© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress
BHF Laboratories, Centre for Clinical Pharmacology, Department of Medicine, University College London, Rayne Institute, 5 University Street, London WC1E 6JJ, United Kingdom
* Corresponding author. Tel.: +44 20 7679 6205; fax: +44 20 7679 6211. E-mail address: b.clapp{at}ucl.ac.uk
Objectives: Our aim was to investigate mechanisms of inflammation-induced endothelial dysfunction in humans. Methods: Endothelial function in twenty-one healthy human volunteers was measured using forearm venous plethysmography before and 8 h after administration of typhoid vaccination to generate an inflammatory response. Basal and stimulated endothelial nitric oxide (NO) bioavailability was assessed by measurement of the responses to intra-arterial NG-monomethyl-L-arginine (L-NMMA) and bradykinin, respectively. The effects of supplementation with L-arginine or ascorbic acid were assessed to probe the effects of substrate deficiency and oxidative stress, respectively. Systemic effects were determined by measuring cytokine response, total anti-oxidant status (TAOS) and urinary protein excretion. Results: Vaccination induced a cytokine response, a fall in total anti-oxidant status and increased urinary albumin excretion (UAE). There was a reduction in the response to bradykinin (BK, P<0.005) and L-NMMA (P<0.0001) with no effect on the response to glyceryl trinitrate (GTN) and norepinephrine (NE). Following vaccination blood flow response to BK (but not GTN) was partially returned to pre-vaccine levels by infusion of ascorbic acid (P=0.01). Supplementation with L-arginine had no effect. Conclusion: Inflammation causes widespread endothelial dysfunction, reduces vascular NO bioavailability and increases oxidative stress. These actions are partially reversible with local anti-oxidants. These findings suggest a role for reactive oxygen species in inflammation-induced endothelial dysfunction.
KEYWORDS Endothelium; Nitric oxide; Inflammation; Coronary disease; Reactive oxygen species
Abbreviations: AUC, area under the curve • BH4, tetrahydrobiopterin • BK, bradykinin • GTN, glyceryl trinitrate • IL, interleukin • IL-1Ra, interleukin-1 receptor antagonist • L-NMMA, NG-monomethyl-L-arginine • NE, norepinephrine • NO, nitric oxide • NOS, nitric oxide synthase • TAOS, total anti-oxidant status • UAC, urinary albumin/creatinine ratio • UAE, urinary albumin excretion
Time for primary review 32 days
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