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


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 micromol/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 micromol/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.
Wettwer
Erich
E
Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany. wettwer@rcs.urz.tu-dresden.de
Hála
Ottó
O
Christ
Torsten
T
Heubach
Jürgen F
JF
Dobrev
Dobromir
D
Knaut
Michael
M
Varró
András
A
Ravens
Ursula
U
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000368:Aged; D020517:Atrial Appendage / Q000187:drug effects / Q000502:physiology*; D001281:Atrial Fibrillation / Q000503:physiopathology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000502:physiology; D002908:Chronic Disease; D003198:Computer Simulation; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D017136:Ion Transport / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology
C501729:AVE 0118; D001713:Biphenyl Compounds; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D015761:4-Aminopyridine; D011188:Potassium