title: Exploration of human, rat, and rabbit embryonic cardiomyocytes suggests K-channel block as a common teratogenic mechanism.
abstract: OBJECTIVE
  Several drugs blocking the rapidly activating potassium (K(r)) channel cause malformations (including cardiac defects) and embryonic death in animal teratology studies. In humans, these drugs have an established risk for acquired long-QT syndrome and arrhythmia. Recently, associations between cardiac defects and spontaneous abortions have been reported for drugs widely used in pregnancy (e.g. antidepressants), with long-QT syndrome risk. To investigate whether a common embryonic adverse-effect mechanism exists in the human, rat, and rabbit embryos, we made a comparative study of embryonic cardiomyocytes from all three species.
  
  
  RESULTS
  Patch-clamp and quantitative-mRNA measurements of K(r) and slowly activating K (K(s)) channels were performed on human, rat, and rabbit primary cardiomyocytes and cardiac samples from different embryo-foetal stages. The K(r) channel was present when the heart started to beat in all species, but was, in contrast to human and rabbit, lost in rats in late organogenesis. The specific K(r)-channel blocker E-4031 prolonged the action potential in a species- and development-dependent fashion, consistent with the observed K(r)-channel expression pattern and reported sensitive periods of developmental toxicity. E-4031 also increased the QT interval and induced 2:1 atrio-ventricular block in multi-electrode array electrographic recordings of rat embryos. The K(s) channel was expressed in human and rat throughout the embryo-foetal period but not in rabbit.
  
  
  CONCLUSIONS
  This first comparison of mRNA expression, potassium currents, and action-potential characteristics, with and without a specific K(r)-channel blocker in human, rat, and rabbit embryos provides evidence of K(r)-channel inhibition as a common mechanism for embryonic malformations and death.
authors.affiliation: Department of Cardiology, Karolinska University Hospital, Huddinge, SE-141 86, Stockholm, Sweden. n.christian.danielsson@gmail.com
authors.forename: Christian
authors.initials: C
authors.lastname: Danielsson
authors.forename: Johan
authors.initials: J
authors.lastname: Brask
authors.forename: Anna-Carin
authors.initials: AC
authors.lastname: Sköld
authors.forename: Rami
authors.initials: R
authors.lastname: Genead
authors.forename: Agneta
authors.initials: A
authors.lastname: Andersson
authors.forename: Ulf
authors.initials: U
authors.lastname: Andersson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Stockling
authors.forename: Rickard
authors.initials: R
authors.lastname: Pehrson
authors.forename: Karl-Henrik
authors.initials: KH
authors.lastname: Grinnemo
authors.forename: Sajjad
authors.initials: S
authors.lastname: Salari
authors.forename: Heike
authors.initials: H
authors.lastname: Hellmold
authors.forename: Bengt
authors.initials: B
authors.lastname: Danielsson
authors.forename: Christer
authors.initials: C
authors.lastname: Sylvén
authors.forename: Fredrik
authors.initials: F
authors.lastname: Elinder
mesh_terms: D000200:Action Potentials; D000818:Animals; D054537:Atrioventricular Block / Q000139:chemically induced / Q000378:metabolism; D002478:Cells, Cultured; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006330:Heart Defects, Congenital / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D008133:Long QT Syndrome / Q000139:chemically induced / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D038081:Organogenesis; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000633:toxicity*; D016133:Polymerase Chain Reaction; D026902:Potassium Channel Blockers / Q000633:toxicity*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013045:Species Specificity; D013723:Teratogens / Q000633:toxicity*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C489619:KCNE2 protein, human; C489621:KCNE2 protein, rat; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C484268:Kcne1 protein, rat; C496911:Kcnq1 protein, rat; D010880:Piperidines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D012333:RNA, Messenger; D013723:Teratogens; C063968:E 4031