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The effect of drugs with ion channel-blocking activity on the early embryonic rat heart
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2010 (English)In: Birth defects research. Part B. Developmental and reproductice toxicology, ISSN 1542-9733, E-ISSN 1542-9741, Vol. 89, no 5, 429-440 p.Article in journal (Refereed) Published
Abstract [en]

This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the IKr/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or IKr/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing.

Place, publisher, year, edition, pages
2010. Vol. 89, no 5, 429-440 p.
Keyword [en]
embryo/fetal physiology, in vitro screens, mechanisms of teratogenesis, pharmaceuticals
National Category
Computer Vision and Robotics (Autonomous Systems) Pharmaceutical Sciences
Research subject
Computerized Image Processing
URN: urn:nbn:se:uu:diva-141481DOI: 10.1002/bdrb.20270ISI: 000283911500008PubMedID: 20973055OAI: oai:DiVA.org:uu-141481DiVA: diva2:385659
Available from: 2011-01-12 Created: 2011-01-12 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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Nilsson, Mats F
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