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

F. László, B. J.R. Whittle, S. Moncada

Research output: Article

42 Citations (Scopus)

Abstract

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. Administration of 1‐NAME (1–10 mg kg−1, s.c.) concurrently with E. coli lipopolysaccharide (LPS; 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. 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.). 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). 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. 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. 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. 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. 1994 British Pharmacological Society

Original languageEnglish
Pages (from-to)1131-1136
Number of pages6
JournalBritish journal of pharmacology
Volume113
Issue number4
DOIs
Publication statusPublished - dec. 1994

ASJC Scopus subject areas

  • Pharmacology

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