Toxicity of beta-blockers in a rat whole embryo culture: concentration-response relationships and tissue concentrations.
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.
Klug
S
S
Institut für Toxikologie und Embryopharmakologie, Freie Universität Berlin, Germany.
Thiel
R
R
Schwabe
R
R
Merker
H J
HJ
Neubert
D
D
D000070:Acebutolol / Q000633:toxicity; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics / Q000633:toxicity*; D000526:Alprenolol / Q000633:toxicity; D000818:Animals; D001262:Atenolol / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000473:pathology; D005314:Embryonic and Fetal Development; D066298:In Vitro Techniques; D008790:Metoprolol / Q000633:toxicity; D010869:Pindolol / Q000633:toxicity; D011433:Propranolol / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
D000319:Adrenergic beta-Antagonists; D001262:Atenolol; D000070:Acebutolol; D000526:Alprenolol; D011433:Propranolol; D010869:Pindolol; D008790:Metoprolol