Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis

Cystic fibrosis (CF) is a genetic disorder associated with vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function, and tetrahydrobiopterin (BH₄) is a critical determinant of NO bioavailability. Thus the purpose of this study was to investigate the effects of oral administration of BH₄ on endothelial function in patients with CF. Twenty-nine patients with CF (18 ± 8 yr old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received a 5 mg/kg dose of oral BH₄ (BH₄-5; n = 17) or a 20 mg/kg dose of oral BH₄ (BH₄-20; n = 12). On a separate visit, a subset of patients from each group was retested following a placebo (PLC; n = 9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function, and a plasma sample was obtained before and 3 h after treatment. Cultured endothelial cells were treated with plasma to assess NO bioavailability. Baseline FMD was lower in patients compared with controls (5.7 ± 3.4 vs. 8.4 ± 3.5%, respectively, P = 0.005). No change in FMD was observed following PLC or BH₄-5 (∆FMD: -0.8 ± 1.9% and -0.5 ± 2.5%; P = 0.273 and 0.132, respectively). Treatment with BH₄-20, however, resulted in significant improvements in FMD (∆FMD: 1.1 ± 1.4%) compared with BH₄-5 ( P = 0.023) and PLC ( P = 0.017). Moreover, BH₄-20 significantly decreased endothelial cell superoxide production and increased NO production. These data suggest that a single oral dose of BH₄ at 20 mg/kg improves vascular endothelial function in patients with CF, likely via increased endothelial NO synthase coupling. These findings support the hypothesis that loss of BH₄ bioactivity contributes, in part, to endothelial dysfunction in patients with CF. NEW & NOTEWORTHY For the first time, the present study documents that a single dose of oral BH₄ can improve vascular endothelial function in patients with cystic fibrosis (CF), and our in vitro data suggest this is via decreasing uncoupled nitric oxide. These data provide insight into the important role of BH₄ bioactivity in vascular dysfunction and provide the foundation for further investigation into the chronic effects of BH₄ treatment in patients with CF.