Protective role of pulmonary nitric oxide in the acute phase of endotoxemia in rats.
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.
Gryglewski
R J
RJ
Department of Pharmacology, Medical College, Jagiellonian University, Cracow, Poland.
Wolkow
P P
PP
Uracz
W
W
Janowska
E
E
Bartus
J B
JB
Balbatun
O
O
Patton
S
S
Brovkovych
V
V
Malinski
T
T
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
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009569:Nitric Oxide