Chronic amiodarone and potentially dronedarone treatment can result in enhanced IK1 by inhibiting KIR2.1 degradation, providing insight into their cellular mechanisms.
Amiodarone may disrupt KIR2.1 lysosomal trafficking; leaves open clinical relevance for proarrhythmia.
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 K 1 ), 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 K 1 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 μM, 24 hrs; 2.3 ± 0.3‐fold with dronedarone: 5 μM, 24 hrs) 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 −120 mV, 5 μM) enhanced I KIR 2.1 upon 24‐hrs treatment, whereas dronedarone tended to increase I KIR 2.1 and it did not reach significance (43.8 ± 5.5%, P = 0.26 at −120 mV; 2 μM). We conclude that chronic amiodarone, and potentially also dronedarone, treatment can result in enhanced I K 1 by inhibiting K IR 2.1 degradation.
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Ji et al. (2017) studied this question.
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