title: Local ascorbate administration augments NO- and non-NO-dependent reflex cutaneous vasodilation in hypertensive humans.
abstract: Full expression of reflex cutaneous vasodilation (VD) is dependent on nitric oxide (NO) and is attenuated with essential hypertension. Decreased NO-dependent VD may be due to 1) increased oxidant stress and/or 2) decreased L-arginine availability through upregulated arginase activity, potentially leading to increased superoxide production through uncoupled NO synthase (NOS). The purpose of this study was to determine the effect of antioxidant supplementation (alone and combined with arginase inhibition) on attenuated NO-dependent reflex cutaneous VD in hypertensive subjects. Nine unmedicated hypertensive [HT; mean arterial pressure (MAP) = 112 +/- 1 mmHg] and nine age-matched normotensive (NT; MAP = 81 +/- 10 mmHg) men and women were instrumented with four intradermal microdialysis (MD) fibers: control (Ringer), NOS inhibited (NOS-I; 10 mM N(G)-nitro-L-arginine), L-ascorbate supplemented (Asc; 10 mM L-ascorbate), and Asc + arginase inhibited [Asc+A-I; 10 mM L-ascorbate + 5 mM (S)-(2-boronoethyl)-L-cysteine-HCl + 5 mM N(omega)-hydroxy-nor-L-arginine]. Oral temperature was increased by 0.8 degrees C via a water-perfused suit. N(G)-nitro-L-arginine was then ultimately perfused through all MD sites to quantify the change in VD due to NO. Red blood cell flux was measured by laser-Doppler flowmetry over each skin MD site, and cutaneous vascular conductance (CVC) was calculated (CVC = flux/MAP) and normalized to maximal CVC (%CVC(max); 28 mM sodium nitroprusside + local heating to 43 degrees C). During the plateau in skin blood flow (Delta T(or) = 0.8 degrees C), cutaneous VD was attenuated in HT skin (NT: 42 +/- 4, HT: 35 +/- 3 %CVC(max); P < 0.05). Asc and Asc+A-I augmented cutaneous VD in HT (Asc: 57 +/- 5, Asc+A-I: 53 +/- 6 %CVC(max); P < 0.05 vs. control) but not in NT. %CVC(max) after NOS-I in the Asc- and Asc+A-I-treated sites was increased in HT (Asc: 41 +/- 4, Asc+A-I: 40 +/- 4, control: 29 +/- 4; P < 0.05). Compared with the control site, the change in %CVC(max) within each site after NOS-I was greater in HT (Asc: -19 +/- 4, Asc+A-I: -17 +/- 4, control: -9 +/- 2; P < 0.05) than in NT. Antioxidant supplementation alone or combined with arginase inhibition augments attenuated reflex cutaneous VD in hypertensive skin through NO- and non-NO-dependent mechanisms.
authors.affiliation: Noll Laboratory, The Pennsylvania State University, Univerisity 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: D000279:Administration, Cutaneous; D000975:Antioxidants / Q000008:administration & dosage*; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001205:Ascorbic Acid / Q000008:administration & dosage*; D001783:Blood Flow Velocity / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000294:innervation / Q000378:metabolism; D001897:Boronic Acids / Q000008:administration & dosage; D016022:Case-Control Studies; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005334:Fever / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D017078:Laser-Doppler Flowmetry; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D012018:Reflex / Q000187:drug effects*; D012867:Skin / Q000098:blood supply*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C425062:(2-boronoethyl)-cysteine; D000975:Antioxidants; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D001119:Arginase; D001205:Ascorbic Acid; D019331:NG-Nitroarginine Methyl Ester