Alterations in nitric oxide production in 8-week-old lambs with increased pulmonary blood flow

Stephen M. Black, Janine M. Bekker, D. Michael McMullan, Andrew J. Parry, Boaz Ovadia, Olaf Reinhartz, Satyan Lakshminrushimha, Eugenia Mata-Greenwood, Robin H Steinhorn, Jeffrey R. Fineman

Research output: Contribution to journalArticle

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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 Nω-nitro-L-arginine, and lung tissue endothelial NO synthase mRNA, endothelial NO synthase protein, NO synthase activity, and NOX 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.

Original languageEnglish (US)
Pages (from-to)233-244
Number of pages12
JournalPediatric Research
Volume52
Issue number2
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

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Nitric Oxide
Lung
Pulmonary Hypertension
Blood Vessels
Nitric Oxide Synthase Type III
Nitric Oxide Synthase
Endothelium
Transplants
Gene Expression
Pulmonary Heart Disease
Pulmonary Artery
Arginine
Up-Regulation
Animal Models
Pressure
Messenger RNA
Proteins

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

Cite this

Black, S. M., Bekker, J. M., McMullan, D. M., Parry, A. J., Ovadia, B., Reinhartz, O., ... Fineman, J. R. (2002). Alterations in nitric oxide production in 8-week-old lambs with increased pulmonary blood flow. Pediatric Research, 52(2), 233-244. https://doi.org/10.1203/00006450-200208000-00016

Alterations in nitric oxide production in 8-week-old lambs with increased pulmonary blood flow. / Black, Stephen M.; Bekker, Janine M.; McMullan, D. Michael; Parry, Andrew J.; Ovadia, Boaz; Reinhartz, Olaf; Lakshminrushimha, Satyan; Mata-Greenwood, Eugenia; Steinhorn, Robin H; Fineman, Jeffrey R.

In: Pediatric Research, Vol. 52, No. 2, 01.01.2002, p. 233-244.

Research output: Contribution to journalArticle

Black, SM, Bekker, JM, McMullan, DM, Parry, AJ, Ovadia, B, Reinhartz, O, Lakshminrushimha, S, Mata-Greenwood, E, Steinhorn, RH & Fineman, JR 2002, 'Alterations in nitric oxide production in 8-week-old lambs with increased pulmonary blood flow', Pediatric Research, vol. 52, no. 2, pp. 233-244. https://doi.org/10.1203/00006450-200208000-00016
Black, Stephen M. ; Bekker, Janine M. ; McMullan, D. Michael ; Parry, Andrew J. ; Ovadia, Boaz ; Reinhartz, Olaf ; Lakshminrushimha, Satyan ; Mata-Greenwood, Eugenia ; Steinhorn, Robin H ; Fineman, Jeffrey R. / Alterations in nitric oxide production in 8-week-old lambs with increased pulmonary blood flow. In: Pediatric Research. 2002 ; Vol. 52, No. 2. pp. 233-244.
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