{"id":6239,"date":"2023-02-17T06:56:54","date_gmt":"2023-02-17T06:56:54","guid":{"rendered":"https:\/\/beta.nanion.de\/resource_library\/2018-evaluation-of-possible-proarrhythmic-potency-comparison-of-the-effect-of-dofetilide-cisapride-sotalol-terfenadine-and-verapamil-on-herg-and-native-ikr-currents-and-on-cardiac-action-potenti\/"},"modified":"2023-02-17T06:56:54","modified_gmt":"2023-02-17T06:56:54","slug":"2018-evaluation-of-possible-proarrhythmic-potency-comparison-of-the-effect-of-dofetilide-cisapride-sotalol-terfenadine-and-verapamil-on-herg-and-native-ikr-currents-and-on-cardiac-action-potenti","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2018-evaluation-of-possible-proarrhythmic-potency-comparison-of-the-effect-of-dofetilide-cisapride-sotalol-terfenadine-and-verapamil-on-herg-and-native-ikr-currents-and-on-cardiac-action-potenti\/","title":{"rendered":"2018 &#8211; Evaluation of possible proarrhythmic potency: comparison of the effect of dofetilide, cisapride, sotalol, terfenadine and verapamil on hERG and native I<sup>Kr<\/sup> currents and on cardiac action potential"},"content":{"rendered":"<p>Introduction: The proarrhythmic potency of drugs is usually attributed to the I<sup>Kr<\/sup>\u00a0current block. During safety pharmacology testing analysis of I<sup>Kr<\/sup>\u00a0in cardiomyocytes was replaced by hERG test using automated patch-clamp systems in stable transfected cell lines. Aim of the present study was to compare the effect of proarrhythmic compounds on hERG and I<sup>Kr<\/sup>\u00a0currents and on cardiac action potential. Methods: The hERG current was measured by using both automated and manual patch-clamp methods on HEK293 cells. The native ion currents (I<sup>Kr<\/sup>, INaL, ICaL) were recorded from rabbit ventricular myocytes by manual patch-clamp technique. Action potentials in rabbit ventricular muscle and undiseased human donor hearts were studied by conventional microelectrode technique. Results: Dofetilide, cisapride, sotalol, terfenadine and verapamil blocked hERG channels at 37\u2009\u00b0C with an IC<sub>50<\/sub>\u00a0of 7\u2009nM, 18\u2009nM, 343\u2009\u03bcM, 165\u2009nM and 214\u2009nM, respectively. Using manual patch-clamp, the IC<sub>50<\/sub>\u00a0values of sotalol and terfenadine were 78 \u00b5M and 31\u2009nM, respectively. The IC<sub>50<\/sub>\u00a0values calculated from I<sup>Kr<\/sup>\u00a0measurements at 37\u2009\u00b0C were 13\u2009nM, 26\u2009nM, 52\u2009\u03bcM, 54\u2009nM and 268\u2009nM, respectively. Cisapride, dofetilide and sotalol excessively lengthened, terfenadine and verapamil did not influence the action potential duration. Terfenadine significantly inhibited INaL\u00a0and moderately ICaL, verapamil blocked only ICaL. Conclusions: Automated hERG assays may over\/underestimate proarrhythmic risk. Manual patch-clamp has substantially higher sensitivity to certain drugs. Action potential studies are also required to analyze complex multichannel effects. Therefore, manual patch-clamp and action potential experiments should be a part of preclinical safety tests.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[44],"resource_type":[75],"application_areas":[50],"therapeutic_areas":[54],"target_categories":[61],"target_families":[333],"targets":[92],"resource_keyword":[],"class_list":["post-6239","resource_library","type-resource_library","status-publish","hentry","products_tags-patchliner","resource_type-publication","application_areas-ion-channels","therapeutic_areas-cardiac-safety-cipa","target_categories-voltage-gated-ion-channels","target_families-kv-channels","targets-kv11-1-herg"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/6239","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=6239"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=6239"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=6239"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=6239"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=6239"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=6239"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=6239"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=6239"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=6239"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}