Center for Cellular and Systems Electrophysiology, State University of New York, University at Buffalo, Buffalo, New York, United States of America.
PLoS One. 2012;7(8):e42295. doi: 10.1371/journal.pone.0042295. Epub 2012 Aug 6.
The fast component of the cardiac transient outward current, I(Ktof), is blocked by a number of drugs. The major molecular bases of I(Ktof) are Kv4.2/Kv4.3 voltage-gated potassium channels. Drugs with similar potencies but different blocking mechanisms have differing effects on action potential duration (APD). We used in silico analysis to determine the effect of I(Ktof)-blocking drugs with different blocking mechanisms on mouse ventricular myocytes. We used our existing mouse model of the action potential, and developed 4 new Markov formulations for I(Ktof), I(Ktos), I(Kur), I(Ks). We compared effects of theoretical I(Ktof)-specific channel blockers: (1) a closed state, and (2) an open channel blocker. At concentrations lower or close to IC(50), the drug which bound to the open state always had a much greater effect on APD than the drug which bound to the closed state. At concentrations much higher than IC(50), both mechanisms had similar effects at very low pacing rates. However, an open state binding drug had a greater effect on APD at faster pacing rates, particularly around 10 Hz. In summary, our data indicate that drug effects on APD are strongly dependent not only on IC(50), but also on the drug binding state.
心脏瞬间外向电流的快成分（I(Ktof)）可被多种药物阻断。I(Ktof)的主要分子基础是电压门控钾通道 Kv4.2/Kv4.3。具有相似效力但阻断机制不同的药物对动作电位时程（APD）有不同的影响。我们使用计算机模拟分析来确定具有不同阻断机制的 I(Ktof)阻断药物对小鼠心室肌细胞的影响。我们使用现有的小鼠动作电位模型，并为 I(Ktos)、I(Kur)、I(Ks) 开发了 4 种新的 Markov 公式。我们比较了理论上的 I(Ktof)-特异性通道阻断剂的作用：（1）关闭状态，和（2）开放通道阻断剂。在较低或接近 IC(50)的浓度下，与开放状态结合的药物对 APD 的影响总是比与关闭状态结合的药物大得多。在远高于 IC(50)的浓度下，两种机制在非常低的起搏率下具有相似的作用。然而，在更快的起搏率下，特别是在 10 Hz 左右，开放状态结合药物对 APD 的影响更大。总之，我们的数据表明，药物对 APD 的影响不仅取决于 IC(50)，还取决于药物结合状态。
