期刊
CARDIOVASCULAR RESEARCH
卷 95, 期 3, 页码 308-316出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvs183
关键词
Transient outward current; Early afterdepolarization; Cardiac arrhythmias; Computer model; Dynamic mechanisms
资金
- American Heart Association Western states affiliate
- NIH/NHLBI [P01 HL078931, R01 HL97979]
- Laubisch endowments
- [HL 66140]
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. We first carried out patch-clamp experiments in isolated rabbit ventricular myocytes exposed to H2O2 (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,I-L) and the late sodium current, H2O2 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,I-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. 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,I-L reactivation is facilitated and I-Ks activation is slowed.
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