Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress.
OBJECTIVE
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 N(G)-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.


CONCLUSIONS
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.
Clapp
Brian R
BR
BHF Laboratories, Centre for Clinical Pharmacology, Department of Medicine, University College London, Rayne Institute, 5 University Street, London WC1E 6JJ, United Kingdom. b.clapp@ucl.ac.uk
Hingorani
Aroon D
AD
Kharbanda
Rajesh K
RK
Mohamed-Ali
Vidya
V
Stephens
Jeffrey W
JW
Vallance
Patrick
P
MacAllister
Raymond J
RJ
D000328:Adult; D000419:Albuminuria / Q000276:immunology; D000704:Analysis of Variance; D001120:Arginine / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D001682:Biological Availability; D001920:Bradykinin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D005996:Nitroglycerin / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D018384:Oxidative Stress; D010991:Plethysmography; D012039:Regional Blood Flow; D018709:Statistics, Nonparametric; D014436:Typhoid-Paratyphoid Vaccines / Q000008:administration & dosage; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D014436:Typhoid-Paratyphoid Vaccines; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D001120:Arginine; D005996:Nitroglycerin; D001205:Ascorbic Acid; D001920:Bradykinin; D009638:Norepinephrine