Department of Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Uppsala, Sweden.
Reprod Toxicol. 2010 Apr;29(2):156-63. doi: 10.1016/j.reprotox.2010.01.014. Epub 2010 Feb 6.
Drugs blocking the potassium current IKr of the heart (via hERG channel-inhibition) have the potential to cause hypoxia-related teratogenic effects. However, this activity may be missed in conventional teratology studies because repeat dosing may cause resorptions. The aim of the present study was to investigate an alternative protocol to reveal the teratogenic potential of IKr-blocking drugs. The IKr blocker astemizole, given as a single dose (80 mg/kg) on gestation day (GD) 13 to pregnant rats caused digital defects. In whole rat embryo culture (2h) on GD 13, astemizole caused a decrease in embryonic heart rate at 20 nM, and arrhythmias at 200-400 nM. Cetirizine, without IKr-blocking properties, did not affect the rat embryonic heart in vitro. The present study shows that single dose testing on sensitive days of development, together with whole embryo culture, can be a useful methodology to better characterize the teratogenic potential of IKr-blocking drugs.
阻断心脏钾电流 IKr（通过 hERG 通道抑制）的药物有可能引起与缺氧相关的致畸作用。然而，这种活性可能会在常规致畸学研究中被忽略，因为重复给药可能会导致吸收。本研究的目的是探索一种替代方案，以揭示 IKr 阻断药物的致畸潜力。在妊娠第 13 天（GD）给怀孕大鼠单次给予 IKr 阻断剂阿司米唑（80mg/kg），导致数字缺陷。在 GD 13 的全大鼠胚胎培养（2h）中，阿司米唑在 20nM 时引起胚胎心率下降，在 200-400nM 时引起心律失常。无 IKr 阻断特性的西替利嗪在体外对大鼠胚胎心脏没有影响。本研究表明，在发育敏感日进行单次剂量测试，结合全胚胎培养，可能是更好地描述 IKr 阻断药物致畸潜力的有用方法。
