Department of Kinesiology, Noll Laboratory, The Pennsylvania State University, University Park, Pennsylvania.
J Appl Physiol (1985). 2013 Oct 1;115(7):972-8. doi: 10.1152/japplphysiol.00481.2013. Epub 2013 Jun 6.
Functional constitutive nitric oxide synthase (NOS) and its cofactor tetrahydrobiopterin (BH4) are required for full reflex cutaneous vasodilation and are attenuated in primary aging. Acute, locally administered BH4 increases reflex vasodilation through NO-dependent mechanisms in aged skin. We hypothesized that oral sapropterin (Kuvan, shelf-stable pharmaceutical formulation of BH4) would augment reflex vasodilation in aged human skin during hyperthermia. Nine healthy human subjects (76 ± 1 yr) ingested sapropterin (10 mg/kg) or placebo in a randomized double-blind crossover design. Venous blood samples were collected prior to, and 3 h following, ingestion of sapropterin for measurement of plasma BH4. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of 1) lactated Ringer's solution, 2) 10 mM BH4, and 3) 20 mM N(G)-nitro-l-arginine methyl ester (l-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced using a water-perfused suit. At 1°C rise in oral temperature, mean body temperature was clamped and 20 mM l-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC = LDF/MAP) and expressed as a percentage of maximum (%CVCmax 28 mM sodium nitroprusside and local heat 43°C). Plasma concentrations of BH4 were significantly elevated 3 h after ingestion of sapropterin (0 h: 19.1 ± 2 pmol/ml vs. 3 h: 43.8 ± 3 pmol/ml; P < 0.001). Sapropterin increased NO-dependent vasodilation at control site (placebo: 14 ± 1 %CVCmax vs. sapropterin: 25 ± 4 %CVCmax; P = 0.004). Local BH4 administration increased NO-dependent vasodilation compared with control in placebo trials only (control: 14 ± 1 %CVCmax vs. BH4-treated: 24 ± 3 %CVCmax; P = 0.02). These data suggest oral sapropterin increases bioavailable BH4 in aged skin microvasculature sufficiently to increase NO synthesis through NOS and that sapropterin may be a viable intervention to increase skin blood flow during hyperthermia in healthy aged humans.
功能性结构型一氧化氮合酶（NOS）及其辅因子四氢生物蝶呤（BH4）是充分反射性皮肤血管舒张所必需的，并且在原发性衰老中减弱。急性、局部给予 BH4 通过一氧化氮依赖机制增加老年皮肤的反射性血管舒张。我们假设口服沙丙蝶呤（Kuvan，BH4 的稳定药用制剂）会在老年人皮肤发热期间增强反射性血管舒张。9 名健康人体受试者（76±1 岁）以随机、双盲交叉设计的方式摄入沙丙蝶呤（10mg/kg）或安慰剂。在摄入沙丙蝶呤之前和之后 3 小时采集静脉血样，以测量血浆 BH4。将 3 根皮内微透析纤维放置在前臂皮肤中，用于局部输送 1）乳酸林格溶液、2）10mM BH4 和 3）20mM N（G）-硝基-L-精氨酸甲酯（l-NAME）以抑制 NOS。通过激光多普勒流量测量法（LDF）测量每个部位的红细胞通量，作为使用水灌注服诱导反射性血管舒张。在口腔温度升高 1°C 时，将平均体温夹在中间，并在每个部位灌注 20mM l-NAME。通过 LDF/MAP 计算皮肤血管传导率（CVC），并表示为最大百分比（28mM 硝普钠和局部热 43°C 的%CVCmax）。摄入沙丙蝶呤后 3 小时，血浆 BH4 浓度显著升高（0 小时：19.1±2pmol/ml vs. 3 小时：43.8±3pmol/ml；P<0.001）。沙丙蝶呤增加了对照部位的一氧化氮依赖性血管舒张（安慰剂：14±1%CVCmax vs. 沙丙蝶呤：25±4%CVCmax；P=0.004）。仅在安慰剂试验中，局部 BH4 给药增加了与对照相比的一氧化氮依赖性血管舒张（对照：14±1%CVCmax vs. BH4 治疗：24±3%CVCmax；P=0.02）。这些数据表明，口服沙丙蝶呤可增加老年皮肤微血管中生物可利用的 BH4，足以通过 NOS 增加一氧化氮合成，并且沙丙蝶呤可能是一种可行的干预措施，可在健康老年人群体发热期间增加皮肤血流量。
