Inhaled nitric oxide fails to confer the pulmonary protection provided by distal stimulation of the nitric oxide pathway at the level of cyclic guanosine monophosphate

Yoshifumi Naka, Dilip K. Roy, Arthur J. Smerling, Robert E. Michler, Craig R. Smith, David Stern, Mehmet C. Oz, David J. Pinsky

Research output: Contribution to journalArticle

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Abstract

It has been suggested that inhaled nitric oxide gas may be beneficial after lung transplantation, because endogenous levels of pulmonary nitric oxide decline rapidly after reperfusion. However theoretical concerns remain about the formation of highly toxic oxidants during the quenching of nitric oxide by superoxide. To determine whether distal stimulation of the nitric oxide-cyclic guanosine monophosphate pathway at the level of cyclic guanosine monophosphate might confer the beneficial vascular effects of nitric oxide without its potential toxicities, we studied an orthotopic rat left lung transplant model. In this model, hemodynamic and survival measurements can be obtained independent of the native right lung. Lungs were preserved for 6 hours at 4°C in Euro-Collins solution alone (control, n = 6) or supplemented with the cyclic guanosine monophosphate analog, 8-(4-chlorophenylthio)-guanosine-3′,5′-cyclic guanosine monophosphate (cGMP, n = 4). In additional experiments in which lungs were preserved with Euro-Collins solution alone, inhaled nitric oxide was administered during reperfusion (NO, n = 12). Thirty minutes after transplantation and ligation of the native right pulmonary artery, pulmonary vascular resistance, arterial oxygenation, graft neutrophil infiltration (myeloperoxidase activity), and recipient survival were evaluated. Cyclic guanosine monophosphate decreased pulmonary vascular resistance (1.1 ± 0.2 vs 12.1 ± 6.3 mm Hg/ml/min, p < 0.05), improved oxygen tension (369 ± 56 vs 82.8 ± 48 mm Hg, p < 0.05), reduced myeloperoxidase activity (1.7 ± 0.3 vs 3.1 ± 0.9 ΔDAbs 460 nm/min, p < 0.05), and improved recipient survival (100% vs 0%, p < 0.005) compared with Euro-Collins solution alone (control group). Animals receiving inhaled nitric oxide during reperfusion did not differ from control animals with respect to any of these parameters. These data suggest that distal stimulation of the nitric oxide-cyclic guanosine monophosphate pathway at the level of cyclic guanosine monophosphate has a protective effect that is not seen with inhaled nitric oxide in the immediate pulmonary reperfusion period. (J THORAC CARDIOVASC SURG 1995;110:1434-41).

Original languageEnglish (US)
Pages (from-to)1434-1441
Number of pages8
JournalThe Journal of Thoracic and Cardiovascular Surgery
Volume110
Issue number5
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

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Cyclic GMP
Nitric Oxide
Lung
Reperfusion
Vascular Resistance
Peroxidase
Guanosine Monophosphate
Transplants
Lung Transplantation
Neutrophil Infiltration
Guanosine
Poisons
Oxidants
Superoxides
Pulmonary Artery
Ligation
Blood Vessels
Transplantation
Gases
Hemodynamics

All Science Journal Classification (ASJC) codes

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

Cite this

Inhaled nitric oxide fails to confer the pulmonary protection provided by distal stimulation of the nitric oxide pathway at the level of cyclic guanosine monophosphate. / Naka, Yoshifumi; Roy, Dilip K.; Smerling, Arthur J.; Michler, Robert E.; Smith, Craig R.; Stern, David; Oz, Mehmet C.; Pinsky, David J.

In: The Journal of Thoracic and Cardiovascular Surgery, Vol. 110, No. 5, 01.01.1995, p. 1434-1441.

Research output: Contribution to journalArticle

Naka, Yoshifumi ; Roy, Dilip K. ; Smerling, Arthur J. ; Michler, Robert E. ; Smith, Craig R. ; Stern, David ; Oz, Mehmet C. ; Pinsky, David J. / Inhaled nitric oxide fails to confer the pulmonary protection provided by distal stimulation of the nitric oxide pathway at the level of cyclic guanosine monophosphate. In: The Journal of Thoracic and Cardiovascular Surgery. 1995 ; Vol. 110, No. 5. pp. 1434-1441.
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AU - Michler, Robert E.

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AU - Oz, Mehmet C.

AU - Pinsky, David J.

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N2 - It has been suggested that inhaled nitric oxide gas may be beneficial after lung transplantation, because endogenous levels of pulmonary nitric oxide decline rapidly after reperfusion. However theoretical concerns remain about the formation of highly toxic oxidants during the quenching of nitric oxide by superoxide. To determine whether distal stimulation of the nitric oxide-cyclic guanosine monophosphate pathway at the level of cyclic guanosine monophosphate might confer the beneficial vascular effects of nitric oxide without its potential toxicities, we studied an orthotopic rat left lung transplant model. In this model, hemodynamic and survival measurements can be obtained independent of the native right lung. Lungs were preserved for 6 hours at 4°C in Euro-Collins solution alone (control, n = 6) or supplemented with the cyclic guanosine monophosphate analog, 8-(4-chlorophenylthio)-guanosine-3′,5′-cyclic guanosine monophosphate (cGMP, n = 4). In additional experiments in which lungs were preserved with Euro-Collins solution alone, inhaled nitric oxide was administered during reperfusion (NO, n = 12). Thirty minutes after transplantation and ligation of the native right pulmonary artery, pulmonary vascular resistance, arterial oxygenation, graft neutrophil infiltration (myeloperoxidase activity), and recipient survival were evaluated. Cyclic guanosine monophosphate decreased pulmonary vascular resistance (1.1 ± 0.2 vs 12.1 ± 6.3 mm Hg/ml/min, p < 0.05), improved oxygen tension (369 ± 56 vs 82.8 ± 48 mm Hg, p < 0.05), reduced myeloperoxidase activity (1.7 ± 0.3 vs 3.1 ± 0.9 ΔDAbs 460 nm/min, p < 0.05), and improved recipient survival (100% vs 0%, p < 0.005) compared with Euro-Collins solution alone (control group). Animals receiving inhaled nitric oxide during reperfusion did not differ from control animals with respect to any of these parameters. These data suggest that distal stimulation of the nitric oxide-cyclic guanosine monophosphate pathway at the level of cyclic guanosine monophosphate has a protective effect that is not seen with inhaled nitric oxide in the immediate pulmonary reperfusion period. (J THORAC CARDIOVASC SURG 1995;110:1434-41).

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