Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41598-017-02496-4
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dc.titleElectronic supplementary materialIdentification of a Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides
dc.contributor.authorKoh, C.H
dc.contributor.authorWu, J
dc.contributor.authorChung, Y.Y
dc.contributor.authorLiu, Z
dc.contributor.authorZhang, R.-R
dc.contributor.authorChong, K
dc.contributor.authorKorzh, V
dc.contributor.authorTing, S
dc.contributor.authorOh, S
dc.contributor.authorShim, W
dc.contributor.authorTian, H.-Y
dc.contributor.authorWei, H
dc.date.accessioned2020-09-04T03:37:15Z
dc.date.available2020-09-04T03:37:15Z
dc.date.issued2017
dc.identifier.citationKoh, 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
dc.identifier.issn2045-2322
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/174411
dc.description.abstractThe 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.
dc.publisherNature Publishing Group
dc.sourceUnpaywall 20200831
dc.subject1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
dc.subjectbufadienolide derivative
dc.subjectbufalin
dc.subjectCACNA1C protein, human
dc.subjectcalcium
dc.subjectcalcium channel L type
dc.subjectcalotropin
dc.subjectcardenolide
dc.subjectcardiac glycoside
dc.subjectcinobufagin
dc.subjectegtazic acid
dc.subjectKCNH2 protein, human
dc.subjectouabain
dc.subjectpotassium channel HERG
dc.subjectSCN1B protein, human
dc.subjectSCN5A protein, human
dc.subjectsodium channel Nav1.5
dc.subjectvoltage gated sodium channel beta 1 subunit
dc.subjectanalogs and derivatives
dc.subjectanimal
dc.subjectcardiac muscle cell
dc.subjectcell differentiation
dc.subjectcell line
dc.subjectchemically induced
dc.subjectCHO cell line
dc.subjectCricetulus
dc.subjectcytology
dc.subjectdrug effect
dc.subjectheart arrhythmia
dc.subjectHEK293 cell line
dc.subjecthuman
dc.subjecthuman embryonic stem cell
dc.subjectlarva
dc.subjectmetabolism
dc.subjectpathophysiology
dc.subjectzebra fish
dc.subjectAnimals
dc.subjectArrhythmias, Cardiac
dc.subjectBufanolides
dc.subjectCalcium
dc.subjectCalcium Channels, L-Type
dc.subjectCardenolides
dc.subjectCardiac Glycosides
dc.subjectCell Differentiation
dc.subjectCell Line
dc.subjectCHO Cells
dc.subjectCricetulus
dc.subjectEgtazic Acid
dc.subjectERG1 Potassium Channel
dc.subjectHEK293 Cells
dc.subjectHuman Embryonic Stem Cells
dc.subjectHumans
dc.subjectLarva
dc.subjectMyocytes, Cardiac
dc.subjectNAV1.5 Voltage-Gated Sodium Channel
dc.subjectOuabain
dc.subjectVoltage-Gated Sodium Channel beta-1 Subunit
dc.subjectZebrafish
dc.typeArticle
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.doi10.1038/s41598-017-02496-4
dc.description.sourcetitleScientific Reports
dc.description.volume7
dc.description.issue1
dc.description.page2465
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