesselkilde, EZ, Pehrson, SM, Carstensen, H, Madsen, MF, Præstegaard, KF, Sørensen, US, Diness, JG, Grunnet, M, Buhl, R & Jespersen, T 2015, 'Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses', Heart rhythm : the official journal of the Heart Rhythm Society, vol. 12, no. 4, pp. 825-835. https://doi.org/10.1016/j.hrthm.2014.12.028

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

abstract = "BACKGROUND: 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.CONCLUSION: 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.",

author = "Haugaard, {Maria Mathilde} and Hesselkilde, {Eva Zander} and Pehrson, {Steen Michael} and Helena Carstensen and Madsen, {Mette Fleth{\o}j} and Pr{\ae}stegaard, {Kirstine F{\ae}rgemand} and S{\o}rensen, {Ulrik Svane} and Diness, {Jonas Goldin} and Morten Grunnet and Rikke Buhl and Thomas Jespersen",

year = "2015",

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doi = "10.1016/j.hrthm.2014.12.028",

language = "English",

volume = "12",

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journal = "Heart Rhythm",

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T1 - Pharmacologic inhibition of small-conductance calcium-activated potassium (SK) channels by NS8593 reveals atrial antiarrhythmic potential in horses

AU - Haugaard, Maria Mathilde

AU - Hesselkilde, Eva Zander

AU - Pehrson, Steen Michael

AU - Carstensen, Helena

AU - Madsen, Mette Flethøj

AU - Præstegaard, Kirstine Færgemand

AU - Sørensen, Ulrik Svane

AU - Diness, Jonas Goldin

AU - Grunnet, Morten

AU - Buhl, Rikke

AU - Jespersen, Thomas

PY - 2015/4/1

Y1 - 2015/4/1

N2 - BACKGROUND: 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.CONCLUSION: 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.

AB - BACKGROUND: 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.CONCLUSION: 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.

U2 - 10.1016/j.hrthm.2014.12.028

DO - 10.1016/j.hrthm.2014.12.028

M3 - Journal article

C2 - 25542425

SN - 1547-5271

VL - 12

SP - 825

EP - 835

JO - Heart Rhythm

JF - Heart Rhythm

IS - 4

ER -

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

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