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Time‐dependent enhancement or inhibition of endotoxin‐induced vascular injury in rat intestine by nitric oxide synthase inhibitors
Author(s) -
Laszlo 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.tb14887.x
Subject(s) - ileum , nitric oxide synthase , nitric oxide , albumin , medicine , omega n methylarginine , lipopolysaccharide , endocrinology , nitroarginine , chemistry , serum albumin , arginine , pharmacology , biochemistry , amino acid
1 The effects of the nitric oxide (NO) synthase inhibitors, N G ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME) and N G ‐monomethyl‐ l ‐arginine ( l ‐NMMA), on the vascular damage induced by the endotoxin, E. coli lipopolysaccharide (LPS), in the ileum and colon were investigated in the conscious rat over a 5 h period. 2 Administration of LPS (3 mg kg −1 , i.v.) increased ileal and colonic vascular injury after a lag period of 2 h, as determined by the leakage of radiolabeled albumin. 3 Administration of l ‐NAME (1–5 mg kg −1 , s.c.) concurrently with LPS, produced a dose‐dependent increase in vascular albumin leakage in the intestinal tissues, when determined over a 5h period. Vascular albumin leakage with LPS and l ‐NAME (5 mg kg −1 ) was substantially increased after 1 h, reached maximal levels 3 h after administration, and then slowly declined. 4 l ‐NMMA (50 mg kg −1 , s.c.), likewise elevated intestinal albumin leakage when administered concurrently with LPS, but this reached maximal levels after 1 h and rapidly declined over the subsequent 2 h. 5 In control rats, in the absence of LPS challenge, neither l ‐NAME (5 mg kg −1 , s.c.) nor l ‐NMMA (50 mg kg −1 , s.c.) increased intestinal vascular leakage of albumin over a 5h period. 6 By contrast, when l ‐NAME (1–5 mg kg −1 , s.c.) or l ‐NMMA (12.5–50 mg kg −1 , s.c.) was injected 3 h after LPS, a dose‐dependent reduction in the LPS‐provoked vascular albumin leakage was observed. 7 Pretreatment with l ‐arginine (300 mg kg −1 , s.c.) 15 min prior to the NO synthase inhibitors, reversed either the potentiation or the inhibition by l ‐NAME (5 mg kg −1 , s.c.) or l ‐NMMA (50 mg kg −1 , s.c.) of the LPS‐induced intestinal vascular damage. 8 These findings indicate that initial suppression of the constitutive NO synthase by l ‐NAME or l ‐NMMA following challenge with LPS aggravates the acute vascular injury in the ileum and colon, suggesting a defensive role of NO. By contrast, the delayed administration of NO synthase inhibitors, at a time of known expression of the inducible NO synthase, provides protection against the subsequent damage to the intestinal vasculature.