{"id":6339,"date":"2023-02-17T06:48:50","date_gmt":"2023-02-17T06:48:50","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2019-pharmacological-enhancement-of-repolarization-reserve-in-human-induced-pluripotent-stem-cells-derived-cardiomyocytes\/"},"modified":"2023-02-17T06:48:51","modified_gmt":"2023-02-17T06:48:51","slug":"2019-pharmacological-enhancement-of-repolarization-reserve-in-human-induced-pluripotent-stem-cells-derived-cardiomyocytes","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2019-pharmacological-enhancement-of-repolarization-reserve-in-human-induced-pluripotent-stem-cells-derived-cardiomyocytes\/","title":{"rendered":"2019 &#8211; Pharmacological enhancement of repolarization reserve in human induced pluripotent stem cells derived cardiomyocytes"},"content":{"rendered":"<p>BACKGROUND:\u00a0Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for many applications including safety pharmacology. However, a deficiency or complete absence of several K<sup>+<\/sup>\u00a0currents suggests repolarization reserve is low in hiPSC-CMs. We determined whether a dual Ito\u00a0and I<sup>Kr<\/sup>\u00a0activator can improve repolarization reserve in hiPSC-CMs resulting in a more electrophysiologically mature phenotype. METHODS AND RESULTS:\u00a0Human iPSC were maintained on growth factor and differentiated into the cardiac phenotype by addition of selective Wnt molecules. Current and voltage clamp recordings in single cells were made using patch electrodes. Extracellular field potentials were made using a microelectrode array on hiPSC monolayers. Action potential recordings from hiPSC-CMs following application of an I<sup>Kr<\/sup>\u00a0inhibitor resulted in depolarization of the membrane potential and prolongation of the APD. A flattening of the T-wave was noted on the pseudo-ECG. In contrast, application of the I<sup>Kr<\/sup>\u00a0and Ito\u00a0agonist, NS3623, resulted in hyperpolarization of the membrane, slowing of the spontaneous rate and shortening of the APD. Voltage clamp recording showed a significant increase in I<sup>Kr<\/sup>; no enhancement of Ito\u00a0in hiPSC-CMs was noted. AP clamp experiments revealed that I<sup>Kr<\/sup>\u00a0plays a role in both phase 3 repolarization and phase 4 depolarization. mRNA analysis revealed that KCNH2 is abundantly expressed in hiPSC-CM, consistent with electrophysiological recordings. CONCLUSIONS:\u00a0Although NS3623 is a dual Ito\u00a0and I<sup>Kr<\/sup>\u00a0activator in ventricular myocytes, application of this compound to hiPSC-CMs enhanced only I<sup>Kr<\/sup>\u00a0and no effect on Ito\u00a0was noted. Our results suggest I<sup>Kr<\/sup>\u00a0enhancement can improve repolarization reserve in this cell type. The disconnect between a dramatic increase in Ito\u00a0in adult myocytes versus the lack of effect in hiPSC-CMs suggest that the translation of pharmacological effects in hiPSC-CM to adult myocytes should be viewed with caution.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[34],"resource_type":[75],"application_areas":[50,77],"therapeutic_areas":[54],"target_categories":[61],"target_families":[333],"targets":[92,97,285],"resource_keyword":[],"class_list":["post-6339","resource_library","type-resource_library","status-publish","hentry","products_tags-cardioexcyte-96","resource_type-publication","application_areas-ion-channels","application_areas-cell-ipscs-profiling","therapeutic_areas-cardiac-safety-cipa","target_categories-voltage-gated-ion-channels","target_families-kv-channels","targets-kv11-1-herg","targets-kv4-3","targets-kv4-2"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/6339","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=6339"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=6339"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=6339"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=6339"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=6339"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=6339"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=6339"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=6339"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=6339"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}