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

Abstract

Reflex vasoconstriction is attenuated in aged skin due to a functional loss of adrenergic vasoconstriction. Bioavailability of tetrahydrobiopterin (BH4), 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 ( T̄sk) 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 BH4 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 T̄sk ≤ 32.5°C ( P < 0.05). Local BH4 perfusion augmented reflex vasoconstriction at T̄sk ≤ 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.