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.
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Authors | R J Gryglewski, P P Wolkow, W Uracz, E Janowska, J B Bartus, O Balbatun, S Patton, V Brovkovych, T Malinski |
Journal | Circulation research
(Circ Res)
Vol. 82
Issue 7
Pg. 819-27
(Apr 20 1998)
ISSN: 0009-7330 [Print] United States |
PMID | 9562442
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Enzyme Inhibitors
- Lipopolysaccharides
- Nitric Oxide
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Topics |
- Acute Disease
- Analysis of Variance
- Animals
- Endotoxemia
(metabolism, physiopathology)
- Enzyme Inhibitors
(pharmacology)
- Hypotension
(physiopathology)
- Lipopolysaccharides
- Lung
(physiology)
- Male
- Nitric Oxide
(metabolism, physiology)
- Rats
- Rats, Sprague-Dawley
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