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Interactions of constitutive nitric oxide with PAF and thromboxane on rat intestinal vascular integrity in acute endotoxaemia
Author(s) -
László F.,
Whittle B.J.R,
Moncada S.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17114.x
Subject(s) - ileum , thromboxane , nitric oxide synthase , phenylephrine , nitric oxide , pharmacology , thromboxane a2 , chemistry , medicine , endocrinology , platelet , blood pressure
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 ( 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 kg 1 , 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 kg 1 ) 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 A 2 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.