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1 Neonatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Neonatology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States; Pediatrics, Medical college of WI, Milwaukee, Wisconsin, United States
3 Pediatric Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
* To whom correspondence should be addressed. E-mail: gkonduri{at}mcw.edu.
Persistent pulmonary hypertension of newborn (PPHN) is associated with decreased nitric oxide (NO) release and impaired pulmonary vasodilation. We investigated the hypothesis that increased superoxide (O2._) release by an uncoupled endothelial NOS (eNOS) contributes to impaired pulmonary vasodilation in PPHN. We investigated the response of isolated pulmonary arteries to NOS agonist, ATP and NO donor, S- nitroso- N-acetyl penicillamine (SNAP) in fetal lambs with PPHN induced by prenatal ligation of ductus arteriosus, and in sham-ligation controls in the presence/absence of NOS antagonist, L-NAME, or O2._ scavenger, Tiron. ATP caused dose dependent relaxation of pulmonary artery rings in control lambs but induced constriction of the rings in PPHN lambs. L-NAME, 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 hsp90-eNOS interactions and release of NO and O2._ 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 O2._ in response to ATP and this was attenuated by NOS antagonist, L-NAME and superoxide dismutase (SOD). ATP stimulated Hsp90-eNOS interactions in PAEC from control but not PPHN lambs. Hsp90 immuno-precipitated from PPHN pulmonary arteries had increased nitro-tyrosine signal. Oxidant stress from uncoupled eNOS contributes to impaired pulmonary vasodilation in PPHN induced by ductal ligation in fetal lambs.
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