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

Gillian A. Gray, Cathy Schott, Géraldine Julou‐Schaeffer, Ingrid Fleming, James R. Parratt, Jean‐Claude ‐C Stoclet

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The effects on blood pressure and on pressor responses to noradrenaline (NA), of NG‐monomethyl‐l‐arginine (l‐NMMA) and NG‐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). Infusion of LPS (10 mg kg−1 h−1) for 50min 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). In LPS‐treated rats, blood pressure responses to NA were only marginally increased by the cyclooxygenase 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. 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. 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). 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. 1991 British Pharmacological Society

Original languageEnglish
Pages (from-to)1218-1224
Number of pages7
JournalBritish journal of pharmacology
Issue number1
Publication statusPublished - May 1991



  • Endotoxin
  • cyclo‐oxygenase pathway
  • indomethacin
  • l‐NAME
  • l‐NMMA
  • l‐arginine pathway
  • nitric oxide
  • vascular reactivity

ASJC Scopus subject areas

  • Pharmacology

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