Platelet-activating factor contributes to the induction of nitric oxide synthase by bacterial lipopolysaccharide.
This study investigates the role of endogenous platelet-activating factor (PAF) in the production of nitric oxide (NO) by constitutive and inducible isoforms of NO synthase (NOS) in endotoxin shock. In anesthetized rats, 3 hours of endotoxemia resulted in a fall in mean arterial blood pressure (MAP) from 127 +/- 5 (control) to 61 +/- 7 mm Hg and a reduction of the pressor responses to norepinephrine (NE, 1 microgram.kg-1) from 33 +/- 3 (control) to 17 +/- 2 mm Hg. Endotoxemia for 3 hours also resulted in a significant reduction in the contractile effects of NE (10(-8) to 10(-6) mol/L) in thoracic aortas ex vivo. This hyporeactivity to NE was due to an enhanced formation of NO, for it was restored by the NOS inhibitor NG-nitro-L-arginine methyl ester. Animals pretreated with the PAF receptor antagonist WEB 2086 maintained higher MAP (MAP at 180 minutes, 98 +/- 6 mm Hg) and exhibited more pronounced pressor responses to NE at 180 minutes after LPS injection. Moreover, WEB 2086 attenuated by 58% the lipopolysaccharide (LPS)-induced hyporeactivity of the rat aortic rings ex vivo. At 3 hours after LPS injection, calcium-independent NOS activity was induced in the lung. The activity of inducible NOS was significantly lower (by 31%) in lungs of rats pretreated with WEB 2086. The hypothesis that WEB 2086 attenuates the induction of NOS in vivo was substantiated in vitro by the finding that pretreatment with WEB 2086 for 30 minutes inhibited the LPS-stimulated NO production in cultured murine macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
Szabó
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C
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, UK.
Wu
C C
CC
Mitchell
J A
JA
Gross
S S
SS
Thiemermann
C
C
Vane
J R
JR
D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D001808:Blood Vessels / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000187:drug effects; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase; D009573:Nitrites / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014230:Triazoles / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects
D001381:Azepines; D008070:Lipopolysaccharides; D009573:Nitrites; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases