title: Human embryonic stem cell derived cardiac myocytes detect hERG-mediated repolarization effects, but not Nav1.5 induced depolarization delay.
abstract: BACKGROUND
  Cardiac safety is of paramount importance in contemporary drug development. Efficient and sensitive evaluation of cardiac safety in the research and development of new molecular agents begins with preclinical in-vitro models. A new model that is currently under evaluation is the human embryonic stem-cell derived cardiac myocytes (hESC-CM) (Peng, Lacerda, Kirsch, Brown, & Bruening-Wright, 2010).
  
  
  METHODS
  hESC-CM were exposed in-vitro to 15 test compounds, and action potentials (AP) recorded with perforated patch-clamp technique to assess changes in AP duration (APD90) and upstroke velocity (Vmax). The test compounds included: 10 hERG channel, 4 Na⁺ channel, and 1 IKs channel inhibitors. For comparison purposes, the test compounds were evaluated in the isolated rabbit heart assay (IRH) to determine changes in conduction (QRS) and repolarization (QTc). Potency at hERG, NaV1.5 and IKs channel was also determined.
  
  
  RESULTS
  For 7 of 10 hERG channel inhibitors, the potency values across the three functional assays were similar (≤5-fold). Three compounds (dofetilide, sertindole, and terfenadine) showed >10-fold discrepancy between hERG potency and inhibitory concentrations in the hESC-CM and IRH assays. Of the four Na⁺ channel inhibitors, only mexiletine exhibited similar potency values across the three assays (~3-fold); the others exhibited marked variation (>10-fold) in inhibitory potency. No effect on repolarization was observed in hESC-CM treated with a potent IKs blocker, but QTc prolongation was evident in the IRH.
  
  
  CONCLUSIONS
  The functional data indicate that hESC-CM are sensitive for detecting repolarization delay induced by hERG channel blockade, and AP prolongation correlated with potency in the hERG channel and IRH assays. However, hESC-CM were less sensitive for detecting depolarizing delay by Na⁺ channel blockers, and unable to detect delayed repolarization caused by IKs blockade.
authors.affiliation: Safety and Exploratory Pharmacology, Toxicological Sciences, Amgen Inc., Thousand Oaks, CA 91320, USA. yqu@amgen.com
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Qu
authors.forename: Baoxi
authors.initials: B
authors.lastname: Gao
authors.forename: Mei
authors.initials: M
authors.lastname: Fang
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Vargas
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000072237:ERG1 Potassium Channel; D053595:Embryonic Stem Cells / Q000166:cytology*; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; C059983:potassium channel protein I(sk)
keywords: APD90; Human embryonic stem cells derived cardiac myocytes; Isolated rabbit heart; Patch-clamp method; QRS intervals; QTc intervals