TY - JOUR
T1 - Sildenafil improves vascular endothelial function in patients with cystic fibrosis
AU - Rodriguez-Miguelez, Paula
AU - Lee, Nichole
AU - Tucker, Matthew A.
AU - Csányi, Gábor
AU - McKie, Kathleen T.
AU - Forseen, Caralee
AU - Harris, Ryan A.
N1 - Funding Information:
This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R21 DK-100783 (to R. A. Harris).
Publisher Copyright:
Copyright © 2018 the American Physiological Society.
PY - 2018/11
Y1 - 2018/11
N2 - 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 (δFMD: 1.5 ± 2.2%). Moreover, pNOS3 protein expression significantly (P = 0.013) increased after 4 wk of treatment (δpNOS3: 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.
AB - 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 (δFMD: 1.5 ± 2.2%). Moreover, pNOS3 protein expression significantly (P = 0.013) increased after 4 wk of treatment (δpNOS3: 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.
KW - Cystic fibrosis
KW - Endothelial nitric oxide synthase
KW - Flow-mediated dilation
KW - Nitric oxide
KW - Phosphodiesterase type 5 inhibitors
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U2 - 10.1152/AJPHEART.00301.2018
DO - 10.1152/AJPHEART.00301.2018
M3 - Article
C2 - 30168731
AN - SCOPUS:85061128602
SN - 0363-6135
VL - 315
SP - H1486-H1494
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 5
ER -