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 ET(A) receptor -/-, +/-, and +/+ genotypes were used. Isolated DA from term ET(A) +/+ fetuses contracted to O(2) (5-95%) and a thromboxane A(2) analog (ONO-11113, 0.1 microM). Instead, ET-1 elicited a dual response with weak relaxation (0.1 nM) preceding contraction (1-100 nM). Indomethacin (2.8 microM) was also a constrictor. ET(A) -/- DA, unlike ET(A) +/+ DA, contracted marginally to O(2) and ET-1 but responded to ONO-11113. O(2) contraction was also reduced in ET(A) +/- DA. In vivo, DA constricted equally in tracheotomized ET(A) -/- and ET(A) +/+ newborns. Conversely, no DA constriction was seen in hyperoxic ET(A) -/- fetuses in utero, although it occurred in ET(A) +/+ 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).