Sensitivity of the Slow Component of the Delayed Rectifier Potassium Current (IKs) to Potassium Channel Blockers: Implications for Clinical Reverse Use-Dependent Effects

The slow delayed rectifier potassium current (IKs) is unique in its slow activation and deactivation kinetics. It is important during cardiac repolarization, especially when the heart rate is fast. We compared the effects of quinidine, procainamide, sotalol, and amiodarone on IKs and correlated the findings with the clinical reverse use-dependent effects of potassium channel blockers. Human minK RNA was obtained by reverse transcription-polymerase chain reaction using explanted human heart. The RNA was injected into Xenopus oocytes for heterologous expression of IKs. A two-electrode voltage clamp technique was performed to investigate the IKs. We demonstrated that quinidine, sotalol and procainamide had no effects on IKs up to a concentration of 300 μM while amiodarone inhibited IKs in a concentration-dependent manner starting from 10 μM. The inhibition by amiodarone was state-dependent with gradual unblocking after depolarization. The degree of inhibition was 53% immediately after depolarization and 19% at the end of a 5-second depolarization. IKs is 30 times more sensitive to amiodarone than to quinidine, sotalol, and procainamide. Quinidine, sotalol and procainamide have reverse use-dependent effects while amiodarone does not. This is compatible with the hypothesis that no inhibition of IKs at clinical concentrations contributes to the clinical reverse use-dependent effects.