Local tetrahydrobiopterin supplementation augments reflex cutaneous vasodilaton in aged human skin

Abstract

NO-synthase (NOS) is necessary for full expression of reflex cutaneous vasodilation (VD). Tetrahydrobiopterin (BH4) is an essential cofactor for NOS. Reduced BH4 bioavailability is associated with aging. We hypothesized that acute local BH4 supplementation would augment NO-dependent VD in aged skin during hyperthermia. Three intradermal microdialysis fibers were placed in the forearm skin of 10 young (Y, 24 ± 6 years) and 7 older (O, 72 ± 6 years) human subjects for local infusion of Ringers solution (control), L-NAME (NOS-inhibition) and 10mM BH4, respectively. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex VD was induced using a water perfused suit. After a 1°C rise in oral temperature, mean body temperature was clamped and L-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC = LDF/MAP) and expressed as percent of maximum (%CVCmax: infusion of 28mM sodium nitroprusside). VD was attenuated at control site in O (O: 35 ± 6 vs. Y: 54 ± 7 %CVCmax; p<0.05). BH4 supplementation augmented VD in O (54 ± 11 %CVCmax; p<0.05) but not Y (57 ± 8 %CVCmax; p<0.05). NOS inhibition equally attenuated VD at the BH4 site in both groups (O: 38 ± 4 vs. Y: 24 ± 5 %CVCmax; p<0.05). Acute local BH4 supplementation augments reflex NO-dependant VD in aged skin, suggesting that reduced BH4 bioavailability contributes to the attenuated VD in older humans. Supported by: NIH AG007-004-20