Georgia Prevention Institute, Department of Population Health Sciences, Augusta University , Augusta, Georgia.
Department of Oral Biology and Pharmacology, Augusta University , Augusta, Georgia.
J Appl Physiol (1985). 2019 Jan 1;126(1):60-66. doi: 10.1152/japplphysiol.00629.2018. Epub 2018 Nov 15.
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 (BH) is a critical determinant of NO bioavailability. Thus the purpose of this study was to investigate the effects of oral administration of BH 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 BH (BH-5; n = 17) or a 20 mg/kg dose of oral BH (BH-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 BH-5 (∆FMD: -0.8 ± 1.9% and -0.5 ± 2.5%; P = 0.273 and 0.132, respectively). Treatment with BH-20, however, resulted in significant improvements in FMD (∆FMD: 1.1 ± 1.4%) compared with BH-5 ( P = 0.023) and PLC ( P = 0.017). Moreover, BH-20 significantly decreased endothelial cell superoxide production and increased NO production. These data suggest that a single oral dose of BH 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 BH 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 BH 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 BH bioactivity in vascular dysfunction and provide the foundation for further investigation into the chronic effects of BH treatment in patients with CF.
囊性纤维化（CF）是一种与血管内皮功能障碍相关的遗传疾病。一氧化氮（NO）在维持血管功能方面起着重要作用，而四氢生物蝶呤（BH）是决定 NO 生物利用度的关键因素。因此，本研究旨在探讨口服 BH 对 CF 患者内皮功能的影响。
招募了 29 名 CF 患者（18±8 岁）和 29 名健康匹配的对照者。CF 患者参与了一项随机试验，他们接受了 5mg/kg 剂量的口服 BH（BH-5；n=17）或 20mg/kg 剂量的口服 BH（BH-20；n=12）。在另一次就诊中，每组的一部分患者在接受安慰剂（PLC；n=9）后进行了重复测试。肱动脉血流介导的扩张（FMD）用于评估血管内皮功能，并在治疗前和治疗后 3 小时获得血浆样本。用血浆处理培养的内皮细胞以评估 NO 生物利用度。
与对照组相比，患者的基础 FMD 较低（分别为 5.7±3.4%和 8.4±3.5%，P=0.005）。PLC 或 BH-5 治疗后 FMD 无变化（ΔFMD：-0.8±1.9%和-0.5±2.5%；P=0.273 和 0.132，分别）。然而，BH-20 治疗可显著改善 FMD（ΔFMD：1.1±1.4%），与 BH-5（P=0.023）和 PLC（P=0.017）相比。此外，BH-20 显著降低了内皮细胞超氧化物的产生并增加了 NO 的产生。
这些数据表明，20mg/kg 剂量的单次口服 BH 可改善 CF 患者的血管内皮功能，可能是通过增加内皮型一氧化氮合酶偶联。这些发现支持这样一种假设，即 BH 生物活性的丧失部分导致 CF 患者的内皮功能障碍。
本研究首次证明，单次口服 BH 可改善 CF 患者的血管内皮功能，我们的体外数据表明，这是通过减少不偶联的一氧化氮来实现的。这些数据深入了解了 BH 生物活性在血管功能障碍中的重要作用，并为进一步研究 CF 患者长期 BH 治疗的效果提供了基础。
