Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms

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, shelfstable 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 (%CVC_max 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 %CVC_max vs. sapropterin: 25 ± 4 %CVC_max; P = 0.004). Local BH₄ administration increased NO-dependent vasodilation compared with control in placebo trials only (control: 14 ± 1 %CVC _max vs. BH₄-treated: 24 ± 3 %CVC_max; P = 0.02). These data suggest oral sapropterin increases bioavailable BH ₄ 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.