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This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/H1491    most recent 00185.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lakshminrusimha, S. Articles by Fineman, J. R. Search for Related Content PubMed PubMed Citation Articles by Lakshminrusimha, S. Articles by Fineman, J. R.

The role of nitric oxide synthase-derived reactive oxygen species in the altered relaxation of pulmonary arteries from lambs with increased pulmonary blood flow

Departments of ¹Pediatrics and ²Physiology and Biophysics, State University of New York at Buffalo, Buffalo, New York; ³Department of Pediatrics, Northwestern University, Chicago, Illinois; ⁴Vascular Biology Center, Medical College of Georgia, Augusta, Georgia; and ⁵Department of Pediatrics, University of California, San Francisco, California

Submitted 12 February 2007 ; accepted in final form 17 May 2007

Congenital cardiac defects associated with increased pulmonary blood flow (Q_p) produce pulmonary hypertension. We have previously reported attenuated endothelium-dependent relaxations in pulmonary arteries (PA) isolated from lambs with increased Q_p and pulmonary hypertension. To better characterize the vascular alterations in the nitric oxide-superoxide system, 12 fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). Twin lambs served as controls. PA were isolated from these lambs at 4–6 wk of age. Electron paramagnetic resonance spectroscopy on fourth-generation PA showed significantly increased superoxide anion generation in shunt PA that were decreased to control levels following inhibition of nitric oxide synthase (NOS) with 2-ethyl-2-thiopseudourea. Preconstricted fifth-generation PA rings were relaxed with a NOS agonist (A-23187), a nitric oxide donor [S-nitrosyl amino penicillamine (SNAP)], polyethylene glycol-conjugated superoxide dismutase (PEG-SOD), or H₂O₂. A-23187-, PEG-SOD-, and H₂O₂-mediated relaxations were impaired in shunt PA compared with controls. Pretreatment with PEG-SOD significantly enhanced the relaxation response to A-23187 and SNAP in shunt but not control PA. Inhibition of NOS with nitro-L-arginine or scavenging superoxide anions with tiron enhanced relaxation to SNAP and inhibited relaxation to PEG-SOD in shunt PA. Pretreatment with catalase inhibited relaxation of shunt PA to A-23187, SOD, and H₂O₂. We conclude that NOS catalyzes the production of superoxide anions in shunt PA. PEG-SOD relaxes shunt PA by converting these anions to H₂O₂, a pulmonary vasodilator. The redox environment, influenced by the balance between production and scavenging of ROS, may have important consequences on pulmonary vascular reactivity in the setting of increased Q_p.

congenital heart disease; hydrogen peroxide; nitric oxide