Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans

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Abstract

Reflex cutaneous vasodilatation is dependent on nitric oxide (NO), which is diminished in hypertension (HTN). Arginase may be up-regulated with HTN, which preferentially metabolizes L-arginine L-arg), competing with NO-synthase (NOS)-mediated pathways and limiting NO synthesis. We hypothesized that NO-dependent vasodilatation would be attenuated in HTN skin, and arginase inhibition (A-I) alone or with concurrent L-arginine supplementation, would augment vasodilatation. Five microdialysis fibres were placed in skin of eight unmedicated subjects with HTN (mean arterial pressure (MAP), 112 ± 1 mmHg) and nine age-matched normotensive (AMN) (MAP: 87 ± 1 mmHg) men and women to serve as: control (C, Ringer solution), NOS inhibited (NOS-I, 10 mm L-NAME), A-I (5 mm BEC + 5 mm nor-NOHA), L-arg supplemented (L-arg, 10 mm L-arg), and combined A-I + L-arg. Reflex vasodilatation was induced by using a water-perfused suit to increase oral temperature (Tor) 1.0°C. Red cell flux was measured by laser-Doppler flowmetry over each site. Cutaneous vascular conductance was calculated (CVC = flux/MAP) and normalized to maximal CVC (28 mm SNP + local heating to 43°C). The δ%CVC max between the control and NOS-I site was calculated as the difference between C and NOS-I sites. Maximal CVC was attenuated in the HTN subjects by ∼25% compared with AMN subjects (P < 0.001). Throughout, whole body heating %CVCmax was not different between the groups (HTN, 43 ± 3%CVCmax versus AMN, 45 ± 3%CVCmax, P > 0.05). NOS-I significantly decreased %CVCmax in both groups but %CVCmax was greater in the HTN group (HTN, 32 ± 4%CVCmax versus AMN, 23 ± 3%CVCmax, P < 0.05). The δ%CVCmax between the control and NOS-I sites was attenuated at δ Tor > 0.5°C in the HTN group (P < 0.001 versus AMN). A-I alone augmented %CVC max only in the HTN group (HTN, 65 ± 5%CVCmax versus AMN, 48 ± 3%CVCmax, P < 0.05). L-Arg alone did not affect %CVCmax in either group (HTN, 49 ± 5%CVCmax versus AMN, 49 ± 3%CVCmax, P > 0.05). Combined A-I + L-arg augmented %CVCmax in both subject groups compared with their respective control sites (HTN, 60 ± 7%CVCmax versus AMN, 61 ± 3%CVCmax, both P < 0.05 versus respective control sites). Vasodilatation is attenuated with HTN due to decreased NO-dependent vasodilatation and can be augmented with arginase inhibition but not L-arg supplementation, suggesting that arginase is up-regulated with HTN.

Original languageEnglish (US)
Pages (from-to)863-872
Number of pages10
JournalJournal of Physiology
Volume581
Issue number2
DOIs
StatePublished - Jun 1 2007

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Arginase
Vasodilation
Reflex
Up-Regulation
Hypertension
Skin
Nitric Oxide Synthase
Glycogen Synthase
Nitric Oxide
Arterial Pressure
Arginine
Laser-Doppler Flowmetry
NG-Nitroarginine Methyl Ester
Microdialysis
Heating
Single Nucleotide Polymorphism
Blood Vessels
Inhibition (Psychology)

All Science Journal Classification (ASJC) codes

  • Physiology

Cite this

@article{b20564fdb4f6413fb6504e7f5aabb564,
title = "Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans",
abstract = "Reflex cutaneous vasodilatation is dependent on nitric oxide (NO), which is diminished in hypertension (HTN). Arginase may be up-regulated with HTN, which preferentially metabolizes L-arginine L-arg), competing with NO-synthase (NOS)-mediated pathways and limiting NO synthesis. We hypothesized that NO-dependent vasodilatation would be attenuated in HTN skin, and arginase inhibition (A-I) alone or with concurrent L-arginine supplementation, would augment vasodilatation. Five microdialysis fibres were placed in skin of eight unmedicated subjects with HTN (mean arterial pressure (MAP), 112 ± 1 mmHg) and nine age-matched normotensive (AMN) (MAP: 87 ± 1 mmHg) men and women to serve as: control (C, Ringer solution), NOS inhibited (NOS-I, 10 mm L-NAME), A-I (5 mm BEC + 5 mm nor-NOHA), L-arg supplemented (L-arg, 10 mm L-arg), and combined A-I + L-arg. Reflex vasodilatation was induced by using a water-perfused suit to increase oral temperature (Tor) 1.0°C. Red cell flux was measured by laser-Doppler flowmetry over each site. Cutaneous vascular conductance was calculated (CVC = flux/MAP) and normalized to maximal CVC (28 mm SNP + local heating to 43°C). The δ{\%}CVC max between the control and NOS-I site was calculated as the difference between C and NOS-I sites. Maximal CVC was attenuated in the HTN subjects by ∼25{\%} compared with AMN subjects (P < 0.001). Throughout, whole body heating {\%}CVCmax was not different between the groups (HTN, 43 ± 3{\%}CVCmax versus AMN, 45 ± 3{\%}CVCmax, P > 0.05). NOS-I significantly decreased {\%}CVCmax in both groups but {\%}CVCmax was greater in the HTN group (HTN, 32 ± 4{\%}CVCmax versus AMN, 23 ± 3{\%}CVCmax, P < 0.05). The δ{\%}CVCmax between the control and NOS-I sites was attenuated at δ Tor > 0.5°C in the HTN group (P < 0.001 versus AMN). A-I alone augmented {\%}CVC max only in the HTN group (HTN, 65 ± 5{\%}CVCmax versus AMN, 48 ± 3{\%}CVCmax, P < 0.05). L-Arg alone did not affect {\%}CVCmax in either group (HTN, 49 ± 5{\%}CVCmax versus AMN, 49 ± 3{\%}CVCmax, P > 0.05). Combined A-I + L-arg augmented {\%}CVCmax in both subject groups compared with their respective control sites (HTN, 60 ± 7{\%}CVCmax versus AMN, 61 ± 3{\%}CVCmax, both P < 0.05 versus respective control sites). Vasodilatation is attenuated with HTN due to decreased NO-dependent vasodilatation and can be augmented with arginase inhibition but not L-arg supplementation, suggesting that arginase is up-regulated with HTN.",
author = "Alexander, {Lacy Marie} and {Kenney, Jr.}, {William Lawrence}",
year = "2007",
month = "6",
day = "1",
doi = "10.1113/jphysiol.2007.128959",
language = "English (US)",
volume = "581",
pages = "863--872",
journal = "Journal of Physiology",
issn = "0022-3751",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans

AU - Alexander, Lacy Marie

AU - Kenney, Jr., William Lawrence

PY - 2007/6/1

Y1 - 2007/6/1

N2 - Reflex cutaneous vasodilatation is dependent on nitric oxide (NO), which is diminished in hypertension (HTN). Arginase may be up-regulated with HTN, which preferentially metabolizes L-arginine L-arg), competing with NO-synthase (NOS)-mediated pathways and limiting NO synthesis. We hypothesized that NO-dependent vasodilatation would be attenuated in HTN skin, and arginase inhibition (A-I) alone or with concurrent L-arginine supplementation, would augment vasodilatation. Five microdialysis fibres were placed in skin of eight unmedicated subjects with HTN (mean arterial pressure (MAP), 112 ± 1 mmHg) and nine age-matched normotensive (AMN) (MAP: 87 ± 1 mmHg) men and women to serve as: control (C, Ringer solution), NOS inhibited (NOS-I, 10 mm L-NAME), A-I (5 mm BEC + 5 mm nor-NOHA), L-arg supplemented (L-arg, 10 mm L-arg), and combined A-I + L-arg. Reflex vasodilatation was induced by using a water-perfused suit to increase oral temperature (Tor) 1.0°C. Red cell flux was measured by laser-Doppler flowmetry over each site. Cutaneous vascular conductance was calculated (CVC = flux/MAP) and normalized to maximal CVC (28 mm SNP + local heating to 43°C). The δ%CVC max between the control and NOS-I site was calculated as the difference between C and NOS-I sites. Maximal CVC was attenuated in the HTN subjects by ∼25% compared with AMN subjects (P < 0.001). Throughout, whole body heating %CVCmax was not different between the groups (HTN, 43 ± 3%CVCmax versus AMN, 45 ± 3%CVCmax, P > 0.05). NOS-I significantly decreased %CVCmax in both groups but %CVCmax was greater in the HTN group (HTN, 32 ± 4%CVCmax versus AMN, 23 ± 3%CVCmax, P < 0.05). The δ%CVCmax between the control and NOS-I sites was attenuated at δ Tor > 0.5°C in the HTN group (P < 0.001 versus AMN). A-I alone augmented %CVC max only in the HTN group (HTN, 65 ± 5%CVCmax versus AMN, 48 ± 3%CVCmax, P < 0.05). L-Arg alone did not affect %CVCmax in either group (HTN, 49 ± 5%CVCmax versus AMN, 49 ± 3%CVCmax, P > 0.05). Combined A-I + L-arg augmented %CVCmax in both subject groups compared with their respective control sites (HTN, 60 ± 7%CVCmax versus AMN, 61 ± 3%CVCmax, both P < 0.05 versus respective control sites). Vasodilatation is attenuated with HTN due to decreased NO-dependent vasodilatation and can be augmented with arginase inhibition but not L-arg supplementation, suggesting that arginase is up-regulated with HTN.

AB - Reflex cutaneous vasodilatation is dependent on nitric oxide (NO), which is diminished in hypertension (HTN). Arginase may be up-regulated with HTN, which preferentially metabolizes L-arginine L-arg), competing with NO-synthase (NOS)-mediated pathways and limiting NO synthesis. We hypothesized that NO-dependent vasodilatation would be attenuated in HTN skin, and arginase inhibition (A-I) alone or with concurrent L-arginine supplementation, would augment vasodilatation. Five microdialysis fibres were placed in skin of eight unmedicated subjects with HTN (mean arterial pressure (MAP), 112 ± 1 mmHg) and nine age-matched normotensive (AMN) (MAP: 87 ± 1 mmHg) men and women to serve as: control (C, Ringer solution), NOS inhibited (NOS-I, 10 mm L-NAME), A-I (5 mm BEC + 5 mm nor-NOHA), L-arg supplemented (L-arg, 10 mm L-arg), and combined A-I + L-arg. Reflex vasodilatation was induced by using a water-perfused suit to increase oral temperature (Tor) 1.0°C. Red cell flux was measured by laser-Doppler flowmetry over each site. Cutaneous vascular conductance was calculated (CVC = flux/MAP) and normalized to maximal CVC (28 mm SNP + local heating to 43°C). The δ%CVC max between the control and NOS-I site was calculated as the difference between C and NOS-I sites. Maximal CVC was attenuated in the HTN subjects by ∼25% compared with AMN subjects (P < 0.001). Throughout, whole body heating %CVCmax was not different between the groups (HTN, 43 ± 3%CVCmax versus AMN, 45 ± 3%CVCmax, P > 0.05). NOS-I significantly decreased %CVCmax in both groups but %CVCmax was greater in the HTN group (HTN, 32 ± 4%CVCmax versus AMN, 23 ± 3%CVCmax, P < 0.05). The δ%CVCmax between the control and NOS-I sites was attenuated at δ Tor > 0.5°C in the HTN group (P < 0.001 versus AMN). A-I alone augmented %CVC max only in the HTN group (HTN, 65 ± 5%CVCmax versus AMN, 48 ± 3%CVCmax, P < 0.05). L-Arg alone did not affect %CVCmax in either group (HTN, 49 ± 5%CVCmax versus AMN, 49 ± 3%CVCmax, P > 0.05). Combined A-I + L-arg augmented %CVCmax in both subject groups compared with their respective control sites (HTN, 60 ± 7%CVCmax versus AMN, 61 ± 3%CVCmax, both P < 0.05 versus respective control sites). Vasodilatation is attenuated with HTN due to decreased NO-dependent vasodilatation and can be augmented with arginase inhibition but not L-arg supplementation, suggesting that arginase is up-regulated with HTN.

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