Time-dependent enhancement or inhibition of endotoxin-induced vascular injury in rat intestine by nitric oxide synthase inhibitors.
1. The effects of the nitric oxide (NO) synthase inhibitors, NG-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA), on the vascular damage induced by the endotoxin, E. coli lipopolysaccharide (LPS), in the ileum and colon were investigated in the conscious rat over a 5 h period. 2. Administration of LPS (3 mg kg-1, i.v.) increased ileal and colonic vascular injury after a lag period of 2 h, as determined by the leakage of radiolabelled albumin. 3. Administration of L-NAME (1-5 mg kg-1, s.c.) concurrently with LPS, produced a dose-dependent increase in vascular albumin leakage in the intestinal tissues, when determined over a 5 h period. Vascular albumin leakage with LPS and L-NAME (5 mg kg-1) was substantially increased after 1 h, reached maximal levels 3 h after administration, and then slowly declined. 4. L-NMMA (50 mg kg-1, s.c.), likewise elevated intestinal albumin leakage when administered concurrently with LPS, but this reached maximal levels after 1 h and rapidly declined over the subsequent 2 h. 5. In control rats, in the absence of LPS challenge, neither L-NAME (5 mg kg-1, s.c.) nor L-NMMA (50 mg kg-1, s.c.) increased intestinal vascular leakage of albumin over a 5 h period. 6. By contrast, when L-NAME (1-5 mg kg-1, s.c.) or L-NMMA (12.5-50 mg kg-1, s.c.) was injected 3 h after LPS, a dose-dependent reduction in the LPS-provoked vascular albumin leakage was observed. 7 Pretreatment with L-arginine (300 mg kg-1, s.c.) 15 min prior to the NO synthase inhibitors, reversed either the potentiation or the inhibition by L-NAME (5 mg kg-1, s.c.) or L-NMMA (50 mg kg-1, s.c.) of the LPS-induced intestinal vascular damage.8. These findings indicate that initial suppression of the constitutive NO synthase by L-NAME orL-NMMA following challenge with LPS aggravates the acute vascular injury in the ileum and colon,suggesting a defensive role of NO. By contrast, the delayed administration of NO synthase inhibitors, ata time of known expression of the inducible NO synthase, provides protection against the subsequent damage to the intestinal vasculature.
Laszlo
F
F
Wellcome Research Laboratories, Beckenham, Kent.
Whittle
B J
BJ
Moncada
S
S
D000594:Amino Acid Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D007422:Intestines / Q000098:blood supply; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D019001:Nitric Oxide Synthase; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D019323:omega-N-Methylarginine
D008070:Lipopolysaccharides; D019323:omega-N-Methylarginine; D001120:Arginine; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D019331:NG-Nitroarginine Methyl Ester