Local tetrahydrobiopterin administration augments reflex cutaneous vasodilation through nitric oxide-dependent mechanisms in aged human skin

Anna E. Stanhewicz, Rebecca S. Bruning, Caroline J. Smith, William Lawrence Kenney, Jr., Lacy Marie Alexander

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Functional constitutive nitric oxide synthase (NOS) is required for full expression of reflex cutaneous vasodilation that is attenuated in aged skin. Both the essential cofactor tetrahydrobiopterin (BH 4) and adequate substrate concentrations are necessary for the functional synthesis of nitric oxide (NO) through NOS, both of which are reduced in aged vasculature through increased oxidant stress and upregulated arginase, respectively. We hypothesized that acute local BH 4 administration or arginase inhibition would similarly augment reflex vasodilation in aged skin during passive whole body heat stress. Four intradermal microdialysis fibers were placed in the forearm skin of 11 young (22 ± 1 yr) and 11 older (73 ± 2 yr) men and women for local infusion of 1) lactated Ringer, 2) 10 mM BH4, 3) 5 mM (S)-(2- boronoethyl)-L-cysteine +5 mM N ωy-nor-L-arginine to inhibit arginase, and 4) 20 mM N G-nitro-L-arginine methyl ester (L-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced. After a 1.0° in oral temperature (T or), mean body temperature was clamped and 20 mM L-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC =LDF/mean arterial pressure) and expressed as a percentage of maximum (%CVC max; 28 mM sodium nitroprusside and local heat, 43°asodilation was attenuated at the control site of the older subjects compared with young beginning at a 0.3° in Tor. BH 4 and arginase inhibition both increased vasodilation in older (BH 4: 55 ± 5%; arginaseinhibited: 47 ± 5% vs. control: 37 ± 3%, both P <1) but not young subjects compared with control (BH 4: 51 ± 4%CVC max; arginase-inhibited: 55 ± 4%CVC max vs. control: 56 ± 6%CVC max, both P <5) at a 1°e in Tor. With a 1°e in Tor, local BH 4 increased NO-dependent vasodilation in the older (BH 4: 31.8 ± 2.4%CVC max vs. control: 11.7 ± 2.0%CVC max, P <1) but not the young (BH 4: 23 ± 4%CVC max vs. control: 21 ± 4%CVC max, P =0.718) subject group. Together these data suggest that reduced BH 4 contributes to attenuated vasodilation in aged human skin and that BH 4 NOS coupling mechanisms may be a potential therapeutic target for increasing skin blood flow during hyperthermia in older humans.

Original languageEnglish (US)
Pages (from-to)791-797
Number of pages7
JournalJournal of Applied Physiology
Volume112
Issue number5
DOIs
StatePublished - Mar 1 2012

Fingerprint

Vasodilation
Arginase
Reflex
Nitric Oxide
Skin
Nitric Oxide Synthase
NG-Nitroarginine Methyl Ester
Laser-Doppler Flowmetry
Hot Temperature
Microdialysis
Nitroprusside
sapropterin
Body Temperature
Forearm
Oxidants
Blood Vessels
Arginine
Arterial Pressure
Fever
Temperature

All Science Journal Classification (ASJC) codes

  • Physiology
  • Physiology (medical)

