The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats

G. A. Gray, C. Schott, G. Julou-Schaeffer, I. Fleming, J. Parratt, J. C. Stoclet

Research output: Contribution to journalArticle

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Abstract

1. The effects on blood pressure and on pressor responses to noradrenaline (NA), of N(G)-monomethyl-L-arginine (L-NMMA) and N(G)-nitro-L-arginine methyl ester (L-NAME), inhibitors of the L-arginine/nitric oxide pathway, were investigated in anaesthetized rats receiving an infusion of bacterial endotoxin (E. coli lipopolysaccharide, LPS). 2. Infusion of LPS (10 mg kg-1 h-1) for 50 min had no effect on mean arterial blood pressure (MABP) but induced a reduction in responsiveness to noradrenaline (100 ng-1 μg kg-1). L-NMMA (30 mg kg-1), but not D-NMMA, caused an increase in MABP of approximately 30 mmHg and restored responses to NA. This effect was reversed by L- but not D-arginine (100 mg kg-1). 3. In LPS-treated rats, blood pressure responses to NA were only marginally increased by the cyclo-oxygenase inhibitor, indomethacin (5 mg kg-1). L-NAME (1 mg kg-1) caused a similar increase in MABP and restored pressor responses to NA both in the presence and absence of indomethacin. 4. Co-infusion of vasopressin (100 ng kg-1, for 10 min) with LPS (10 mg kg-1 h-1) in order to reproduce the hypertensive effect of L-NMMA and L-NAME increased pressor responsiveness to 100 and 300 ng kg-1 NA but not to 1 μg kg-1 NA. 5. Infusion of sodium nitroprusside (30 μg kg-1 min-1) decreased responsiveness to NA even when the hypotension was corrected by co-infusion of vasopressin (50 ng kg-1 min-1). 6. These results demonstrate that the restoration of vascular responsiveness to NA in LPS-treated anaesthetized rats by inhibitors of the L-arginine/nitric oxide pathway is stereospecific and reversible. Furthermore, the experiments involving indomethacin suggest that although cyclo-oxygenase products of arachidonic acid may contribute to the development of LPS-induced hyporeactivity, the effect of L-NAME is unlikely to involve inhibition of the cyclo-oxygenase pathway. Comparison of NA responsiveness during vasopressin and L-NMMA/L-NAME-induced hypertension shows that increasing the blood pressure may modify LPS-induced hyporeactivity, but cannot account for the complete restoration of responses to NA by L-NMMA and L-NAME. These observations suggest that activation of nitric oxide formation from L-arginine makes a direct contribution to the production of vascular hyporeactivity by LPS in vivo.

Original languageEnglish
Pages (from-to)1218-1224
Number of pages7
JournalBritish Journal of Pharmacology
Volume103
Issue number1
Publication statusPublished - 1991

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Endotoxins
Blood Vessels
Arginine
Norepinephrine
Nitric Oxide
omega-N-Methylarginine
NG-Nitroarginine Methyl Ester
Lipopolysaccharides
Arterial Pressure
Vasopressins
Indomethacin
Prostaglandin-Endoperoxide Synthases
Blood Pressure
Cyclooxygenase Inhibitors
Nitroprusside
Arachidonic Acid
Hypotension
Escherichia coli
Hypertension

Keywords

  • Cyclo-oxygenase pathway
  • Endotoxin
  • Indomethacin
  • L-arginine pathway
  • L-NAME
  • L-NMMA
  • Nitric oxide
  • Vascular reactivity

ASJC Scopus subject areas

  • Pharmacology

Cite this

The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats. / Gray, G. A.; Schott, C.; Julou-Schaeffer, G.; Fleming, I.; Parratt, J.; Stoclet, J. C.

In: British Journal of Pharmacology, Vol. 103, No. 1, 1991, p. 1218-1224.

Research output: Contribution to journalArticle

Gray, G. A. ; Schott, C. ; Julou-Schaeffer, G. ; Fleming, I. ; Parratt, J. ; Stoclet, J. C. / The effect of inhibitors of the L-arginine/nitric oxide pathway on endotoxin-induced loss of vascular responsiveness in anaesthetized rats. In: British Journal of Pharmacology. 1991 ; Vol. 103, No. 1. pp. 1218-1224.
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N2 - 1. The effects on blood pressure and on pressor responses to noradrenaline (NA), of N(G)-monomethyl-L-arginine (L-NMMA) and N(G)-nitro-L-arginine methyl ester (L-NAME), inhibitors of the L-arginine/nitric oxide pathway, were investigated in anaesthetized rats receiving an infusion of bacterial endotoxin (E. coli lipopolysaccharide, LPS). 2. Infusion of LPS (10 mg kg-1 h-1) for 50 min had no effect on mean arterial blood pressure (MABP) but induced a reduction in responsiveness to noradrenaline (100 ng-1 μg kg-1). L-NMMA (30 mg kg-1), but not D-NMMA, caused an increase in MABP of approximately 30 mmHg and restored responses to NA. This effect was reversed by L- but not D-arginine (100 mg kg-1). 3. In LPS-treated rats, blood pressure responses to NA were only marginally increased by the cyclo-oxygenase inhibitor, indomethacin (5 mg kg-1). L-NAME (1 mg kg-1) caused a similar increase in MABP and restored pressor responses to NA both in the presence and absence of indomethacin. 4. Co-infusion of vasopressin (100 ng kg-1, for 10 min) with LPS (10 mg kg-1 h-1) in order to reproduce the hypertensive effect of L-NMMA and L-NAME increased pressor responsiveness to 100 and 300 ng kg-1 NA but not to 1 μg kg-1 NA. 5. Infusion of sodium nitroprusside (30 μg kg-1 min-1) decreased responsiveness to NA even when the hypotension was corrected by co-infusion of vasopressin (50 ng kg-1 min-1). 6. These results demonstrate that the restoration of vascular responsiveness to NA in LPS-treated anaesthetized rats by inhibitors of the L-arginine/nitric oxide pathway is stereospecific and reversible. Furthermore, the experiments involving indomethacin suggest that although cyclo-oxygenase products of arachidonic acid may contribute to the development of LPS-induced hyporeactivity, the effect of L-NAME is unlikely to involve inhibition of the cyclo-oxygenase pathway. Comparison of NA responsiveness during vasopressin and L-NMMA/L-NAME-induced hypertension shows that increasing the blood pressure may modify LPS-induced hyporeactivity, but cannot account for the complete restoration of responses to NA by L-NMMA and L-NAME. These observations suggest that activation of nitric oxide formation from L-arginine makes a direct contribution to the production of vascular hyporeactivity by LPS in vivo.

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