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

Satyan Lakshminrusimha, Dean Wiseman, Stephen M. Black, James A. Russell, Sylvia F. Gugino, Peter Oishi, Robin H. Steinhorn, Jeffrey R. Fineman

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Congenital cardiac defects associated with increased pulmonary blood flow (Qp) produce pulmonary hypertension. We have previously reported attenuated endothelium-dependent relaxations in pulmonary arteries (PA) isolated from lambs with increased Qp 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 H 2O2-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 Qp.

Original languageEnglish (US)
Pages (from-to)H1491-H1497
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume293
Issue number3
DOIs
StatePublished - Sep 1 2007

Fingerprint

Nitric Oxide Synthase
Pulmonary Artery
Reactive Oxygen Species
Lung
Calcimycin
Superoxides
Penicillamine
Blood Vessels
Pulmonary Hypertension
1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt
Nitric Oxide Donors
Electron Spin Resonance Spectroscopy
Vasodilator Agents
Catalase
Oxidation-Reduction
Endothelium
Anions
Arginine
Spectrum Analysis
Nitric Oxide

Keywords

  • Congenital heart disease
  • Hydrogen peroxide
  • Nitric oxide

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

The role of nitric oxide synthase-derived reactive oxygen species in the altered relaxation of pulmonary arteries from lambs with increased pulmonary blood flow. / Lakshminrusimha, Satyan; Wiseman, Dean; Black, Stephen M.; Russell, James A.; Gugino, Sylvia F.; Oishi, Peter; Steinhorn, Robin H.; Fineman, Jeffrey R.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 293, No. 3, 01.09.2007, p. H1491-H1497.

Research output: Contribution to journalArticle

Lakshminrusimha, Satyan ; Wiseman, Dean ; Black, Stephen M. ; Russell, James A. ; Gugino, Sylvia F. ; Oishi, Peter ; Steinhorn, Robin H. ; Fineman, Jeffrey 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. In: American Journal of Physiology - Heart and Circulatory Physiology. 2007 ; Vol. 293, No. 3. pp. H1491-H1497.
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abstract = "Congenital cardiac defects associated with increased pulmonary blood flow (Qp) produce pulmonary hypertension. We have previously reported attenuated endothelium-dependent relaxations in pulmonary arteries (PA) isolated from lambs with increased Qp 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 H 2O2-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 Qp.",
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AU - Russell, James A.

AU - Gugino, Sylvia F.

AU - Oishi, Peter

AU - Steinhorn, Robin H.

AU - Fineman, Jeffrey R.

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