title: Oral atorvastatin therapy increases nitric oxide-dependent cutaneous vasodilation in humans by decreasing ascorbate-sensitive oxidants.
abstract: Elevated low-density lipoproteins (LDL) are associated with cutaneous microvascular dysfunction partially mediated by increased arginase activity, which is decreased following a systemic atorvastatin therapy. We hypothesized that increased ascorbate-sensitive oxidant stress, partially mediated through uncoupled nitric oxide synthase (NOS) induced by upregulated arginase, contributes to cutaneous microvascular dysfunction in hypercholesterolemic (HC) humans. Four microdialysis fibers were placed in the skin of nine HC (LDL = 177 ± 6 mg/dl) men and women before and after 3 mo of a systemic atorvastatin intervention and at baseline in nine normocholesterolemic (NC) (LDL = 95 ± 4 mg/dl) subjects. Sites served as control, NOS inhibited, L-ascorbate, and arginase-inhibited+L-ascorbate. Skin blood flow was measured while local skin heating (42°C) induced NO-dependent vasodilation. After the established plateau in all sites, 20 mM ≪ngname≫ was infused to quantify NO-dependent vasodilation. Data were normalized to maximum cutaneous vascular conductance (CVC) (sodium nitroprusside + 43°C). The plateau in vasodilation during local heating (HC: 78 ± 4 vs. NC: 96 ± 2% CVC(max), P < 0.01) and NO-dependent vasodilation (HC: 40 ± 4 vs. NC: 54 ± 4% CVC(max), P < 0.01) was reduced in the HC group. Acute L-ascorbate alone (91 ± 5% CVC(max), P < 0.001) or combined with arginase inhibition (96 ± 3% CVC(max), P < 0.001) augmented the plateau in vasodilation in the HC group but not the NC group (ascorbate: 96 ± 2; combo: 93 ± 4% CVC(max), both P > 0.05). After the atorvastatin intervention NO-dependent vasodilation was augmented in the HC group (HC postatorvastatin: 64 ± 4% CVC(max), P < 0.01), and there was no further effect of ascorbate alone (58 ± 4% CVC(max,) P > 0.05) or combined with arginase inhibition (67 ± 4% CVC(max,) P > 0.05). Increased ascorbate-sensitive oxidants contribute to hypercholesteromic associated cutaneous microvascular dysfunction which is partially reversed with atorvastatin therapy.
authors.affiliation: Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania, 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: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000975:Antioxidants / Q000008:administration & dosage*; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism; D001205:Ascorbic Acid / Q000008:administration & dosage*; D000069059:Atorvastatin; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006361:Heating; D006538:Heptanoic Acids / Q000008:administration & dosage*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D017551:Microdialysis; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010414:Pennsylvania; D011758:Pyrroles / Q000008:administration & dosage*; D012867:Skin / Q000098:blood supply*; D013997:Time Factors; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase; D001119:Arginase; D001205:Ascorbic Acid