Vascular hporeactivity to vasoconstrictor agents and hemodynamic decompensation in hemorrhagic shock is mediated by nitric oxide

Christoph Thiemermann, Csaba Szabo, Jane A. Mitchell, John R. Vane

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Abstract

This study investigates the role of nitric oxide (NO) and the induction of a calcium-independent NO synthase (NOS) in development of vascular hyporeactivity to norepinephrine (NE) and vascular decompensation associated with hemorrhagic shock (HS) in the anesthetized rat. HS for 120 min caused a time-dependent reduction of the presser responses to NE. This hyporeactivity is mediated by an enhanced release of NO by the constitutive NOS, for it was reversed by AG-nitro-L-arginine methyl ester (NO2Arg), an inhibitor of both constitutive and inducible NOS, but it was not prevented by dexamethasone, an inhibitor of NOS induction. Vascular decompensation following prolonged periods of HS was characterized by a failure of control animals to maintain arterial blood pressures despite reinfusion of blood. This progressive decrease in blood pressure is mediated by enhanced formation of NO by the inducible NOS, for it was prevented by NO2Arg or dexamethasone. A strong increase in calcium-independent (inducible) NOS activity was observed in several organs after 150 and 330 min of HS, being most pronounced in lung, liver, and spleen. HS for 330, but not 150, min also caused hyporeactivity of rat aortic rings to vasoconstrictors, which was associated with induction of calcium-independent NOS activity in this tissue. Aortic hyporeactivity was prevented by dexamethasone pretreatment in vivo and reversed by NO2Arg in vitro. HS was not associated with an increase in plasma endotoxin levels, showing that endotoxin does not account for induction of NOS in this model. Thus, excessive NO formation induces vascular hyporeactivity and decompensation in HS, indicating that NOS inhibitors, particularly of the inducible NOS, may improve the therapeutic outcome of patients suffering from HS.

Original languageEnglish (US)
Pages (from-to)267-271
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number1
StatePublished - Jan 1 1993
Externally publishedYes

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Keywords

  • Dexamethasone
  • Hemorrhagic hypotension
  • Hypovolaemic hypotension
  • Lipopolysaccharide
  • N-nitro-L-arginine methyl ester

ASJC Scopus subject areas

  • General
  • Genetics

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