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 bet a-adrenoceptor blockers were tested at various concentrations (10-5000 mu M) in a rat whole embryo culture. Although inducing a very similar pattern of dysmorphogenetic effects (incomplete flexure, disturbed de velopment of the neural tube, the head, the heart and the tail bud), t he compounds exhibited a wide range of embryotoxic potency. Estimation of the EC(50) (median-concentration producing dysmorphogenesis in 50% of the embryos) for the six compounds revealed differences of more th an two orders of magnitude: propranolol 25 mu M, alprenolol 30 mu M, m etoprolol 100 mu M, pindolol 150 mu M, acebutolol 500 mu M, atenolol 4 000 mu M. Measurements of the concentrations of the various drugs in t he cultured embryos at corresponding EC(50) levels showed differing va lues: metoprolol 4.5 mu M, propranolol 5.2 mu M, alprenolol 8.4 mu M, pindolol 9.0 mu M, acebutolol 12.5 mu M and atenolol 77.0 mu M. With r egard to the EC(50) and the degree of substance transfer to the embryo it can be stated that propranolol and metoprolol show a much higher i ntrinsic potency to interfere with normal in vitro embryonic developme nt than, e.g. atenolol.