ZFIN ID: ZDB-PUB-170528-3
Electronic supplementary materialIdentification of a Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides.
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.
Date: 2017
Source: Scientific Reports   7: 2465 (Journal)
Registered Authors: Korzh, Vladimir
Keywords: Cardiology, Drug discovery
MeSH Terms:
  • Animals
  • Arrhythmias, Cardiac/chemically induced*
  • Arrhythmias, Cardiac/metabolism
  • Arrhythmias, Cardiac/physiopathology
  • Bufanolides/pharmacology*
  • CHO Cells
  • Calcium/metabolism*
  • Calcium Channels, L-Type/metabolism
  • Cardenolides/pharmacology
  • Cardiac Glycosides/pharmacology*
  • Cell Differentiation/drug effects
  • Cell Line
  • Cricetulus
  • ERG1 Potassium Channel/metabolism
  • Egtazic Acid/analogs & derivatives
  • Egtazic Acid/pharmacology
  • HEK293 Cells
  • Human Embryonic Stem Cells/cytology
  • Human Embryonic Stem Cells/drug effects
  • Human Embryonic Stem Cells/metabolism
  • Humans
  • Larva
  • Myocytes, Cardiac/cytology
  • Myocytes, Cardiac/drug effects
  • Myocytes, Cardiac/metabolism*
  • NAV1.5 Voltage-Gated Sodium Channel/metabolism
  • Ouabain/pharmacology
  • Voltage-Gated Sodium Channel beta-1 Subunit/metabolism
  • Zebrafish
PubMed: 28550304 Full text @ Sci. Rep.
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.
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