Amiodarone, an Antiarrhythmic Drug, Affects Cardiac Valve Development in the Zebrafish Embryos
Date Issued
2007
Date
2007
Author(s)
Huang, Yu-Kai
DOI
zh-TW
Abstract
Amiodarone is a potent anti-arrhythmic drug and widely used in clinic, but it is classified as FDA category D. Some adverse effects to the fetus have been reported with amiodarone, including fetal hypothyroidism, low birth weight and bradycardia. However, amiodarone is still used in case other agents are failure treatment and the benefit from using this drug in pregnant women outweighs the fetal risk. To develop an animal model for studying the drug effects on embryonic heart development, we used zebrafish due to a transgenic line is available, which has heart-specific fluorescent signal, and its transparent embryo, which makes direct observation of the spatiotemporal expression become possible. When we continuously treated embryos with 15 μM amiodarone from 12 hours post-fertilization (hpf), the accumulated mortality rate reached 36.5% at 72 hpf. A regurgitation of blood in the heart of some embryos was observed, so was observed in the embryos that were stated treatment with amiodarone from 48 hpf to 60 hpf. Based on the combination of harmonic optical microscopy and two-photon fluorescence microscopy with heart-specific HcRFP expression transgenic zebrafish Tg(cmlc2:HcRFP), we directly observed in vivo that valve failed to form completely in some amiodarone-treated embryos. The endocushion was not observed at 87 hpf. TUNEL assay confirmed that apoptosis did not occur in endocushion forming region. Whole mount in situ hybridization showed that treatment with amiodarone resulted in ectopic over-expression of versican, a valve marker, in embryonic heart; but the expression of bmp4, a marker for the differentiation of the myocardial cells, and notch1b, a marker for epithelial to mesenchymal transformation, were not affected. In addition, the embryos treated with cyclosporine A, a chemical that inhibits valve development, also produced ectopic over-expression of versican. In conclusion, we develop an animal model that enables us to demonstrate in vivo the effect of amiodarone on the valve formation during heart development. Furthermore, we suggest that amiodarone affects cardiac valve development in zebrafish heart through versican ectopic over-expression in all myocardial cells.
Subjects
斑馬魚
瓣膜
胚胎發育
抗心律不整藥物
zebrafish
amiodarone
valve
antiarrhythmic drug
Type
other
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