Cite this

@article{127371eb229546a1a31dbe1e0a73cccf,
title = "Local tetrahydrobiopterin administration augments reflex cutaneous vasodilation through nitric oxide-dependent mechanisms in aged human skin",
abstract = "Functional constitutive nitric oxide synthase (NOS) is required for full expression of reflex cutaneous vasodilation that is attenuated in aged skin. Both the essential cofactor tetrahydrobiopterin (BH 4) and adequate substrate concentrations are necessary for the functional synthesis of nitric oxide (NO) through NOS, both of which are reduced in aged vasculature through increased oxidant stress and upregulated arginase, respectively. We hypothesized that acute local BH 4 administration or arginase inhibition would similarly augment reflex vasodilation in aged skin during passive whole body heat stress. Four intradermal microdialysis fibers were placed in the forearm skin of 11 young (22 ± 1 yr) and 11 older (73 ± 2 yr) men and women for local infusion of 1) lactated Ringer, 2) 10 mM BH4, 3) 5 mM (S)-(2- boronoethyl)-L-cysteine +5 mM N ωy-nor-L-arginine to inhibit arginase, and 4) 20 mM N G-nitro-L-arginine methyl ester (L-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced. After a 1.0° in oral temperature (T or), mean body temperature was clamped and 20 mM L-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC =LDF/mean arterial pressure) and expressed as a percentage of maximum ({\%}CVC max; 28 mM sodium nitroprusside and local heat, 43°asodilation was attenuated at the control site of the older subjects compared with young beginning at a 0.3° in Tor. BH 4 and arginase inhibition both increased vasodilation in older (BH 4: 55 ± 5{\%}; arginaseinhibited: 47 ± 5{\%} vs. control: 37 ± 3{\%}, both P <1) but not young subjects compared with control (BH 4: 51 ± 4{\%}CVC max; arginase-inhibited: 55 ± 4{\%}CVC max vs. control: 56 ± 6{\%}CVC max, both P <5) at a 1°e in Tor. With a 1°e in Tor, local BH 4 increased NO-dependent vasodilation in the older (BH 4: 31.8 ± 2.4{\%}CVC max vs. control: 11.7 ± 2.0{\%}CVC max, P <1) but not the young (BH 4: 23 ± 4{\%}CVC max vs. control: 21 ± 4{\%}CVC max, P =0.718) subject group. Together these data suggest that reduced BH 4 contributes to attenuated vasodilation in aged human skin and that BH 4 NOS coupling mechanisms may be a potential therapeutic target for increasing skin blood flow during hyperthermia in older humans.",
author = "Stanhewicz, {Anna E.} and Bruning, {Rebecca S.} and Smith, {Caroline J.} and {Kenney, Jr.}, {William Lawrence} and Alexander, {Lacy Marie}",
year = "2012",
month = "3",
day = "1",
doi = "10.1152/japplphysiol.01257.2011",
language = "English (US)",
volume = "112",
pages = "791--797",
journal = "Journal of Applied Physiology",
issn = "8750-7587",
publisher = "American Physiological Society",
number = "5",

}

Local tetrahydrobiopterin administration augments reflex cutaneous vasodilation through nitric oxide-dependent mechanisms in aged human skin. / Stanhewicz, Anna E.; Bruning, Rebecca S.; Smith, Caroline J.; Kenney, Jr., William Lawrence; Alexander, Lacy Marie.

In: Journal of Applied Physiology, Vol. 112, No. 5, 01.03.2012, p. 791-797.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Local tetrahydrobiopterin administration augments reflex cutaneous vasodilation through nitric oxide-dependent mechanisms in aged human skin

AU - Stanhewicz, Anna E.

AU - Bruning, Rebecca S.

AU - Smith, Caroline J.

