title: Alterations in ET-1, not nitric oxide, in 1-week-old lambs with increased pulmonary blood flow.
abstract: Altered pulmonary vascular reactivity is a source of morbidity and mortality for children with congenital heart disease and increased pulmonary blood flow. Nitric oxide (NO) and endothelin (ET)-1 are important mediators of pulmonary vascular reactivity. We hypothesize that early alterations in endothelial function contribute to the altered vascular reactivity associated with congenital heart disease. The objective of this study was to characterize endothelial function in our lamb model of increased pulmonary blood flow at 1 wk of life. Eleven fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 7 days after delivery. The pulmonary vasodilator response to both intravenous ACh (endothelium dependent) and inhaled NO (endothelium independent) was similar in shunted and control lambs. In addition, tissue NO(x), NO synthase (NOS) activity, and endothelial NOS protein levels were similar. Conversely, the vasodilator response to both ET-1 and 4Ala-ET-1 (an ET(B) receptor agonist) were attenuated in shunted lambs, and tissue ET-1 concentrations were increased (P < 0.05). Associated with these changes were an increase in ET-converting enzyme-1 protein and a decrease in ET(B) receptor protein levels (P < 0.05). These data demonstrate that increased pulmonary blood flow induces alterations in ET-1 signaling before NO signaling and suggest an early role for ET-1 in the altered vascular reactivity associated with increased pulmonary blood flow.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, 94143, USA.
authors.forename: Boaz
authors.initials: B
authors.lastname: Ovadia
authors.forename: Olaf
authors.initials: O
authors.lastname: Reinhartz
authors.forename: Robert
authors.initials: R
authors.lastname: Fitzgerald
authors.forename: Janine M
authors.initials: JM
authors.lastname: Bekker
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Johengen
authors.forename: Anthony
authors.initials: A
authors.lastname: Azakie
authors.forename: Stephan
authors.initials: S
authors.lastname: Thelitz
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D008666:Metalloendopeptidases; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists / Q000378:metabolism; D012756:Sheep; D014664:Vasodilation
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C061779:endothelin 1, Ala(1,3,11,15)-; D009569:Nitric Oxide; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D000109:Acetylcholine