Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
Toxicol Appl Pharmacol. 2013 Oct 15;272(2):306-12. doi: 10.1016/j.taap.2013.06.023. Epub 2013 Jul 8.
This study was undertaken to examine the effect on the rat embryonic heart of two experimental drugs (AZA and AZB) which are known to block the sodium channel Nav1.5, the hERG potassium channel and the l-type calcium channel. The sodium channel blockers bupivacaine, lidocaine, and the l-type calcium channel blocker nifedipine were used as reference substances. The experimental model was the gestational day (GD) 13 rat embryo cultured in vitro. In this model the embryonic heart activity can be directly observed, recorded and analyzed using computer assisted image analysis as it responds to the addition of test drugs. The effect on the heart was studied for a range of concentrations and for a duration up to 3h. The results showed that AZA and AZB caused a concentration-dependent bradycardia of the embryonic heart and at high concentrations heart block. These effects were reversible on washout. In terms of potency to cause bradycardia the compounds were ranked AZB>bupivacaine>AZA>lidocaine>nifedipine. Comparison with results from previous studies with more specific ion channel blockers suggests that the primary effect of AZA and AZB was sodium channel blockage. The study shows that the short-term rat whole embryo culture (WEC) is a suitable system to detect substances hazardous to the embryonic heart.
本研究旨在研究两种已知可阻断钠通道 Nav1.5、hERG 钾通道和 L 型钙通道的实验药物（AZA 和 AZB）对大鼠胚胎心脏的影响。作为参考物质，使用了钠通道阻滞剂布比卡因、利多卡因和 L 型钙通道阻滞剂硝苯地平。实验模型为体外培养的妊娠第 13 天大鼠胚胎。在该模型中，胚胎心脏活动可以在添加测试药物后直接观察、记录和使用计算机辅助图像分析进行分析。研究了一系列浓度和长达 3 小时的作用时间对心脏的影响。结果表明，AZA 和 AZB 导致胚胎心脏呈浓度依赖性心动过缓，并在高浓度下引起心脏阻滞。这些作用在洗脱时是可逆的。在引起心动过缓的效力方面，化合物的排序为 AZB>布比卡因>AZA>利多卡因>硝苯地平。与以前使用更具特异性离子通道阻滞剂的研究结果进行比较表明，AZA 和 AZB 的主要作用是钠通道阻断。该研究表明，短期大鼠全胚胎培养（WEC）是一种检测对胚胎心脏有害物质的合适系统。
