1. The involvement of endogenous
platelet activating factor (PAF) and
thromboxane A2 in the acute microvascular damage in the ileum and colon induced by the
nitric oxide (
NO) synthase inhibitor,
NG-nitro-L-arginine methyl ester (
L-NAME) following
endotoxin administration was investigated in the rat over a 1 h period. 2. Administration of
L-NAME (1-10 mg kg-1, s.c.) concurrently with E. coli
lipopolysaccharide (LPS; 3 mg kg-1, i.v.) dose-dependently increased vascular permeability in the ileum and colon, as determined by the leakage of radiolabelled
albumin, and caused macroscopic mucosal damage in the ileum determined 1 h later. Neither LPS administration nor
L-NAME (5 mg kg-1) alone affected resting vascular permeability. 3. Infusion of
phenylephrine (10 micrograms kg-1 min-1, i.v. for 1 h) caused an elevation in blood pressure similar to that found following
L-NAME administration (5 mg kg-1, i.v. or s.c.), but did not increase intestinal vascular permeability, when administered with LPS (3 mg kg-1, i.v.). 4. The increased vascular permeability in the ileum and colon and macroscopic damage in the ileum, induced by
L-NAME (5 mg kg-1, s.c.) and LPS (3 mg kg-1, i.v.) was dose-dependently inhibited following s.c. pretreatment (15 min before challenge) with the
thromboxane synthase inhibitors,
OKY 1581 (5-25 mg kg-1) or 1-benzyl-imidazole (1-50 mg kg-1), or with the
thromboxane receptor antagonist,
BM 13177 (0.2-2 mg kg-1). 5. Pretreatment with the
cyclo-oxygenase inhibitor,
indomethacin (2-5 mg kg-', s.c., 15 min before challenge) reduced the microvascular injury in the ileum and colon and macroscopic lesions in the ileum,observed after the concurrent administration of
L-NAME and LPS.6. Pretreatment (15 min) with the PAF-receptor antagonists,
WEB 2086 (0.5-1 mg kg-', s.c.) or BN52021 (2.5-10 mg kg-', s.c.) likewise attenuated this intestinal
vascular injury.7. Combined administration of low doses of l-benzyl-
imidazole (1 mg kg-') with
WEB 2086(0.5 mg kg-')15 min before
L-NAME and LPS challenge, abolished this vascular damage and macroscopic injury.8. These results suggest that PAF and
thromboxane A2 are released acutely following challenge with a low dose of
endotoxin. However, these mediators do not appear to injure the intestinal micro vascular bed unless
NO synthase is concurrently inhibited. Such findings support the protective role of constitutively-formed NO, counteracting the injurious vascular actions of cytotoxic mediators released under pathological conditions.