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 language | English (US) |
|---|---|
| Pages (from-to) | 791-797 |
| Number of pages | 7 |
| Journal | Journal of Applied Physiology |
| Volume | 112 |
| Issue number | 5 |
| DOIs | |
| State | Published - Mar 1 2012 |
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All Science Journal Classification (ASJC) codes
- Physiology
- Physiology (medical)
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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 journal › Article
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.
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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 -