Effect of hyperpolarization-activated current If on robustness of sinoatrial node pacemaking: theoretical study on influence of intracellular Na+ concentration
Effect of hyperpolarization-activated current If on robustness of sinoatrial node pacemaking: theoretical study on influence of intracellular Na+ concentration
复制标题
DOI：
10.1152/ajpheart.00777.2012
复制
发表时间：
2013-05-01
影响因子：
4.8
通讯作者：
Shibamoto, Toshishige
中科院分区：
文献类型：
--
作者：
Kurata, Yasutaka;Hisatome, Ichiro;Shibamoto, Toshishige
为了阐明超极化激活电流I-f与细胞内Na+浓度（Na-i）变化对窦房结（SAN）起搏稳健性的影响，我们从理论上研究了1)在l型Ca2+通道电流（I-CaL）或超极化负荷抑制期间，I-f对SAN模型细胞动力学特性的影响，以及2)Nai依赖于I-f的变化及其对模型细胞动力学特性的影响。对兔SAN细胞数学模型的na -i变量和na -i固定版本进行分岔分析；确定了平衡点（EPs）、极限环（lc）及其稳定性作为模型参数的函数。在na -i可变系统中，增加I-f电导（g(f)）使不稳定EPs和稳定LCs（节律性放电）的I-CaL电导（g(CaL)）区缩小，但在na -i固定系统中，在较低gf时节律性放电的I-CaL电导（g(CaL)）区略有扩大。在Na-i变量系统中，g(f)的增加导致EP和自发振荡期间Na-i的升高，这导致EP稳定和不稳定EP和节律性放电参数区域的收缩。随着g(f)的增大，在na -i可变体系中不稳定EPs和稳定lc的参数区变小，而在na -i固定体系中增大。这些发现表明，1)即使在生理g(f)范围内，I-f也不会通过促进EP稳定和LC不稳定而增强而减弱兔SAN细胞的稳健性；2)当Na-i固定时，在较低的gf下可以观察到I-f对起搏器活动稳健性的增强作用，但实际上被Na-i的I-f依赖性变化所逆转。
To elucidate the effects of hyperpolarization-activated current I-f on robustness of sinoatrial node (SAN) pacemaking in connection with intracellular Na+ concentration (Na-i) changes, we theoretically investigated 1) the impacts of I-f on dynamical properties of SAN model cells during inhibition of L-type Ca2+ channel currents (I-CaL) or hyperpolarizing loads and 2) I-f-dependent changes in Nai and their effects on dynamical properties of model cells. Bifurcation analyses were performed for Na-i-variable and Na-i-fixed versions of mathematical models for rabbit SAN cells; equilibrium points (EPs), limit cycles (LCs), and their stability were determined as functions of model parameters. Increasing I-f conductance (g(f)) shrank I-CaL conductance (g(CaL)) regions of unstable EPs and stable LCs (rhythmic firings) in the Na-i-variable system but slightly broadened that of rhythmic firings at lower gf in the Na-i-fixed system. In the Na-i-variable system, increased g(f) yielded elevations in Na-i at EPs and during spontaneous oscillations, which caused EP stabilization and shrinkage in the parameter regions of unstable EPs and rhythmic firings. As g(f) increased, parameter regions of unstable EPs and stable LCs determined for hyperpolarizing loads shrank in the Na-i-variable system but were enlarged in the Na-i-fixed system. These findings suggest that 1) I-f does not enhance but rather attenuates robustness of rabbit SAN cells via facilitating EP stabilization and LC destabilization even in physiological g(f) ranges; and 2) the enhancing effect of I-f on robustness of pacemaker activity, which could be observed at lower gf when Na-i was fixed, is actually reversed by I-f-dependent changes in Na-i.