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Exogenous Tetrahydrobiopterin Restores Cutaneous Vasodilation in Hypercholesterolemic Humans by Stabilizing eNOS
Author(s) -
Kutz Jessica Leigh,
Smith Caroline J.,
Holowatz Lacy A.,
Kenney W. Larry
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1084.6
Subject(s) - vasodilation , enos , microdialysis , chemistry , medicine , endocrinology , nitric oxide , population , tetrahydrobiopterin , perfusion , antioxidant , nitric oxide synthase , biochemistry , extracellular , environmental health
Local perfusion of exogenous BH 4 corrects the deficit in heat‐induced vasodilation (VD) in hypercholesterolemic human skin through one of two plausible mechanisms: by stabilizing eNOS or through generalized antioxidant effects. We used the stereoisomer S‐BH 4 , which has the same antioxidant properties but does not function as a NOS cofactor, to elucidate the mechanism by which BH 4 restores cutaneous VD in this population. Microdialysis fibers were placed in the skin of 17 normocholesterolemic (NC) and 15 hypercholesterolemic (LDL 91± 3 vs. 189±5 mg/dl) men and women to infuse Ringers (control site) and R‐BH 4 . In 6 NC and 6 HC subjects, S‐BH 4 was dialyzed at a third site. Skin blood flow was measured during local heating. After cutaneous vascular conductance (CVC) plateaued, the NO‐dependent proportion of the total VD was quantified by perfusing L‐NAME (ΔNO). Data were normalized as %CVC max . Fully‐expressed VD (NC: 98±2 vs. HC: 72±5%CVC max ) and the NO‐dependent portion (NC: 63±4 vs. HC: 47±4%CVC max ) were reduced in HC (both p<0.001). R‐BH 4 increased full (94±4%CVC max ; p<0.001) and NO‐dependent VD (59±6%CVC max ; p<0.001) in HC but not in NC. S‐BH 4 increased full (88±6%CVC max, p=0.04) but not NO‐dependent vasodilation (37±9%CVC max ; p=0.3) in HC. Exogenous BH 4 restores NO‐dependent VD in hypercholesterolemic human skin through NOS coupling mechanisms, not through generalized antioxidant properties.