Nilsson Mats F, Ritchie Helen, Webster William S
Drug Safety and Toxicology, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Birth Defects Res B Dev Reprod Toxicol. 2013 Oct;98(5):416-27. doi: 10.1002/bdrb.21084. Epub 2013 Dec 9.
In this study, we compared the effects of four ion channel blockers on rat embryonic heart function during the organogenic period from gestational day (GD) 10 to 15, to determine the changes in dependence on ion channels during rat cardiac development. Rat embryos in culture were exposed to either the human ether-á-go-go-related gene potassium channel blocker, dofetilide (400 nM); the sodium channel blocker, lidocaine (250 μM); the L-type calcium channel blocker, nifedipine (1.8 μM); or the multichannel blocker, phenytoin (200 μM). Lidocaine slowed the heart rate (HR) with the effect becoming more severe with increasing GD. Dofetilide slowed the embryonic HR and caused arrhythmias with the most severe effect on GD 11 to 13. Nifedipine primarily caused a negative inotropic effect except on GD 10 when it stopped the heart in most embryos. Phenytoin stopped the heart of most GD 10 to 12 embryos while on GD 13 to 15 phenytoin slowed the heart. The results demonstrate that as the rat heart develops during the organogenic period its functional dependence on ion channels changes markedly. These changes are important for understanding drug effects on the embryo during pregnancy and the methodology used provides a simple procedure for assessing drug effects on the developing heart.
在本研究中，我们比较了四种离子通道阻滞剂对妊娠第10至15天器官形成期大鼠胚胎心脏功能的影响，以确定大鼠心脏发育过程中对离子通道依赖性的变化。培养的大鼠胚胎分别暴露于人类醚 - 去极化相关基因钾通道阻滞剂多非利特（400 nM）、钠通道阻滞剂利多卡因（250 μM）、L型钙通道阻滞剂硝苯地平（1.8 μM）或多通道阻滞剂苯妥英（200 μM）。利多卡因使心率（HR）减慢，且随着妊娠天数增加，这种影响变得更严重。多非利特使胚胎心率减慢并导致心律失常，对妊娠第11至13天的影响最为严重。硝苯地平主要引起负性肌力作用，但在妊娠第10天，它使大多数胚胎心脏停搏。苯妥英使大多数妊娠第10至12天的胚胎心脏停搏，而在妊娠第13至15天，苯妥英使心脏减慢。结果表明，在器官形成期大鼠心脏发育过程中，其对离子通道的功能依赖性发生了显著变化。这些变化对于理解孕期药物对胚胎的影响很重要，并且所使用的方法提供了一种评估药物对发育中心脏影响的简单程序。
