Amiodarone Inhibits Apamin-Sensitive Potassium Currents

BACKGROUND: Apamin sensitive potassium current (I (KAS)), carried by the type 2 small conductance Ca(2+)-activated potassium (SK2) channels, plays an important role in post-shock action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (VF) in failing ventricles. OBJECTIVE: To test the hypothesis that amiodarone inhibits I (KAS) in human embryonic kidney 293 (HEK-293) cells. METHODS: We used the patch-clamp technique to study I (KAS) in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration. RESULTS: Amiodarone inhibited I(KAS) in a dose-dependent manner (IC(50), 2.67±0.25 µM with 1 µM intrapipette Ca(2+)). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6±3.1% of I(KAS) induced with 1 µM intrapipette Ca(2+) (n = 3). I(KAS) inhibition by amiodarone was not voltage-dependent, but was Ca(2+)-dependent: 30 µM amiodarone inhibited 81.5±1.9% of I (KAS) induced with 1 µM Ca(2+) (n = 4), and 16.4±4.9% with 250 nM Ca(2+) (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca(2+) dependent inhibition of I (KAS). CONCLUSION: Both amiodarone and desethylamiodarone inhibit I (KAS) at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca(2+) concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles.