These data suggest that four weeks of sildenafil treatment can improve vascular endothelial function in patients with CF, likely through an increase in NOS3 phosphorylation.

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.

Ventilatory parameters obtained during exercise predict survival in several chronic diseases; however, long-term changes in exercise ventilatory parameters in patients with CF have yet to be examined and potential differences between sexes in CF are unknown. Purpose: we sought to examine the change in exercise ventilatory parameters over time in patients with CF and determine if the change is different between sexes. Methods: exercise capacity (VO2 peak) and exercise ventilatory parameters (VE/VO2 peak, VE/VCO2 peak, and VE/VCO2 slope) were determined from a maximal cardio-pulmonary test on a cycle ergometer on two visits separated by 39 ± 16 months in 20 patients with CF (10 female, 10 male). Results: no differences between sexes were observed at visit 1 (all p>0.05). Overall, exercise ventilatory parameters significantly (p<0.05) deteriorated between visits, with no change (p>0.05) in VO2 peak. Moreover, compared with males, female patients exhibited greater deteriorations in VE/VO2 peak (p=0.001), VE/VCO2 peak (p=0.002), and VE/VCO2 slope (p=0.016) between visits. Conclusions: these data in patients with CF indicate that exercise ventilatory parameters decline over time despite no change in VO2 peak, and female patients exhibit a more rapid deterioration compared with males.