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

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 (T-or) 1.0 degrees 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 degrees C). The Delta%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 similar to 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 Delta%CVCmax between the control and NOS-I sites was attenuated at Delta T-or > 0.5 degrees C in the HTN group (P < 0.001 versus AMN). A-I alone augmented %CVCmax 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.