Role of the transient outward potassium current in the genesis of early afterdepolarizations in cardiac cells.
Role of the transient outward potassium current in the genesis of early afterdepolarizations in cardiac cells.
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瞬时外向钾电流在心肌细胞早期后去极化发生中的作用。
DOI：
10.1093/cvr/cvs183
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发表时间：
2012
影响因子：
10.8
通讯作者：
Xie,Lai-Hua
中科院分区：
文献类型：
--
作者：
Zhao,Zhenghang;Xie,Yuanfang;Wen,Hairuo;Xiao,Dandan;Allen,Charelle;Fefelova,Nadezhda;Dun,Wen;Boyden,PenelopeA;Qu,Zhilin;Xie,Lai-Hua
瞬时外向钾电流（Ito）在动作电位（AP）的形态学和动力学中起重要作用，但其在早期后除极（埃兹）发生中的作用尚不清楚。我们的目的是研究的影响和机制ofItoon EAD的成因在心脏cells使用相结合的实验和computational approaches.Methods和resultsWe首先进行了膜片钳实验在离体兔心室肌细胞暴露于H2 O2（0.2或1 mM），其中埃兹诱导在缓慢的起搏速率。通过增加起搏频率或用2 mM 4-氨基吡啶阻断Ito来消除埃兹。除了增强L型钙电流（伊卡，L）和晚期钠电流外，H2 O2还增加了Ito的电导，减慢了Ito的失活，并加速了Ito失活的恢复。计算机模拟结果表明，在复极储备减少的情况下，I促进埃兹与实验观察一致。然而，埃兹仅在Itoconductance和失活时间常数的中间范围内被促进。其机制是I降低AP平台电压，使时间依赖性钾电流（IKs）激活进一步减慢，使ICa，L可用于再激活，导致电压振荡而出现埃兹。结论在心肌细胞中，Ito具有适当的电导率和失活速度，通过将AP平台设置在ICa，L再激活容易和IKs激活减慢的电压范围内，增强埃兹。
AimsThe transient outward potassium current (Ito) 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 ofItoon EAD genesis in cardiac cells using combined experimental and computational approaches.Methods and resultsWe 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 blockingItowith 2 mM 4-aminopyridine. In addition to enhancing the L-type calcium current (ICa,L) and the late sodium current, H2O2also increased the conductance, slowed inactivation, and accelerated recovery from the inactivation ofIto. Computer simulations showed thatItopromoted EADs under the condition of reduced repolarization reserve, consistent with the experimental observations. However, EADs were only promoted in the intermediate ranges of theItoconductance and the inactivation time constant. The underlying mechanism is thatItolowers the AP plateau voltage into the range at which the time-dependent potassium current (namelyIKs) activation is further slowed andICa,Lis available for reactivation, leading to voltage oscillations to manifest EADs. Further experimental studies in cardiac cells of other species validated the theoretical predictions.ConclusionIn cardiac cells,Ito, with a proper conductance and inactivation speed, potentiates EADs by setting the AP plateau into the voltage range whereICa,Lreactivation is facilitated andIKsactivation is slowed.