Role of nitric oxide in maintaining vascular integrity in endotoxin-induced acute intestinal damage in the rat.
1. The role of endogenous nitric oxide (NO) in maintaining intestinal vascular integrity following acute endotoxin (E. coli. lipopolysaccharide) challenge was investigated in the anaesthetized rat by use of NG-monomethyl-L-arginine (L-NMMA), a selective inhibitor of NO synthesis. 2. L-NMMA (10-50 mg kg-1, i.v.) pretreatment enhanced both the macroscopic and histological intestinal damage and the increases in vascular permeability, measured as the leakage of [125I]-labelled human serum albumen, induced after 15 min by endotoxin (50 mg kg-1, i.v.). 3. The effects of L-NMMA (50 mg kg-1, i.v.) were enantiomer specific, as D-NMMA had no effect. Furthermore, these effects were reversed by L-arginine (300 mg kg-1, i.v.), the precursor of NO synthesis but not by D-arginine (300 mg kg-1, i.v.). 4. L-NMMA (10-50 mg kg-1, i.v.) increased mean systemic arterial blood pressure but this does not appear to be the mechanism by which endotoxin-induced intestinal damage was enhanced, since similar systemic pressor responses induced by phenylephrine (10 micrograms kg-1 min-1, i.v.), had no such effect. 5. The results suggest that synthesis of NO from L-arginine has a role in maintaining the microvascular integrity of the intestinal mucosa following acute endotoxin challenge.
Hutcheson
I R
IR
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent.
Whittle
B J
BJ
Boughton-Smith
N K
NK
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001772:Blood Cell Count; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects; D004731:Endotoxins / Q000633:toxicity*; D006470:Hemorrhage / Q000139:chemically induced / Q000503:physiopathology; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007457:Iodine Radioisotopes; D007583:Jejunum / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D019323:omega-N-Methylarginine
D004731:Endotoxins; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine