Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-017-02496-4
Title: Electronic supplementary materialIdentification of a Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides
Authors: Koh, C.H
Wu, J
Chung, Y.Y
Liu, Z
Zhang, R.-R
Chong, K
Korzh, V
Ting, S
Oh, S
Shim, W 
Tian, H.-Y
Wei, H 
Keywords: 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
bufadienolide derivative
bufalin
CACNA1C protein, human
calcium
calcium channel L type
calotropin
cardenolide
cardiac glycoside
cinobufagin
egtazic acid
KCNH2 protein, human
ouabain
potassium channel HERG
SCN1B protein, human
SCN5A protein, human
sodium channel Nav1.5
voltage gated sodium channel beta 1 subunit
analogs and derivatives
animal
cardiac muscle cell
cell differentiation
cell line
chemically induced
CHO cell line
Cricetulus
cytology
drug effect
heart arrhythmia
HEK293 cell line
human
human embryonic stem cell
larva
metabolism
pathophysiology
zebra fish
Animals
Arrhythmias, Cardiac
Bufanolides
Calcium
Calcium Channels, L-Type
Cardenolides
Cardiac Glycosides
Cell Differentiation
Cell Line
CHO Cells
Cricetulus
Egtazic Acid
ERG1 Potassium Channel
HEK293 Cells
Human Embryonic Stem Cells
Humans
Larva
Myocytes, Cardiac
NAV1.5 Voltage-Gated Sodium Channel
Ouabain
Voltage-Gated Sodium Channel beta-1 Subunit
Zebrafish
Issue Date: 2017
Publisher: Nature Publishing Group
Citation: Koh, C.H, Wu, J, Chung, Y.Y, Liu, Z, Zhang, R.-R, Chong, K, Korzh, V, Ting, S, Oh, S, Shim, W, Tian, H.-Y, Wei, H (2017). Electronic supplementary materialIdentification of a Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides. Scientific Reports 7 (1) : 2465. ScholarBank@NUS Repository. https://doi.org/10.1038/s41598-017-02496-4
Abstract: The current study explored the Na+/K+-ATPase (NKA) inhibition-independent proarrhythmic mechanisms of cardiac glycosides (CGs) which are well-known NKA inhibitors. With the cytosolic Ca2+ chelated by EGTA and BAPTA or extracellular Ca2+ replaced by Ba2+, effects of bufadienolides (bufalin (BF) and cinobufagin (CBG)) and cardenolides (ouabain (Oua) and pecilocerin A (PEA)) on the L-type calcium current (I Ca,L) were recorded in heterologous expression Cav1.2-CHO cells and human embryonic stem cell-derived cardiomyocytes (hESC-CMs). BF and CBG demonstrated a concentration-dependent (0.1 to100 ?M) I Ca,L inhibition (maximal ?50%) without and with the NKA activity blocked by 10 ?M Oua. BF significantly shortened the action potential duration at 1.0 ?M and shortened the extracellular field potential duration at 0.01?1.0 ?M. On the other hand, BF and CBG at 100 ?M demonstrated a strong inhibition (?40%) of the rapidly activating component of the delayed rectifier K+ current (I Kr) in heterologous expression HEK293 cells and prolonged the APD of the heart of day-3 Zebrafish larva with disrupted rhythmic contractions. Moreover, hESC-CMs treated with BF (10 nM) for 24 hours showed moderate yet significant prolongation in APD90. In conclusion, our data indicate that CGs particularly bufadienolides possess cytosolic [Ca2+]i- and NKA inhibition- independent proarrhythmic potential through I Ca,L and I Kr inhibitions. © The Author(s) 2017.
Source Title: Scientific Reports
URI: https://scholarbank.nus.edu.sg/handle/10635/174411
ISSN: 2045-2322
DOI: 10.1038/s41598-017-02496-4
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