Role of IKur in controlling action potential shape and contractility in the human atrium: Influence of chronic atrial fibrillation

Erich Wettwer, O. Hála, Torsten Christ, Jürgen F. Heubach, Dobromir Dobrev, Michael Knaut, A. Varró, Ursula Ravens

Research output: Contribution to journalArticle

199 Citations (Scopus)

Abstract

Background - The ultrarapid outward current IKur is a major repolarizing current in human atrium and a potential target for treating atrial arrhythmias. The effects of selective block of IKur by low concentrations of 4-aminopyridine of or the biphenyl derivative AVE 0118 were investigated on right atrial action potentials (APs) in trabeculae from patients in sinus rhythm (SR) or chronic atrial fibrillation (AF). Methods and Results - AP duration at 90% repolarization (APD90) was shorter in AF than in SR (300±16 ms, n = 6, versus 414±10 ms, n = 15), whereas APD 20 was longer (35±9 ms in AF versus 5±2 ms in SR, P <0.05). 4-Aminopyridine (5 μmol/L) elevated the plateau to more positive potentials from -21±3 to -6±3 mV in SR and 0±3 to +12±3 mV in AF. 4-Aminopyridine reversibly shortened APD90 from 414±10 to 350±10 ms in SR but prolonged APD90 from 300±16 to 320±13 ms in AF. Similar results were obtained with AVE 0118 (6 μmol/L). Computer simulations of IKur block in human atrial APs predicted secondary increases in ICa.L and in the outward rectifiers IKr and IKs, with smaller changes in AF than SR. The indirect increase in ICa.L was supported by a positive inotropic effect of 4-aminopyridine without direct effects on ICa.L in atrial but not ventricular preparations. In accordance with the model predictions, block of IKr with E-4031 converted APD shortening effects of IKur block in SR into AP prolongation. Conclusions - Whether inhibition of IKur prolongs or shortens APD depends on the disease status of the atria and is determined by the level of electrical remodeling.

Original languageEnglish
Pages (from-to)2299-2306
Number of pages8
JournalCirculation
Volume110
Issue number16
DOIs
Publication statusPublished - Oct 19 2004

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pamidronate
Atrial Fibrillation
Action Potentials
4-Aminopyridine
Atrial Remodeling
Computer Simulation
Cardiac Arrhythmias

Keywords

  • Action potentials
  • Contraction
  • Fibrillation
  • Ion channels
  • Potassium channel blockers

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Role of IKur in controlling action potential shape and contractility in the human atrium : Influence of chronic atrial fibrillation. / Wettwer, Erich; Hála, O.; Christ, Torsten; Heubach, Jürgen F.; Dobrev, Dobromir; Knaut, Michael; Varró, A.; Ravens, Ursula.

In: Circulation, Vol. 110, No. 16, 19.10.2004, p. 2299-2306.

Research output: Contribution to journalArticle

Wettwer, Erich ; Hála, O. ; Christ, Torsten ; Heubach, Jürgen F. ; Dobrev, Dobromir ; Knaut, Michael ; Varró, A. ; Ravens, Ursula. / Role of IKur in controlling action potential shape and contractility in the human atrium : Influence of chronic atrial fibrillation. In: Circulation. 2004 ; Vol. 110, No. 16. pp. 2299-2306.
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T1 - Role of IKur in controlling action potential shape and contractility in the human atrium

T2 - Influence of chronic atrial fibrillation

AU - Wettwer, Erich

AU - Hála, O.

AU - Christ, Torsten

AU - Heubach, Jürgen F.

AU - Dobrev, Dobromir

AU - Knaut, Michael

AU - Varró, A.

AU - Ravens, Ursula

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N2 - Background - The ultrarapid outward current IKur is a major repolarizing current in human atrium and a potential target for treating atrial arrhythmias. The effects of selective block of IKur by low concentrations of 4-aminopyridine of or the biphenyl derivative AVE 0118 were investigated on right atrial action potentials (APs) in trabeculae from patients in sinus rhythm (SR) or chronic atrial fibrillation (AF). Methods and Results - AP duration at 90% repolarization (APD90) was shorter in AF than in SR (300±16 ms, n = 6, versus 414±10 ms, n = 15), whereas APD 20 was longer (35±9 ms in AF versus 5±2 ms in SR, P <0.05). 4-Aminopyridine (5 μmol/L) elevated the plateau to more positive potentials from -21±3 to -6±3 mV in SR and 0±3 to +12±3 mV in AF. 4-Aminopyridine reversibly shortened APD90 from 414±10 to 350±10 ms in SR but prolonged APD90 from 300±16 to 320±13 ms in AF. Similar results were obtained with AVE 0118 (6 μmol/L). Computer simulations of IKur block in human atrial APs predicted secondary increases in ICa.L and in the outward rectifiers IKr and IKs, with smaller changes in AF than SR. The indirect increase in ICa.L was supported by a positive inotropic effect of 4-aminopyridine without direct effects on ICa.L in atrial but not ventricular preparations. In accordance with the model predictions, block of IKr with E-4031 converted APD shortening effects of IKur block in SR into AP prolongation. Conclusions - Whether inhibition of IKur prolongs or shortens APD depends on the disease status of the atria and is determined by the level of electrical remodeling.

AB - Background - The ultrarapid outward current IKur is a major repolarizing current in human atrium and a potential target for treating atrial arrhythmias. The effects of selective block of IKur by low concentrations of 4-aminopyridine of or the biphenyl derivative AVE 0118 were investigated on right atrial action potentials (APs) in trabeculae from patients in sinus rhythm (SR) or chronic atrial fibrillation (AF). Methods and Results - AP duration at 90% repolarization (APD90) was shorter in AF than in SR (300±16 ms, n = 6, versus 414±10 ms, n = 15), whereas APD 20 was longer (35±9 ms in AF versus 5±2 ms in SR, P <0.05). 4-Aminopyridine (5 μmol/L) elevated the plateau to more positive potentials from -21±3 to -6±3 mV in SR and 0±3 to +12±3 mV in AF. 4-Aminopyridine reversibly shortened APD90 from 414±10 to 350±10 ms in SR but prolonged APD90 from 300±16 to 320±13 ms in AF. Similar results were obtained with AVE 0118 (6 μmol/L). Computer simulations of IKur block in human atrial APs predicted secondary increases in ICa.L and in the outward rectifiers IKr and IKs, with smaller changes in AF than SR. The indirect increase in ICa.L was supported by a positive inotropic effect of 4-aminopyridine without direct effects on ICa.L in atrial but not ventricular preparations. In accordance with the model predictions, block of IKr with E-4031 converted APD shortening effects of IKur block in SR into AP prolongation. Conclusions - Whether inhibition of IKur prolongs or shortens APD depends on the disease status of the atria and is determined by the level of electrical remodeling.

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KW - Potassium channel blockers

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