Klug S, Thiel R, Schwabe R, Merker H J, Neubert D
Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Germany.
Arch Toxicol. 1994;68(6):375-84. doi: 10.1007/s002040050085.
Beta-adrenoceptor blockers are widely used drugs for the treatment of cardiovascular diseases. Since beta-blockers cross the placenta, it is essential to consider possible adverse effects on the embryo. Six beta-adrenoceptor blockers were tested at various concentrations (10-5000 microM) in a rat whole embryo culture. Although inducing a very similar pattern of dysmorphogenetic effects (incomplete flexure, disturbed development of the neural tube, the head, the heart and the tail bud), the compounds exhibited a wide range of embryotoxic potency. Estimation of the EC50 (median-concentration producing dysmorphogenesis in 50% of the embryos) for the six compounds revealed differences of more than two orders of magnitude: propranolol 25 microM, alprenolol 30 microM, metoprolol 100 microM, pindolol 150 microM, acebutolol 500 microM, atenolol 4000 microM. Measurements of the concentrations of the various drugs in the cultured embryos at corresponding EC50 levels showed differing values: metoprolol 4.5 microM, propranolol 5.2 microM, alprenolol 8.4 microM, pindolol 9.0 microM, acebutolol 12.5 microM and atenolol 77.0 microM. With regard to the EC50 and the degree of substance transfer to the embryo it can be stated that propranolol and metoprolol show a much higher intrinsic potency to interfere with normal in vitro embryonic development than, e.g. atenolol.
β-肾上腺素能受体阻滞剂是广泛用于治疗心血管疾病的药物。由于β-阻滞剂可穿过胎盘，因此必须考虑其对胚胎可能产生的不良影响。在大鼠全胚胎培养中，对六种β-肾上腺素能受体阻滞剂进行了不同浓度（10 - 5000微摩尔）的测试。尽管这些化合物诱导出非常相似的畸形发生效应模式（弯曲不完全、神经管、头部、心脏和尾芽发育受阻），但它们表现出广泛的胚胎毒性效力。对这六种化合物的半数有效浓度（EC50，即导致50%胚胎发生畸形的中位浓度）进行估算，结果显示差异超过两个数量级：普萘洛尔为25微摩尔，阿普洛尔为30微摩尔，美托洛尔为100微摩尔，吲哚洛尔为150微摩尔，醋丁洛尔为500微摩尔，阿替洛尔为4000微摩尔。在相应EC50水平下测量培养胚胎中各种药物的浓度，结果显示不同的值：美托洛尔为4.5微摩尔，普萘洛尔为5.2微摩尔，阿普洛尔为8.4微摩尔，吲哚洛尔为9.0微摩尔，醋丁洛尔为12.5微摩尔，阿替洛尔为77.0微摩尔。关于EC50以及物质向胚胎的转移程度，可以说普萘洛尔和美托洛尔比例如阿替洛尔对干扰正常体外胚胎发育具有更高的内在效力。
