Tetrahydrobiopterin does not affect end-organ responsiveness to norepinephrine-mediated vasoconstriction in aged skin

Abstract

We have recently demonstrated that tetrahydrobiopterin (BH4) augments reflex vasoconstriction (VC) in aged skin. Although this appears to occur through its role in norepinephrine (NE) biosynthesis, the extent with which vascular mechanisms are affected are unknown. We hypothesized that localized BH4 supplementation would not affect the VC response to exogenous NE when sympathetic nerves were blocked. Two microdialysis fibers were placed in bretylium tosylate pretreated (presynaptically blocks neurotransmitter release from sympathetic adrenergic nerve terminals; iontophoresis, 200 μA for 20 min) 3-cm2 forearm skin of 10 young (Y) and 10 older (O) subjects for perfusion of 1) Ringer (control) and 2) 5 mM BH4. While local skin temperature was clamped at 34°C, six concentrations of NE (10−12, 10−10, 10−8, 10−6, 10−4, 10−2 M) were infused at each drug-treated site. Cutaneous vascular conductance (CVC) was calculated (CVC = laser Doppler flux/mean arterial pressure) and normalized to baseline (%ΔCVCbase). Despite prejunctional adrenergic blockade, NE-mediated VC was blunted in aged skin at each NE dose (10−12: −12 ± 2 vs. −21 ± 2; 10−10: −15 ± 2 vs. −27 ± 1; 10−8: −22 ± 2 vs. −32 ± 2; 10−6: −27 ± 2 vs. −38 ± 1; 10−4: −52 ± 3 vs. −66 ± 5; 10−2: −62 ± 3 vs. −75 ± 4%ΔCVCbase; P < 0.01), and this response was not affected by pretreatment with BH4 ( P > 0.05). Localized BH4 did not affect end-organ responsiveness to exogenous NE, suggesting that the effects of BH4 on cutaneous VC are primarily isolated to the NE biosynthetic pathway.