ClassIIIantiarrhythmic drugs amiodarone and dronedarone impairKIR2.1 backward trafficking

Journal of Cellular and Molecular Medicine - Tập 21 Số 10 - Trang 2514-2523 - 2017
Yuan Ji1, Hiroki Takanari1, Muge Qile1, Lukáš Nalos2, Marien J. C. Houtman1, Fee L. Romunde1, Raimond Heukers3, Paul M.P. van Bergen en Henegouwen3, Marc A. Vos1, Marcel A. G. van der Heyden1
1Division of Heart & Lungs, Department of Medical Physiology, UMCU, Utrecht, The Netherlands
2Department of Physiology, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic
3Cell Biology, Department of Biology, Science Faculty; Utrecht University; Utrecht The Netherlands

Tóm tắt

Abstract

Drug‐induced ion channel trafficking disturbance can cause cardiac arrhythmias. The subcellular level at which drugs interfere in trafficking pathways is largely unknown.KIR2.1 inward rectifier channels, largely responsible for the cardiac inward rectifier current (IK1), are degraded in lysosomes. Amiodarone and dronedarone are classIIIantiarrhythmics. 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 inKIR2.1 backward trafficking by amiodarone and dronedarone. Both drugs inhibitedIK1in isolated rabbit ventricular cardiomyocytes at supraclinical doses only. InHK‐KWGFcells, both drugs dose‐ and time‐dependently increasedKIR2.1 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/lysosomalKIR2.1 accumulation. IncreasedKIR2.1 expression level was also observed in the presence of Nav1.5 co‐expression. AugmentedKIR2.1 protein levels and intracellular accumulation were also observed inCOS‐7,END‐2,MES‐1 andEPI‐7 cells. Both drugs had no effect on Kv11.1 ion channel protein expression levels. Finally, amiodarone (73.3 ± 10.3%P < 0.05 at −120 mV, 5 μM) enhancedIKIR2.1upon 24‐hrs treatment, whereas dronedarone tended to increaseIKIR2.1and 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 enhancedIK1by inhibitingKIR2.1 degradation.

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Thông tin xuất bản

Journal of Cellular and Molecular Medicine

Tập 21 Số 10

2514-2523

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