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Oxidant stress from uncoupled nitric oxide synthase impairs vasodilation in fetal lambs with persistent pulmonary hypertension. Am J Physiol Heart Circ Physiol 2007 Apr;292(4):H1812-20

Date

12/05/2006

Pubmed ID

17142346

DOI

10.1152/ajpheart.00425.2006

Scopus ID

2-s2.0-34147118950   89 Citations

Abstract

Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased NO release and impaired pulmonary vasodilation. We investigated the hypothesis that increased superoxide (O(2)(*-)) release by an uncoupled endothelial nitric oxide synthase (eNOS) contributes to impaired pulmonary vasodilation in PPHN. We investigated the response of isolated pulmonary arteries to the NOS agonist ATP and the NO donor S-nitroso-N-acetylpenicillamine (SNAP) in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus and in sham-ligated controls in the presence or absence of the NOS antagonist nitro-L-arginine methyl ester (L-NAME) or the O(2)(*-) scavenger 4,5-dihydroxy-1,3-benzenedisulfonate (Tiron). ATP caused dose-dependent relaxation of pulmonary artery rings in control lambs but induced constriction of the rings in PPHN lambs. L-NAME, the NO precursor L-arginine, and Tiron restored the relaxation response of pulmonary artery rings to ATP in PPHN. Relaxation to NO was attenuated in arteries from PPHN lambs, and the response was improved by L-NAME and by Tiron. We also investigated the alteration in heat shock protein (HSP)90-eNOS interactions and release of NO and O(2)(*-) in response to ATP in the pulmonary artery endothelial cells (PAEC) from these lambs. Cultured PAEC and endothelium of freshly isolated pulmonary arteries from PPHN lambs released O(2)(*-) in response to ATP, and this was attenuated by the NOS antagonist L-NAME and superoxide dismutase (SOD). ATP stimulated HSP90-eNOS interactions in PAEC from control but not PPHN lambs. HSP90 immunoprecipitated from PPHN pulmonary arteries had increased nitrotyrosine signal. Oxidant stress from uncoupled eNOS contributes to impaired pulmonary vasodilation in PPHN induced by ductal ligation in fetal lambs.

Author List

Konduri GG, Bakhutashvili I, Eis A, Pritchard K Jr

Authors

Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Animals
Disease Models, Animal
Enzyme Inhibitors
Female
Fetus
HSP90 Heat-Shock Proteins
Humans
Infant, Newborn
Ligation
NG-Nitroarginine Methyl Ester
Nitric Oxide
Nitric Oxide Donors
Nitric Oxide Synthase Type III
Oxidative Stress
Persistent Fetal Circulation Syndrome
Pregnancy
Pulmonary Artery
S-Nitroso-N-Acetylpenicillamine
Sheep
Superoxides
Tyrosine
Vasodilation
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0