Endothelin A receptor is necessary for [O.sub.2] constriction but not closure of ductus arteriosus

Coceani, F., Y.-A. Liu, E. Seidlitz, L. Kelsey, T. Kuwaki, C. Ackerley, and M. Yanagisawa. Endothelin A receptor is necessary for 02 constriction but not closure of ductus arteriosus. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H1521-H1531, 1999.--In vitro and in vivo techniques were developed with genetically modified mice to determine whether endothelin-1 (ET-1) functions as an [O.sub.2] mediator in closure of the ductus arteriosus (DA) at birth. Wild-type CD-1 and 129/SvEv mice with [ET.sub.A] receptor -/-, +/-, and +/+ genotypes were used. Isolated DA from term [ET.sub.A] +/+ fetuses contracted to [O.sub.2] (5-95%) and a thromboxane [A.sub.2] analog (ONO-11113, 0.1 [micro] M). Instead, ET-1 elicited a dual response with weak relaxation (0.1 nM) preceding contraction (1-100 nM). Indomethacin (2.8 [micro] M) was also a constrictor. [ET.sub.A] -/- DA, unlike [ET.sub.A] +/+ DA, contracted marginally to [O.sub.2] and ET-1 but responded to ONO-11113. [O.sub.2] contraction was also reduced in [ET.sub.A] +/- DA. In vivo, DA constricted equally in tracheotomized [ET.sub.A] -/- and [ET.sub.A] +/+ newborns. Conversely, no DA constriction was seen in hyperoxic [ET.sub.A] -/- fetuses in utero, although it occurred in [ET.sub.A] +/+ and +/- littermates. We conclude that ET-1 mediates the DA constrictor response to [O.sub.2.] Without ET-1, however, the vessel still closes postnatally, conceivably caused by the withdrawal of relaxing influence(s). oxygen; endothelin