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With the cytosolic Ca<jats:sup>2+<\/jats:sup>chelated by EGTA and BAPTA or extracellular Ca<jats:sup>2+<\/jats:sup>replaced by Ba<jats:sup>2+<\/jats:sup>, effects of bufadienolides (bufalin (BF) and cinobufagin (CBG)) and cardenolides (ouabain (Oua) and pecilocerin A (PEA)) on the L-type calcium current (<jats:italic>I<\/jats:italic><jats:sub>Ca,L<\/jats:sub>) 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\u2009\u00b5M)<jats:italic>I<\/jats:italic><jats:sub>Ca,L<\/jats:sub>inhibition (maximal \u226550%) without and with the NKA activity blocked by 10\u2009\u00b5M Oua. BF significantly shortened the action potential duration at 1.0\u2009\u00b5M and shortened the extracellular field potential duration at 0.01~1.0\u2009\u00b5M. On the other hand, BF and CBG at 100\u2009\u00b5M demonstrated a strong inhibition (\u226540%) of the rapidly activating component of the delayed rectifier K<jats:sup>+<\/jats:sup>current (<jats:italic>I<\/jats:italic><jats:sub>Kr<\/jats:sub>) 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\u2009nM) for 24\u2009hours showed moderate yet significant prolongation in APD90. In conclusion, our data indicate that CGs particularly bufadienolides possess cytosolic [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>- and NKA inhibition- independent proarrhythmic potential through<jats:italic>I<\/jats:italic><jats:sub>Ca,L<\/jats:sub>and<jats:italic>I<\/jats:italic><jats:sub>Kr<\/jats:sub>inhibitions.<\/jats:p>","DOI":"10.1038\/s41598-017-02496-4","type":"journal-article","created":{"date-parts":[[2017,5,22]],"date-time":"2017-05-22T14:59:47Z","timestamp":1495465187000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Identification of Na+\/K+-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides"],"prefix":"10.1038","volume":"7","author":[{"given":"Cai Hong","family":"Koh","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianjun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying Ying","family":"Chung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenfeng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong-Rong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ketpin","family":"Chong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vladimir","family":"Korzh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sherwin","family":"Ting","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Oh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Winston","family":"Shim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai-Yan","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heming","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,5,26]]},"reference":[{"key":"2496_CR1","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1038\/nrd2682","volume":"7","author":"I Prassas","year":"2008","unstructured":"Prassas, I. & Diamandis, E. 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