SOD and inhaled nitric oxide normalize phosphodiesterase 5 expression and activity in neonatal lambs with persistent pulmonary hypertension

Kathryn N. Farrow, Satyanarayana Lakshminrusimha, Lyubov Czech, Beezly S. Groh, Sylvia F. Gugino, Jonathan M. Davis, James A. Russell, Robin H Steinhorn

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Phosphodiesterase 5 (PDE5) and soluble guanylate cyclase (sGC) are key regulators of cGMP and pulmonary vascular tone. We sought to determine the impact of mechanical ventilation with O2 with or without inhaled nitric oxide (iNO) or recombinant human Cu/Zn SOD (rhSOD) on sGC, PDE5, and cGMP in the ovine ductal ligation model of persistent pulmonary hypertension of the newborn (PPHN). PPHN lambs were ventilated with 100% O2 for 24 h alone or combined with either inhalation of 20 parts per million (ppm) iNO continuously or a single intratracheal dose of rhSOD (5 mg/kg). Ventilated PPHN lambs were compared with PPHN fetuses, control fetuses, and 1-day-old spontaneously breathing lambs (1DSB). In the small pulmonary arteries of 1DSB lambs, sGC expression increased, PDE5 expression decreased, and cGMP concentrations increased relative to fetal levels. In PPHN lambs ventilated with 100% O2, sGC activity increased to levels comparable with 1DSB levels. However, PDE5 expression and activity increased, and cGMP levels remained at fetal levels. Addition of either iNO or rhSOD decreased PDE5 expression and activity in PPHN lambs and increased cGMP levels to levels comparable with 1DSB lambs. These data suggest that ventilation of PPHN lambs with 100% O2 impairs cGMP-mediated vasodilation in part due to increased PDE5 expression and activity. The addition of either iNO or rhSOD normalized PDE5 and cGMP levels. Thus therapies designed to decrease PDE5 and increase cGMP, such as iNO and rhSOD, may prove useful in the treatment of PPHN in newborn infants.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume299
Issue number1
DOIs
StatePublished - Jul 2010
Externally publishedYes

Fingerprint

Persistent Fetal Circulation Syndrome
Type 5 Cyclic Nucleotide Phosphodiesterases
Pulmonary Hypertension
Nitric Oxide
Respiration
Fetus
Artificial Respiration
Vasodilation
Inhalation
Pulmonary Artery
Ligation
Blood Vessels
Ventilation
Sheep
Newborn Infant
Lung

Keywords

  • cGMP
  • Reactive oxygen species

ASJC Scopus subject areas

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

Cite this

SOD and inhaled nitric oxide normalize phosphodiesterase 5 expression and activity in neonatal lambs with persistent pulmonary hypertension. / Farrow, Kathryn N.; Lakshminrusimha, Satyanarayana; Czech, Lyubov; Groh, Beezly S.; Gugino, Sylvia F.; Davis, Jonathan M.; Russell, James A.; Steinhorn, Robin H.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 299, No. 1, 07.2010.

Research output: Contribution to journalArticle

Farrow, Kathryn N. ; Lakshminrusimha, Satyanarayana ; Czech, Lyubov ; Groh, Beezly S. ; Gugino, Sylvia F. ; Davis, Jonathan M. ; Russell, James A. ; Steinhorn, Robin H. / SOD and inhaled nitric oxide normalize phosphodiesterase 5 expression and activity in neonatal lambs with persistent pulmonary hypertension. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2010 ; Vol. 299, No. 1.
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abstract = "Phosphodiesterase 5 (PDE5) and soluble guanylate cyclase (sGC) are key regulators of cGMP and pulmonary vascular tone. We sought to determine the impact of mechanical ventilation with O2 with or without inhaled nitric oxide (iNO) or recombinant human Cu/Zn SOD (rhSOD) on sGC, PDE5, and cGMP in the ovine ductal ligation model of persistent pulmonary hypertension of the newborn (PPHN). PPHN lambs were ventilated with 100{\%} O2 for 24 h alone or combined with either inhalation of 20 parts per million (ppm) iNO continuously or a single intratracheal dose of rhSOD (5 mg/kg). Ventilated PPHN lambs were compared with PPHN fetuses, control fetuses, and 1-day-old spontaneously breathing lambs (1DSB). In the small pulmonary arteries of 1DSB lambs, sGC expression increased, PDE5 expression decreased, and cGMP concentrations increased relative to fetal levels. In PPHN lambs ventilated with 100{\%} O2, sGC activity increased to levels comparable with 1DSB levels. However, PDE5 expression and activity increased, and cGMP levels remained at fetal levels. Addition of either iNO or rhSOD decreased PDE5 expression and activity in PPHN lambs and increased cGMP levels to levels comparable with 1DSB lambs. These data suggest that ventilation of PPHN lambs with 100{\%} O2 impairs cGMP-mediated vasodilation in part due to increased PDE5 expression and activity. The addition of either iNO or rhSOD normalized PDE5 and cGMP levels. Thus therapies designed to decrease PDE5 and increase cGMP, such as iNO and rhSOD, may prove useful in the treatment of PPHN in newborn infants.",
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