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.
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 degrees 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 delta Abs 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.
D000280:Administration, Inhalation; D000818:Animals; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism*; D005260:Female; D006982:Hypertonic Solutions; D008168:Lung / Q000187:drug effects; D016040:Lung Transplantation; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology*; D010100:Oxygen / Q000097:blood; D009195:Peroxidase / Q000097:blood; D051381:Rats; D011917:Rats, Inbred Lew; D014022:Tissue Survival / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
C037096:Euro-Collins' solution; D006982:Hypertonic Solutions; D009569:Nitric Oxide; D009195:Peroxidase; D006152:Cyclic GMP; D010100:Oxygen