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This Article Full Text Full Text (PDF) All Versions of this Article: 289/4/H1752    most recent 00057.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Mittermayer, F. Articles by Wolzt, M. Search for Related Content PubMed PubMed Citation Articles by Mittermayer, F. Articles by Wolzt, M.

Tetrahydrobiopterin corrects Escherichia coli endotoxin-induced endothelial dysfunction

¹Department of Clinical Pharmacology and ²Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Vienna, Austria; ³Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany; and ⁴Centre for Clinical Pharmacology and Therapeutics, Department of Medicine, University College London, London, United Kingdom

Submitted 19 January 2005 ; accepted in final form 2 June 2005

Acute inflammation causes endothelial dysfunction, which is partly mediated by oxidant stress and inactivation of nitric oxide. The contribution of depletion of tetrahydrobiopterin (BH₄), the cofactor required for nitric oxide generation, is unclear. In this randomized, double-blind, three-way crossover study, forearm blood flow (FBF) responses to ACh and glyceryltrinitrate (GTN) were measured before and 3.5 h after infusion of Escherichia coli endotoxin (LPS, 20 IU/kg iv) in eight healthy men. The effect of intra-arterial BH₄ (500 µg/min), placebo, or vitamin C (24 mg/min) was studied on separate days 3.5 h after LPS infusion. In addition, human umbilical vein endothelial cells were incubated for 24 h with vitamin C and LPS. ACh and GTN caused dose-dependent forearm vasodilation. The FBF response to ACh, which was decreased by 23 ± 17% (P < 0.05) by LPS infusion, was restored to baseline reactivity by BH₄ and vitamin C. FBF responses to GTN were not affected by BH₄ or vitamin C. LPS increased leukocyte count, high-sensitivity C-reactive protein, IL-6, IL-1, IFN-, monocyte chemoattractant protein-1, pulse rate, and body temperature and decreased platelet count and vitamin C concentration. Vitamin C increased forearm plasma concentration of BH₄ by 32% (P < 0.02). Incubation with LPS and vitamin C, but not LPS alone, increased intracellular BH₄ concentration in human umbilical vein endothelial cells. Impaired endothelial function during acute inflammation can be restored by BH₄ or vitamin C. Vitamin C may exert some of its salutary effects by increasing BH₄ concentration.

inflammation; forearm blood flow; endothelial function; nitric oxide

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