Oral sapropterin augments reflex vasoconstriction in aged human skin through noradrenergic mechanisms

Reflex vasoconstriction is attenuated in aged skin due to a functional loss of adrenergic vasoconstriction. Bioavailability of tetrahydrobiopterin (BH ₄), an essential cofactor for catecholamine synthesis, is reduced with aging. Locally administered BH₄ increases vasoconstriction through adrenergic mechanisms in aged human skin. We hypothesized that oral sapropterin (Kuvan, a pharmaceutical BH₄) would augment vasoconstriction elicited by whole-body cooling and tyramine perfusion in aged skin. Ten healthy subjects (age 75 ± 2 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. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of 1) lactated Ringer, 2) 5 mM BH₄, and 3) 5 mM yohimbine + 1 mM propranolol (Y+P; to inhibit adrenergic vasoconstriction). Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasoconstriction was induced by lowering and then clamping whole-body skin temperature (T_sk) using a water-perfused suit. Following whole-body cooling, subjects were rewarmed and 1 mM tyramine was perfused at each site to elicit endogenous norepinephrine release from the perivascular nerve terminal. Cutaneous vascular conductance was calculated as CVC = LDF/mean arterial pressure and expressed as change from baseline (ΔCVC). Plasma BH ₄ was elevated 3 h after ingestion of sapropterin (43.8 ± 3 vs. 19.1 ± 2 pmol/ml; P < 0.001). Sapropterin increased reflex vasoconstriction at the Ringer site at T_sk ≤ 32.5°C (P < 0.05). Local BH₄ perfusion augmented reflex vasoconstriction at T_sk ≤ 31.5°C with placebo treatment only (P < 0.05). There was no treatment effect on reflex vasoconstriction at the BH₄- perfused or Y+P-perfused sites. Sapropterin increased pharmacologically induced vasoconstriction at the Ringer site (-0.19 ± 0.03 vs. -0.08 ± 0.02 ΔCVC; P = 0.01). There was no difference in pharmacologically induced vasoconstriction between treatments at the BH₄-perfused site (-0.16 ± 0.04 vs. -0.14 ± 0.03 ΔCVC; P = 0.60) or the Y+P-perfused site (-0.05 ± 0.02 vs.-0.06 ± 0.02 ΔCVC; P = 0.79). Sapropterin increases both reflex (cold-induced) and pharmacologically induced vasoconstriction through adrenergic mechanisms and may be a viable intervention to improve reflex vasoconstriction in aged humans.