Department of Physiology, Medical Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, Korea.
J Pharmacol Exp Ther. 2011 Dec;339(3):952-8. doi: 10.1124/jpet.111.184176. Epub 2011 Sep 22.
The effects of ranolazine, an antianginal drug, on potassium channel Kv4.3 were examined by using the whole-cell patch-clamp technique. Ranolazine inhibited the peak amplitude of Kv4.3 in a reversible, concentration-dependent manner with an IC(50) of 128.31 μM. The activation kinetics were not significantly affected by ranolazine at concentrations up to 100 μM. Applications of 10 and 30 μM ranolazine had no effect on the fast and slow inactivation of Kv4.3. However, at concentrations of 100 and 300 μM ranolazine caused a significant decrease in the rate of fast inactivation, and at a concentration of 300 μM it caused a significant decrease in the rate of slow inactivation, resulting in a crossover of the current traces during depolarization. The Kv4.3 inhibition by ranolazine increased steeply between -20 and +20 mV. In the full activation voltage range, however, no voltage-dependent inhibition was found. Ranolazine shifted the voltage dependence of the steady-state inactivation of Kv4.3 in the hyperpolarizing direction in a concentration-dependent manner. The apparent dissociation constant (K(i)) for ranolazine for interacting with the inactivated state of Kv4.3 was calculated to be 0.32 μM. Ranolazine produced little use-dependent inhibition at frequencies of 1 and 2 Hz. Ranolazine did not affect the time course of recovery from the inactivation of Kv4.3. The results indicated that ranolazine inhibited Kv4.3 and exhibited a low affinity for Kv4.3 channels in the closed state but a much higher affinity for Kv4.3 channels in the inactivated state.
采用全细胞膜片钳技术研究了抗心绞痛药物雷诺嗪对钾通道 Kv4.3 的作用。雷诺嗪以可逆、浓度依赖性方式抑制 Kv4.3 的峰电流，IC50 为 128.31 μM。雷诺嗪浓度高达 100 μM 时，对 Kv4.3 的激活动力学无显著影响。应用 10 和 30 μM 雷诺嗪对 Kv4.3 的快速和缓慢失活无影响。然而，在 100 和 300 μM 浓度下，雷诺嗪显著降低快速失活的速率，在 300 μM 浓度下，它显著降低缓慢失活的速率，导致去极化时电流轨迹交叉。雷诺嗪对 Kv4.3 的抑制作用在-20 至+20 mV 之间急剧增加。然而，在整个激活电压范围内，未发现电压依赖性抑制。雷诺嗪以浓度依赖性方式使 Kv4.3 的稳态失活的电压依赖性向超极化方向移动。雷诺嗪与 Kv4.3 失活状态相互作用的表观解离常数（K(i)）计算为 0.32 μM。雷诺嗪在 1 和 2 Hz 的频率下产生的使用依赖性抑制作用较小。雷诺嗪不影响 Kv4.3 从失活中恢复的时间进程。结果表明，雷诺嗪抑制 Kv4.3，对关闭状态的 Kv4.3 通道具有低亲和力，但对失活状态的 Kv4.3 通道具有更高的亲和力。
