title: Effects of an hERG activator, ICA-105574, on electrophysiological properties of canine hearts.
abstract: In short QT syndrome, inherited gain-of-function mutations in the human ether a-gogo-related gene (hERG) K(+) channel have been associated with development of fatal arrhythmias. This implies that drugs that activate hERG as a side effect may likewise pose significant arrhythmia risk. hERG activators have been found to have diverse mechanisms of activation, which may reflect their distinct binding sites. Recently, the new hERG activator ICA-105574 was introduced, which disables inactivation of the hERG channel with very high potency. We explored characteristics of this new drug in several experimental models. Patch clamp experiments were used to verify activation of hERG channels by ICA-105574 in human embryonic kidney cells stably-expressing hERG channels. ICA-105574 significantly shortened QT and QTc intervals and monophasic action potential duration (MAP(90)) in Langendorff-perfused guinea-pig hearts. We also administered ICA-105574 to anesthetized dogs while recording ECG and drug plasma concentrations. ICA-105574 (10 mg/kg) significantly shortened QT and QTc intervals, with a free plasma concentration of approximately 1.7 µM at the point of maximal effect. Our data showed that unbound ICA-105574 caused QT shortening in dogs at concentrations comparable to the half maximal effective concentration (EC(50), 0.42 µM) of hERG activation in the patch clamp studies.
authors.affiliation: Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
authors.forename: Mahoko
authors.initials: M
authors.lastname: Asayama
authors.forename: Junko
authors.initials: J
authors.lastname: Kurokawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Shirakawa
authors.forename: Hisashi
authors.initials: H
authors.lastname: Okuyama
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kagawa
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Okada
authors.forename: Seiryo
authors.initials: S
authors.lastname: Sugiura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hisada
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Furukawa
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002478:Cells, Cultured; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D018408:Patch-Clamp Techniques
chemical_list: C576778:3-nitro-N-(4-phenoxyphenyl)benzamide; D001549:Benzamides; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human