title: Alterations in nitric oxide production in 8-week-old lambs with increased pulmonary blood flow.
abstract: Nitric oxide (NO) is an important mediator of pulmonary vascular reactivity, and decreased NO synthase expression has been demonstrated in children with advanced pulmonary hypertension secondary to congenital heart disease and increased pulmonary blood flow. Using aortopulmonary vascular graft placement in the fetal lamb, we have established a unique animal model of pulmonary hypertension with increased pulmonary blood flow. At 4 wk of age, these lambs display an early, selective impairment in agonist-induced NO responses, but an up-regulation of basal NO activity and gene expression. We hypothesized that further exposure to increased flow and/or pressure results in progressive endothelial dysfunction and a subsequent decrease in basal NO production. The objective of this study was to characterize potential later alterations in agonist-induced NO responses and basal NO activity and gene expression induced by 8 wk of increased pulmonary blood flow and pulmonary hypertension. Twenty-two fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt), and were studied 8 wk after delivery. Both in vivo and in isolated pulmonary arteries, the pulmonary vasodilating response to endothelium-dependent agents was attenuated in shunted lambs (p < 0.05), whereas the response to endothelium-independent agents was unchanged. The pulmonary vasoconstricting responses to Nomega-nitro-L-arginine, and lung tissue endothelial NO synthase mRNA, endothelial NO synthase protein, NO synthase activity, and NO(X) levels were all unchanged. These data suggest that the increase in basal NO activity demonstrated after 4 wk of increased pulmonary blood flow is lost by 8 wk of age, whereas the attenuation of agonist-induced responses persists. We speculate that the progressive decrease in basal NO activity participates in the development of pulmonary hypertension secondary to increased pulmonary blood flow.
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Illinois, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.forename: Janine M
authors.initials: JM
authors.lastname: Bekker
authors.forename: D Michael
authors.initials: DM
authors.lastname: McMullan
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Parry
authors.forename: Boaz
authors.initials: B
authors.lastname: Ovadia
authors.forename: Olaf
authors.initials: O
authors.lastname: Reinhartz
authors.forename: Satyan
authors.initials: S
authors.lastname: Lakshminrushimha
authors.forename: Eugenia
authors.initials: E
authors.lastname: Mata-Greenwood
authors.forename: Robin H
authors.initials: RH
authors.lastname: Steinhorn
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000714:Anastomosis, Surgical; D000818:Animals; D001011:Aorta / Q000601:surgery; D051242:Caveolin 1; D022461:Caveolins / Q000032:analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000032:analysis; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D008168:Lung / Q000737:chemistry / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000601:surgery; D011652:Pulmonary Circulation / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D012756:Sheep; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D051242:Caveolin 1; D022461:Caveolins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III