Amiodarone Inhibits Apamin-Sensitive Potassium Currents

Abstract

BackgroundApamin sensitive potassium current (I KAS), carried by the type 2 small conductance Ca2+-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.ObjectiveTo test the hypothesis that amiodarone inhibits I KAS in human embryonic kidney 293 (HEK-293) cells.MethodsWe used the patch-clamp technique to study I KAS in HEK-293 cells transiently expressing human SK2 before and after amiodarone administration.ResultsAmiodarone inhibited IKAS in a dose-dependent manner (IC50, 2.67±0.25 µM with 1 µM intrapipette Ca2+). Maximal inhibition was observed with 50 µM amiodarone which inhibited 85.6±3.1% of IKAS induced with 1 µM intrapipette Ca2+ (n = 3). IKAS inhibition by amiodarone was not voltage-dependent, but was Ca2+-dependent: 30 µM amiodarone inhibited 81.5±1.9% of I KAS induced with 1 µM Ca2+ (n = 4), and 16.4±4.9% with 250 nM Ca2+ (n = 5). Desethylamiodarone, a major metabolite of amiodarone, also exerts voltage-independent but Ca2+ dependent inhibition of I KAS.ConclusionBoth amiodarone and desethylamiodarone inhibit I KAS at therapeutic concentrations. The inhibition is independent of time and voltage, but is dependent on the intracellular Ca2+ concentration. SK2 current inhibition may in part underlie amiodarone's effects in preventing electrical storm in failing ventricles.

Synergistic antiarrhythmic effect of combining inhibition of Ca2+-activated K+ (SK) channels and voltage-gated Na+ channels in an isolated heart model of atrial fibrillation

“…31 Whether flecainide and ranolazine likewise inhibit the SK current at the concentrations applied has not been tested.…”

Small Conductance Calcium-Activated Potassium Current Is Important in Transmural Repolarization of Failing Human Ventricles

“…A possible mechanism for differential APD response to apamin is pre-transplant treatment with amiodarone, a known inhibitor of I KAS . 20 However, the magnitudes of APD prolongation in patients treated with amiodarone (11.6% [CI, −0.5 to 23.7], N=7) did not differ significantly from patients not treated with amiodarone (14.9% [CI, −8.2 to 38.0], N=7) at 1000 ms PCL (p=0.55). None of the other clinical characteristics was significantly associated with APD prolongation induced by apamin (See Supplement Results).…”

“…Previous reports about the I Ks and I Kr in transmural preparations were mostly performed in canine models using pharmacological interventions. Because E4031 and chromanol 293 also blocks the SK current, 20 APD prolongation in those studies may be in part due to the inhibition of the SK currents. In our study, we gave apamin first, followed by chromanol 293 and E4031.…”

Effect of antiarrhythmic drugs on small conductance calcium – activated potassium channels

“…It has been revealed that both chronic (Voigt et al, 2012) and paroxysmal AF (Voigt et al, 2014) for treating AF target a number of ion channels and receptors, but whether they can inhibit K Ca 2.X channels has not been systematically tested until now. Amiodarone has previously been reported to inhibit K Ca 2.2 channels expressed in HEK-293 cells (Turker et al, 2013), but this study is the first to test a large number of the recommended AADs for treatment of AF on the hK Ca 2 channel. Ten AADs at six different concentrations ranging between 0.1 -30 µmol/l on the hK Ca 2.3 channel were tested.…”

“…The study published by Turker et al (2013) characterized the effect of amiodarone on the hK Ca 2.2 channel and showed that amiodarone was able to inhibit the I KCa current with an IC 50 of 3 µmol/l when intracellular free Ca 2+ concentration was 1 µmol/l. Our experiments failed to show any effect of amiodarone at any of the tested concentrations on any of the K Ca 2 subtypes (data not shown for hK Ca 2.2).…”