Department of Pharmacology, University of California, 451 Health Sciences Drive, GBSF Room 3513, Davis, CA 95616-8636, USA.
J Mol Cell Cardiol. 2010 Jan;48(1):112-21. doi: 10.1016/j.yjmcc.2009.09.019. Epub 2009 Oct 14.
We have developed a detailed mathematical model for Ca handling and ionic currents in the human ventricular myocyte. Our aims were to: (1) simulate basic excitation-contraction coupling phenomena; (2) use realistic repolarizing K current densities; (3) reach steady-state. The model relies on the framework of the rabbit myocyte model previously developed by our group, with subsarcolemmal and junctional compartments where ion channels sense higher [Ca] vs. bulk cytosol. Ion channels and transporters have been modeled on the basis of the most recent experimental data from human ventricular myocytes. Rapidly and slowly inactivating components of I(to) have been formulated to differentiate between endocardial and epicardial myocytes. Transmural gradients of Ca handling proteins and Na pump were also simulated. The model has been validated against a wide set of experimental data including action potential duration (APD) adaptation and restitution, frequency-dependent increase in Ca transient peak and Na. Interestingly, Na accumulation at fast heart rate is a major determinant of APD shortening, via outward shifts in Na pump and Na-Ca exchange currents. We investigated the effects of blocking K currents on APD and repolarization reserve: I(Ks) block does not affect the former and slightly reduces the latter; I(K1) blockade modestly increases APD and more strongly reduces repolarization reserve; I(Kr) blockers significantly prolong APD, an effect exacerbated as pacing frequency is decreased, in good agreement with experimental results in human myocytes. We conclude that this model provides a useful framework to explore excitation-contraction coupling mechanisms and repolarization abnormalities at the single myocyte level.
我们开发了一个详细的数学模型，用于处理人和人心室肌中的钙离子和离子电流。我们的目的是：（1）模拟基本的兴奋-收缩偶联现象；（2）使用现实的复极化 K 电流密度；（3）达到稳态。该模型依赖于我们小组之前开发的兔心肌细胞模型框架，亚细胞和连接区室中的离子通道感知较高的 [Ca] 与胞质溶胶相比。基于人心室肌细胞的最新实验数据，对离子通道和转运体进行了建模。快速和缓慢失活的 Ito 成分被制定为区分心内膜和心外膜心肌细胞。还模拟了钙处理蛋白和 Na 泵的跨壁梯度。该模型已经过广泛的实验数据验证，包括动作电位持续时间 (APD) 适应和恢复、钙瞬变峰值和 [Na]（i）随频率的增加。有趣的是，在快速心率下，Na 积累是 APD 缩短的主要决定因素，这是通过 Na 泵和 Na-Ca 交换电流的外向移动实现的。我们研究了阻断 K 电流对 APD 和复极化储备的影响：I（Ks）阻断不会影响前者，只会略微减少后者；I（K1）阻断适度增加 APD，更强烈地减少复极化储备；I（Kr）阻断剂显著延长 APD，随着起搏频率的降低，这种效应会加剧，这与人心肌细胞的实验结果非常吻合。我们得出的结论是，该模型为在单个心肌细胞水平上探索兴奋-收缩偶联机制和复极化异常提供了一个有用的框架。
