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

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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 micro-dialysis 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 BH 4 (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.

Original languageEnglish (US)
Pages (from-to)R1651-R1655
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume299
Issue number6
DOIs
StatePublished - Dec 1 2010

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Vasoconstriction
Norepinephrine
Skin
Blood Vessels
Adrenergic Agents
Bretylium Tosylate
Iontophoresis
Skin Temperature
Biosynthetic Pathways
sapropterin
Forearm
Neurotransmitter Agents
Reflex
Dialysis
Arterial Pressure
Lasers
Perfusion
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)

Cite this

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title = "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 micro-dialysis 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 BH 4 (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.",
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T1 - Tetrahydrobiopterin does not affect end-organ responsiveness to norepinephrine-mediated vasoconstriction in aged skin

AU - Lang, James A.

AU - Holowatz, Lacy A.

AU - Kenney, W. Larry

PY - 2010/12/1

Y1 - 2010/12/1

N2 - 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 micro-dialysis 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 BH 4 (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.

AB - 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 micro-dialysis 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 BH 4 (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.

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