The Effect of Dofetilide on the Heart Rate of GD11 and GD13 Rat Embryos, in vivo, Using Ultrasound

Ritchie, Helen E.; Oakes, Diana J.; Hung, Tzong-Tyng; Hegedus, Elizabeth; Sood, Shreya; Webster, William S.

doi:10.1002/bdrb.21162

Cited by 13 publications

(16 citation statements)

References 23 publications

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“…In this regard, it is not surprising that fetal heart rates were not affected. However, whether fetal cardiac responses to anaemia differ from adults, and whether there are developmental differences between rats and sheep in heart rate regulation3539 may provide some insights into the mechanisms of fetal cardiovascular compensation to anaemia.…”

Section: Discussionmentioning

confidence: 99%

Modest and Severe Maternal Iron Deficiency in Pregnancy are Associated with Fetal Anaemia and Organ-Specific Hypoxia in Rats

Woodman

Care

Mansour

et al. 2017

Sci Rep

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Prenatal iron-deficiency (ID) is known to alter fetal developmental trajectories, which predisposes the offspring to chronic disease in later life, although the underlying mechanisms remain unclear. Here, we sought to determine whether varying degrees of maternal anaemia could induce organ-specific patterns of hypoxia in the fetuses. Pregnant female Sprague Dawley rats were fed iron-restricted or iron-replete diets to induce a state of moderate (M-ID) or severe ID (S-ID) alongside respective controls. Ultrasound biomicroscopy was performed on gestational day (GD)20 to assess uterine and umbilical artery blood flow patterns. On GD21, tissues were collected and assessed for hypoxia using pimonidazole staining. Compared to controls, maternal haemoglobin (Hb) in M- and S-ID were reduced 17% (P < 0.01) and 48% (P < 0.001), corresponding to 39% (P < 0.001) and 65% (P < 0.001) decreases in fetal Hb. Prenatal ID caused asymmetric fetal growth restriction, which was most pronounced in S-ID. In both severities of ID, umbilical artery resistive index was increased (P < 0.01), while pulsatility index only increased in S-ID (P < 0.05). In both M-and S-ID, fetal kidneys and livers showed evidence of hypoxia (P < 0.01 vs. controls), whereas fetal brains and placentae remained normoxic. These findings indicate prenatal ID causes organ-specific fetal hypoxia, even in the absence of severe maternal anaemia.

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Section: Discussionmentioning

confidence: 99%

Modest and Severe Maternal Iron Deficiency in Pregnancy are Associated with Fetal Anaemia and Organ-Specific Hypoxia in Rats

Woodman

Care

Mansour

et al. 2017

Sci Rep

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“…The particular subtype of channel varies between the adult and embryo, and also varies with stage of embryonic development (Nilsson et al, ). The most compelling evidence of fetal bradycardia causing hypoxia and birth defects has come from studies of the drugs, dofetilide and almokalant, which block the rapidly activating delayed rectifier potassium current (IKr) (Spence et al, ; Webster et al, ; Ritchie et al, , ).…”

Section: Introductionmentioning

confidence: 99%

“…The class III antiarrhythmics, dofetilide, amiodarone, and sotalol, have been tested in vitro using whole rat embryos inducing a dose‐related bradycardia (Spence et al, ; Webster et al, ; Danielsson et al, ; Abela et al, ; Ritchie et al, , ). During preclinical testing, these drugs caused limb defects, including adactyly and an increased incidence of embryonic death when administered to pregnant rats during a sensitive window of development (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…Other malformations included maxillary hypoplasia, open eyes, ventricular septal defects (VSDs), and other cardiovascular defects (GD 10–13) (Skold et al, ). Localized hemorrhage and hypoxia preceded the limb malformations (Webster et al, ; Ritchie et al, , ). By GD 15, the rat embryo is no longer dependent on IKr and even very high doses of dofetilide or almokalant were without effect (Webster et al, ).…”

Section: Introductionmentioning

confidence: 99%

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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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“…In pregnant rats, it's observed effect is more severe on the embryonic heart than the adult heart. Depending on dose, when administered in the organogenic period of rat pregnancy, dofetilide causes severe embryonic bradycardia resulting in embryonic hypoxia leading to birth defects and/or embryonic death (Ritchie, Ababneh, Oakes, Power, & Webster, ; Ritchie et al, ). An embryotoxic dose of dofetilide has little or no effect on the adult rat heart.…”

Section: Introductionmentioning

confidence: 99%

The effects of nifedipine and ivabradine on the functionality of the early rat embryonic heart. Are these drugs a risk in early human pregnancy?

Ritchie

Telenius

Gustaffson

et al. 2019

Birth Defects Research

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Background: When the human heart begins its earliest contractions from day 21, it lacks a functional autonomic nerve supply. Instead, contractions are generated by regular calcium transients later augmented by the funny current (I f ) produced by sinoatrial-like cells. This study examined effects of blocking these currents in the early rat embryonic heart. Methods: Rat embryos were incubated in vitro with either the calcium channel blocker nifedipine and/or the funny current (I f ) blocker ivabradine for 1 hr to examine the effects of these drugs on the activity of the embryonic heart. Results: On gestational day (GD) 10, nifedipine (0.45-1.8 μM) caused asystole at high concentrations (8/10 embryos at 1.8 μM and 3/10 embryos at 0.9 μM) and markedly increased embryonic heart rate (EHR) in all surviving embryos but likely reduced blood flow due to weak contractions. Ivabradine (1.5 μM) caused a 29% reduction in EHR in GD 10 embryos and a greater than 50% reduction in EHR for GD 11-14 embryos. Combined exposure to both nifedipine and ivabradine resulted in an additive effect. The increased EHR due to nifedipine was reduced by the ivabradine. Conclusion:The results suggest that exposure to nifedipine in human pregnancy 3-4 weeks postfertilization may cause a direct effect on the embryonic heart resulting in reduced blood flow leading to abnormal heart and/or blood vessel development and/or embryonic death. Accidental exposure to ivabradine in the organogenic period would be expected to cause embryonic bradycardia, hypoxia, malformations, and embryonic death. This drug is currently contraindicated in pregnancy.

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The Effect of Dofetilide on the Heart Rate of GD11 and GD13 Rat Embryos, in vivo, Using Ultrasound

Abstract: Ultrasound is a useful technique to investigate the effect of maternally administered drugs on the embryonic HR in the rat. The results may provide more information about the safety of these drugs in pregnancy leading to better risk assessment for the human.

Cited by 13 publications

References 23 publications

Modest and Severe Maternal Iron Deficiency in Pregnancy are Associated with Fetal Anaemia and Organ-Specific Hypoxia in Rats

Modest and Severe Maternal Iron Deficiency in Pregnancy are Associated with Fetal Anaemia and Organ-Specific Hypoxia in Rats

Early Gestational Hypoxia and Adverse Developmental Outcomes

The effects of nifedipine and ivabradine on the functionality of the early rat embryonic heart. Are these drugs a risk in early human pregnancy?

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