Assessment of Drug-Induced Cardiotoxicity during Rat Embryo Development

Sammanfattning: 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 The results of the paper I show that the teratogenic properties of the drug astemizole (withdrawn from the market several years ago because of fatal cardiac arrhythmias in adults related to the blockade of hERG/IKr) were missed in the initial safety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.