title: Nitric oxide-endothelin-1 interactions after acute ductal constriction in fetal lambs.
abstract: Acute partial compression of the fetal ductus arteriosus (DA) results in an initial increase in pulmonary blood flow (PBF) that is followed by acute vasoconstriction. The objective of the present study was to determine the role of nitric oxide (NO)-endothelin-1 (ET-1) interactions in the acute changes in pulmonary vascular tone after in utero partial constriction of the DA. Twelve late-gestation fetal lambs (132-140 days) were instrumented to measure vascular pressures and left PBF. After a 24-h recovery period, acute constriction of the DA was performed by partially inflating a vascular occluder, and the hemodynamic variables were observed for 4 h. In control lambs (n = 7), acute ductal constriction initially increased PBF by 627% (P < 0.05). However, this was followed by active vasoconstriction, such that PBF was restored to preconstriction values by 4 h. This was associated with a 43% decrease in total NO synthase (NOS) activity (P < 0.05) and a 106% increase in plasma ET-1 levels (P < 0.05). Western blot analysis demonstrated no changes in lung tissue endothelial NOS, preproET-1, endothelin-converting enzyme-1, or ET(B) receptor protein levels. The infusion of PD-156707 (an ET(A) receptor antagonist, n = 5) completely blocked the vasoconstriction and preserved NOS activity. These data suggest that the fetal pulmonary vasoconstriction after acute constriction of the DA is mediated by NO-ET-1 interactions. These include an increase in ET(A) receptor-mediated vasoconstriction and an ET(A) receptor-mediated decrease in NOS activity. The mechanisms of these NO-ET-1 interactions, and their role in mediating acute changes in PBF, warrant further studies.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, California 94143-0106, USA.
authors.forename: Boaz
authors.initials: B
authors.lastname: Ovadia
authors.forename: Janine M
authors.initials: JM
authors.lastname: Bekker
authors.forename: Robert K
authors.initials: RK
authors.lastname: Fitzgerald
authors.forename: Alexander
authors.initials: A
authors.lastname: Kon
authors.forename: Stephan
authors.initials: S
authors.lastname: Thelitz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Johengen
authors.forename: Karen
authors.initials: K
authors.lastname: Hendricks-Munoz
authors.forename: Rene
authors.initials: R
authors.lastname: Gerrets
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
mesh_terms: D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001794:Blood Pressure; D004149:Dioxoles / Q000494:pharmacology; D004373:Ductus Arteriosus / Q000187:drug effects / Q000502:physiology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000502:physiology*; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000502:physiology; D005865:Gestational Age; D006439:Hemodynamics / Q000187:drug effects; D008666:Metalloendopeptidases; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011247:Pregnancy; D011498:Protein Precursors / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000196:embryology / Q000502:physiology; D011652:Pulmonary Circulation / Q000502:physiology*; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology; D012016:Reference Values; D012039:Regional Blood Flow; D012756:Sheep; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D004149:Dioxoles; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; C093321:PD 156707; D011498:Protein Precursors; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes