Cardiovascular malformations associated with administration of prenalterol to young chick embryos

Prenalterol (levo-1-[4-hydroxyphenoxy]-3-isopropyl-amino-2-propanol), a new stimulant of cardiac beta-adrenergic receptors in man, induces cardiovascular malformations when topically administered to 2 1/2- through 5 1/2-day chick embryos (Hamburger-Hamilton stages 17-27). Ventricular septal defects (VSD) located in the middle portion of the conal septum and classified as the simple, punched-out type VSD without septal malalignment were the predominant malformations observed throughout the developmental period tested. Arch malformations of the aortic circulation were also observed throughout the test interval, while anomalies of the pulmonary system were observed only at Hamburger-Hamilton stages 17 and 26-27. At stage 25 prenalterol demonstrated an acute toxicity significantly less than (1/50-1/20) epinephrine (P = .035 at concentrations of 8-10 mM) but was relatively equipotent with epinephrine in producing cardiovascular malformations. The effective median concentrations of the two agents were comparable (0.5-1.0 mM). The spectra of malformations induced by prenalterol and epinephrine were qualitatively similar. Malformations included absence of the right and/or left third aortic arch (innominate arteries), persistent remnant of the left fourth aortic arch, and VSD. These results support a previously proposed theory by these investigators that hyperstimulation of cardiac beta-adrenergic receptors in the chick embryo produces cardiovascular malformations.