Progressive dysfunction of nitric oxide synthase in a lamb model of chronically increased pulmonary blood flow

A role for oxidative stress

Peter E. Oishi, Dean A. Wiseman, Shruti Sharma, Sanjiv Kumar, Yali Hou, Sanjeev A. Datar, Anthony Azakie, Michael J. Johengen, Cynthia Harmon, Sohrab Fratz, Jeffrey R. Fineman, Stephen Matthew Black

Research output: Contribution to journalArticle

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Abstract

Cardiac defects associated with increased pulmonary blood flow result in pulmonary vascular dysfunction that may relate to a decrease in bioavailable nitric oxide (NO). An 8-mm graft (shunt) was placed between the aorta and pulmonary artery in 30 late gestation fetal lambs; 27 fetal lambs underwent a sham procedure. Hemodynamic responses to ACh (1 μg/kg) and inhaled NO (40 ppm) were assessed at 2, 4, and 8 wk of age. Lung tissue nitric oxide synthase (NOS) activity, endothelial NOS (eNOS), neuronal NOS (nNOS), inducible NOS (iNOS), and heat shock protein 90 (HSP90), lung tissue and plasma nitrate and nitrite (NOx), and lung tissue superoxide anion and nitrated eNOS levels were determined. In shunted lambs, ACh decreased pulmonary artery pressure at 2 wk (P < 0.05) but not at 4 and 8 wk. Inhaled NO decreased pulmonary artery pressure at each age (P < 0.05). In control lambs, ACh and inhaled NO decreased pulmonary artery pressure at each age (P < 0.05). Total NOS activity did not change from 2 to 8 wk in control lambs but increased in shunted lambs (ANOVA, P < 0.05). Conversely, NOx levels relative to NOS activity were lower in shunted lambs than controls at 4 and 8 wk (P < 0.05). eNOS protein levels were greater in shunted lambs than controls at 4 wk of age (P < 0.05). Superoxide levels increased from 2 to 8 wk in control and shunted lambs (ANOVA, P < 0.05) and were greater in shunted lambs than controls at all ages (P < 0.05). Nitrated eNOS levels were greater in shunted lambs than controls at each age (P < 0.05). We conclude that increased pulmonary blood flow results in progressive impairment of basal and agonist-induced NOS function, in part secondary to oxidative stress that decreases bioavailable NO.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume295
Issue number5
DOIs
StatePublished - Nov 1 2008

Fingerprint

Nitric Oxide Synthase
Oxidative Stress
Nitric Oxide
Lung
Pulmonary Artery
Pressure
Superoxides
Analysis of Variance
HSP90 Heat-Shock Proteins
Nitric Oxide Synthase Type III
Nitric Oxide Synthase Type II
Nitrites
Nitrates
Blood Vessels
Aorta
Hemodynamics
Transplants
Pregnancy
Proteins

Keywords

  • Congenital heart disease
  • Oxidant stress
  • Pulmonary circulation
  • Reactive oxygen species

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Progressive dysfunction of nitric oxide synthase in a lamb model of chronically increased pulmonary blood flow : A role for oxidative stress. / Oishi, Peter E.; Wiseman, Dean A.; Sharma, Shruti; Kumar, Sanjiv; Hou, Yali; Datar, Sanjeev A.; Azakie, Anthony; Johengen, Michael J.; Harmon, Cynthia; Fratz, Sohrab; Fineman, Jeffrey R.; Black, Stephen Matthew.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 295, No. 5, 01.11.2008.

Research output: Contribution to journalArticle

Oishi, Peter E. ; Wiseman, Dean A. ; Sharma, Shruti ; Kumar, Sanjiv ; Hou, Yali ; Datar, Sanjeev A. ; Azakie, Anthony ; Johengen, Michael J. ; Harmon, Cynthia ; Fratz, Sohrab ; Fineman, Jeffrey R. ; Black, Stephen Matthew. / Progressive dysfunction of nitric oxide synthase in a lamb model of chronically increased pulmonary blood flow : A role for oxidative stress. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2008 ; Vol. 295, No. 5.
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