Journal article
Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms
Journal of applied physiology (1985), Vol.115(7), pp.972-978
10/01/2013
DOI: 10.1152/japplphysiol.00481.2013
PMCID: PMC3798819
PMID: 23743404
Abstract
Functional constitutive nitric oxide synthase (NOS) and its cofactor tetrahydrobiopterin (BH4) are required for full reflex cutaneous vasodilation and are attenuated in primary aging. Acute, locally administered BH4 increases reflex vasodilation through NO-dependent mechanisms in aged skin. We hypothesized that oral sapropterin (Kuvan, shelfstable pharmaceutical formulation of BH4) would augment reflex vasodilation in aged human skin during hyperthermia. Nine healthy human subjects (76 +/- 1 yr) ingested sapropterin (10 mg/kg) or placebo in a randomized double-blind crossover design. Venous blood samples were collected prior to, and 3 h following, ingestion of sapropterin for measurement of plasma BH4. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of 1) lactated Ringer's solution, 2) 10 mM BH4, and 3) 20 mM N-G-nitro-L-arginine methyl ester (L-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced using a water-perfused suit. At 1 degrees C rise in oral temperature, mean body temperature was clamped and 20 mM L-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC = LDF/MAP) and expressed as a percentage of maximum (% CVCmax 28 mM sodium nitroprusside and local heat 43 degrees C). Plasma concentrations of BH4 were significantly elevated 3 h after ingestion of sapropterin (0 h: 19.1 +/- 2 pmol/ml vs. 3 h: 43.8 +/- 3 pmol/ml; P = 0.001). Sapropterin increased NO-dependent vasodilation at control site (placebo: 14 +/- 1 % CVCmax vs. sapropterin: 25 +/- 4 % CVCmax; P = 0.004). Local BH4 administration increased NO-dependent vasodilation compared with control in placebo trials only (control: 14 +/- 1 % CVCmax vs. BH4-treated: 24 +/- 3 % CVCmax; P = 0.02). These data suggest oral sapropterin increases bioavailable BH4 in aged skin microvasculature sufficiently to increase NO synthesis through NOS and that sapropterin may be a viable intervention to increase skin blood flow during hyperthermia in healthy aged humans.
Details
- Title: Subtitle
- Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms
- Creators
- Anna E. Stanhewicz - Pennsylvania State UniversityLacy M. Alexander - Pennsylvania State UniversityW. Larry Kenney - Pennsylvania State University
- Resource Type
- Journal article
- Publication Details
- Journal of applied physiology (1985), Vol.115(7), pp.972-978
- DOI
- 10.1152/japplphysiol.00481.2013
- PMID
- 23743404
- PMCID
- PMC3798819
- NLM abbreviation
- J Appl Physiol (1985)
- ISSN
- 8750-7587
- eISSN
- 1522-1601
- Publisher
- Amer Physiological Soc
- Number of pages
- 7
- Grant note
- R01-AG-07004-21 / National Institute on Aging; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) R01AG007004 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA)
- Language
- English
- Date published
- 10/01/2013
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Health, Sport, and Human Physiology ; Internal Medicine
- Record Identifier
- 9984259397002771
Metrics
2 Record Views