Evidence for an effector role of endothelin in closure of the ductus arteriosus at birth

The ductus arteriosus is a special muscular shunt that in the fetus allows blood to bypass the unexpanded lungs. It closes rapidly after birth and this event is initiated by the physiologic rise in blood oxygen tension. Endothelin-1 has been proposed by us as a local mediator for oxygen after demonstrating that it is formed within the ductus and is a potent ductus constrictor. To confirm this possibility, we have now measured the release of endothelin-1 from the isolated ductus of near-term fetal lambs at different oxygen concentrations of the medium. In addition, using the same preparation, we have examined the effect on contractile tone of compounds interfering with the synthesis (phosphoramidon, 50 microM) and action (BQ123, 1 microM) of endothelin-1. We report that release of endothelin-1 from the ductus tends to increase with the oxygen concentration up to a value mimicking the neonatal condition. Phosphoramidon and, to a greater degree, BQ123 inhibit the contraction of the vessel to oxygen. These results implicate endothelin-1 as the effector agent for oxygen in the ductus and, by extension, assign to this peptide a critical role in the closure of the vessel at birth.