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.