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 (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%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 approximately 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 Delta%CVC(max) between the control and NOS-I sites was attenuated at DeltaT(or) > 0.5 degrees 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.
authors.affiliation: Pennsylvania State University, Noll Laboratory, Department of Kinesiology, University Park, PA 16802, USA. lma191@psu.edu
authors.forename: Lacy A
authors.initials: LA
authors.lastname: Holowatz
authors.forename: W Larry
authors.initials: WL
authors.lastname: Kenney
mesh_terms: D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D001783:Blood Flow Velocity; D001831:Body Temperature; D001897:Boronic Acids / Q000494:pharmacology; D016022:Case-Control Studies; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D012018:Reflex / Q000187:drug effects; D012867:Skin / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects
chemical_list: C425062:(2-boronoethyl)-cysteine; D001897:Boronic Acids; D004791:Enzyme Inhibitors; C404735:N(omega)-hydroxynorarginine; D001120:Arginine; D001119:Arginase; D019331:NG-Nitroarginine Methyl Ester