title: Effects of inhaled nitric oxide on platelet-activating factor-induced pulmonary hypertension in dogs.
abstract: BACKGROUND
  Platelet-activating factor (PAF), a lipid mediator released during endotoxin shock, induces pulmonary hypertension, systemic hypotension and cardiac dysfunction. In this study, we compared the effect of inhaled nitric oxide (NO) on PAF-induced pulmonary hypertension and NO metabolism with that on pulmonary hypertension induced by a stable thromboxane A2 mimetic, U46619. Since PAF-induced hypotension might be mediated by NO, the effect of inhaled NO combined with an intravenously administered NO synthase inhibitor, NG-nitro-L-arginine (L-NNA), 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 microgram.kg-1.min-1 (group PAF), L-NNA 10 mg.kg-1 + PAF 0.04 +/- 0.03 microgram.kg-1.min-1 (group L-NNA + PAF), U46619 0.60 +/- 0.11 microgram.kg-1.min-1 (group U46619) or L-NNA 10 mg.kg-1 + U46619 0.61 +/- 0.23 microgram.kg-1.min-1 (group L-NNA + U46619) to obtain a mean pulmonary arterial pressure (MPAP) of 25 mmHg. Nitric oxide was then inhaled at 5, 10, 20 and 40 ppm for 15 min at 15-min intervals in the order of increasing concentration. An additional 7 dogs (control group) inhaled NO at normal MPAP (17 mmHg). Hemodynamic and respiratory parameters, NOHb, NO2- + NO3-, and MetHb levels in blood were measured before and during NO administration.
  
  
  RESULTS
  In the control group, hemodynamic and respiratory values did not change significantly during NO administration. In group PAF, NO significantly reversed the PAF-induced pulmonary hypertension. PAF induced a marked systemic hypotension and cardiac output reduction, but these changes were not affected by inhalation of NO. L-NNA pretreatment 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 resistance (PVR) was significantly greater than that in group PAF. U46619 induced pulmonary hypertension and increases in blood pressure, intrapulmonary shunt and peak airway pressure. L-NNA pretreatment did not change the dose of U46619 required to maintain a MPAP of 25 mmHg. The effects of inhaled NO on PVR decrease were similar in groups U46619 and L-NNA + U46619. No NOHb was detected in any group. NO2- + NO3- concentration increased during NO administrations. There were no significant differences in NO2- + NO3- concentration among groups.
  
  
  CONCLUSIONS
  Inhaled NO at the dose of 5-40 ppm effectively reversed PAF-induced pulmonary hypertension, especially following pretreatment with L-NNA. Inhaled NO did not affect PAF-induced hypotension or cardiac dysfunction. These findings indicate that low concentrations of inhaled NO may be useful in reversing pulmonary hypertension in the endotoxemia where PAF may be one mediator.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Osaka City University Medical School, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamada
authors.forename: H
authors.initials: H
authors.lastname: Yukioka
authors.forename: M
authors.initials: M
authors.lastname: Hayashi
authors.forename: A
authors.initials: A
authors.lastname: Asada
authors.forename: M
authors.initials: M
authors.lastname: Inoue
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D006454:Hemoglobins / Q000032:analysis; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D007275:Injections, Intravenous; D008706:Methemoglobin / Q000032:analysis; D009569:Nitric Oxide / Q000008:administration & dosage*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D010100:Oxygen / Q000097:blood; D010972:Platelet Activating Factor / Q000502:physiology; D011652:Pulmonary Circulation / Q000187:drug effects; D014662:Vasoconstrictor Agents
chemical_list: D006454:Hemoglobins; D010972:Platelet Activating Factor; D014662:Vasoconstrictor Agents; C008657:nitrosyl hemoglobin; D019335:Nitroarginine; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D008706:Methemoglobin; D019001:Nitric Oxide Synthase; D010100:Oxygen