title: Tetrahydrobiopterin increases NO-dependent vasodilation in hypercholesterolemic human skin through eNOS-coupling mechanisms.
abstract: Localized exogenous R-tetrahydrobiopterin (R-BH(4)) corrects the deficit in local heat-induced vasodilation (VD) in hypercholesterolemic (HC) human skin through one of two plausible mechanisms: by serving as an essential cofactor to stabilizing endothelial nitric oxide (NO) synthase (eNOS) or through generalized antioxidant effects. We used the stereoisomer S-BH(4), which has the same antioxidant properties but does not function as an essential NOS cofactor, to elucidate the mechanism by which R-BH(4) restores cutaneous VD in HC humans. Intradermal microdialysis fibers were placed in 20 normocholesterolemic (NC), 13 midrange cholesterolemic (MC), and 18 HC (LDL: 94 ± 3, 124 ± 3 and 179 ± 6 mg/dl, respectively) men and women to perfuse Ringer (control site) and R-BH(4). In 10 NC, 13 MC, and 9 HC subjects (LDL: 94 ± 3, 124 ± 3, 180 ± 10 mg/dl), S-BH(4) was perfused at a third microdialysis site. Skin blood flow was measured during a standardized local heating protocol to elicit eNOS-dependent VD. After cutaneous vascular conductance (CVC = LDF/MAP) plateaued, NO-dependent VD was quantified by perfusing N(G)-nitro-l-arginine methyl ester (l-NAME). Data were normalized as %CVC(max). Fully expressed VD (NC: 97.9 ± 2.3 vs. MC: 85.4 ± 5.4, HC: 79.9 ± 4.2%CVC(max)) and the NO-dependent portion (NC: 62.1 ± 3 vs. MC: 45.8 ± 3.9, HC: 35.7 ± 2.8%CVC(max)) were reduced in HC (both P < 0.01 vs. NC), but only the fully expressed VD was reduced in MC (P < 0.01 vs. NC). R-BH(4) increased the fully expressed (93.9 ± 3.4%CVC(max); P < 0.01) and NO-dependent VD (52.1 ± 5.1%CVC(max); P < 0.01) in HC but not in NC or MC. S-BH(4) increased full-expressed VD in HC (P < 0.01) but did not affect NO-dependent VD in HC or MC. In contrast S-BH(4) attenuated NO-dependent VD in NC (control: 62.1 ± 3 vs. S-BH(4): 41.6 ± 7%CVC(max); P < 0.001). Exogenous R-BH(4) restores NO-dependent VD in HC human skin predominantly through NOS coupling mechanisms but increases full expression of the local heating response through generalized antioxidant properties.
authors.affiliation: Department of Kinesiology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. Lma191@psu.edu
authors.forename: Lacy M
authors.initials: LM
authors.lastname: Alexander
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Kutz
authors.forename: W Larry
authors.initials: WL
authors.lastname: Kenney
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D000975:Antioxidants / Q000494:pharmacology; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000201:enzymology* / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D017551:Microdialysis; D055806:Microvessels / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply*; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D001708:Biopterins; D009569:Nitric Oxide; D002784:Cholesterol; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin; D019331:NG-Nitroarginine Methyl Ester