Effects of Ranolazine on Cloned Cardiac Kv4.3 Potassium Channels

Abstract

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.