title: Compound ICA-105574 prevents arrhythmias induced by cardiac delayed repolarization.
abstract: Impaired ventricular repolarization can lead to long QT syndrome (LQT), a proarrhythmic disease with high risk of developing lethal ventricular tachyarrhythmias. The compound ICA-105574 is a recently developed hERG activator and it enhances IKr current with very high potency by removing the channel inactivation. The present study was designed to investigate antiarrhythmic properties of ICA-105574. For comparison, the effects of another compound NS1643 was in-parallel assessed, which also acts primarily to attenuate channel inactivation with moderate potency. We found that both ICA-105574 and NS1643 concentration-dependently shortened action potential duration (APD) in ventricular myocytes, and QT/QTc intervals in isolated guinea-pig hearts. ICA-105574, but not NS1643, completely prevented ventricular arrhythmias in intact guinea-pig hearts caused by IKr and IKs inhibitors, although both ICA-105574 and NS1643 could reverse the drug-induced prolongation of APD in ventricular myocytes. Reversing prolongation of QT/QTc intervals and antagonizing the increases in transmural dispersion of repolarization and instability of the QT interval induced by IKr and IKs inhibitors contributed to antiarrhythmic effect of ICA-105574. Meanwhile, ICA-105574 at higher concentrations showed a potential proarrhythmic risk in normal hearts. Our results suggest that ICA-105574 has more efficient antiarrhythmic activity than NS1643. However, its potential proarrhythmic risk implies that benefits and risks should be seriously taken into consideration for further developing this type of hERG activators.
authors.affiliation: The Key Laboratory of Neural and Vascular Biology, Ministry of Education; The Key Laboratory of New Drug Pharmacology and Toxicology, Department of Pharmacology, Hebei Medical University, Hebei Province, Shijiazhuang 050017, China; Department of Pharmaceutical Chemistry, Hebei Medical University, Shijiazhuang, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Meng
authors.forename: Chenxia
authors.initials: C
authors.lastname: Shi
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Yumin
authors.initials: Y
authors.lastname: Du
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D001549:Benzamides / Q000494:pharmacology*; D003408:Cresols / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010477:Perfusion; D010671:Phenylurea Compounds / Q000494:pharmacology
chemical_list: C576778:3-nitro-N-(4-phenoxyphenyl)benzamide; D001549:Benzamides; D003408:Cresols; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D010671:Phenylurea Compounds; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea
keywords: Action potential; Antiarrhythmic activity; ICA-105574; Long QT syndrome; NS1643; Proarrhythmic risk; hERG activator