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-...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.展开更多
文摘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.
