{"id":6193,"date":"2023-02-17T06:56:39","date_gmt":"2023-02-17T06:56:39","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2017-identification-of-na-k-atpase-inhibition-independent-proarrhythmic-ionic-mechanisms-of-cardiac-glycosides\/"},"modified":"2023-02-17T06:56:39","modified_gmt":"2023-02-17T06:56:39","slug":"2017-identification-of-na-k-atpase-inhibition-independent-proarrhythmic-ionic-mechanisms-of-cardiac-glycosides","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2017-identification-of-na-k-atpase-inhibition-independent-proarrhythmic-ionic-mechanisms-of-cardiac-glycosides\/","title":{"rendered":"2017 &#8211; Identification of Na<sup>+<\/sup>\/K<sup>+<\/sup>-ATPase inhibition-independent proarrhythmic ionic mechanisms of cardiac glycosides"},"content":{"rendered":"<p>The current study explored the Na<sup>+<\/sup>\/K<sup>+<\/sup>-ATPase (NKA) inhibition-independent proarrhythmic mechanisms of cardiac glycosides (CGs) which are well-known NKA inhibitors. With the cytosolic Ca<sup>2+<\/sup>\u00a0chelated by EGTA and BAPTA or extracellular Ca<sup>2+<\/sup>\u00a0replaced by B<sup>a2+<\/sup>, effects of bufadienolides (bufalin (BF) and cinobufagin (CBG)) and cardenolides (ouabain (Oua) and pecilocerin A (PEA)) on the L-type calcium current (I\u00a0Ca,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\u2009\u00b5M) I Ca,L\u00a0inhibition (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<sup>+<\/sup>\u00a0current (I\u00a0Kr) 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<sup>2+<\/sup>]i- and NKA inhibition- independent proarrhythmic potential through I\u00a0Ca,L\u00a0and I\u00a0Kr\u00a0inhibitions.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[44],"resource_type":[75],"application_areas":[50,108],"therapeutic_areas":[54],"target_categories":[61,60],"target_families":[332,340,344],"targets":[91,92,93,208],"resource_keyword":[],"class_list":["post-6193","resource_library","type-resource_library","status-publish","hentry","products_tags-patchliner","resource_type-publication","application_areas-ion-channels","application_areas-transporters","therapeutic_areas-cardiac-safety-cipa","target_categories-voltage-gated-ion-channels","target_categories-transporters","target_families-nav-channels","target_families-cav-channels","target_families-p-type-atpases","targets-cav1-2","targets-kv11-1-herg","targets-nav1-5","targets-na-k-atpase"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/6193","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=6193"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=6193"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=6193"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=6193"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=6193"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=6193"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=6193"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=6193"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=6193"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}