Inhaled nitric oxide decreases pulmonary soluble guanylate cyclase protein levels in 1-month-old lambs

Stephan Thelitz, Janine M. Bekker, Boaz Ovadia, Regan B. Stuart, Michael J. Johengen, Stephen Matthew Black, Jeffrey R. Fineman

Research output: Contribution to journalArticle

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Abstract

Background: Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of cyclic guanosine monophosphate. However, responses are often nonsustained, and clinically significant increases in pulmonary vascular resistance have been noted on its acute withdrawal. In vitro and in vivo data suggest that inhaled nitric oxide decreases endogenous nitric oxide synthase activity. The effects of inhaled nitric oxide on the downstream mediators of the nitric oxide/cyclic guanosine monophosphate cascade, soluble guanylate cyclase and phosphodiesterase 5, have not been investigated. We sought to determine the effects of inhaled nitric oxide on endogenous cyclic guanosine monophosphate levels, soluble guanylate cyclase, and phosphodiesterase 5 protein levels in the intact lamb. Methods: Eleven 1-month-old lambs were mechanically ventilated. In 7 lambs, inhaled nitric oxide (40 ppm) was administered for 24 hours and then acutely withdrawn. Intermittent lung biopsy samples were obtained for cyclic guanosine monophosphate concentrations and soluble guanylate cyclase and phosphodiesterase 5 protein levels (Western blot analysis). Results: Initiation of nitric oxide decreased left pulmonary vascular resistance by 26.2%, and withdrawal rapidly increased pulmonary vascular resistance by 77.8% (P < .05). Tissue cyclic guanosine monophosphate concentrations initially increased during nitric oxide therapy but were not maintained during the 24-hour exposure. In addition, cyclic guanosine monophosphate concentrations rapidly decreased after nitric oxide withdrawal (P < .05). The a soluble guanylate cyclase (-45.7%) and β soluble guanylate cyclase (-48.4%) protein levels decreased during nitric oxide therapy (P < .05), whereas phosphodiesterase 5 proteins levels were unchanged. Conclusions: These data suggest a role for decreased soluble guanylate cyclase and its resulting decrease in cyclic guanosine monophosphate concentrations in the nonsustained response to nitric oxide and the rebound pulmonary hypertension noted on its acute withdrawal. Phosphodiesterase 5 inhibitors may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic guanosine monophosphate levels and thereby preserve nitric oxide responsiveness and prevent rebound pulmonary hypertension.

Original languageEnglish (US)
Pages (from-to)1285-1292
Number of pages8
JournalJournal of Thoracic and Cardiovascular Surgery
Volume127
Issue number5
DOIs
StatePublished - Jan 1 2004

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Nitric Oxide
Cyclic GMP
Lung
Type 5 Cyclic Nucleotide Phosphodiesterases
Proteins
Vascular Resistance
Pulmonary Hypertension
Soluble Guanylyl Cyclase
Phosphodiesterase 5 Inhibitors
Vasodilation
Nitric Oxide Synthase
Smooth Muscle Myocytes
Therapeutics
Western Blotting
Biopsy

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Thelitz, S., Bekker, J. M., Ovadia, B., Stuart, R. B., Johengen, M. J., Black, S. M., & Fineman, J. R. (2004). Inhaled nitric oxide decreases pulmonary soluble guanylate cyclase protein levels in 1-month-old lambs. Journal of Thoracic and Cardiovascular Surgery, 127(5), 1285-1292. https://doi.org/10.1016/j.jtcvs.2003.07.024

Inhaled nitric oxide decreases pulmonary soluble guanylate cyclase protein levels in 1-month-old lambs. / Thelitz, Stephan; Bekker, Janine M.; Ovadia, Boaz; Stuart, Regan B.; Johengen, Michael J.; Black, Stephen Matthew; Fineman, Jeffrey R.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 127, No. 5, 01.01.2004, p. 1285-1292.

Research output: Contribution to journalArticle

Thelitz, S, Bekker, JM, Ovadia, B, Stuart, RB, Johengen, MJ, Black, SM & Fineman, JR 2004, 'Inhaled nitric oxide decreases pulmonary soluble guanylate cyclase protein levels in 1-month-old lambs', Journal of Thoracic and Cardiovascular Surgery, vol. 127, no. 5, pp. 1285-1292. https://doi.org/10.1016/j.jtcvs.2003.07.024
Thelitz, Stephan ; Bekker, Janine M. ; Ovadia, Boaz ; Stuart, Regan B. ; Johengen, Michael J. ; Black, Stephen Matthew ; Fineman, Jeffrey R. / Inhaled nitric oxide decreases pulmonary soluble guanylate cyclase protein levels in 1-month-old lambs. In: Journal of Thoracic and Cardiovascular Surgery. 2004 ; Vol. 127, No. 5. pp. 1285-1292.
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abstract = "Background: Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of cyclic guanosine monophosphate. However, responses are often nonsustained, and clinically significant increases in pulmonary vascular resistance have been noted on its acute withdrawal. In vitro and in vivo data suggest that inhaled nitric oxide decreases endogenous nitric oxide synthase activity. The effects of inhaled nitric oxide on the downstream mediators of the nitric oxide/cyclic guanosine monophosphate cascade, soluble guanylate cyclase and phosphodiesterase 5, have not been investigated. We sought to determine the effects of inhaled nitric oxide on endogenous cyclic guanosine monophosphate levels, soluble guanylate cyclase, and phosphodiesterase 5 protein levels in the intact lamb. Methods: Eleven 1-month-old lambs were mechanically ventilated. In 7 lambs, inhaled nitric oxide (40 ppm) was administered for 24 hours and then acutely withdrawn. Intermittent lung biopsy samples were obtained for cyclic guanosine monophosphate concentrations and soluble guanylate cyclase and phosphodiesterase 5 protein levels (Western blot analysis). Results: Initiation of nitric oxide decreased left pulmonary vascular resistance by 26.2{\%}, and withdrawal rapidly increased pulmonary vascular resistance by 77.8{\%} (P < .05). Tissue cyclic guanosine monophosphate concentrations initially increased during nitric oxide therapy but were not maintained during the 24-hour exposure. In addition, cyclic guanosine monophosphate concentrations rapidly decreased after nitric oxide withdrawal (P < .05). The a soluble guanylate cyclase (-45.7{\%}) and β soluble guanylate cyclase (-48.4{\%}) protein levels decreased during nitric oxide therapy (P < .05), whereas phosphodiesterase 5 proteins levels were unchanged. Conclusions: These data suggest a role for decreased soluble guanylate cyclase and its resulting decrease in cyclic guanosine monophosphate concentrations in the nonsustained response to nitric oxide and the rebound pulmonary hypertension noted on its acute withdrawal. Phosphodiesterase 5 inhibitors may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic guanosine monophosphate levels and thereby preserve nitric oxide responsiveness and prevent rebound pulmonary hypertension.",
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AU - Thelitz, Stephan

