Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR 2.1 backward trafficking

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11140%2F17%3A10362846" target="_blank" >RIV/00216208:11140/17:10362846 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1111/jcmm.13172" target="_blank" >http://dx.doi.org/10.1111/jcmm.13172</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/jcmm.13172" target="_blank" >10.1111/jcmm.13172</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR 2.1 backward trafficking

Popis výsledku v původním jazyce

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&lt;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.

Název v anglickém jazyce

Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR 2.1 backward trafficking

Popis výsledku anglicky

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&lt;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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30105 - Physiology (including cytology)

Projekt

<a href="/cs/project/EE2.3.30.0061" target="_blank" >EE2.3.30.0061: Zvýšení kapacity vědecko-výzkumných týmů Univerzity Karlovy prostřednictvím nových pozic pro absolventy doktorandských studií</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2017

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Cellular and Molecular Medicine [online]

ISSN

1582-4934

e-ISSN

—

Svazek periodika

21

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

10

Strana od-do

2514-2523

Kód UT WoS článku

000411875400024

EID výsledku v databázi Scopus

2-s2.0-85018657730