Sensitivity of the slow component of the delayed rectifier potassium current (I-Ks) to potassium channel blockers: Implications for clinical reverse use-dependent effects

The slow delayed rectifier potassium current (I-Ks) is unique in its slow a ctivation and deactivation kinetics. It is important during cardiac repolar ization, especially when the heart rate is fast. We compared the effects of quinidine, procainamide, sotalol, and amiodarone on I-Ks and correlated th e findings with the clinical reverse use-dependent effects of potassium cha nnel blockers. Human minK RNA was obtained by reverse transcription-polymer ase chain reaction using explanted human heart. The RNA was injected into X enopus oocytes for heterologous expression of I-Ks. A two-electrode voltage clamp technique was performed to investigate the I-Ks. We demonstrated tha t quinidine, sotalol and procainamide had no effects on I-Ks up to a concen tration of 300 mu M while amiodarone inhibited I-Ks in a concentration-depe ndent manner starting from 10 mu M. The inhibition by amiodarone was state- dependent with gradual unblocking after depolarization, The degree of inhib ition was 53% immediately after depolarization and 19% at the end of a 5-se cond depolarization. I-Ks is 30 times more sensitive to amiodarone than to quinidine, sotalol, and procainamide, Quinidine, sotalol and procainamide h ave reverse use-dependent effects while amiodarone does not, This is compat ible with the hypothesis that no inhibition of I-Ks at clinical concentrati ons contributes to the clinical reverse use-dependent effects.