Role of nitric oxide and platelet-activating factor in the initiation of indomethacin-provoked intestinal inflammation in rats.
The effect of indomethacin following the concurrent administration of the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) on acute intestinal microvascular permeability has been investigated in the rat. Administration of indomethacin (10 mg/kg, s.c.) or L-NAME (10 mg/kg, s.c.) alone did not affect jejunal and ileal vascular permeability over a 12 h period, as determined by the leakage of radiolabelled serum albumin. By contrast, when indomethacin (10 mg/kg, s.c.) was injected concurrently with L-NAME (2-10 mg/kg, s.c.) significant time-dependent plasma leakage occurred in intestinal tissues over 12 h, being apparent within 1 h. Pretreatment with L-arginine (300 mg/kg, s.c.) 15 min prior L-NAME prevented these changes in microvascular permeability. Likewise, pretreatment with the platelet-activating factor receptor antagonist, WEB 2086 ((3-[4-(2-chlorophenyl)-9-methyl-6H-thienol[3,2-f][1,2,4]triazolo- [4,3-a][1,4]diazepine-2-yl]-1-(4-morpholynil)-1-propanone), 0.1-1 mg/kg, s.c.) dose-dependently attenuated such damage. These findings suggest that following indomethacin administration, the early inhibition of NO synthase leads to acute microvascular injury involving platelet-activating factor in the rat jejunum and ileum, indicating a protective role of NO, formed by constitutive NO synthase.
László
F
F
First Department of Medicine, Albert Szent-Györgyi Medical University, Szeged, Hungary.
Whittle
B J
BJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D004751:Enteritis / Q000209:etiology*; D007082:Ileum / Q000187:drug effects / Q000503:physiopathology; D007213:Indomethacin / Q000633:toxicity*; D007583:Jejunum / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D010972:Platelet Activating Factor / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; D007213:Indomethacin