Teratogenic effects of the endothelin receptor antagonist L-753,037 in the rat

The studies presented in this paper were undertaken to investigate the effects of L-753,037, a balanced endothelin receptor antagonist with similar affinity for the ET(A) and ET(B) receptors (Ki = 0.03 to 0.12 nM and 0.1 to 3.33 nM, respectively), when administered to pregnant female rats by oral gavage, on the development, growth, maturation, and reproductive performance of the F1 generation. Following embryonic exposure to L-753,037, profound craniofacial, cardiovascular, and viscerocranial malformations were noted in the F1 generation. All of the affected organs are derived, in part, from cranial neural crest cells predominantly originating from the posterior midbrain through the hindbrain and destined for the pharyngeal arches. In contrast, cranial structures derived from the paraxial mesoderm (i.e., basisphenoid) were of normal shape and size. There were no apparent effects on enteric neural crest cell derivatives. Based on the phenotype of affected fetuses and their similarity to fetuses with gene knockouts of ET-1 or the ET(A) receptor, the observed alterations are considered to be a pharmacologically mediated class effect on cranial neural crest cells. The phenotype observed suggests that ET(A) receptor antagonism may have specific effects on cranial neural crest cell migration and/or proliferation.