Cardiovascular teratogenicity of terbutaline and ritodrine in the chick embryo

Abstract

We determined the teratogenic effects of terbutaline and ritodrine, both beta 2-sympathomimetic agonists, on the stage 24 (4-day) chick embryo. We used a topical method of application of terbutaline or ritodrine to the stage 24 chick embryo in ovo. Doses of terbutaline ranged from 5.5 x 10(-10) to 6.5 x 10(-9) mol per embryo, and ritodrine doses ranged from 4.6 x 10(-11) to 4.6 x 10(-8) mol per embryo. To further determine the pharmacologic nature of the teratogenic potential of terbutaline or ritodrine, the experiments were repeated after pretreatment with butoxamine hydrochloride, a preferential beta 2-antagonist, or metoprolol tartrate, a preferential beta 1-antagonist, 4 hours before application of terbutaline or ritodrine. Terbutaline treatment was associated with significantly higher rates of anomalies than in controls at all dosages used, whereas ritodrine induced significantly more anomalies at or above doses of 4.6 x 10(-9) mol per embryo. At an equimolar dose pretreatment with butoxamine hydrochloride significantly reduced the cardiovascular teratogenic effects of terbutaline and ritodrine. Pretreatment with metoprolol tartrate at any dose did not significantly reduce terbutaline's potential. Metoprolol, at doses tenfold or 100-fold higher than ritodrine, was able to significantly reduce the teratogenic effects of ritodrine. Our data suggest that terbutaline and ritodrine are teratogenic in the chick and that these agents exert their teratogenic effects primarily through stimulation of the beta 2-adrenergic receptor.