Effects of pacemaker currents on creation and modulation of human ventricular pacemaker: theoretical study with application to biological pacemaker engineering
Effects of pacemaker currents on creation and modulation of human ventricular pacemaker: theoretical study with application to biological pacemaker engineering
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DOI：
10.1152/ajpheart.00426.2006
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发表时间：
2007-01-01
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
通过抑制内向整流钾电流（I-K1）或过表达超极化激活电流（I-h），可产生心脏生物起搏器（BP）。我们从理论上研究了掺入I（h）、T型Ca 2+电流（I-Ca，I-T）、持续内向电流（I-st）和/或低压激活L型Ca 2+通道电流（I-Ca，I-LD）对1）BP细胞的产生、2）BP活性对非起搏（NP）细胞的电紧张负荷的鲁棒性和3）BP细胞驱动NP细胞的能力的影响。我们使用了人心室肌细胞（HVMs）的单细胞模型，以及由BP和NP细胞组成的偶联细胞模型。在电流电导和间隙连接的变化过程中，探讨了模型细胞的分叉结构。在IK 1正常的HVM中，增加起搏电流并不产生BP活动，但增加了BP活动出现的临界IK 1电导。表达Ih似乎最有助于通过IK 1抑制促进BP细胞的产生。在耦合细胞模型中，Ist显着扩大了发生稳定BP细胞起搏和NP细胞驱动的差距电导（GC）区域，减少了稳健起搏和驱动所需的BP细胞数量。相反，Ih仅在NP细胞IK 1相对较低时扩大起搏和驱动的GC区域。伊卡，T或伊卡，LD的作用与Ist相似，但引起BP振荡的收缩或不规则。这些发现表明，表达Ist最有效地提高了BP对电紧张负荷的结构稳定性和BP驱动心室的能力。
A cardiac biological pacemaker (BP) has been created by suppression of the inward rectifier K+ current (I-K1) or overexpression of the hyperpolarization-activated current (I-h). We theoretically investigated the effects of incorporating 1(h), T-type Ca2+ current (I-Ca,I-T), sustained inward current (I-st), and/or low-voltage-activated L-type Ca2+ channel current (I-Ca,I-LD) on 1) creation of BP cells, 2) robustness of BP activity to electrotonic loads of nonpacemaking (NP) cells, and 3) BP cell ability to drive NP cells. We used a single-cell model for human ventricular myocytes (HVMs) and also coupled-cell models composed of BP and NP cells. Bifurcation structures of the model cells were explored during changes in conductance of the currents and gap junction. Incorporating the pacemaker currents did not yield BP activity in HVM with normal IK1 but increased the critical IK1 conductance for BP activity to emerge. Expressing Ih appeared to be most helpful in facilitating creation of BP cells via IK1 suppression. In the coupled-cell model, Ist significantly enlarged the gap conductance (GC) region where stable BP cell pacemaking and NP cell driving occur, reducing the number of BP cells required for robust pacemaking and driving. In contrast, Ih enlarged the GC region of pacemaking and driving only when IK1 of the NP cell was relatively low. ICa, T or ICa, LD exerted effects similar to those of Ist but caused shrinkage or irregularity of BP oscillations. These findings suggest that expressing Ist most effectively improves the structural stability of BPs to electrotonic loads and the BP ability to drive the ventricle.