Embryonic Arrhythmia by Inhibition of HERG Channels: A Common Hypoxia‐related Teratogenic Mechanism for Antiepileptic Drugs?

Abstract

Summary:Purpose: There is evidence that drug-induced embryonic arrhythmia initiates phenytoin (PHT) teratogenicity. The arrhythmia, which links to the potential of PHT to inhibit a specific potassium channel (I kr ), may result in episodes of embryonic ischemia and generation of reactive oxygen species (ROS) at reperfusion. This study sought to determine whether the proposed mechanism might be relevant for the teratogenic antiepileptic drug trimethadione (TMO).Methods: Effects on embryonic heart rhythm during various stages of organogenesis were examined in CD-1 mice after maternal administration (125-1,000 mg/kg) of dimethadione (DMO), the pharmacologically active metabolite of TMO. Palatal development was examined after administration of a teratogenic dose of DMO and after simultaneous treatment with DMO and a ROS-capturing agent (␣-phenyl-N-tert-butylnitrone; PBN). The I kr blocking potentials of TMO and DMO were investigated in HERG-transfected cells by using voltage patch-clamping tests.Results: DMO caused stage-specific (gestation days 9-13 only) and dose-dependent embryonic bradycardia and arrhythmia at clinically relevant maternal plasma concentrations (3-11 mM). Hemorrhage in the nasopharyngeal part of the embryonic palate (within 24 h) preceded cleft palate in fetuses at term. Simultaneous treatment with PBN significantly reduced the incidence of DMO-induced cleft palate, from 40 to 13%. Voltage patch-clamping studies showed that particularly DMO (70% inhibition), but also TMO, had I kr blocking potential at clinically relevant concentrations.Conclusions: TMO teratogenicity, in the same way as previously shown for PHT, was associated with I kr -mediated episodes of embryonic cardiac arrhythmia and hypoxia/ reoxygenation damage.

Functional consequences of methionine oxidation of hERG potassium channels

“…Excess liberation of RS in the central nervous system could therefore affect the neuronal function via the modification of hERG channels. In fact, indications that hERG oxidation may play a role in neuronal diseases such as epilepsy do exist [48]. In conclusion, the function of hERG channels to conduct K + current is modulated by the redox status of the Met residues.…”

hERG channel function: beyond long QT

“…This harmful effect is amplified when blood flow is restored due to the generation of reactive oxygen species (ROS), which can lead to developmental abnormalities 84 , such as cleft palate defects or ventricular malformations observed in rat models 28,85 . Similar teratogenic effects have been reported for other medications including erythromycin, almokalant, dofetilide, phenytoin, cisapride, and astemizole 84,86 .…”

Developmental Toxicity of Antiepileptic Drugs

“…Some of the strain differences in susceptibility to teratogenesis might be explained, in part, by strain differences in the effects on embryonic heart rate. This arrhythmia might be due to the inhibition of human ether-a-go-go related gene (HERG) by PHT (Azarbayjani and Danielsson 2002). Not only limb defects, but also cleft palate, appeared to be due to this bradycardia effect in that embryonic arrhythmia and hemorrhage in the orofacial region preceded cleft palate (Azarbayjani and Danielsson 2001).…”