Endothelin A receptor is necessary for O(2) 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).
Coceani
F
F
Integrative Biology Programme, The Hospital for Sick Children, Toronto, Ontario, Canada M5G 1X8. coceani@sssup.it
Liu
Y
Y
Seidlitz
E
E
Kelsey
L
L
Kuwaki
T
T
Ackerley
C
C
Yanagisawa
M
M
D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D004373:Ductus Arteriosus / Q000033:anatomy & histology / Q000196:embryology / Q000502:physiology* / Q000648:ultrastructure; D005333:Fetus / Q000502:physiology; D005838:Genotype; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D010100:Oxygen / Q000502:physiology*; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000235:genetics / Q000502:physiology*; D013552:Swine; D014661:Vasoconstriction / Q000502:physiology*
D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D010100:Oxygen