Masonic Medical Research Laboratory, 2150 Bleecker St., Utica, NY 13501, USA.
Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1615-24. doi: 10.1152/ajpheart.00243.2011. Epub 2011 Aug 5.
Block of Na(+) channel conductance by ranolazine displays marked atrial selectivity that is an order of magnitude higher that of other class I antiarrhythmic drugs. Here, we present a Markovian model of the Na(+) channel gating, which includes activation-inactivation coupling, aimed at elucidating the mechanisms underlying this potent atrial selectivity of ranolazine. The model incorporates experimentally observed differences between atrial and ventricular Na(+) channel gating, including a more negative position of the steady-state inactivation curve in atrial versus ventricular cells. The model assumes that ranolazine requires a hydrophilic access pathway to the channel binding site, which is modulated by both activation and inactivation gates of the channel. Kinetic rate constants were obtained using guarded receptor analysis of the use-dependent block of the fast Na(+) current (I(Na)). The model successfully reproduces all experimentally observed phenomena, including the shift of channel availability, the sensitivity of block to holding or diastolic potential, and the preferential block of slow versus fast I(Na.) Using atrial and ventricular action potential-shaped voltage pulses, the model confirms significantly greater use-dependent block of peak I(Na) in atrial versus ventricular cells. The model highlights the importance of action potential prolongation and of a steeper voltage dependence of the time constant of unbinding of ranolazine from the atrial Na(+) channel in the development of use-dependent I(Na) block. Our model predictions indicate that differences in channel gating properties as well as action potential morphology between atrial and ventricular cells contribute equally to the atrial selectivity of ranolazine. The model indicates that the steep voltage dependence of ranolazine interaction with the Na(+) channel at negative potentials underlies the mechanism of the predominant block of I(Na) in atrial cells by ranolazine.
雷诺嗪阻断钠通道电导显示出明显的心房选择性，比其他 I 类抗心律失常药物高一个数量级。在这里，我们提出了一个钠离子通道门控的马尔可夫模型，其中包括激活失活偶联，旨在阐明雷诺嗪这种强大的心房选择性的机制。该模型纳入了心房和心室钠通道门控之间观察到的实验差异，包括在心房细胞中稳态失活曲线的位置比心室细胞更负。该模型假设雷诺嗪需要亲水通道结合位点的进入途径，这是由通道的激活和失活门调制的。使用快速钠电流（I(Na)）的依赖使用阻断的受保护受体分析获得了动力学速率常数。该模型成功地再现了所有观察到的实验现象，包括通道可用性的转移、阻断对保持或舒张电位的敏感性以及慢 I(Na)对快 I(Na)的优先阻断。使用心房和心室动作电位形状的电压脉冲，该模型证实了在心房细胞中与心室细胞相比，快速 I(Na)的依赖使用阻断更大。该模型强调了动作电位延长以及雷诺嗪与心房钠通道结合的解结合时间常数的电压依赖性更陡在发展依赖使用的 I(Na)阻断中的重要性。我们的模型预测表明，通道门控特性以及心房和心室细胞之间的动作电位形态的差异对雷诺嗪的心房选择性同样重要。该模型表明，在负电位下，雷诺嗪与钠通道相互作用的陡峭电压依赖性是雷诺嗪在心房细胞中主要阻断 I(Na)的机制。
