Role of small-conductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog

Xiao-Yan Qi, Jonas G Diness, Bianca J J M Brundel, Xiao-Bo Zhou, Patrice Naud, Chia-Tung Wu, Hai Huang, Masahide Harada, Mona Aflaki, Dobromir Dobrev, Morten Grunnet, Stanley Nattel

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Recent evidence points to functional Ca²⁺-dependent K⁺ (SK) channels in the heart that may govern atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. This study addressed the role of SK channels in atrial repolarization and AF persistence in a canine AF model.

METHODS AND RESULTS: Electrophysiological variables were assessed in dogs subjected to atrial remodeling by 7-day atrial tachypacing (AT-P), as well as controls. Ionic currents and single-channel properties were measured in isolated canine atrial cardiomyocytes by patch clamp. NS8593, a putative selective SK blocker, suppressed SK current with an IC₅₀ of ≈5 μmol/L, without affecting Na⁺, Ca²⁺, or other K⁺ currents. Whole-cell SK current sensitive to NS8593 was significantly larger in pulmonary vein (PV) versus left atrial (LA) cells, without a difference in SK single-channel open probability (P(o)), whereas AT-P enhanced both whole-cell SK currents and single-channel P(o). SK-current block increased action potential duration in both PV and LA cells after AT-P; but only in PV cells in absence of AT-P. SK2 expression was more abundant at both mRNA and protein levels for PV versus LA in control dogs, in both control and AT-P; AT-P upregulated only SK1 at the protein level. Intravenous administration of NS8593 (5 mg/kg) significantly prolonged atrial refractoriness and reduced AF duration without affecting the Wenckebach cycle length, left ventricular refractoriness, or blood pressure.

CONCLUSIONS: SK currents play a role in canine atrial repolarization, are larger in PVs than LA, are enhanced by atrial-tachycardia remodeling, and appear to participate in promoting AF maintenance. These results are relevant to the potential mechanisms underlying the association between SK single-nucleotide polymorphisms and AF and suggest SK blockers as potentially interesting anti-AF drugs.

Original languageEnglish
Pages (from-to)430-40
Number of pages11
JournalCirculation
Volume129
Issue number4
DOIs
Publication statusPublished - 28 Jan 2014

Cite this

Qi, Xiao-Yan ; Diness, Jonas G ; Brundel, Bianca J J M ; Zhou, Xiao-Bo ; Naud, Patrice ; Wu, Chia-Tung ; Huang, Hai ; Harada, Masahide ; Aflaki, Mona ; Dobrev, Dobromir ; Grunnet, Morten ; Nattel, Stanley. / Role of small-conductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog. In: Circulation. 2014 ; Vol. 129, No. 4. pp. 430-40.
@article{3b52147e56f948f089fe375036231a49,
title = "Role of small-conductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog",
abstract = "BACKGROUND: Recent evidence points to functional Ca²⁺-dependent K⁺ (SK) channels in the heart that may govern atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. This study addressed the role of SK channels in atrial repolarization and AF persistence in a canine AF model.METHODS AND RESULTS: Electrophysiological variables were assessed in dogs subjected to atrial remodeling by 7-day atrial tachypacing (AT-P), as well as controls. Ionic currents and single-channel properties were measured in isolated canine atrial cardiomyocytes by patch clamp. NS8593, a putative selective SK blocker, suppressed SK current with an IC₅₀ of ≈5 μmol/L, without affecting Na⁺, Ca²⁺, or other K⁺ currents. Whole-cell SK current sensitive to NS8593 was significantly larger in pulmonary vein (PV) versus left atrial (LA) cells, without a difference in SK single-channel open probability (P(o)), whereas AT-P enhanced both whole-cell SK currents and single-channel P(o). SK-current block increased action potential duration in both PV and LA cells after AT-P; but only in PV cells in absence of AT-P. SK2 expression was more abundant at both mRNA and protein levels for PV versus LA in control dogs, in both control and AT-P; AT-P upregulated only SK1 at the protein level. Intravenous administration of NS8593 (5 mg/kg) significantly prolonged atrial refractoriness and reduced AF duration without affecting the Wenckebach cycle length, left ventricular refractoriness, or blood pressure.CONCLUSIONS: SK currents play a role in canine atrial repolarization, are larger in PVs than LA, are enhanced by atrial-tachycardia remodeling, and appear to participate in promoting AF maintenance. These results are relevant to the potential mechanisms underlying the association between SK single-nucleotide polymorphisms and AF and suggest SK blockers as potentially interesting anti-AF drugs.",
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author = "Xiao-Yan Qi and Diness, {Jonas G} and Brundel, {Bianca J J M} and Xiao-Bo Zhou and Patrice Naud and Chia-Tung Wu and Hai Huang and Masahide Harada and Mona Aflaki and Dobromir Dobrev and Morten Grunnet and Stanley Nattel",
year = "2014",
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language = "English",
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pages = "430--40",
journal = "Circulation",
issn = "0009-7322",
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Qi, X-Y, Diness, JG, Brundel, BJJM, Zhou, X-B, Naud, P, Wu, C-T, Huang, H, Harada, M, Aflaki, M, Dobrev, D, Grunnet, M & Nattel, S 2014, 'Role of small-conductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog' Circulation, vol. 129, no. 4, pp. 430-40. https://doi.org/10.1161/CIRCULATIONAHA.113.003019

Role of small-conductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog. / Qi, Xiao-Yan; Diness, Jonas G; Brundel, Bianca J J M; Zhou, Xiao-Bo; Naud, Patrice; Wu, Chia-Tung; Huang, Hai; Harada, Masahide; Aflaki, Mona; Dobrev, Dobromir; Grunnet, Morten; Nattel, Stanley.

