INTERACTIONS OF CONSTITUTIVE NITRIC-OXIDE WITH PAF AND THROMBOXANE ON RAT INTESTINAL VASCULAR INTEGRITY IN ACUTE ENDOTOXEMIA

1 The involvement of endogenous platelet activating factor (PAF) and thromboxane A(2) in the acute microvascular damage in the ileum and colon induced by the nitric oxide (NO) synthase inhibitor, N-G-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 mu g 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(-1), 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(-1), s.c.) or BN 52021 (2.5-10 mg kg(-1), s.c.) likewise attenuated this intestinal vascular injury. 7 Combined administration of low doses of 1-benzyl-imidazole (1 mg kg(-1)) with WEB 2086 (0.5 mg kg(-1)) 15 min before L-NAME and LPS challenge, abolished this vascular damage and macroscopic injury. 8 These results suggest that PAF and thromboxane A(2) are released acutely following challenge with a low dose of endotoxin. However, these mediators do not appear to injury the intestinal microvascular 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.