Fraunhofer-Chalmers Centre, Chalmers Science Park, Göteborg, Sweden.
Biophys J. 2010 Nov 3;99(9):2726-36. doi: 10.1016/j.bpj.2010.08.062.
A wide range of ion channels have been considered as potential targets for pharmacological treatment of atrial fibrillation. The Kv1.5 channel, carrying the I(Kur) current, has received special attention because it contributes to repolarization in the atria but is absent or weakly expressed in ventricular tissue. The dog serves as an important animal model for electrophysiological studies of the heart and mathematical models of the canine atrial action potential (CAAP) have been developed to study the interplay between ionic currents. To enable more-realistic studies on the effects of Kv1.5 blockers on the CAAP in silico, two continuous-time Markov models of the guarded receptor type were formulated for Kv1.5 and subsequently inserted into the Ramirez-Nattel-Courtemanche model of the CAAP. The main findings were: 1), time- and state-dependent Markov models of open-channel Kv1.5 block gave significantly different results compared to a time- and state-independent model with a downscaled conductance; 2), the outcome of Kv1.5 block on the macroscopic system variable APD(90) was dependent on the precise mechanism of block; and 3), open-channel block produced a reverse use-dependent prolongation of APD(90). This study suggests that more-complex ion-channel models are a prerequisite for quantitative modeling of drug effects.
已将多种离子通道视为治疗心房颤动的潜在药物靶点。Kv1.5 通道携带 I(Kur)电流，因其对心房复极有贡献，但在心室组织中缺失或表达较弱，故受到特别关注。犬是心脏电生理研究的重要动物模型，已开发出犬心房动作电位（CAAP）的数学模型，以研究离子电流之间的相互作用。为了能够在计算机上更真实地研究 Kv1.5 阻滞剂对 CAAP 的影响，我们针对 Kv1.5 构建了两种连续时间 Markov 门控受体模型，并随后将其插入 Ramirez-Nattel-Courtemanche 型 CAAP 模型中。主要发现包括：1）与采用缩小电导的时变和状态无关模型相比，时变和状态依赖的开放通道 Kv1.5 阻滞的 Markov 模型给出了显著不同的结果；2）Kv1.5 阻滞对宏观系统变量 APD(90)的影响取决于阻滞的精确机制；3）开放通道阻滞导致 APD(90)出现反向使用依赖性延长。本研究表明，更复杂的离子通道模型是定量药物效应建模的前提。
