Nitric oxide alterations following acute ductal constriction in the fetal lamb: A role for superoxide

Jong Hau Hsu, Peter Oishi, Dean A. Wiseman, Yali Hou, Omar Chikovani, Sanjeev Datar, Eniko Sajti, Michael J. Johengen, Cynthia Harmon, Stephen M. Black, Jeffrey R. Fineman

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Acute partial compression of the fetal ductus arteriosus (DA) results in an initial abrupt increase in pulmonary blood flow (PBF), which is followed by a significant reduction in PBF to baseline values over the ensuing 2-4 h. We have previously demonstrated that this potent vasoconstricting response is due, in part, to an endothelin-1 (ET-1)-mediated decrease in nitric oxide synthase (NOS) activity. In addition, in vitro data demonstrate that ET-1 increases superoxide levels in pulmonary arterial smooth muscle cells and that oxidative stress alters NOS activity. Therefore, the objectives of this study were to determine the potential role of superoxide in the alterations of hemodynamics and NOS activity following acute ductal constriction in the late-gestation fetal lamb. Eighteen anesthetized near-term fetal lambs were instrumented, and a lung biopsy was performed. After a 48-h recovery, acute constriction of the DA was performed by inflating a vascular occluder. Polyethylene glycol-superoxide dismutase (PEG-SOD; 1,000-1,500 units/kg, n = 7) or PEG-alone (vehicle control group, n = 5) was injected into the pulmonary artery before ductal constriction. Six animals had a sham operation. In PEG-alone-treated lambs, acute ductal constriction rapidly decreased pulmonary vascular resistance (PVR) by 88%. However, by 4 h, PVR returned to preconstriction baseline. This vasoconstriction was associated with an increase in lung superoxide levels (82%), a decrease in total NOS activity (50%), and an increase in P-eNOS-Thr495 (52%) (P < 0.05). PEG-SOD prevented the increase of superoxide after ductal constriction, attenuated the vasoconstriction, preserved NOS activity, and increased P-eNOS Ser1177 (307%, P < 0.05). Sham procedure induced no changes. These data suggest that an acute decrease in NOS activity that is mediated, in part, by increased superoxide levels, and alterations in the phosphorylation status of the endothelial NOS isoform, underlie the pulmonary vascular response to acute ductal constriction.

Original languageEnglish (US)
Pages (from-to)L880-L887
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume298
Issue number6
DOIs
StatePublished - Jun 1 2010

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Constriction
Nitric Oxide Synthase
Superoxides
Nitric Oxide
Lung
Ductus Arteriosus
Endothelin-1
Vasoconstriction
Vascular Resistance
Blood Vessels
Nitric Oxide Synthase Type III
Pulmonary Artery
Smooth Muscle Myocytes
Protein Isoforms
Oxidative Stress
Hemodynamics
Phosphorylation
Biopsy
Pregnancy
Control Groups

Keywords

  • Ductus arteriosus
  • Pulmonary circulation

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Nitric oxide alterations following acute ductal constriction in the fetal lamb : A role for superoxide. / Hsu, Jong Hau; Oishi, Peter; Wiseman, Dean A.; Hou, Yali; Chikovani, Omar; Datar, Sanjeev; Sajti, Eniko; Johengen, Michael J.; Harmon, Cynthia; Black, Stephen M.; Fineman, Jeffrey R.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 298, No. 6, 01.06.2010, p. L880-L887.

Research output: Contribution to journalArticle

Hsu, JH, Oishi, P, Wiseman, DA, Hou, Y, Chikovani, O, Datar, S, Sajti, E, Johengen, MJ, Harmon, C, Black, SM & Fineman, JR 2010, 'Nitric oxide alterations following acute ductal constriction in the fetal lamb: A role for superoxide', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 298, no. 6, pp. L880-L887. https://doi.org/10.1152/ajplung.00384.2009
Hsu, Jong Hau ; Oishi, Peter ; Wiseman, Dean A. ; Hou, Yali ; Chikovani, Omar ; Datar, Sanjeev ; Sajti, Eniko ; Johengen, Michael J. ; Harmon, Cynthia ; Black, Stephen M. ; Fineman, Jeffrey R. / Nitric oxide alterations following acute ductal constriction in the fetal lamb : A role for superoxide. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2010 ; Vol. 298, No. 6. pp. L880-L887.
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abstract = "Acute partial compression of the fetal ductus arteriosus (DA) results in an initial abrupt increase in pulmonary blood flow (PBF), which is followed by a significant reduction in PBF to baseline values over the ensuing 2-4 h. We have previously demonstrated that this potent vasoconstricting response is due, in part, to an endothelin-1 (ET-1)-mediated decrease in nitric oxide synthase (NOS) activity. In addition, in vitro data demonstrate that ET-1 increases superoxide levels in pulmonary arterial smooth muscle cells and that oxidative stress alters NOS activity. Therefore, the objectives of this study were to determine the potential role of superoxide in the alterations of hemodynamics and NOS activity following acute ductal constriction in the late-gestation fetal lamb. Eighteen anesthetized near-term fetal lambs were instrumented, and a lung biopsy was performed. After a 48-h recovery, acute constriction of the DA was performed by inflating a vascular occluder. Polyethylene glycol-superoxide dismutase (PEG-SOD; 1,000-1,500 units/kg, n = 7) or PEG-alone (vehicle control group, n = 5) was injected into the pulmonary artery before ductal constriction. Six animals had a sham operation. In PEG-alone-treated lambs, acute ductal constriction rapidly decreased pulmonary vascular resistance (PVR) by 88{\%}. However, by 4 h, PVR returned to preconstriction baseline. This vasoconstriction was associated with an increase in lung superoxide levels (82{\%}), a decrease in total NOS activity (50{\%}), and an increase in P-eNOS-Thr495 (52{\%}) (P < 0.05). PEG-SOD prevented the increase of superoxide after ductal constriction, attenuated the vasoconstriction, preserved NOS activity, and increased P-eNOS Ser1177 (307{\%}, P < 0.05). Sham procedure induced no changes. These data suggest that an acute decrease in NOS activity that is mediated, in part, by increased superoxide levels, and alterations in the phosphorylation status of the endothelial NOS isoform, underlie the pulmonary vascular response to acute ductal constriction.",
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AU - Hsu, Jong Hau

AU - Oishi, Peter

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AU - Hou, Yali

AU - Chikovani, Omar

AU - Datar, Sanjeev

AU - Sajti, Eniko

AU - Johengen, Michael J.

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