Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration
Electrophysiologic effects of acute myocardial ischemia: a theoretical study of altered cell excitability and action potential duration
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DOI：
10.1016/s0008-6363(97)00093-x
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发表时间：
1997-08-01
影响因子：
10.8
通讯作者：
Rudy, Y
中科院分区：
文献类型：
--
作者：
Shaw, RM;Rudy, Y
目的：探讨心肌缺血急性期细胞兴奋性和动作电位持续时间变化的离子机制。方法：采用基于离子的心脏心室细胞理论模型——动态LRd模型，在单个离子电流和离子浓度水平上模拟了急性缺血的三种主要组成条件（[K](o)升高、酸中毒和缺氧）。这些条件被单独或联合应用，以确定导致静止电位下兴奋性降低、兴奋性恢复延迟和动作电位持续时间缩短的离子机制。结果：增加的细胞外钾（[K](o)）通过去极化静息膜电位（V-rest）对细胞兴奋性产生主要影响，导致钠通道可用性降低。酸中毒导致最大上冲程速度（dV(m)/dt）（max）的[K](o)独立降低。发生了从钠电流为主到钙电流为主的上冲程转变，并且只有在钠通道几乎完全（97%）失活后，钙电流才能维持上冲程。酸性条件通过钠和钙电流的酸性还原阻止了向钙主导的上冲程过渡。通过降低[ATP](i)和激活依赖于ATP的钾电流i - k （ATP）来模拟缺氧，这是唯一能使动作电位持续时间减少50%以上并重现实验观察到的AP形状变化的过程。l型钙电流的酸性或缺氧抑制不能重现所观察到的动作电位形状变化和APD缩短。兴奋性的延迟恢复，被称为“复极化后耐火度”，是由钠通道恢复的电压依赖动力学决定的；[K](o)升高引起的V-rest去极化使（dV(m)/dt）（max）恢复的时间常数从[K](o) = 4.5 mM时的tau = 10.3 ms增加到[K](o) = 12 mM时的tau = 81.4 ms，反映了钠通道恢复的主要减慢。缺氧和酸中毒对tau的影响较小。结论：离子通道水平上施加的[K](o)升高、酸中毒和缺氧等急性缺血的主要条件足以模拟与缺血相关的主要电变化。细胞膜兴奋性的降低和单个无负荷细胞兴奋性的延迟恢复是由[K](o)升高和酸中毒引起的额外兴奋性降低引起的。动作电位持续时间和形状的主要变化只能通过缺氧依赖性的I-K（ATP）开放来解释。(C) 1997爱思唯尔科学有限公司
Objective: To study the ionic mechanisms of electrophysiologic changes in cell excitability and action potential duration during the acute phase of myocardial ischemia. Methods: Using an ionic-based theoretical model of the cardiac ventricular cell, the dynamic LRd model, we have simulated the three major component conditions of acute ischemia (elevated [K](o), acidosis and anoxia) at the level of individual ionic currents and ionic concentrations. The conditions were applied individually and in combination to identify ionic mechanisms responsible for reduced excitability at rest potentials, delayed recovery of excitability, and shortened action potential duration. Results: Increased extracellular potassium ([K](o)) had the major effect on cell excitability by depolarizing resting membrane potential (V-rest), causing reduction in sodium channel availability. Acidosis caused a [K](o)-independent reduction in maximum upstroke velocity, (dV(m)/dt)(max). A transition from sodium-current dominated to calcium-current dominated upstroke occurred, and calcium current alone was able to sustain the upstroke, but only after sodium channels were almost completely (97%) inactivated. Acidic conditions prevented the transition to calcium dominated upstroke by acidic reduction of both sodium and calcium currents. Anoxia, simulated by lowering [ATP](i) and activating the ATP-dependent potassium current, I-K(ATP), was the only process that could decrease action potential duration by more than 50% and reproduce AP shape changes that are observed experimentally. Acidic or anoxic depression of the L-type calcium current could not reproduce the observed action potential shape changes and APD shortening. Delayed recovery of excitability, known as 'post-repolarization refractoriness', was determined by the voltage-dependent kinetics of sodium channel recovery; V-rest depolarization caused by elevated [K](o) increased the time constant of (dV(m)/dt)(max) recovery from tau = 10.3 ms at [K](o) = 4.5 mM to tau = 81.4 ms at [K](o) = 12 mM, reflecting major slowing of sodium-channel recovery. Anoxia and acidosis had little affect on tau. Conclusions: The major conditions of acute ischemia, namely elevated [K](o), acidosis and anoxia, applied at the ionic channel level are sufficient to simulate the major electrical changes associated with ischemia. Depression of membrane excitability and delayed recovery of excitability in the single, unloaded cell are caused by elevated [K](o) with additional excitability depression by acidosis. Major changes in action potential duration and shape can only be accounted for by anoxia-dependent opening of I-K(ATP). (C) 1997 Elsevier Science B.V.