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°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 %CVC_max was not different between the groups (HTN, 43 ± 3%CVC_max versus AMN, 45 ± 3%CVC_max, P > 0.05). NOS-I significantly decreased %CVC_max in both groups but %CVC_max was greater in the HTN group (HTN, 32 ± 4%CVC_max versus AMN, 23 ± 3%CVC_max, P < 0.05). The δ%CVC_max between the control and NOS-I sites was attenuated at δ T_or > 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%CVC_max versus AMN, 48 ± 3%CVC_max, P < 0.05). L-Arg alone did not affect %CVC_max in either group (HTN, 49 ± 5%CVC_max versus AMN, 49 ± 3%CVC_max, P > 0.05). Combined A-I + L-arg augmented %CVC_max in both subject groups compared with their respective control sites (HTN, 60 ± 7%CVC_max versus AMN, 61 ± 3%CVC_max, 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.