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

LA Holowatz, WL Kenney - The Journal of physiology, 2007 - Wiley Online Library
The Journal of physiology, 2007Wiley Online Library
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 …
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%CVCmax 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%CVCmaxversus 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%CVCmaxversus AMN, 23 ± 3%CVCmax, P < 0.05). The Δ%CVCmax between the control and NOS‐I sites was attenuated at ΔTor > 0.5°C in the HTN group (P < 0.001 versus AMN). A‐I alone augmented %CVCmax only in the HTN group (HTN, 65 ± 5%CVCmaxversus AMN, 48 ± 3%CVCmax, P < 0.05). l‐Arg alone did not affect %CVCmax in either group (HTN, 49 ± 5%CVCmaxversus 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%CVCmaxversus 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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