Sildenafil improves vascular endothelial function in patients with cystic fibrosis

Abstract

Cystic fibrosis (CF), characterized by defective CFTR function, is associated with multiple systemic complications, including vascular dysfunction. Sildenafil, a phosphodiesterase type 5 inhibitor, not only enhances nitric oxide (NO) metabolism but has been shown to improve CFTR functionality as well. Thus, sildenafil has been proposed as a therapy to improve vascular health in CF; however, its potential therapeutic role has yet to be determined. We sought to investigate the effect of sildenafil on endothelial function in patients with CF. Patients with CF completed a randomized, double-blind, placebo-controlled, crossover study with an acute dose of sildenafil (50 mg) or placebo followed by a 4-wk open-label extension with sildenafil (20 mg/day). Flow-mediated dilation (FMD) was used to evaluate endothelial function before and after treatments. In addition, phosphorylated endothelial NO synthase (pNOS3) and total NOS3 protein expression was determined from endothelial cells that were exposed to plasma from the patients before and after 4 wk of sildenafil treatment. No changes ( P ≥ 0.110) in endothelial function were observed after the acute dose of sildenafil. However, FMD significantly ( P = 0.029) increased after 4 wk of treatment (∆FMD: 1.5 ± 2.2%). Moreover, pNOS3 protein expression significantly ( P = 0.013) increased after 4 wk of treatment (∆pNOS3: 0.31 ± 0.39 arbitrary units) and was associated ( r = 0.593, P = 0.033) with the change in FMD. These data suggest that 4 wk of sildenafil treatment can improve vascular endothelial function in patients with CF, likely through an increase in NOS3 phosphorylation. NEW & NOTEWORTHY Findings from the present study demonstrate, for the first time, significant improvement of endothelial function in patients with cystic fibrosis treated with sildenafil that is associated with greater phosphorylation of endothelial nitric oxide synthase. These results support the use of sildenafil as a potential novel therapy for this patient population.

Keywords: cystic fibrosis; endothelial nitric oxide synthase; flow-mediated dilation; nitric oxide; phosphodiesterase type 5 inhibitors.

Figures

Fig. 1.

Clinical trial flowchart.

Fig. 2.

Vascular endothelial function at baseline and after 4 wk of sildenafil treatment in patients with cystic fibrosis. A: brachial artery baseline diameter. B: flow-mediated dilation (FMD). C: FMD normalized for shear rate. AU, arbitrary units. Values are means ± SE. *P < 0.05 vs. baseline.

Fig. 3.

Nitric oxide synthase (NOS3) protein expression in human aortic endothelial cells exposed to plasma from patients with cystic fibrosis at baseline and after 4 wk of sildenafil treatment. A and C: representative Western blots for phosphorylated NOS3 (pNOS3) and total NOS3 with their corresponding β-actin protein expression from 2 patients at baseline (BL) and after 4 wk of treatment with sildenafil (SIL). B and D: quantitative analysis of pNOS3 and total NOS3 expressed relative to β-actin. E: ratio of pNOS3 to total NOS3. AU, arbitrary units. Values are means ± SE. *P < 0.05 vs. baseline.