title: The role of nitric oxide synthase-derived reactive oxygen species in the altered relaxation of pulmonary arteries from lambs with increased pulmonary blood flow.
abstract: 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 H(2)O(2). A-23187-, PEG-SOD-, and H(2)O(2)-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 H(2)O(2). We conclude that NOS catalyzes the production of superoxide anions in shunt PA. PEG-SOD relaxes shunt PA by converting these anions to H(2)O(2), 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).
authors.affiliation: Department of Pediatrics, Women's and Children's Hospital of Buffalo, State University of New York at Buffalo, NY 14222, USA. slakshmi@buffalo.edu
authors.forename: Satyan
authors.initials: S
authors.lastname: Lakshminrusimha
authors.forename: Dean
authors.initials: D
authors.lastname: Wiseman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.forename: Sylvia F
authors.initials: SF
authors.lastname: Gugino
authors.forename: Peter
authors.initials: P
authors.lastname: Oishi
authors.forename: Robin H
authors.initials: RH
authors.lastname: Steinhorn
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
mesh_terms: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D005260:Female; D007476:Ionophores / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012756:Sheep; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D007476:Ionophores; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; C110881:S-nitro-N-acetylpenicillamine; D013481:Superoxides; D000001:Calcimycin; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; D002374:Catalase; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D013482:Superoxide Dismutase; D010396:Penicillamine