The effect of drugs with ion channel‐blocking activity on the early embryonic rat heart

Abstract

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 I(Kr)/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 I(Kr)/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.

Effects of Macrolide Antibiotics on Rat Embryonic Heart Function In Vitro

“…The suggestion that erythromycin might cause heart malformations is based on the contention that erythromycin administered in pregnancy would affect the embryonic heart by inhibiting the hERG/I Kr current necessary for cardiac repolarization (Kallen et al., ; MPA, ). In the GD 13 rat embryo model system, highly selective I Kr blockers such as dofetilide, almokalant, and the antihistamine astemizole produce a distinct concentration‐dependent pattern of bradycardia with subsequent irregular and uncoordinated heart rhythm at higher concentration (Webster et al., ; Abela et al., ; Nilsson et al., ). The observed arrhythmias seen in this study with erythromycin (Fig.…”

“…As in previously published studies (Abela et al., ; Nilsson et al., , ; Ababneh et al., ; Gunnstrom et al., ), the video recordings of the embryonic hearts were examined and analyzed using software developed at the University of Uppsala (Khan et al., ; Khan Niazi et al, 2011). In this software, the atria and ventricles of the heart are identified on the video image and are manually marked.…”

A comparison of drug-induced cardiotoxicity in rat embryos cultured in human serum or protein free media

“…The concentrations to be tested for the other drugs were selected from previous publications as concentrations that caused a significant reduction in heart rate when the drug was administered in DMEM (Ababneh et al, 2011;Abela et al, 2010;Gunnstrom et al, 2012).…”

“…The embryos in their culture bottles were placed in a rotating culture system (BTC Engineering, Cambridge, UK). The culture bottles were rotated at 11 rotations per minute and were continuously gassed with 95% O 2 and 5% CO 2 at 38°C (Abela et al, 2010).…”

“…In this assay, whole rat embryos are exposed to therapeutic drugs with ion channel blocking properties and the effect on the function on the embryonic heart is observed and recorded (Ababneh, Ritchie, & Webster, 2011;Abela et al, 2010;Gunnstrom, Ababneh, Webster, Oakes, & Ritchie, 2012). The impetus for these studies is that many therapeutic drugs block ion channels, sometimes as a desired therapeutic effect or as an unwanted side-effect.…”