Endothelin A receptor is necessary for O2 constriction but not closure of ductus arteriosus

In vitro and in vivo techniques were developed with genetically modified mice to determine whether endothelin-1 (ET-1) functions as an O-2 mediator in closure of the ductus arteriosus (DA) at birth: Wild-type CD-1 and 129/SvEv mice with ETA receptor -/-, +/-, and +/+ genotypes were used. Isolated DA from term ETA +/+ fetuses contracted to O-2 (5-95%) and a thromboxane A(2) analog (ONO-11113, 0.1 mu M). Instead, ET-1 elicited a dual response with weak relaxation (0.1 nM) preceding contraction (1-100 nM). Indomethacin (2.8 mu M) was also a constrictor. ETA -/- DA, unlike ETA +/+ DA, contracted marginally to O-2 and ET-1 but responded to ONO-11113. O-2 contraction was also reduced in ETA +/- DA. In vivo, DA constricted equally in tracheotomized ETA -/- and ETA +/+ newborns. Conversely, no DA constriction was seen in hyperoxic ETA -/- fetuses in utero, although it occurred in ETA +/+ and +/- littermates. We conclude that ET-1 mediates the DA constrictor response to O-2. Without ET-1, however, the vessel still closes postnatally, conceivably caused by the withdrawal of relaxing influence(s).