title: A novel method of selecting human embryonic stem cell-derived cardiomyocyte clusters for assessment of potential to influence QT interval.
abstract: Physiologically relevant assessment of delayed repolarization is necessary in drug development. In our preliminary experiments on the evaluation using a multielectrode recording system, we had found that the responsiveness of field potential duration (FPD), as QT-like intervals, to hERG channel blockers differed greatly from non-responders to excessive responders in human embryonic stem cell-derived cardiomyocyte clusters. Thus, we report a novel method of selecting clusters suitable for evaluating compounds for the assessment. Clusters were treated with cisapride, a hERG channel blocker, at 100nM, and selected with criteria of 5-20% of corrected FPD (FPDc) prolongation. Then, selected clusters were treated with reference compounds. FPDc was prolonged by blockade of the hERG channel (E-4031 and dl-sotalol) and KvLQT1 channel (chromanol 293B and HMR1556), and by activation of the sodium channel (veratridine) and calcium channel (Bay K8644). FPDc was shortened by calcium channel blockage (verapamil, nifedipine and diltiazem) and by K(ATP) channel activation (pinacidil). Class Ia antiarrhythmic drugs, quinidine and disopyramide, prolonged FPDc. Selected clusters are appropriate for assessing the effects of compounds on ion channels affecting QT intervals. This is the first report of the establishment of an assessment system of potential to influence QT interval, using pharmacologically selected clusters.
authors.affiliation: Eisai Product Creation Systems, Eisai Co., Ltd., 5-1-3, Tokodai, Tsukuba, Ibaraki 300-2635, Japan. k5-yamazaki@hhc.eisai.co.jp
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Taro
authors.initials: T
authors.lastname: Hihara
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kohmura
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshinaga
authors.forename: Masashi
authors.initials: M
authors.lastname: Ito
authors.forename: Kohei
authors.initials: K
authors.lastname: Sawada
mesh_terms: D020117:Cisapride / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D053595:Embryonic Stem Cells / Q000166:cytology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006801:Humans; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; D026902:Potassium Channel Blockers; D011725:Pyridines; C063968:E 4031; D020117:Cisapride