Tetrahydrobiopterin corrects Escherichia coli endotoxin-induced endothelial dysfunction.
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.
Mittermayer
Friedrich
F
Medical University Vienna, Department of Clinical Pharmacology, AKH-Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
Pleiner
Johannes
J
Schaller
Georg
G
Zorn
Stefan
S
Namiranian
Khodadad
K
Kapiotis
Stylianos
S
Bartel
Gregor
G
Wolfrum
Mathias
M
Brügel
Mathias
M
Thiery
Joachim
J
Macallister
Raymond J
RJ
Wolzt
Michael
M
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
D000975:Antioxidants; D016207:Cytokines; D004731:Endotoxins; D001708:Biopterins; D009569:Nitric Oxide; C044101:endotoxin, Escherichia coli; C003402:sapropterin; D000109:Acetylcholine; D001205:Ascorbic Acid