Roles of hyperpolarization-activated current If in sinoatrial node pacemaking: insights from bifurcation analysis of mathematical models
Roles of hyperpolarization-activated current If in sinoatrial node pacemaking: insights from bifurcation analysis of mathematical models
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DOI：
10.1152/ajpheart.00729.2009
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发表时间：
2010-06-01
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;Matsuda, Hiroyuki;Shibamoto, Toshishige
仓田勇，松田H，Hisatome I，Shibamoto T。超极化激活电流I-f在窦房结起搏中的作用：数学模型分叉分析的启示。Am J Physiol心脏圈Physiol 298：H1748-H1760,2010。-为了阐明超极化激活电流(I-f)在窦房结(SAN)起搏中的作用，我们从理论上研究了1)I-f对窦房结细胞超极化过程中稳定性和分叉的影响；2)I-f和持续内向电流(I-st)或Na+通道电流(I-Na)对起搏抗超极化的稳健性的联合影响；以及3)在特定条件下阻断I-f是否取消了起搏器的活动。对兔窦房结细胞的数学模型进行了分叉分析，确定了平衡点、周期轨道及其稳定性作为参数的函数。通过施加恒定偏置电流确定的不稳定稳态电位区随着i-f密度的增加而缩小。在中央窦房结细胞中，发生分支以产生稳定的EP和静止的临界乙酰胆碱浓度随较小的I-f而增加，但随较大的I-f而降低。相反，窦房结和心房分叉处缝隙连接的临界乙酰胆碱浓度和电导随着外周窦房结i-f的增加而逐渐增加。通过消除I-st或I-Na或加速它们的失活，I-f的这些效应显著减弱。在超极化条件下，阻断i-f可通过分叉取消窦房结起搏。这些结果表明：1)i-f本身不能破坏EP的稳定性；2)i-f通过在i-st或i-Na存在的情况下阻止分叉而提高SAN细胞对副交感刺激的稳健性；3)i-f显著增强外周细胞对抗心房电紧张性负荷的稳健性；以及4)阻断i-f可取消超极化SAN细胞的起搏活动。
Kurata Y, Matsuda H, Hisatome I, Shibamoto T. Roles of hyperpolarization-activated current I-f in sinoatrial node pacemaking: insights from bifurcation analysis of mathematical models. Am J Physiol Heart Circ Physiol 298: H1748-H1760, 2010. First published April 2, 2010; doi:10.1152/ajpheart.00729.2009.-To elucidate the roles of hyperpolarization-activated current (I-f) in sinoatrial node (SAN) pacemaking, we theoretically investigated 1) the effects of I-f on stability and bifurcation during hyperpolarization of SAN cells; 2) combined effects of I-f and the sustained inward current (I-st) or Na+ channel current (I-Na) on robustness of pacemaking against hyperpolarization; and 3) whether blocking I-f abolishes pacemaker activity under certain conditions. Bifurcation analyses were performed for mathematical models of rabbit SAN cells; equilibrium points (EPs), periodic orbits, and their stability were determined as functions of parameters. Unstable steady-state potential region determined with applications of constant bias currents shrunk as I-f density increased. In the central SAN cell, the critical acetylcholine concentration at which bifurcations, to yield a stable EP and quiescence, occur was increased by smaller I-f, but decreased by larger I-f. In contrast, the critical acetylcholine concentration and conductance of gap junctions between SAN and atrial cells at bifurcations progressively increased with enhancing I-f in the peripheral SAN cell. These effects of I-f were significantly attenuated by eliminating I-st or I-Na, or by accelerating their inactivation. Under hyperpolarized conditions, blocking I-f abolished SAN pacemaking via bifurcations. These results suggest that 1) I-f itself cannot destabilize EPs; 2) I-f improves SAN cell robustness against parasympathetic stimulation via preventing bifurcations in the presence of I-st or I-Na; 3) I-f dramatically enhances peripheral cell robustness against electrotonic loads of the atrium in combination with I-Na; and 4) pacemaker activity of hyperpolarized SAN cells could be abolished by blocking I-f.