Sildenafil improves vascular endothelial function in patients with cystic fibrosis.
Sildenafil improves vascular endothelial function in patients with cystic fibrosis.
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DOI：
10.1152/ajpheart.00301.2018
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发表时间：
2018-11
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通讯作者：
Paula Rodriguez-Miguelez;N. Lee;M. Tucker;G. Csányi;K. McKie;C. Forseen;R. Harris
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作者：
Paula Rodriguez-Miguelez;N. Lee;M. Tucker;G. Csányi;K. McKie;C. Forseen;R. Harris
囊性纤维化（CF）的特征是CFTR功能缺陷，与多种全身并发症相关，包括血管功能障碍。西地那非是一种5型磷酸二酯酶抑制剂，不仅能增强一氧化氮（NO）代谢，而且还能改善CFTR功能。因此，西地那非已被提议作为改善CF血管健康的疗法;然而，其潜在的治疗作用尚未确定。我们试图研究西地那非对CF患者内皮功能的影响。CF患者完成了一项随机、双盲、安慰剂对照、交叉研究，接受西地那非（50 mg）或安慰剂急性给药，随后接受西地那非（20 mg/天）4周开放标签扩展治疗。采用血流介导的血管舒张功能（FMD）评价治疗前后的内皮功能。此外，磷酸化内皮NO合酶（pNOS 3）和总NOS 3蛋白表达测定内皮细胞暴露于血浆从患者的西地那非治疗前后4周。西地那非急性给药后未观察到内皮功能变化（P ≥ 0.110）。治疗4 wk后FMD显著增加（P = 0.029），FMD为1.5 ± 2.2%。治疗4 wk后，pNOS 3蛋白表达显著增加（P = 0.013）（P <0.01），且与FMD的变化相关（r = 0.593，P = 0.033）。这些数据表明，4周的西地那非治疗可以改善CF患者的血管内皮功能，可能是通过增加NOS 3磷酸化。新&值得注意的是，本研究的发现首次表明，接受西地那非治疗的囊性纤维化患者的内皮功能显着改善，这与内皮一氧化氮合酶的磷酸化程度增加有关。这些结果支持使用西地那非作为该患者人群的潜在新型治疗。
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.