PUBLICATION
Identification 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.
- ID
- ZDB-PUB-170528-3
- Date
- 2017
- Source
- Scientific Reports 7: 2465 (Journal)
- Registered Authors
- Korzh, Vladimir
- Keywords
- Cardiology, Drug discovery
- MeSH Terms
-
- Cardenolides/pharmacology
- NAV1.5 Voltage-Gated Sodium Channel/metabolism
- Egtazic Acid/analogs & derivatives
- Egtazic Acid/pharmacology
- CHO Cells
- Human Embryonic Stem Cells/cytology
- Human Embryonic Stem Cells/drug effects
- Human Embryonic Stem Cells/metabolism
- Cell Line
- Cardiac Glycosides/pharmacology*
- Bufanolides/pharmacology*
- Calcium Channels, L-Type/metabolism
- Humans
- Zebrafish
- ERG1 Potassium Channel/metabolism
- Animals
- Larva
- Myocytes, Cardiac/cytology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism*
- Arrhythmias, Cardiac/chemically induced*
- Arrhythmias, Cardiac/metabolism
- Arrhythmias, Cardiac/physiopathology
- Cell Differentiation/drug effects
- HEK293 Cells
- Ouabain/pharmacology
- Voltage-Gated Sodium Channel beta-1 Subunit/metabolism
- Calcium/metabolism*
- Cricetulus
- PubMed
- 28550304 Full text @ Sci. Rep.
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) Identification of a Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides.. Scientific Reports. 7:2465.
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 µM) I Ca,L inhibition (maximal ≥50%) without and with the NKA activity blocked by 10 µM Oua. BF significantly shortened the action potential duration at 1.0 µM and shortened the extracellular field potential duration at 0.01~1.0 µM. On the other hand, BF and CBG at 100 µM 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.
Errata / Notes
This article is corrected by ZDB-PUB-220906-83 .
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