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The effect on rat embryonic heart rate of Na+-, K+ and Ca2+ channel blockers, and the human teratogen phenytoin, changes with gestational age
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
University of Sydney.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. University of Sydney.
2013 (English)In: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 98, no 5, 416-427 p.Article in journal (Refereed) Published
Abstract [en]

To determine the changes in dependence on ion channels during rat cardiac development we compared the effects of four ion channel blockers on rat embryonic heart function during the organogenic period from gestational day (GD) 10-15. Rat embryos in culture were exposed to either the hERG potassium channel blocker dofetilide (400 nM), the sodium channel blocker lidocaine (250 μM) the L-type calcium channel blocker nifedipine (1.8 μM), or the multi-channel blocker phenytoin (200 μM). Lidocaine slowed the heart rate (HR) with the effect becoming more severe with increasing GD. Dofetilide slowed the embryonic HR and caused arrhythmias with the most severe effect on GD 11-13. Nifedipine primarily caused a negative inotropic effect except on GD 10 when it stopped the heart in most embryos. Phenytoin stopped the heart of most GD 10-12 embryos while on GD 13-15 phenytoin it slowed the heart. The results demonstrate that as the rat heart develops during the organogenic period its functional dependence on ion channels changes markedly. These changes are important for understanding drug effects on the embryo during pregnancy and the methodology used provides a simple procedure for assessing drug effects on the developing heart.

Place, publisher, year, edition, pages
2013. Vol. 98, no 5, 416-427 p.
National Category
Pharmacology and Toxicology
Research subject
Behavioural Neuroscience; Toxicology
URN: urn:nbn:se:uu:diva-206881DOI: 10.1002/bdrb.21084ISI: 000328470100005OAI: oai:DiVA.org:uu-206881DiVA: diva2:645862
Available from: 2013-09-05 Created: 2013-09-05 Last updated: 2014-01-23Bibliographically approved
In thesis
1. Assessment of Drug-Induced Cardiotoxicity during Rat Embryo Development
Open this publication in new window or tab >>Assessment of Drug-Induced Cardiotoxicity during Rat Embryo Development
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The potassium ion channel (hERG/IKr) is important for normal heart function and drug-induced blockade of the channel in adult humans can lead to irregular heart rhythms (arrhythmia).  The ion channel is also essential for early cardiac function in the embryo and therapeutic drugs which block this channel have been shown to cause birth defects in animal studies.  A wide range of birth defects have been seen including cleft lip/palate, distal limb defects and heart malformations.

These malformations are associated with periods of hypoxia and altered blood flow in the embryo associated with the drug-induced heart rhythm disorders and bradycardia. It is also well known that other experimental procedures causing periods of hypoxia in the embryo can give rise to similar defects as those seen with drugs that block the hERG/IKr channel. Paper I on the thesis deals with risk assessment for use in pregnancy of drugs which block hERG/IKr.   Evaluation of the risk of birth defects is largely based on the results of experimental studies on animals. Guidelines for how such standard tests are to be performed were determined by regulatory authorities several decades ago. However, there are examples where safety studies for drugs blocking hERG/IKr, although fulfilling regulatory guidelines, have been carried out at a suboptimal dose range and failed to detect teratogenicity.  A consequence of this is that the teratogenic potential of hERG/IKr blocking drugs have been missed in standard safety testing. The results of the paper I show that the teratogenic properties of the drug astemizole (withdrawn from the market several years ago because of fatal cardiac arrhythmias in adults related to the blockade of hERG/IKr) were missed in the initial safety studies.

Paper II shows that several drugs that block cardiac ion channels other than hERG/IKr can also disrupt fetal cardiac function during embryonic development. However, the concentrations required to cause these changes are much higher than is likely to occur during normal use of the medicines and based on these results that are not considered a risk when taken during pregnancy.

Paper III deals with the possible teratogenicity of erythromycin.  From the Swedish Birth Defects Register there have been signals that use of erythromycin (which has hERG/IKr-blocking properties) during pregnancy is associated with an increased risk of cardiovascular malformations. Paper III shows that the levels of erythromycin needed to disrupt fetal cardiac function during embryonic development are unlikely to occur after normal oral treatment with erythromycin.

Paper IV shows that the embryonic rat heart undergoes major changes in sensitivity to blockade of specific cardiac ion channels during the organogenic period. This is an important observation from the perspective that there may be periods during embryonic development when the embryo is more or less sensitive to the effect of drugs that affect specific ion channels.

To conclude, papers I-IV show that the study of drug effects on the gestation day 13 rat embryonic heart, together with the use of computational assisted image analysis of the cardiac response, provides an in vitro model for hazard identification of compounds with the potential to adversely affect heart function in the developing embryo.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 77 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 177
National Category
Pharmacology and Toxicology
urn:nbn:se:uu:diva-206882 (URN)978-91-554-8745-4 (ISBN)
Public defence
2013-10-18, A1:107a, Biomedicinskt Centrum, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2013-09-27 Created: 2013-09-05 Last updated: 2014-01-23

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