title: Protective role of pulmonary nitric oxide in the acute phase of endotoxemia in rats.
abstract: We present for the first time direct continuous assay of NO concentration (porphyrinic sensor) in the lung parenchyma of Sprague-Dawley rats in vivo during endotoxemia. Intravenous infusion of lipopolysaccharide (LPS, 2 mg x kg(-1) x min(-1) for 10 minutes) stimulated an acute burst of NO from constitutive NO synthase (NOS) that peaked 10 to 15 minutes after the start of LPS infusion, mirroring a coincident peak drop in arterial pressure. NO concentration declined over the next hour to twice above pre-LPS infusion NO levels, where it remained until the rats died, 5 to 6 hours after LPS infusion. The chronic drop in arterial pressure observed from 70 minutes to 6 hours after the start of LPS infusion was not convincingly mirrored by a chronic increase in NO concentration, even though indirect NO assay (Griess method, assaying NO decay products NO2-/NO3-) showed that NO production was increasing as a result of continuous NO release by inducible NOS. A NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA, 10 mg/kg i.v.) injected 45 minutes before LPS infusion, resulted in sudden death accompanied by macroscopically/microscopically diagnosed symptoms similar to acute respiratory distress syndrome <25 minutes after the start of LPS infusion. Pharmacological analysis of this L-NNA+LPS model by replacing L-NNA with 1-amino-2-hydroxy-guanidine (selective inhibitor of inducible NOS) or by pretreatment with S-nitroso-N-acetyl-penicillamine (NO donor), camonagrel (thromboxane synthase inhibitor), or WEB2170 (platelet-activating factor receptor antagonist) indicated that in the early acute phase of endotoxemia, LPS stimulated the production of cytoprotective NO, cytotoxic thromboxane A2, and platelet-activating factor.
authors.affiliation: Department of Pharmacology, Medical College, Jagiellonian University, Cracow, Poland.
authors.forename: R J
authors.initials: RJ
authors.lastname: Gryglewski
authors.forename: P P
authors.initials: PP
authors.lastname: Wolkow
authors.forename: W
authors.initials: W
authors.lastname: Uracz
authors.forename: E
authors.initials: E
authors.lastname: Janowska
authors.forename: J B
authors.initials: JB
authors.lastname: Bartus
authors.forename: O
authors.initials: O
authors.lastname: Balbatun
authors.forename: S
authors.initials: S
authors.lastname: Patton
authors.forename: V
authors.initials: V
authors.lastname: Brovkovych
authors.forename: T
authors.initials: T
authors.lastname: Malinski
mesh_terms: D000208:Acute Disease; D000704:Analysis of Variance; D000818:Animals; D019446:Endotoxemia / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007022:Hypotension / Q000503:physiopathology*; D008070:Lipopolysaccharides; D008168:Lung / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009569:Nitric Oxide