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 (B[H.sub.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 B[H.sub.4] (500 [micro]g/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 [+ or -] 17% (P < 0.05) by LPS infusion, was restored to baseline reactivity by B[H.sub.4] and vitamin C. FBF responses to GTN were not affected by B[H.sub.4] or vitamin C. LPS increased leukocyte count, high-sensitivity C-reactive protein, IL-6, IL-1[beta], IFN-[gamma] monocyte chemoattractant protein-l, pulse rate, and body temperature and decreased platelet count and vitamin C concentration. Vitamin C increased forearm plasma concentration of B[H.sub.4] by 32% (P < 0.02). Incubation with LPS and vitamin C, but not LPS alone, increased intracellular B[H.sub.4] concentration in human umbilical vein endothelial cells. Impaired endothelial function during acute inflammation can be restored by B[H.sub.4] or vitamin C. Vitamin C may exert some of its salutary effects by increasing B[H.sub.4] concentration. inflammation; forearm blood flow; endothelial function; nitric oxide