Experiments were carried out in mutant 129/SvEv mice lacking the endothelin-A (ETA)-receptor to determine whether endothelin-1 (ET-1), acting as a messenger for oxygen constriction, is responsible for closure of the ductus arteriosus at birth. The isolated ductus from ETA −/− fetuses, unlike that from ETA +/+ littermates, contracted marginally to oxygen and ET-1 but responded to a thromboxane analog. In vivo, reduction in ductus lumen was equally pronounced in tracheotomized ETA −/− and ETA +/+ newborns. Conversely, no such vessel narrowing was seen in hyperoxic ETA −/− fetuses, although it occurred in ETA +/+ littermates. Notwithstanding the uneven behaviour of the ductus in vitro and in vivo, no ETA genotype-related difference was noted in the morphology of the vessel on both light and electron microscopy. We conclude that ET-1 mediates the ductus constriction to oxygen. Without ET-1, however, the vessel still closes postnatally probably as a result of the withdrawal of the relaxing influence of prostaglandin E2 (PGE2).
*Integrative Biology Programme and †Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada; ‡Department of Physiology, School of Medicine, Chiba University, Chiba, Japan; and §Howard Hughes Medical Institute and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.
Address correspondence and reprint requests to F. Coceani, Scuola Superiore S. Anna, via Carducci 40, 56127 Pisa, Italy.
© 2000 Lippincott Williams & Wilkins, Inc.