AU - Bekker, Janine M.

AU - Ovadia, Boaz

AU - Stuart, Regan B.

AU - Johengen, Michael J.

AU - Black, Stephen Matthew

AU - Fineman, Jeffrey R.

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N2 - Background: Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of cyclic guanosine monophosphate. However, responses are often nonsustained, and clinically significant increases in pulmonary vascular resistance have been noted on its acute withdrawal. In vitro and in vivo data suggest that inhaled nitric oxide decreases endogenous nitric oxide synthase activity. The effects of inhaled nitric oxide on the downstream mediators of the nitric oxide/cyclic guanosine monophosphate cascade, soluble guanylate cyclase and phosphodiesterase 5, have not been investigated. We sought to determine the effects of inhaled nitric oxide on endogenous cyclic guanosine monophosphate levels, soluble guanylate cyclase, and phosphodiesterase 5 protein levels in the intact lamb. Methods: Eleven 1-month-old lambs were mechanically ventilated. In 7 lambs, inhaled nitric oxide (40 ppm) was administered for 24 hours and then acutely withdrawn. Intermittent lung biopsy samples were obtained for cyclic guanosine monophosphate concentrations and soluble guanylate cyclase and phosphodiesterase 5 protein levels (Western blot analysis). Results: Initiation of nitric oxide decreased left pulmonary vascular resistance by 26.2%, and withdrawal rapidly increased pulmonary vascular resistance by 77.8% (P < .05). Tissue cyclic guanosine monophosphate concentrations initially increased during nitric oxide therapy but were not maintained during the 24-hour exposure. In addition, cyclic guanosine monophosphate concentrations rapidly decreased after nitric oxide withdrawal (P < .05). The a soluble guanylate cyclase (-45.7%) and β soluble guanylate cyclase (-48.4%) protein levels decreased during nitric oxide therapy (P < .05), whereas phosphodiesterase 5 proteins levels were unchanged. Conclusions: These data suggest a role for decreased soluble guanylate cyclase and its resulting decrease in cyclic guanosine monophosphate concentrations in the nonsustained response to nitric oxide and the rebound pulmonary hypertension noted on its acute withdrawal. Phosphodiesterase 5 inhibitors may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic guanosine monophosphate levels and thereby preserve nitric oxide responsiveness and prevent rebound pulmonary hypertension.

AB - Background: Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of cyclic guanosine monophosphate. However, responses are often nonsustained, and clinically significant increases in pulmonary vascular resistance have been noted on its acute withdrawal. In vitro and in vivo data suggest that inhaled nitric oxide decreases endogenous nitric oxide synthase activity. The effects of inhaled nitric oxide on the downstream mediators of the nitric oxide/cyclic guanosine monophosphate cascade, soluble guanylate cyclase and phosphodiesterase 5, have not been investigated. We sought to determine the effects of inhaled nitric oxide on endogenous cyclic guanosine monophosphate levels, soluble guanylate cyclase, and phosphodiesterase 5 protein levels in the intact lamb. Methods: Eleven 1-month-old lambs were mechanically ventilated. In 7 lambs, inhaled nitric oxide (40 ppm) was administered for 24 hours and then acutely withdrawn. Intermittent lung biopsy samples were obtained for cyclic guanosine monophosphate concentrations and soluble guanylate cyclase and phosphodiesterase 5 protein levels (Western blot analysis). Results: Initiation of nitric oxide decreased left pulmonary vascular resistance by 26.2%, and withdrawal rapidly increased pulmonary vascular resistance by 77.8% (P < .05). Tissue cyclic guanosine monophosphate concentrations initially increased during nitric oxide therapy but were not maintained during the 24-hour exposure. In addition, cyclic guanosine monophosphate concentrations rapidly decreased after nitric oxide withdrawal (P < .05). The a soluble guanylate cyclase (-45.7%) and β soluble guanylate cyclase (-48.4%) protein levels decreased during nitric oxide therapy (P < .05), whereas phosphodiesterase 5 proteins levels were unchanged. Conclusions: These data suggest a role for decreased soluble guanylate cyclase and its resulting decrease in cyclic guanosine monophosphate concentrations in the nonsustained response to nitric oxide and the rebound pulmonary hypertension noted on its acute withdrawal. Phosphodiesterase 5 inhibitors may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic guanosine monophosphate levels and thereby preserve nitric oxide responsiveness and prevent rebound pulmonary hypertension.

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