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(Circulation. 2004;110:2299-2306.)
© 2004 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Role of I_Kur in Controlling Action Potential Shape and Contractility in the Human Atrium

Influence of Chronic Atrial Fibrillation

Erich Wettwer, PhD^*; Ottó Hála, PhD^*; Torsten Christ, MD; Jürgen F. Heubach, MD; Dobromir Dobrev, MD, PhD; Michael Knaut, MD; András Varró, MD; Ursula Ravens, MD, PhD

From the Department of Pharmacology and Toxicology, Dresden University of Technology (E.W., T.C., J.F.H., D.D., U.R.), and the Cardiovascular Center (M.K.), Dresden, Germany; and the Department of Pharmacology and Pharmacotherapy, Medical University of Szeged, Szeged, Hungary (O.H., A.V.).

Correspondence to Dr Erich Wettwer, Fetscherstraße 74, 01307 Dresden, Germany. E-mail wettwer{at}rcs.urz.tu-dresden.de

Received November 4, 2003; de novo received April 5, 2004; revision received May 17, 2004; accepted May 21, 2004.

Background— The ultrarapid outward current I_Kur is a major repolarizing current in human atrium and a potential target for treating atrial arrhythmias. The effects of selective block of I_Kur by low concentrations of 4-aminopyridine 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 APD₂₀ 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 I_Kur block in human atrial APs predicted secondary increases in I_Ca,L and in the outward rectifiers I_Kr and I_Ks, with smaller changes in AF than SR. The indirect increase in I_Ca,L was supported by a positive inotropic effect of 4-aminopyridine without direct effects on I_Ca,L in atrial but not ventricular preparations. In accordance with the model predictions, block of I_Kr with E-4031 converted APD shortening effects of I_Kur block in SR into AP prolongation.

Conclusions— Whether inhibition of I_Kur prolongs or shortens APD depends on the disease status of the atria and is determined by the level of electrical remodeling.

Key Words: ion channels • potassium channel blockers • contraction • action potentials • fibrillation

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