Time‐dependent enhancement or inhibition of endotoxin‐induced vascular injury in rat intestine by nitric oxide synthase inhibitors

Abstract

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.