Local tetrahydrobiopterin administration augments cutaneous vasoconstriction in aged humans

Reflex vasoconstriction (VC) is attenuated in aged skin resulting in greater skin blood flow and heat loss during cold exposure. We hypothesized that adrenergic function is compromised due to depletion of tetrahydrobiopterin (BH₄), an essential cofactor required for catecholamine synthesis, and therefore local BH₄ supplementation would functionally augment reflex and pharmacologically induced VC elicited by gradual whole-body cooling (skin temperature (T_sk) =30.5°C) and tyramine infusion, respectively. Four microdialysis (MD) fibres were placed in the forearm skin of 11 young (Y) and 11 older (O) human subjects for infusion of (1) Ringer solution (control), (2) 5 mM BH₄, (3) 5 mM BH₄ + 10 mM ascorbate, and (4) 5 mM BH₄ + adrenoreceptor blockade (5 mM yohimbine + 1 mM propranolol). Laser Doppler flux (LDF) was measured over each MD site and cutaneous vascular conductance was calculated as CVC = LDF/MAP and expressed as per cent change from baseline (% Δ CVC_base). The VC response was lower at the control site in O during cooling (Y: -34 ± 2% Δ CVC_base, O: -17 ± 25 Δ CVC_base; P < 0.001) and tyramine infusion (Y: -33 ± 4% Δ CVC_base, O: -15 ± 3% Δ CVC_base; P < 0.001). BH₄ infusion normalized O to Y values during both cooling (Y: -34 ± 4% Δ CVC_base, O: -34 ± 2% Δ CVC_base; P < 0.001) and tyramine (Y: -38 ± 4%ΔCVC_base, O: -35 ± 3% Δ CVC_base; P < 0.001), however, adding adrenoreceptor blockade abolished VC in aged skin indicating that BH₄ acts through adrenergic, not cotransmitter, mechanisms. Local BH₄ supplementation augments reflex and tyramine-induced VC in aged skin, suggesting that reduced BH₄ bioavailability may contribute to attenuated VC during whole-body cooling.