In: Circulation, Vol. 129, No. 4, 28.01.2014, p. 430-40.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Role of small-conductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog

AU - Qi, Xiao-Yan

AU - Diness, Jonas G

AU - Brundel, Bianca J J M

AU - Zhou, Xiao-Bo

AU - Naud, Patrice

AU - Wu, Chia-Tung

AU - Huang, Hai

AU - Harada, Masahide

AU - Aflaki, Mona

AU - Dobrev, Dobromir

AU - Grunnet, Morten

AU - Nattel, Stanley

PY - 2014/1/28

Y1 - 2014/1/28

N2 - BACKGROUND: Recent evidence points to functional Ca²⁺-dependent K⁺ (SK) channels in the heart that may govern atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. This study addressed the role of SK channels in atrial repolarization and AF persistence in a canine AF model.METHODS AND RESULTS: Electrophysiological variables were assessed in dogs subjected to atrial remodeling by 7-day atrial tachypacing (AT-P), as well as controls. Ionic currents and single-channel properties were measured in isolated canine atrial cardiomyocytes by patch clamp. NS8593, a putative selective SK blocker, suppressed SK current with an IC₅₀ of ≈5 μmol/L, without affecting Na⁺, Ca²⁺, or other K⁺ currents. Whole-cell SK current sensitive to NS8593 was significantly larger in pulmonary vein (PV) versus left atrial (LA) cells, without a difference in SK single-channel open probability (P(o)), whereas AT-P enhanced both whole-cell SK currents and single-channel P(o). SK-current block increased action potential duration in both PV and LA cells after AT-P; but only in PV cells in absence of AT-P. SK2 expression was more abundant at both mRNA and protein levels for PV versus LA in control dogs, in both control and AT-P; AT-P upregulated only SK1 at the protein level. Intravenous administration of NS8593 (5 mg/kg) significantly prolonged atrial refractoriness and reduced AF duration without affecting the Wenckebach cycle length, left ventricular refractoriness, or blood pressure.CONCLUSIONS: SK currents play a role in canine atrial repolarization, are larger in PVs than LA, are enhanced by atrial-tachycardia remodeling, and appear to participate in promoting AF maintenance. These results are relevant to the potential mechanisms underlying the association between SK single-nucleotide polymorphisms and AF and suggest SK blockers as potentially interesting anti-AF drugs.

AB - BACKGROUND: Recent evidence points to functional Ca²⁺-dependent K⁺ (SK) channels in the heart that may govern atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. This study addressed the role of SK channels in atrial repolarization and AF persistence in a canine AF model.METHODS AND RESULTS: Electrophysiological variables were assessed in dogs subjected to atrial remodeling by 7-day atrial tachypacing (AT-P), as well as controls. Ionic currents and single-channel properties were measured in isolated canine atrial cardiomyocytes by patch clamp. NS8593, a putative selective SK blocker, suppressed SK current with an IC₅₀ of ≈5 μmol/L, without affecting Na⁺, Ca²⁺, or other K⁺ currents. Whole-cell SK current sensitive to NS8593 was significantly larger in pulmonary vein (PV) versus left atrial (LA) cells, without a difference in SK single-channel open probability (P(o)), whereas AT-P enhanced both whole-cell SK currents and single-channel P(o). SK-current block increased action potential duration in both PV and LA cells after AT-P; but only in PV cells in absence of AT-P. SK2 expression was more abundant at both mRNA and protein levels for PV versus LA in control dogs, in both control and AT-P; AT-P upregulated only SK1 at the protein level. Intravenous administration of NS8593 (5 mg/kg) significantly prolonged atrial refractoriness and reduced AF duration without affecting the Wenckebach cycle length, left ventricular refractoriness, or blood pressure.CONCLUSIONS: SK currents play a role in canine atrial repolarization, are larger in PVs than LA, are enhanced by atrial-tachycardia remodeling, and appear to participate in promoting AF maintenance. These results are relevant to the potential mechanisms underlying the association between SK single-nucleotide polymorphisms and AF and suggest SK blockers as potentially interesting anti-AF drugs.

KW - 1-Naphthylamine/analogs & derivatives

KW - Animals

KW - Atrial Fibrillation/pathology

KW - Disease Models, Animal

KW - Dogs

KW - Electrophysiologic Techniques, Cardiac

KW - Electrophysiological Phenomena/physiology

KW - Heart Atria/drug effects

KW - Myocytes, Cardiac/pathology

KW - Patch-Clamp Techniques

KW - Potassium Channel Blockers/pharmacology

KW - Pulmonary Veins/drug effects

KW - Small-Conductance Calcium-Activated Potassium Channels/drug effects

U2 - 10.1161/CIRCULATIONAHA.113.003019

DO - 10.1161/CIRCULATIONAHA.113.003019

M3 - Article

VL - 129

SP - 430

EP - 440

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 4

ER -