Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides

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 (...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Cai Hong Koh, Jianjun Wu, Ying Ying Chung, Zhenfeng Liu, Rong-Rong Zhang, Ketpin Chong, Vladimir Korzh, Sherwin Ting, Steve Oh, Winston Shim, Hai-Yan Tian, Heming Wei
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/264c50ca7b3246abb2da30023aced565
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:264c50ca7b3246abb2da30023aced565
record_format	dspace
spelling	oai:doaj.org-article:264c50ca7b3246abb2da30023aced5652021-12-02T11:53:09ZIdentification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides10.1038/s41598-017-02496-42045-2322https://doaj.org/article/264c50ca7b3246abb2da30023aced5652017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02496-4https://doaj.org/toc/2045-2322Abstract 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 to 100 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.Cai Hong KohJianjun WuYing Ying ChungZhenfeng LiuRong-Rong ZhangKetpin ChongVladimir KorzhSherwin TingSteve OhWinston ShimHai-Yan TianHeming WeiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cai Hong Koh Jianjun Wu Ying Ying Chung Zhenfeng Liu Rong-Rong Zhang Ketpin Chong Vladimir Korzh Sherwin Ting Steve Oh Winston Shim Hai-Yan Tian Heming Wei Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides
description	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 to 100 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.
format	article
author	Cai Hong Koh Jianjun Wu Ying Ying Chung Zhenfeng Liu Rong-Rong Zhang Ketpin Chong Vladimir Korzh Sherwin Ting Steve Oh Winston Shim Hai-Yan Tian Heming Wei
author_facet	Cai Hong Koh Jianjun Wu Ying Ying Chung Zhenfeng Liu Rong-Rong Zhang Ketpin Chong Vladimir Korzh Sherwin Ting Steve Oh Winston Shim Hai-Yan Tian Heming Wei
author_sort	Cai Hong Koh
title	Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides
title_short	Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides
title_full	Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides
title_fullStr	Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides
title_full_unstemmed	Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides
title_sort	identification of na+/k+-atpase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/264c50ca7b3246abb2da30023aced565
work_keys_str_mv	AT caihongkoh identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides AT jianjunwu identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides AT yingyingchung identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides AT zhenfengliu identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides AT rongrongzhang identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides AT ketpinchong identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides AT vladimirkorzh identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides AT sherwinting identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides AT steveoh identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides AT winstonshim identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides AT haiyantian identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides AT hemingwei identificationofnakatpaseinhibitionindependentproarrhythmicionicmechanismsofcardiacglycosides
_version_	1718394856225636352

Identification of Na+/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides

Ejemplares similares