EFFECTS OF INHALED NITRIC-OXIDE ON PLATELET-ACTIVATING FACTOR-INDUCEDPULMONARY-HYPERTENSION IN DOGS

Background: Platelet-activating factor (PAF), a lipid mediator release d during endotoxin shock, induces pulmonary hypertension, systemic hyp otension and cardiac dysfunction. In this study, we compared the effec t of inhaled nitric oxide (NO) on PAF-induced pulmonary hypertension a nd NO metabolism with that on pulmonary hypertension induced by a stab le thromboxane A(2) mimetic, U46619. Since PAF-induced hypotension mig ht be mediated by NO, the effect of inhaled NO combined with an intrav enously administered NO synthase inhibitor, N-G-nitro-L-arginine (L-NN A), on PAF-induced hemodynamic change was also investigated. Methods: In a total of 28 beagles anesthetized with pentobarbital the following substances were intravenously administered: PAF 0.56+/-0.30 mu g.kg(- 1).min(-1) (group PAF), L-NNA 10 mg.kg(-1) + PAF 0.04+/-0.03 mu g.kg(- 1).min(-1) (group L-NNA + PAF), U46619 0.60+/-0.11 mu g.kg(-1).min(-1) (group U46619) or L-NNA 10 mg.kg(-1) + U46619 0.61+/-0.23 mu g.kg(-1) .min(-1) (group L-NNA + U46619) to obtain a mean pulmonary arterial pr essure (MPAP) of 25 mmHg. Nitric oxide was then inhaled at 5, 10, 20 a nd 40 ppm for 15 min at 15-min intervals in the order of increasing co ncentration. An additional 7 dogs (control group) inhaled NO at normal MPAP (17 mmHg). Hemodynamic and respiratory parameters, NOHb, NO2-+NO 3-, and MetHb levels in blood were measured before and during NO admin istration. Results: In the control group, hemodynamic and respiratory values did not change significantly during NO administration. in group I NO significantly reversed the PAF-induced pulmonary hypertension. P AF induced a marked systemic hypotension and cardiac output reduction, but these changes were not affected by inhalation of NO. L-NNA pretre atment markedly decreased the dose of PAF required to maintain a MPAP of 25 mmHg, and abolished the PAF-induced hypotension. In group L-NNA + PAF, the diminishing effect of inhaled NO on pulmonary vascular resi stance (PVR) was significantly greater than that in group PAF. U46619 induced pulmonary hypertension and increases in blood pressure, intrap ulmonary shunt and peak airway pressure. L-NNA pretreatment did not ch ange the dose of U46619 required to maintain a MPAP of 25 mmHg. The ef fects of inhaled NO on PVR decrease were similar in groups U46619 and L-NNA + U46619. No NOHb was detected in any group. NO2-+NO3- concentra tion increased during NO administrations. There were no significant di fferences in NO2-+NO3- concentration among groups. Conclusions: Inhale d NO at the dose of 5-40 ppm effectively reversed PAF-induced pulmonar y hypertension, especially following pretreatment with L-NNA. Inhaled NO did not affect PAF-induced hypotension or cardiac dysfunction. Thes e findings indicate that low concentrations of inhaled NO may be usefu l in reversing pulmonary hypertension in the endotoxemia where PAF may be one mediator.