Dynamical mechanisms of pacemaker generation in IK1-downregulated human ventricular myocytes: Insights from bifurcation analyses of a mathematical model
Dynamical mechanisms of pacemaker generation in IK1-downregulated human ventricular myocytes: Insights from bifurcation analyses of a mathematical model
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DOI：
10.1529/biophysj.105.060830
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发表时间：
2005-10-01
影响因子：
3.4
通讯作者：
Shibamoto, T
中科院分区：
文献类型：
--
作者：
Kurata, Y;Hisatome, I;Shibamoto, T
通过对一个数学模型的分岔分析，研究了人心室肌细胞产生生物起搏点（BP）的动力学机制。平衡点（EPs），周期轨道，EPs的稳定性，和分岔点确定为分岔参数的函数，如内向整流K+电流的最大电导（I-K1），用于构建分岔图。当I-K1被抑制84.6%时，稳定极限环（BP活性）突然出现在不稳定的EP周围，通过鞍结分叉。在稳定的EP消失的分叉之后，I-K1简化系统仅具有不稳定的EP，这对于稳定的起搏至关重要。为了阐明单个肌膜电流如何影响EP不稳定性和BP的产生，我们进一步探讨了L型Ca ~（2+）通道电流（I-Ca，I-L）、延迟整流K ~+电流（I-K）或Na ~+/Ca ~（2+）交换器电流（I-NaCa）变化时系统的分叉结构。我们的研究结果表明，1），I-Ca，I-L是，但IK或I-NaCa不是，负责EP不稳定作为稳定BP产生的必要条件; 2），I-K是不可或缺的强大的起搏与大振幅，高上行速度，和稳定的频率;和3），I-NaCa是主导的起搏电流，但不一定需要产生自发振荡。
Dynamical mechanisms of the biological pacemaker ( BP) generation in human ventricular myocytes were investigated by bifurcation analyses of a mathematical model. Equilibrium points (EPs), periodic orbits, stability of EPs, and bifurcation points were determined as functions of bifurcation parameters, such as the maximum conductance of inward-rectifier K+ current (I-K1), for constructing bifurcation diagrams. Stable limit cycles ( BP activity) abruptly appeared around an unstable EP via a saddle-node bifurcation when I-K1 was suppressed by 84.6%. After the bifurcation at which a stable EP disappears, the I-K1-reduced system has an unstable EP only, which is essentially important for stable pacemaking. To elucidate how individual sarcolemmal currents contribute to EP instability and BP generation, we further explored the bifurcation structures of the system during changes in L-type Ca2+ channel current (I-Ca,I-L), delayed-rectifier K+ currents (I-K), or Na+/Ca2+ exchanger current (I-NaCa). Our results suggest that 1), I-Ca,I-L is, but IK or I-NaCa is not, responsible for EP instability as a requisite to stable BP generation; 2), I-K is indispensable for robust pacemaking with large amplitude, high upstroke velocity, and stable frequency; and 3), I-NaCa is the dominant pacemaker current but is not necessarily required for the generation of spontaneous oscillations.