title: Responsiveness to inhaled NO in isolated-perfused lungs from endotoxin-challenged rats is dependent on endogenous nitrite/nitrate synthesis.
abstract: OBJECTIVE
  In isolated-perfused lungs of lipopolysaccharide (LPS)-challenged rats, vasodilatation to inhaled nitric oxide (NO) is impaired. Inhibition of nitric oxide synthase 2 (NOS2) by aminoguanidine (AG) prevented hyporesponsiveness to inhaled NO. Here, we investigated whether NOS2-mediated nitrite/nitrate synthesis modulates responsiveness to inhaled NO.
  
  
  METHODS
  Sprague-Dawley rats received intraperitoneally 0.5 mg kg(-1) LPS. Four hours later, LPS-treated rats received 3, 10 or 30 mg kg(-1) AG or 0.01, 0.1 or 1 mg kg(-1) S-methylisothiourea (SMT) by intraperitoneal injection. Sixteen to eighteen hours later, lungs were isolated and perfused, and pulmonary artery pressure (PAP) was elevated by 6-8 mmHg using the thromboxane analogue U46619. The decrease of PAP in response to inhaled NO and nitrate/nitrite levels in serum and perfusate was measured.
  
  
  RESULTS
  In rats treated with LPS alone or 0.01 or 0.1 mg kg(-1) SMT, 40 ppm NO decreased PAP less than in rats treated with AG and 1 mg kg(-1) SMT (-1.8 mmHg (95% confidence interval: -1.5 to -2.1) vs. -6.0 mmHg (-5.7 to -6.3), P < 0.01). Improved NO responsiveness was associated with lower serum and perfusate nitrite/nitrate levels than in rats with hyporesponsiveness to inhaled NO (102 micromol (82-122) vs. 282 micromol (261-303) and 8.1 micromol (6.9-9.3) vs. 19.8 micromol (17.2-22.4), respectively, P < 0.01).
  
  
  CONCLUSIONS
  These observations demonstrate that in isolated-perfused lungs of LPS-treated rats, NOS2 inhibition improved responsiveness to inhaled NO. Here, responsiveness to inhaled NO is dependent on the ability of NOS2 inhibitors to reduce nitrite and nitrate levels in serum and released in the lung.
authors.affiliation: University of Heidelberg, Department of Anaesthesiology, Heidelberg, Germany.
authors.forename: Ch
authors.initials: Ch
authors.lastname: Bopp
authors.forename: R
authors.initials: R
authors.lastname: Gust
authors.forename: F
authors.initials: F
authors.lastname: Taut
authors.forename: A
authors.initials: A
authors.lastname: Gries
authors.forename: E
authors.initials: E
authors.lastname: Martin
authors.forename: A
authors.initials: A
authors.lastname: Klein
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000502:physiology; D009573:Nitrites / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D006146:Guanidines; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D007550:Isothiuronium; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C027744:S-methylisothiopseudouronium; C004479:pimagedine