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 IKAS in a dose-dependent manner (IC50, 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 IKAS induced with 1 µM intrapipette Ca(2+) (n = 3). IKAS 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.


CONCLUSIONS
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.
Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Isik
I
Turker
Chih-Chieh
CC
Yu
Po-Cheng
PC
Chang
Zhenhui
Z
Chen
Yoshiro
Y
Sohma
Shien-Fong
SF
Lin
Peng-Sheng
PS
Chen
Tomohiko
T
Ai
D000638:Amiodarone / Q000031:analogs & derivatives / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001030:Apamin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D014693:Ventricular Fibrillation / Q000378:metabolism
D000889:Anti-Arrhythmia Agents; C496897:KCNN2 protein, human; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin; C036116:desethylamiodarone; D000638:Amiodarone; D002118:Calcium