Abela Dominique, Ritchie Helen, Ababneh Deena, Gavin Caroline, Nilsson Mats F, Khan Muhammad Khalid, Carlsson Kristin, Webster William S
Department of Anatomy and Histology, Sydney Medical School, University of Sydney, Sydney, Australia.
Birth Defects Res B Dev Reprod Toxicol. 2010 Oct;89(5):429-40. doi: 10.1002/bdrb.20270.
This study investigated the effects of a range of pharmaceutical drugs with ion channel-blocking activity on the heart of gestation day 13 rat embryos in vitro. The general hypothesis was that the blockade of the I(Kr)/hERG channel, that is highly important for the normal functioning of the embryonic rat heart, would cause bradycardia and arrhythmia. Concomitant blockade of other channels was expected to modify the effects of hERG blockade. Fourteen drugs with varying degrees of specificity and affinity toward potassium, sodium, and calcium channels were tested over a range of concentrations. The rat embryos were maintained for 2 hr in culture, 1 hr to acclimatize, and 1 hr to test the effect of the drug. All the drugs caused a concentration-dependent bradycardia except nifedipine, which primarily caused a negative inotropic effect eventually stopping the heart. A number of drugs induced arrhythmias and these appeared to be related to either sodium channel blockade, which resulted in a double atrial beat for each ventricular beat, or I(Kr)/hERG blockade, which caused irregular atrial and ventricular beats. However, it is difficult to make a precise prediction of the effect of a drug on the embryonic heart just by looking at the polypharmacological action on ion channels. The results indicate that the use of the tested drugs during pregnancy could potentially damage the embryo by causing periods of hypoxia. In general, the effects on the embryonic heart were only seen at concentrations greater than those likely to occur with normal therapeutic dosing.
本研究在体外研究了一系列具有离子通道阻断活性的药物对妊娠第13天大鼠胚胎心脏的影响。总的假设是，对胚胎大鼠心脏正常功能至关重要的I(Kr)/hERG通道的阻断会导致心动过缓和心律失常。预期同时阻断其他通道会改变hERG阻断的效果。在一系列浓度范围内测试了14种对钾、钠和钙通道具有不同程度特异性和亲和力的药物。将大鼠胚胎在培养中维持2小时，1小时用于适应环境，1小时用于测试药物的效果。除硝苯地平外，所有药物均引起浓度依赖性心动过缓，硝苯地平主要引起负性肌力作用，最终使心脏停搏。一些药物诱发心律失常，这些心律失常似乎与钠通道阻断有关，钠通道阻断导致每一次心室搏动出现两次心房搏动，或者与I(Kr)/hERG阻断有关，I(Kr)/hERG阻断导致心房和心室搏动不规则。然而，仅仅通过观察药物对离子通道的多药作用，很难精确预测药物对胚胎心脏的影响。结果表明，孕期使用受试药物可能会因导致缺氧期而潜在地损害胚胎。一般来说，只有在高于正常治疗剂量可能出现的浓度时才会观察到对胚胎心脏的影响。
