Exploration of human, rat, and rabbit embryonic cardiomyocytes suggests K-channel block as a common teratogenic mechanism
2013 (English)In: Cardiovascular Research, ISSN 0008-6363, E-ISSN 1755-3245, Vol. 97, no 1, 23-32 p.Article in journal (Refereed) Published
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. less thanbrgreater than less thanbrgreater thanPatch-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. less thanbrgreater than less thanbrgreater thanThis 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.
Place, publisher, year, edition, pages
Oxford University Press (OUP): Policy B , 2013. Vol. 97, no 1, 23-32 p.
Arrhythmia, Embryo, K-channel, Long-QT syndrome, Teratogenicity
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-87461DOI: 10.1093/cvr/cvs296ISI: 000312656700007OAI: oai:DiVA.org:liu-87461DiVA: diva2:589483
Funding Agencies|Swedish Governmental Agency for Innovation systems (Vinnova)|P3349-1|Swedish Research Council||Swedish Heart-Lung Foundation||County Council of Ostergotland||King Gustaf V and Queen Victorias Freemasons Foundation||2013-01-182013-01-182013-01-18