Jafri M S, Rice J J, Winslow R L
Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Biophys J. 1998 Mar;74(3):1149-68. doi: 10.1016/S0006-3495(98)77832-4.
We construct a detailed mathematical model for Ca2+ regulation in the ventricular myocyte that includes novel descriptions of subcellular mechanisms based on recent experimental findings: 1) the Keizer-Levine model for the ryanodine receptor (RyR), which displays adaptation at elevated Ca2+; 2) a model for the L-type Ca2+ channel that inactivates by mode switching; and 3) a restricted subspace into which the RyRs and L-type Ca2+ channels empty and interact via Ca2+. We add membrane currents from the Luo-Rudy Phase II ventricular cell model to our description of Ca2+ handling to formulate a new model for ventricular action potentials and Ca2+ regulation. The model can simulate Ca2+ transients during an action potential similar to those seen experimentally. The subspace [Ca2+] rises more rapidly and reaches a higher level (10-30 microM) than the bulk myoplasmic Ca2+ (peak [Ca2+]i approximately 1 microM). Termination of sarcoplasmic reticulum (SR) Ca2+ release is predominately due to emptying of the SR, but is influenced by RyR adaptation. Because force generation is roughly proportional to peak myoplasmic Ca2+, we use [Ca2+]i in the model to explore the effects of pacing rate on force generation. The model reproduces transitions seen in force generation due to changes in pacing that cannot be simulated by previous models. Simulation of such complex phenomena requires an interplay of both RyR adaptation and the degree of SR Ca2+ loading. This model, therefore, shows improved behavior over existing models that lack detailed descriptions of subcellular Ca2+ regulatory mechanisms.
我们构建了一个用于心室肌细胞中Ca2+调节的详细数学模型，该模型基于最近的实验结果对亚细胞机制进行了新颖的描述：1）用于兰尼碱受体（RyR）的Keizer-Levine模型，其在Ca2+浓度升高时表现出适应性；2）一个通过模式转换失活的L型Ca2+通道模型；3）一个受限的子空间，RyRs和L型Ca2+通道向其中排空并通过Ca2+相互作用。我们将来自Luo-Rudy II期心室细胞模型的膜电流添加到我们对Ca2+处理的描述中，以建立一个新的心室动作电位和Ca2+调节模型。该模型可以模拟动作电位期间的Ca2+瞬变，类似于实验中观察到的情况。子空间中的[Ca2+]上升得更快，达到比肌浆总体Ca2+更高的水平（10 - 30 microM）（肌浆Ca2+峰值[Ca2+]i约为1 microM）。肌浆网（SR）Ca2+释放的终止主要是由于SR排空，但受RyR适应性影响。由于力的产生大致与肌浆Ca2+峰值成正比，我们在模型中使用[Ca2+]i来探索起搏率对力产生的影响。该模型再现了由于起搏变化导致的力产生中的转变，而这是以前的模型无法模拟的。对这种复杂现象的模拟需要RyR适应性和SR Ca2+负载程度的相互作用。因此，该模型比缺乏亚细胞Ca2+调节机制详细描述的现有模型表现出更好的性能。
