Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR2.1 backward trafficking
| Autor: | Ji, Yuan, Takanari, Hiroki, Qile, Muge, Nalos, Lukas, Houtman, Marien J.C., Romunde, Fee L., Heukers, Raimond, van Bergen en Henegouwen, Paul M.P., Vos, Marc A., van der Heyden, Marcel A.G., Sub Cell Biology, Celbiologie |
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| Přispěvatelé: | Sub Cell Biology, Celbiologie |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty 030204 cardiovascular system & hematology Pharmacology Amiodarone 03 medical and health sciences 0302 clinical medicine dronedarone Internal medicine Lysosome medicine Ion channel amiodarone degradation Chemistry Inward-rectifier potassium ion channel Kir2.1 Cell Biology inward rectifier Dronedarone 030104 developmental biology medicine.anatomical_structure KIR2.1 Cardiology lysosome Molecular Medicine Intracellular medicine.drug Anti-Arrhythmia Agents |
| Zdroj: | Journal of Cellular and Molecular Medicine, 21(10), 2514. Wiley-Blackwell |
| ISSN: | 1582-1838 |
| Popis: | Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. The subcellular level at which drugs interfere in trafficking pathways is largely unknown. KIR 2.1 inward rectifier channels, largely responsible for the cardiac inward rectifier current (IK1 ), 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 KIR 2.1 backward trafficking by amiodarone and dronedarone. Both drugs inhibited IK1 in isolated rabbit ventricular cardiomyocytes at supraclinical doses only. In HK-KWGF cells, both drugs dose- and time-dependently increased KIR 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 KIR 2.1 accumulation. Increased KIR 2.1 expression level was also observed in the presence of Nav 1.5 co-expression. Augmented KIR 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 Kv 11.1 ion channel protein expression levels. Finally, amiodarone (73.3 ± 10.3% P < 0.05 at -120 mV, 5 μM) enhanced IKIR2.1 upon 24-hrs treatment, whereas dronedarone tended to increase IKIR2.1 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 IK1 by inhibiting KIR 2.1 degradation. |
| Databáze: | OpenAIRE |
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