Nitric oxide alterations following acute ductal constriction in the fetal lamb: a role for superoxide.
Acute partial compression of the fetal ductus arteriosus (DA) results in an initial abrupt increase in pulmonary blood flow (PBF), which is followed by a significant reduction in PBF to baseline values over the ensuing 2-4 h. We have previously demonstrated that this potent vasoconstricting response is due, in part, to an endothelin-1 (ET-1)-mediated decrease in nitric oxide synthase (NOS) activity. In addition, in vitro data demonstrate that ET-1 increases superoxide levels in pulmonary arterial smooth muscle cells and that oxidative stress alters NOS activity. Therefore, the objectives of this study were to determine the potential role of superoxide in the alterations of hemodynamics and NOS activity following acute ductal constriction in the late-gestation fetal lamb. Eighteen anesthetized near-term fetal lambs were instrumented, and a lung biopsy was performed. After a 48-h recovery, acute constriction of the DA was performed by inflating a vascular occluder. Polyethylene glycol-superoxide dismutase (PEG-SOD; 1,000-1,500 units/kg, n = 7) or PEG-alone (vehicle control group, n = 5) was injected into the pulmonary artery before ductal constriction. Six animals had a sham operation. In PEG-alone-treated lambs, acute ductal constriction rapidly decreased pulmonary vascular resistance (PVR) by 88%. However, by 4 h, PVR returned to preconstriction baseline. This vasoconstriction was associated with an increase in lung superoxide levels (82%), a decrease in total NOS activity (50%), and an increase in P-eNOS-Thr495 (52%) (P < 0.05). PEG-SOD prevented the increase of superoxide after ductal constriction, attenuated the vasoconstriction, preserved NOS activity, and increased P-eNOS Ser1177 (307%, P < 0.05). Sham procedure induced no changes. These data suggest that an acute decrease in NOS activity that is mediated, in part, by increased superoxide levels, and alterations in the phosphorylation status of the endothelial NOS isoform, underlie the pulmonary vascular response to acute ductal constriction.
Hsu
Jong-Hau
JH
Department of Pediatrics, University of California, San Francisco, California 94143-0106, USA.
Oishi
Peter
P
Wiseman
Dean A
DA
Hou
Yali
Y
Chikovani
Omar
O
Datar
Sanjeev
S
Sajti
Eniko
E
Johengen
Michael J
MJ
Harmon
Cynthia
C
Black
Stephen M
SM
Fineman
Jeffrey R
JR
D000818:Animals; D004373:Ductus Arteriosus / Q000502:physiology*; D005333:Fetus / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000196:embryology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D012756:Sheep; D013481:Superoxides / Q000378:metabolism*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction
D013481:Superoxides; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III