Role of the transient outward potassium current in the genesis of early afterdepolarizations in cardiac cells.
OBJECTIVE
The transient outward potassium current (I(to)) plays important roles in action potential (AP) morphology and dynamics; however, its role in the genesis of early afterdepolarizations (EADs) is not well understood. We aimed to study the effects and mechanisms of I(to) on EAD genesis in cardiac cells using combined experimental and computational approaches.


RESULTS
We first carried out patch-clamp experiments in isolated rabbit ventricular myocytes exposed to H(2)O(2) (0.2 or 1 mM), in which EADs were induced at a slow pacing rate. EADs were eliminated by either increasing the pacing rate or blocking I(to) with 2 mM 4-aminopyridine. In addition to enhancing the L-type calcium current (I(Ca,L)) and the late sodium current, H(2)O(2) also increased the conductance, slowed inactivation, and accelerated recovery from the inactivation of I(to). Computer simulations showed that I(to) promoted EADs under the condition of reduced repolarization reserve, consistent with the experimental observations. However, EADs were only promoted in the intermediate ranges of the I(to) conductance and the inactivation time constant. The underlying mechanism is that I(to) lowers the AP plateau voltage into the range at which the time-dependent potassium current (namely I(Ks)) activation is further slowed and I(Ca,L) is available for reactivation, leading to voltage oscillations to manifest EADs. Further experimental studies in cardiac cells of other species validated the theoretical predictions.


CONCLUSIONS
In cardiac cells, I(to), with a proper conductance and inactivation speed, potentiates EADs by setting the AP plateau into the voltage range where I(Ca,L) reactivation is facilitated and I(Ks) activation is slowed.
Department of Pharmacology, School of Medicine,  Xi'an Jiaotong University, Xi'an,  China.
Zhenghang
Z
Zhao
Yuanfang
Y
Xie
Hairuo
H
Wen
Dandan
D
Xiao
Charelle
C
Allen
Nadezhda
N
Fefelova
Wen
W
Dun
Penelope A
PA
Boyden
Zhilin
Z
Qu
Lai-Hua
LH
Xie
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D003198:Computer Simulation; D004285:Dogs; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012964:Sodium / Q000378:metabolism
D020746:Calcium Channels, L-Type; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012964:Sodium; D006861:Hydrogen Peroxide; D015761:4-Aminopyridine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D011188:Potassium; D002118:Calcium