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Am J Physiol Heart Circ Physiol 277: H1521-H1531, 1999;
0363-6135/99 $5.00
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Vol. 277, Issue 4, H1521-H1531, October 1999

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

F. Coceani1, Y.-A. Liu1, E. Seidlitz1, L. Kelsey1, T. Kuwaki3, C. Ackerley2, and M. Yanagisawa4

1 Integrative Biology Programme and 2 Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8; 3 Department of Physiology, School of Medicine, Chiba University, Chiba, 260-8670 Japan; and 4 Howard Hughes Medical Institute and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75235

In vitro and in vivo techniques were developed with genetically modified mice to determine whether endothelin-1 (ET-1) functions as an O2 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 O2 (5-95%) and a thromboxane A2 analog (ONO-11113, 0.1 µM). Instead, ET-1 elicited a dual response with weak relaxation (0.1 nM) preceding contraction (1-100 nM). Indomethacin (2.8 µM) was also a constrictor. ETA -/- DA, unlike ETA +/+ DA, contracted marginally to O2 and ET-1 but responded to ONO-11113. O2 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 O2. Without ET-1, however, the vessel still closes postnatally, conceivably caused by the withdrawal of relaxing influence(s).

oxygen; endothelin


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