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

Abstract

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 (APD 90 ) 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 APD 90 from 414±10 to 350±10 ms in SR but prolonged APD 90 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.