Local Tetrahydrobiopterin Administration Augments Reflex And Tyramine-induced Cutaneous Vasoconstriction In Aged Human Skin

Abstract

Reflex vasoconstriction (VC) is attenuated in aged skin resulting in greater heat loss during cold exposure. Reflex VC in young skin is comprised of both adrenergic (∼60%) and nonadrenergic (i.e. coreleased sympathetic neurotransmitters) components (∼40%); however, cotransmitter-mediated VC is functionally lost and responsiveness of adrenergic receptors are diminished in older subjects. Adrenergic function may be further compromised in aged skin due to depletion of an oxidant-sensitive essential cofactor for tyrosine hydroxylase, tetrahydrobiopterin (BH4), which is required for catecholamine synthesis. PURPOSE: We hypothesized that local BH4 supplementation would functionally augment reflex-induced and pharmacologically-induced VC elicited by gradual whole-body cooling (Tsk=30.5°C) and tyramine infusion (which displaces norepinephrine (NE) in storage vesicles), respectively. METHODS: Three microdialysis (MD) fibers were placed in the forearm skin of 11 young (Y) and 11 older (O) human subjects for infusion of 1) Ringers solution (control), 2) 5 mM BH4, and 3) 5mM BH4 + adrenoreceptor blockade (5mM yohimbine + 1mM propranolol). Red blood cell flux (LDF) was measured by laser Doppler flowmetry over each MD site. Cutaneous vascular conductance was calculated (CVC = LDF/MAP) and expressed as percent change from baseline (DCVCbase). RESULTS: VC was lower at the control site in O during cooling (Y: -34 ± 2, O: -17 ± 2%; DCVCbase; P<0.001) and tyramine infusion (Y: -33 ± 4, O: -15 ± 3%; DCVCbase; P<0.001). BH4 infusion normalized VC to Y values in O during cooling (Y: -34 ± 4, O: -34 ± 2%; DCVCbase; P<0.001) and tyramine (Y: -38 ± 4, O: -35 ± 3%; DCVCbase; P<0.001), both of which were abolished with adrenoreceptor blockade in aged skin (P<0.001 versus control). CONCLUSION: Local BH4 supplementation augments reflex and tyramine-induced VC in aged skin, suggesting that reduced BH4 bioavailability significantly contributes to the attenuated VC response. Supported by NIH RO1-AG-07004-18 and the Carl V. Gisolfi Memorial Research Fund, ACSM