Rate dependence and regulation of action potential and calcium transient in a canine cardiac ventricular cell model
Rate dependence and regulation of action potential and calcium transient in a canine cardiac ventricular cell model
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DOI：
10.1161/01.cir.0000147231.69595.d3
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发表时间：
2004-11-16
期刊：
影响因子：
37.8
通讯作者：
Rudy, Y
中科院分区：
文献类型：
--
作者：
Hund, TJ;Rudy, Y
背景-计算生物学是一个强大的工具，阐明在细胞水平上，离子过程之间的复杂相互作用决定行为的致突变机制。建立了一个新的犬心室心外膜动作电位和钙循环的理论模型，并用于研究Ca 2+瞬时（CaT）和动作电位时程（APD）率依赖性的离子机制。方法和结果-将Ca 2 +/钙调素依赖性蛋白激酶（CaMKII）调节途径整合到模型中，该模型包括一个新的Ca 2+释放公式，Ca 2+子空间，动态氯化物处理和基于犬心室数据的主要离子电流的制剂。起搏周期长度从8000 ms缩短至300 ms缩短APD主要是因为I-Ca（L）减少，I-tol、I-NaK和晚期I-Na也有贡献。CaT振幅增加，周期长度从8000到500毫秒。这种积极的速率依赖性依赖于CaMKII activity.Conclusions - CaMKII是一个重要的决定因素的CaT的速率依赖性，但不是APD，这取决于离子通道动力学。CaMKII调节的模型可以作为其他调节途径对细胞功能影响的模型。
Background - Computational biology is a powerful tool for elucidating arrhythmogenic mechanisms at the cellular level, where complex interactions between ionic processes determine behavior. A novel theoretical model of the canine ventricular epicardial action potential and calcium cycling was developed and used to investigate ionic mechanisms underlying Ca2+ transient (CaT) and action potential duration (APD) rate dependence.Methods and Results - The Ca2+/calmodulin-dependent protein kinase (CaMKII) regulatory pathway was integrated into the model, which included a novel Ca2+-release formulation, Ca2+ subspace, dynamic chloride handling, and formulations for major ion currents based on canine ventricular data. Decreasing pacing cycle length from 8000 to 300 ms shortened APD primarily because of I-Ca(L) reduction, with additional contributions from I-tol, I-NaK, and late I-Na. CaT amplitude increased as cycle length decreased from 8000 to 500 ms. This positive rate - dependent property depended on CaMKII activity.Conclusions - CaMKII is an important determinant of the rate dependence of CaT but not of APD, which depends on ion-channel kinetics. The model of CaMKII regulation may serve as a paradigm for modeling effects of other regulatory pathways on cell function.