AU - Kenney, Jr., William Lawrence

AU - Alexander, Lacy Marie

PY - 2012/3/1

Y1 - 2012/3/1

N2 - Functional constitutive nitric oxide synthase (NOS) is required for full expression of reflex cutaneous vasodilation that is attenuated in aged skin. Both the essential cofactor tetrahydrobiopterin (BH 4) and adequate substrate concentrations are necessary for the functional synthesis of nitric oxide (NO) through NOS, both of which are reduced in aged vasculature through increased oxidant stress and upregulated arginase, respectively. We hypothesized that acute local BH 4 administration or arginase inhibition would similarly augment reflex vasodilation in aged skin during passive whole body heat stress. Four intradermal microdialysis fibers were placed in the forearm skin of 11 young (22 ± 1 yr) and 11 older (73 ± 2 yr) men and women for local infusion of 1) lactated Ringer, 2) 10 mM BH4, 3) 5 mM (S)-(2- boronoethyl)-L-cysteine +5 mM N ωy-nor-L-arginine to inhibit arginase, and 4) 20 mM N G-nitro-L-arginine methyl ester (L-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced. After a 1.0° in oral temperature (T or), mean body temperature was clamped and 20 mM L-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC =LDF/mean arterial pressure) and expressed as a percentage of maximum (%CVC max; 28 mM sodium nitroprusside and local heat, 43°asodilation was attenuated at the control site of the older subjects compared with young beginning at a 0.3° in Tor. BH 4 and arginase inhibition both increased vasodilation in older (BH 4: 55 ± 5%; arginaseinhibited: 47 ± 5% vs. control: 37 ± 3%, both P <1) but not young subjects compared with control (BH 4: 51 ± 4%CVC max; arginase-inhibited: 55 ± 4%CVC max vs. control: 56 ± 6%CVC max, both P <5) at a 1°e in Tor. With a 1°e in Tor, local BH 4 increased NO-dependent vasodilation in the older (BH 4: 31.8 ± 2.4%CVC max vs. control: 11.7 ± 2.0%CVC max, P <1) but not the young (BH 4: 23 ± 4%CVC max vs. control: 21 ± 4%CVC max, P =0.718) subject group. Together these data suggest that reduced BH 4 contributes to attenuated vasodilation in aged human skin and that BH 4 NOS coupling mechanisms may be a potential therapeutic target for increasing skin blood flow during hyperthermia in older humans.

AB - Functional constitutive nitric oxide synthase (NOS) is required for full expression of reflex cutaneous vasodilation that is attenuated in aged skin. Both the essential cofactor tetrahydrobiopterin (BH 4) and adequate substrate concentrations are necessary for the functional synthesis of nitric oxide (NO) through NOS, both of which are reduced in aged vasculature through increased oxidant stress and upregulated arginase, respectively. We hypothesized that acute local BH 4 administration or arginase inhibition would similarly augment reflex vasodilation in aged skin during passive whole body heat stress. Four intradermal microdialysis fibers were placed in the forearm skin of 11 young (22 ± 1 yr) and 11 older (73 ± 2 yr) men and women for local infusion of 1) lactated Ringer, 2) 10 mM BH4, 3) 5 mM (S)-(2- boronoethyl)-L-cysteine +5 mM N ωy-nor-L-arginine to inhibit arginase, and 4) 20 mM N G-nitro-L-arginine methyl ester (L-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced. After a 1.0° in oral temperature (T or), mean body temperature was clamped and 20 mM L-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC =LDF/mean arterial pressure) and expressed as a percentage of maximum (%CVC max; 28 mM sodium nitroprusside and local heat, 43°asodilation was attenuated at the control site of the older subjects compared with young beginning at a 0.3° in Tor. BH 4 and arginase inhibition both increased vasodilation in older (BH 4: 55 ± 5%; arginaseinhibited: 47 ± 5% vs. control: 37 ± 3%, both P <1) but not young subjects compared with control (BH 4: 51 ± 4%CVC max; arginase-inhibited: 55 ± 4%CVC max vs. control: 56 ± 6%CVC max, both P <5) at a 1°e in Tor. With a 1°e in Tor, local BH 4 increased NO-dependent vasodilation in the older (BH 4: 31.8 ± 2.4%CVC max vs. control: 11.7 ± 2.0%CVC max, P <1) but not the young (BH 4: 23 ± 4%CVC max vs. control: 21 ± 4%CVC max, P =0.718) subject group. Together these data suggest that reduced BH 4 contributes to attenuated vasodilation in aged human skin and that BH 4 NOS coupling mechanisms may be a potential therapeutic target for increasing skin blood flow during hyperthermia in older humans.

UR - http://www.scopus.com/inward/record.url?scp=84859611770&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859611770&partnerID=8YFLogxK

U2 - 10.1152/japplphysiol.01257.2011

DO - 10.1152/japplphysiol.01257.2011

M3 - Article

C2 - 22162527

AN - SCOPUS:84859611770

VL - 112

SP - 791

EP - 797

JO - Journal of Applied Physiology

JF - Journal of Applied Physiology

SN - 8750-7587

IS - 5

ER -