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

The studies presented in this paper were undertaken to investigate the effe cts of L-753,037, a balanced endothelin receptor antagonist with similar af finity for the ETA and ETB receptors (K-i = 0.03 to 0.12 and 0.1 to 3.33, r espectively), when administered to pregnant female rats by oral gavage, on the development, growth, maturation, and reproductive performance of the F- 1, generation. Following embryonic exposure to L-753,037, profound craniofa cial, cardiovascular, and viscerocranial malformations were noted in the F- 1, generation. All of the affected organs are derived, in part, from crania l 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 ne ural crest cell derivatives. Based on the phenotype of affected fetuses and their similarity to fetuses with gene knockouts of ET-1 or the ETA recepto r, the observed alterations are considered to be a pharmacologically mediat ed class effect on cranial neural crest cells. The phenotype observed sugge sts that ETA receptor antagonism may have specific effects on cranial neura l crest cell migration and/or proliferation.