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

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Abstract
1 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). 2 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). 3 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. 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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