title: Tetrahydrobiopterin corrects Escherichia coli endotoxin-induced endothelial dysfunction.
abstract: Acute inflammation causes endothelial dysfunction, which is partly mediated by oxidant stress and inactivation of nitric oxide. The contribution of depletion of tetrahydrobiopterin (BH(4)), 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 BH(4) (500 microg/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 BH(4) and vitamin C. FBF responses to GTN were not affected by BH(4) or vitamin C. LPS increased leukocyte count, high-sensitivity C-reactive protein, IL-6, IL-1beta, IFN-gamma, monocyte chemoattractant protein-1, pulse rate, and body temperature and decreased platelet count and vitamin C concentration. Vitamin C increased forearm plasma concentration of BH(4) by 32% (P < 0.02). Incubation with LPS and vitamin C, but not LPS alone, increased intracellular BH(4) concentration in human umbilical vein endothelial cells. Impaired endothelial function during acute inflammation can be restored by BH(4) or vitamin C. Vitamin C may exert some of its salutary effects by increasing BH(4) concentration.
authors.affiliation: Medical University Vienna, Department of Clinical Pharmacology, AKH-Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Mittermayer
authors.forename: Johannes
authors.initials: J
authors.lastname: Pleiner
authors.forename: Georg
authors.initials: G
authors.lastname: Schaller
authors.forename: Stefan
authors.initials: S
authors.lastname: Zorn
authors.forename: Khodadad
authors.initials: K
authors.lastname: Namiranian
authors.forename: Stylianos
authors.initials: S
authors.lastname: Kapiotis
authors.forename: Gregor
authors.initials: G
authors.lastname: Bartel
authors.forename: Mathias
authors.initials: M
authors.lastname: Wolfrum
authors.forename: Mathias
authors.initials: M
authors.lastname: Brügel
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiery
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Macallister
authors.forename: Michael
authors.initials: M
authors.lastname: Wolzt
mesh_terms: D000109:Acetylcholine / Q000008:administration & dosage; D000328:Adult; D000975:Antioxidants / Q000008:administration & dosage*; D001205:Ascorbic Acid / Q000008:administration & dosage; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D002478:Cells, Cultured; D018592:Cross-Over Studies; D016207:Cytokines / Q000097:blood; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy*; D004731:Endotoxins / Q000009:adverse effects*; D005542:Forearm / Q000098:blood supply; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D016207:Cytokines; D004731:Endotoxins; D001708:Biopterins; D009569:Nitric Oxide; C044101:endotoxin, Escherichia coli; C003402:sapropterin; D000109:Acetylcholine; D001205:Ascorbic Acid