Interactions of pro-inflammatory and vasoactive mediators with nitric oxide in the regulation of rat vascular permeability during laparotomy

Inhibition of constitutive nitric oxide (NO) synthases by administration of N-G-nitro-L-arginine methyl ester (L-NAME) during abdominal laparotomy pro vokes extensive vascular leakage in the rat gastrointestinal tract, assesse d by the extravasation of [I-125]human serum albumin. In the present study, the role of vasoactive or neutrophil-derived pro-inflammatory mediators in this process has been investigated. Administration of the thromboxane synt hase inhibitor, 1-benzyl-imidazole (BZI, 25-50 mg kg(-1), s.c.), the platel et-activating factor (PAF) receptor antagonist, 3-[4-(2-chlorophenyl)-9-met hyl-6H-thienol-[3,2-f][1,2,4]-triazolo-[4,3-a][1,4]-diazepine-2-yl]-1-(4-mo rpholynil)-1-propionate (WEB 2086; 0.5-1 mg kg(-1), s.c.), the 5-lipoxygena se synthase inhibitor, N-(4-benzyloxybenzyl)-acetohydroxamic acid (BW A137C ; 4-20 mg kg(-1), s.c.) or the vasopressin presser receptor antagonist ([Mc a(1),Tyr(Me)(2),Arg(8)]vasopressin/Manning peptide; 0.01-0.2 mu g kg(-1), s .c.) dose-dependently reduced the intestinal plasma leakage provoked by L-N AME (5 mg kg(-1), s.c.), following a 5-cm abdominal laparotomy in anaesthet ised rats. These findings suggest that constitutive NO synthase effectively counteracts the damaging actions on microvascular integrity of mediators, including thromboxanes, PAF, leukotrienes and vasopressin, released during surgical intervention. (C) 2000 Elsevier Science B.V. All rights reserved.