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Acute oral sapropterin (Kuvan®) augments NO‐dependent reflex vasodilation in aged human skin
Author(s) -
Stanhewicz Anna Elizabeth,
Alexander Lacy M,
Kenney W. Larry
Publication year - 2013
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.27.1_supplement.1133.12
Subject(s) - vasodilation , sodium nitroprusside , reflex , microdialysis , bioavailability , nitric oxide , nitric oxide synthase , placebo , medicine , crossover study , chemistry , anesthesia , endocrinology , pharmacology , pathology , alternative medicine , central nervous system
Nitric oxide‐synthase (NOS) and its essential cofactor tetrahydrobiopterin (BH 4 ) are required for full expression of reflex cutaneous vasodilation (VD). BH 4 bioavailability is reduced with aging, as is VD. We hypothesized that oral sapropterin (S; BH 4 sold as Kuvan®) would augment NO‐dependent VD in aged skin. Seven subjects (76±3 yrs) ingested S (10mg/kg) or placebo (P) in a randomized double‐blind crossover study design. Three microdialysis fibers were placed in the forearm skin for local delivery of Ringer's solution (control), 10mM BH 4 , or 20mM L‐NAME (NOS inhibitor). Three h later, red cell flux was measured over each site by laser‐Doppler flowmetry (LDF) as reflex VD was induced using a water perfused suit. At a 1°C rise in oral temperature (T or ) body temperature was clamped and L‐NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC = LDF/MAP) and normalized to maximum (sodium nitroprusside). S increased VD at the control site (S: 50±4 vs. P: 33±2%CVCmax; p<0.001). Locally adding additional BH 4 increased VD in the P trial only (P: 49±5 vs. S: 49±6%CVCmax; p=0.86). At a 1°C rise in T or S increased NOS‐dependent VD in the control site (S: 27±4 vs. P: 14±2 %CVCmax; p=0.008). Acute oral sapropterin increases NO‐dependent reflex VD in aged skin, suggesting that oral BH 4 becomes bioavailable in aged skin microvasculature sufficiently to increase NO synthesis through NOS. NIH RO1‐AG07004–25