January C T, Riddle J M
Department of Medicine, University of Chicago, IL 60637.
Circ Res. 1989 May;64(5):977-90. doi: 10.1161/01.res.64.5.977.
Early afterdepolarizations (EADs) are a type of triggered activity found in heart muscle. We used voltage-clamped sheep cardiac Purkinje fibers to examine the mechanism underlying EADs induced near action potential plateau voltages with the Ca2+ current agonist Bay K 8644 and the effect of several interventions known to suppress or enhance these EADs. Bay K 8644 produced an inward shift of the steady-state current-voltage relation near plateau voltages. Tetrodotoxin, lidocaine, verapamil, nitrendipine, and raising [K]o abolish EADs and shift the steady-state current-voltage relations outwardly. Using a two-pulse voltage-clamp protocol, an inward current transient was present at voltages where EADs were induced. The voltage-dependence of availability of the inward current transient and of EAD induction were similar. The time-dependence of recovery from inactivation of the inward current transient and of EAD amplitude were nearly identical. Without recovery of the inward current transient, EADs could not be elicited. The inward current transient was enhanced with Bay K 8644 and blocked by nitrendipine, but was not abolished by tetrodotoxin or replacement of [Na]o with an impermeant cation. These results support a hypothesis that the induction of EADs near action potential plateau voltages requires 1) a conditioning phase controlled by the sum of membrane currents present near the action potential plateau and characterized by lengthening and flattening of the plateau within a voltage range where, 2) recovery from inactivation and reactivation of L-type Ca2+ channels to carry the depolarizing charge can occur. Our results suggest an essential role for the L-type Ca2+ "window" current and provide a framework for understanding the role of several membrane currents in the induction and block of EADs.
早期后去极化（EADs）是在心肌中发现的一种触发活动。我们使用电压钳制的绵羊心脏浦肯野纤维，以研究在动作电位平台期电压附近由Ca2+电流激动剂Bay K 8644诱导的EADs的潜在机制，以及几种已知可抑制或增强这些EADs的干预措施的作用。Bay K 8644在平台期电压附近使稳态电流-电压关系向内偏移。河豚毒素、利多卡因、维拉帕米、尼群地平和提高细胞外钾离子浓度可消除EADs，并使稳态电流-电压关系向外偏移。使用双脉冲电压钳制方案，在诱导EADs的电压处存在内向电流瞬变。内向电流瞬变和EADs诱导的电压依赖性相似。内向电流瞬变和EADs幅度从失活恢复的时间依赖性几乎相同。没有内向电流瞬变的恢复，就无法诱发EADs。内向电流瞬变被Bay K 8644增强并被尼群地平阻断，但不被河豚毒素或用不透性阳离子替代细胞外钠离子所消除。这些结果支持一个假说，即在动作电位平台期电压附近诱导EADs需要1）一个由动作电位平台期附近存在的膜电流总和控制的预处理阶段，其特征是在一个电压范围内平台期延长和平坦化，在这个电压范围内，2）L型Ca2+通道从失活恢复并重新激活以携带去极化电荷可以发生。我们的结果表明L型Ca2+“窗口”电流的重要作用，并为理解几种膜电流在EADs诱导和阻断中的作用提供了一个框架。
