Interactions of constitutive nitric oxide with PAF and thromboxane on rat intestinal vascular integrity in acute endotoxaemia

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Abstract
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 (1-NAME) following endotoxin administration was investigated in the rat over a 1 h period. 2 Administration of 1-NAME (1–10 mg kg−1, s.c.) concurrently with E. coli lipopolysaccharide (LPS; 3 mg kg1, i.v.) dose-dependently increased vascular permeability in the ileum and colon, as determined by the leakage of radiolabeled albumin, and caused macroscopic mucosal damage in the ileum determined 1 h later. Neither LPS administration nor 1-NAME (5 mg kg1) alone affected resting vascular permeability. 3 Infusion of phenylephrine (lOμg kg−1 min−1, i.v. for 1 h) caused an elevation in blood pressure similar to that found following 1-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 1-NAME (5 mg kg−1, s.c.) and LPS (3 mg kg−1, i.v.) was dose-dependently inhibited following s.c. pretreatment (15min 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 (2-5mg kg−1, s.c, 15min before challenge) reduced the microvascular injury in the ileum and colon and macroscopic lesions in the ileum, observed after the concurrent administration of 1-NAME and LPS. 6 Pretreatment (15min) 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) 15min before 1-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 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.