Machin Daniel R, Clifton Heather L, Richardson Russell S, Wray D Walter, Donato Anthony J, Frech Tracy M
Department of Internal Medicine, University of Utah; Geriatric Research, Education, and Clinical Center, VA Medical Center, Salt Lake City, UT, USA.
Geriatric Research, Education, and Clinical Center, VA Medical Center, Salt Lake City, UT, USA.
Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 106(4):167-172. doi: 10.55563/clinexprheumatol/cqyllj. Epub 2017 Sep 14.
Systemic sclerosis (SSc) is a rare, autoimmune disease characterised by endothelial dysfunction, which is associated with peripheral vasculopathy, such as digital ulcers (DU). We sought to determine if acute oral administration of tetrahydrobiopterin (BH4), an essential cofactor for endothelial nitric oxide synthase, would augment endothelial function in patients with SSc.
Twelve SSc patients, of whom a majority had a history of DU, were studied 5 hours after oral BH4 administration (10 mg/kg body mass) or placebo on separate days using controlled, counterbalanced, double-blind, crossover experimental design.
There were no differences in blood markers of oxidative stress and brachial artery blood pressure, diameter, blood velocity, shear rate, or blood flow at rest between placebo and BH4 (p>0.05). Whereas, after a 5 minute suprasystolic forearm cuff occlusion, brachial artery peak reactive hyperemia (placebo: 313±30 vs. BH4: 347±37 ml/min, p<0.05) and flow-mediated dilation (FMD) (placebo: 3.0±0.8 vs. BH4: 4.8±0.8%, p<0.05) were significantly higher after acute BH4 administration, indicating an improvement in endothelial function. To determine if the vasodilatory effects of BH4 were specific to the vascular endothelium, brachial artery blood flow and vasodilation in response to sublingual nitroglycerin were assessed, and were found to be unaffected by BH4 (p>0.05).
These findings indicate that acute BH4 administration ameliorates endothelial dysfunction in patients with SSc. Given that endothelial dysfunction is known to be associated with DU in SSc patients, this study provides a proof-of-concept for the potential therapeutic benefits of BH4 in the prevention or treatment of DU in this population.
系统性硬化症（SSc）是一种罕见的自身免疫性疾病，其特征为内皮功能障碍，这与外周血管病变相关，如指端溃疡（DU）。我们试图确定急性口服四氢生物蝶呤（BH4）（一种内皮型一氧化氮合酶的必需辅助因子）是否会增强SSc患者的内皮功能。
12例SSc患者，其中大多数有DU病史，在分别口服BH4（10mg/kg体重）或安慰剂5小时后进行研究，采用对照、平衡、双盲、交叉实验设计。
安慰剂组和BH4组在静息时氧化应激的血液标志物、肱动脉血压、直径、血流速度、切变率或血流量方面无差异（p>0.05）。然而，在进行5分钟的收缩期前臂袖带超灌注阻断后，急性给予BH4后肱动脉峰值反应性充血（安慰剂组：313±30 vs. BH4组：347±37 ml/min，p<0.05）和血流介导的血管舒张（FMD）（安慰剂组：3.0±0.8 vs. BH4组：4.8±0.8%，p<0.05）显著更高，表明内皮功能有所改善。为了确定BH4的血管舒张作用是否特异于血管内皮，评估了舌下含服硝酸甘油后的肱动脉血流量和血管舒张情况，发现不受BH4影响（p>0.05）。
这些发现表明急性给予BH4可改善SSc患者的内皮功能障碍。鉴于已知内皮功能障碍与SSc患者的DU相关，本研究为BH4在预防或治疗该人群DU方面的潜在治疗益处提供了概念验证证据。
