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Embryonic arrhythmia by inhibition of HERG channels: a common hypoxia-related teratogenic mechanism for antiepileptic drugs?
Epilepsia. 2002 May; 43(5):457-68.E

Abstract

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 (Ikr), 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 (alpha-phenyl-N-tert-butyl-nitrone; PBN). The Ikr 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 Ikr blocking potential at clinically relevant concentrations.

CONCLUSIONS

TMO teratogenicity, in the same way as previously shown for PHT, was associated with Ikr-mediated episodes of embryonic cardiac arrhythmia and hypoxia/reoxygenation damage.

Authors+Show Affiliations

Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Uppsala, Sweden.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12027905

Citation

Azarbayjani, Faranak, and Bengt R. Danielsson. "Embryonic Arrhythmia By Inhibition of HERG Channels: a Common Hypoxia-related Teratogenic Mechanism for Antiepileptic Drugs?" Epilepsia, vol. 43, no. 5, 2002, pp. 457-68.
Azarbayjani F, Danielsson BR. Embryonic arrhythmia by inhibition of HERG channels: a common hypoxia-related teratogenic mechanism for antiepileptic drugs? Epilepsia. 2002;43(5):457-68.
Azarbayjani, F., & Danielsson, B. R. (2002). Embryonic arrhythmia by inhibition of HERG channels: a common hypoxia-related teratogenic mechanism for antiepileptic drugs? Epilepsia, 43(5), 457-68.
Azarbayjani F, Danielsson BR. Embryonic Arrhythmia By Inhibition of HERG Channels: a Common Hypoxia-related Teratogenic Mechanism for Antiepileptic Drugs. Epilepsia. 2002;43(5):457-68. PubMed PMID: 12027905.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Embryonic arrhythmia by inhibition of HERG channels: a common hypoxia-related teratogenic mechanism for antiepileptic drugs? AU - Azarbayjani,Faranak, AU - Danielsson,Bengt R, PY - 2002/5/25/pubmed PY - 2002/6/22/medline PY - 2002/5/25/entrez SP - 457 EP - 68 JF - Epilepsia JO - Epilepsia VL - 43 IS - 5 N2 - 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 (Ikr), 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 (alpha-phenyl-N-tert-butyl-nitrone; PBN). The Ikr 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 Ikr blocking potential at clinically relevant concentrations. CONCLUSIONS: TMO teratogenicity, in the same way as previously shown for PHT, was associated with Ikr-mediated episodes of embryonic cardiac arrhythmia and hypoxia/reoxygenation damage. SN - 0013-9580 UR - https://www.unboundmedicine.com/medline/citation/12027905/Embryonic_arrhythmia_by_inhibition_of_HERG_channels:_a_common_hypoxia_related_teratogenic_mechanism_for_antiepileptic_drugs L2 - https://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0013-9580&date=2002&volume=43&issue=5&spage=457 DB - PRIME DP - Unbound Medicine ER -