Department of Cardiology, Karolinska University Hospital, Huddinge, SE-141 86, Stockholm, Sweden.
Cardiovasc Res. 2013 Jan 1;97(1):23-32. doi: 10.1093/cvr/cvs296. Epub 2012 Sep 20.
Several drugs blocking the rapidly activating potassium (K(r)) channel cause malformations (including cardiac defects) and embryonic death in animal teratology studies. In humans, these drugs have an established risk for acquired long-QT syndrome and arrhythmia. Recently, associations between cardiac defects and spontaneous abortions have been reported for drugs widely used in pregnancy (e.g. antidepressants), with long-QT syndrome risk. To investigate whether a common embryonic adverse-effect mechanism exists in the human, rat, and rabbit embryos, we made a comparative study of embryonic cardiomyocytes from all three species.
Patch-clamp and quantitative-mRNA measurements of K(r) and slowly activating K (K(s)) channels were performed on human, rat, and rabbit primary cardiomyocytes and cardiac samples from different embryo-foetal stages. The K(r) channel was present when the heart started to beat in all species, but was, in contrast to human and rabbit, lost in rats in late organogenesis. The specific K(r)-channel blocker E-4031 prolonged the action potential in a species- and development-dependent fashion, consistent with the observed K(r)-channel expression pattern and reported sensitive periods of developmental toxicity. E-4031 also increased the QT interval and induced 2:1 atrio-ventricular block in multi-electrode array electrographic recordings of rat embryos. The K(s) channel was expressed in human and rat throughout the embryo-foetal period but not in rabbit.
This first comparison of mRNA expression, potassium currents, and action-potential characteristics, with and without a specific K(r)-channel blocker in human, rat, and rabbit embryos provides evidence of K(r)-channel inhibition as a common mechanism for embryonic malformations and death.
几种阻断快速激活钾（K(r)）通道的药物在动物致畸学研究中导致畸形（包括心脏缺陷）和胚胎死亡。在人类中，这些药物已被确定有致获得性长 QT 综合征和心律失常的风险。最近，广泛用于妊娠的药物（例如抗抑郁药）与长 QT 综合征风险相关，已报道与心脏缺陷和自然流产之间存在关联。为了研究人类、大鼠和兔胚胎中是否存在共同的胚胎不良效应机制，我们对来自这三个物种的胚胎心肌细胞进行了比较研究。
对来自不同胚胎-胎儿阶段的人类、大鼠和兔原代心肌细胞和心脏样本进行了 K(r)和缓慢激活钾（K(s)）通道的膜片钳和定量 mRNA 测量。在所有物种中，当心脏开始跳动时，都存在 K(r)通道，但与人类和兔不同，在大鼠的晚期器官发生中丢失了。特定的 K(r)通道阻滞剂 E-4031 以物种和发育依赖性的方式延长动作电位，与观察到的 K(r)通道表达模式和报告的发育毒性敏感期一致。E-4031 还增加了 QT 间期，并在大鼠胚胎的多电极阵列电描记记录中诱导 2:1 房室传导阻滞。K(s)通道在人类和大鼠的整个胚胎-胎儿期表达，但在兔中不表达。
这是首次在人类、大鼠和兔胚胎中比较 mRNA 表达、钾电流和动作电位特征，以及在存在和不存在特定的 K(r)通道阻滞剂的情况下进行的比较，为 K(r)通道抑制作为胚胎畸形和死亡的共同机制提供了证据。
