Local tetrahydrobiopterin administration augments cutaneous vasoconstriction in aged humans

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Abstract

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 (Tsk) =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 CVCbase). The VC response was lower at the control site in O during cooling (Y: -34 ± 2% Δ CVCbase, O: -17 ± 25 Δ CVCbase; P < 0.001) and tyramine infusion (Y: -33 ± 4% Δ CVCbase, O: -15 ± 3% Δ CVCbase; P < 0.001). BH4 infusion normalized O to Y values during both cooling (Y: -34 ± 4% Δ CVCbase, O: -34 ± 2% Δ CVCbase; P < 0.001) and tyramine (Y: -38 ± 4%ΔCVCbase, O: -35 ± 3% Δ CVCbase; 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.

Original languageEnglish (US)
Pages (from-to)3967-3974
Number of pages8
JournalJournal of Physiology
Volume587
Issue number15
DOIs
StatePublished - Aug 10 2009

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Cutaneous Administration
Vasoconstriction
Tyramine
Skin
Reflex
Microdialysis
Adrenergic Agents
Lasers
Yohimbine
Skin Temperature
Forearm
Propranolol
Biological Availability
Catecholamines
Blood Vessels
sapropterin
Hot Temperature

All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

@article{4d7222647e444211babeb531bfca4859,
title = "Local tetrahydrobiopterin administration augments cutaneous vasoconstriction in aged humans",
abstract = "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 (Tsk) =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 CVCbase). The VC response was lower at the control site in O during cooling (Y: -34 ± 2{\%} Δ CVCbase, O: -17 ± 25 Δ CVCbase; P < 0.001) and tyramine infusion (Y: -33 ± 4{\%} Δ CVCbase, O: -15 ± 3{\%} Δ CVCbase; P < 0.001). BH4 infusion normalized O to Y values during both cooling (Y: -34 ± 4{\%} Δ CVCbase, O: -34 ± 2{\%} Δ CVCbase; P < 0.001) and tyramine (Y: -38 ± 4{\%}ΔCVCbase, O: -35 ± 3{\%} Δ CVCbase; 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.",
author = "Lang, {James A.} and Alexander, {Lacy Marie} and {Kenney, Jr.}, {William Lawrence}",
year = "2009",
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Local tetrahydrobiopterin administration augments cutaneous vasoconstriction in aged humans. / Lang, James A.; Alexander, Lacy Marie; Kenney, Jr., William Lawrence.

In: Journal of Physiology, Vol. 587, No. 15, 10.08.2009, p. 3967-3974.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Local tetrahydrobiopterin administration augments cutaneous vasoconstriction in aged humans

AU - Lang, James A.

AU - Alexander, Lacy Marie

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N2 - 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 (Tsk) =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 CVCbase). The VC response was lower at the control site in O during cooling (Y: -34 ± 2% Δ CVCbase, O: -17 ± 25 Δ CVCbase; P < 0.001) and tyramine infusion (Y: -33 ± 4% Δ CVCbase, O: -15 ± 3% Δ CVCbase; P < 0.001). BH4 infusion normalized O to Y values during both cooling (Y: -34 ± 4% Δ CVCbase, O: -34 ± 2% Δ CVCbase; P < 0.001) and tyramine (Y: -38 ± 4%ΔCVCbase, O: -35 ± 3% Δ CVCbase; 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.

AB - 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 (Tsk) =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 CVCbase). The VC response was lower at the control site in O during cooling (Y: -34 ± 2% Δ CVCbase, O: -17 ± 25 Δ CVCbase; P < 0.001) and tyramine infusion (Y: -33 ± 4% Δ CVCbase, O: -15 ± 3% Δ CVCbase; P < 0.001). BH4 infusion normalized O to Y values during both cooling (Y: -34 ± 4% Δ CVCbase, O: -34 ± 2% Δ CVCbase; P < 0.001) and tyramine (Y: -38 ± 4%ΔCVCbase, O: -35 ± 3% Δ CVCbase; 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.

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