Association of microvascular leakage with induction of nitric oxide synthase: effects of nitric oxide synthase inhibitors in various organs

Ferenc László, Brendan J.R. Whittle, Steven M. Evans, Salvador Moncada

Research output: Contribution to journalArticle

88 Citations (Scopus)

Abstract

Endotoxin (Escherichia coli lipopolysaccharide 0111:B4, 3 mg/kg i.v.) induced the expression of a calcium-independent nitric oxide (NO) synthase, determined after 5 h in cardiac, hepatic, pulmonary and renal tissues, as assessed by the conversion of radiolabelled l-arginine to l-citrulline. This widespread induction of NO synthase in these conscious rats was associated with microvascular injury, as assessed by the vascular leakage of radiolabelled human serum albumin. Concurrent administration of the NO synthase inhibitor, NG-nitro-l-arginine methyl ester (L-NAME, 1-5 mg/kg s.c.) with endotoxin, provoked acute vascular leakage within 2 h in the various organs. By contrast, the delayed injection of L-NAME (1-5 mg/kg s.c.) or NG-monomethyl-l-arginine (12.5-50 mg/kg s.c.) until 3 h after endotoxin challenge inhibited the subsequent microvascular leakage in these organs. These effects of NO synthase inhibitors were reversed by l-arginine (300 mg/kg s.c.) pretreatment. These results support a protective role of constitutive NO synthase in the early phase of endotoxin shock. Such actions contrast with the aggressive actions of the products of inducible NO synthase in the development of widespread microvascular injury in endotoxemic states.

Original languageEnglish
Pages (from-to)47-53
Number of pages7
JournalEuropean Journal of Pharmacology
Volume283
Issue number1-3
DOIs
Publication statusPublished - Sep 5 1995

Keywords

  • Endotoxin
  • Microcirculation
  • Multiple organ failure
  • N-Monomethyl-l-arginine
  • N-Nitro-l-arginine methyl ester
  • Nitric oxide (NO)
  • Sepsis

ASJC Scopus subject areas

  • Pharmacology

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