Antipsychotic drugs cause bradycardia in GD 13 rat embryos in vitro

Gunnström, M.; Ababneh, Deena; Webster, William S.; Oakes, Diana J.; Ritchie, Helen E.

doi:10.1016/j.reprotox.2012.06.008

Cited by 10 publications

(16 citation statements)

References 46 publications

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“…They are best described as heart block and this pattern of arrhythmia has previously been seen with Na + channel blockers (Abela et al., ; Nilsson et al., ). There was also a very weak heartbeat at high concentrations of clarithromycin likely to be associated with L‐type Ca channel inhibition (Abela et al., ; Gunnstrom et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Methodsmentioning

confidence: 99%

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Effects of Macrolide Antibiotics on Rat Embryonic Heart Function In Vitro

Nilsson

Webster

2014

Birth Defects Research Pt B

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The Swedish Medical Product Agency (MPA) has listed erythromycin as a suggested human teratogen, causing cardiovascular malformations. It is further suggested that this may be a class effect of macrolide antibiotics. The proposed teratogenic mechanism is blockade of the human ether-á-go-go-related (hERG)/IKr current in the embryonic heart causing bradycardia and arrhythmia resulting in altered cardiac blood flow and/or embryonic hypoxia. To test this hypothesis, we examined the effect of three macrolide antibiotics on the function of the rat embryonic heart. Gestational day 13 rat embryos in vitro were exposed to erythromycin (25-500 μM), clarithromycin (25-500 μM), or azithromycin (100 μM to 1 mM) for 3 hr. The effect on the embryonic heart was monitored every hour. The results showed that erythromycin and clarithromycin caused a concentration-dependent bradycardia. Twenty-five micromolar was a no-effect concentration for erythromycin and was close to a no-effect concentration for clarithromycin. Azithromycin only caused significant bradycardia at 1 mM. Additional studies were performed with the embryos cultured at 40°C instead of 38°C, to mimic fever. The increased temperature increased the number of arrhythmias but did not worsen the drug-induced bradycardia. The results support the concept that erythromycin and clarithromycin can adversely affect the embryonic heart but only at concentrations well outside expected embryonic exposure in the human.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Effects of Macrolide Antibiotics on Rat Embryonic Heart Function In Vitro

Nilsson

Webster

2014

Birth Defects Research Pt B

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“…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).…”

Section: Test Chemicalsmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

“…All the tested drugs blocked hERG potassium and/or sodium ion channels (not necessarily as their therapeutic effect) and caused a concentration-dependent bradycardia in the rat embryonic heart (Ababneh et al, 2011;Abela et al, 2005;Gunnstrom et al, 2012). For each drug we determined the concentration that caused severe bradycardia down to the no-effect concentration.…”

Section: Introductionmentioning

confidence: 99%

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

Ritchie

Svensson

Nilsson

et al. 2014

Journal of Pharmacological and Toxicological Methods

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Early Gestational Hypoxia and Adverse Developmental Outcomes

Ritchie

Oakes

Kennedy

et al. 2017

Birth Defects Research

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Hypoxia is a normal and essential part of embryonic development. However, this state may leave the embryo vulnerable to damage when oxygen supply is disturbed. Embryofetal response to hypoxia is dependent on duration and depth of hypoxia, as well as developmental stage. Early postimplantation rat embryos were resilient to hypoxia, with many surviving up to 1.5 hr of uterine clamping, while most mid-gestation embryos were dead after 1 hour of clamping. Survivors were small and many had a range of defects, principally terminal transverse limb reduction defects. Similar patterns of malformations occurred when embryonic hypoxia was induced by maternal hypoxia, interruption of uteroplacental flow, or perfusion and embryonic bradycardia. There is good evidence that high altitude pregnancies are associated with smaller babies and increased risk of some malformations, but these results are complicated by increased risk of pre-eclampsia. Early onset pre-eclampsia itself is associated with small for dates and increased risk of atrio-ventricular septal defects. Limb defects have clearly been associated with chorionic villus sampling, cocaine, and misoprostol use. Similar defects are also observed with increased frequency among fetuses who are homozygous for thalassemia. Drugs that block the potassium current, whether as the prime site of action or as a side effect, are highly teratogenic in experimental animals. They induce embryonic bradycardia, hypoxia, hemorrhage, and blisters, leading to transverse limb defects as well as craniofacial and cardiovascular defects. While evidence linking these drugs to birth defects in humans is not compelling, the reason may methodological rather than biological. Birth Defects Research 109:1358-1376, 2017.© 2017 Wiley Periodicals, Inc.

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Antipsychotic drugs cause bradycardia in GD 13 rat embryos in vitro

Cited by 10 publications

References 46 publications

Effects of Macrolide Antibiotics on Rat Embryonic Heart Function In Vitro

Effects of Macrolide Antibiotics on Rat Embryonic Heart Function In Vitro

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

Early Gestational Hypoxia and Adverse Developmental Outcomes

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