Phenytoin-induced cleft palate:: Evidence for embryonic cardiac bradyarrhythmia due to inhibition of delayed rectifier K+ channels resulting in hypoxia-reoxygenation damage
Phenytoin-induced cleft palate:: Evidence for embryonic cardiac bradyarrhythmia due to inhibition of delayed rectifier K+ channels resulting in hypoxia-reoxygenation damage
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DOI：
10.1002/tera.1026
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发表时间：
2001-03-01
期刊：
影响因子：
--
通讯作者：
Danielsson, BR
中科院分区：
文献类型：
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作者：
Azarbayjani, F;Danielsson, BR
背景：苯妥英（PHT）致畸性与胚胎性心律失常有关，因为苯妥英能从药理学上阻断I，通道，导致缺氧再氧化损伤。本研究的目的是进一步阐明所提出的机制。方法：在妊娠10 ~ 11天给予妊娠CD-1小鼠PHT （85 mg/kg）或生理盐水腹腔注射。第12天记录胚胎心律和口面出血，第18天检查胎儿是否畸形。在给药后第9-16天记录胚胎心率。此外，在第12天以10、25或85 mg/kg的剂量给予PHT，以分析血浆浓度。结果：甲状旁腺激素引起的心动过缓和心律失常发生率与20%相似，48%表现为口面部出血；39%的胎儿患有腭裂。胚胎中可见的出血区域与足月胎儿中可见的组织缺陷（腭裂）区域相对应。对照组没有出现出血、心律失常或腭裂。PHT对第9-13天的胚胎心率有影响，但对第14-16天没有影响。在最敏感的第12天单次给药，导致胚胎心率呈剂量依赖性降低（12-34%）。在25和85时发生胚胎心律失常，但在10 mg/kg或对照组中没有发生。10 mg/kg组和25 mg/kg组的平均血浆游离浓度分别为6和14 μ mol/L。结论：pht诱发的腭裂以胚胎性心律失常和口面部出血为主。正如选择性I-Kr通道阻滞剂所描述的，在临床相关浓度下，胚胎心律受到期特异性影响。结果支持PHT致畸性是药理学诱导的心律失常和缺氧相关损伤的结果。
Background: Phenytoin (PHT) teratogenicity has been related to embryonic arrhythmia due to the capacity of PHT to block I, channels pharmacologically, resulting in hypoxia-reoxygenation damage. The aim of this study was to further elucidate the proposed mechanism.Methods: Pregnant CD-1 mice were given PHT (85 mg/kg) or saline intraperitoneally on gestational days 10-11. Embryonic heart rhythm and presence of hemorrhage in orofacial region was recorded on day 12, fetuses were examined for malformations on day 18. Embryonic heart rate was also recorded on individual days after dosing days 9-16. In addition, PHT was given at doses of 10, 25, or 85 mg/kg on day 12 for analysis of plasma concentrations.Results: PTH-induced bradycardia and arrhythmia in similar to 20% of the embryos, 48% showed hemorrhage in the orofacial region; 39% of the fetuses had cleft palate. The region in which hemorrhages were visible in the embryo corresponded with the region where tissue deficiency (cleft palate) was visible in the fetus at term. None of the controls showed hemorrhages, dysrhythmia, or cleft palate. PHT affected embryonic heart rates on days 9-13, but not on days 14-16. Single dose administration an day 12, the most sensitive day, resulted in a dose-dependent decrease in embryonic heart rate (12-34%). Embryonic arrhythmia occurred at 25 and 85, but not at 10 mg/kg or in the controls. Mean maternal free plasma concentrations were 6 and 14 mu mol/L in the 10- and 25-mg/kg groups, respectively.Conclusions: PHT-induced cleft palate was preceded by embryonic dysrhythmia and hemorrhage in the orofacial region. Embryonic heart rhythm was phase specifically affected, as described for selective I-Kr channel blockers, at clinically relevant concentrations. The results support the idea that PHT teratogenicity is a consequence of pharmacologically induced dysrhythmia and hypoxia-related damage.