Abstrakt
Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. The subcellular level at which drugs interfere in trafficking pathways is largely unknown.
K(IR)2.1 inward rectifier channels, largely responsible for the cardiac inward rectifier current (I-K1), are degraded in lysosomes. Amiodarone and dronedarone are class III antiarrhythmics.
Chronic use of amiodarone, and to a lesser extent dronedarone, causes serious adverse effects to several organs and tissue types, including the heart. Both drugs have been described to interfere in the late-endosome/lysosome system.
Here we defined the potential interference in K(IR)2.1 backward trafficking by amiodarone and dronedarone. Both drugs inhibited I-K1 in isolated rabbit ventricular cardiomyocytes at supraclinical doses only.
In HK-KWGF cells, both drugs dose- and time-dependently increased K(IR)2.1 expression (2.0 +/- 0.2-fold with amiodarone: 10 mu M, 24hrs; 2.3 +/- 0.3-fold with dronedarone: 5 mu M, 24hrs) and late-endosomal/lysosomal K(IR)2.1 accumulation. Increased K(IR)2.1 expression level was also observed in the presence of Na(v)1.5 co-expression.
Augmented K(IR)2.1 protein levels and intracellular accumulation were also observed in COS-7, END-2, MES-1 and EPI-7 cells. Both drugs had no effect on K(v)11.1 ion channel protein expression levels.
Finally, amiodarone (73.3 +/- 10.3% P<0.05 at -120mV, 5 mu M) enhanced I-KIR2.1 upon 24-hrs treatment, whereas dronedarone tended to increase I-KIR2.1 and it did not reach significance (43.8 +/- 5.5%, P=0.26 at -120mV; 2 mu M). We conclude that chronic amiodarone, and potentially also dronedarone, treatment can result in enhanced I-K1 by inhibiting K(IR)2.1 degradation.