title: Effects of sodium nitrite supplementation on vascular function and related small metabolite signatures in middle-aged and older adults.
abstract: Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction and arterial stiffening with aging. Supplementation with sodium nitrite, a precursor of NO, ameliorates age-related vascular endothelial dysfunction and arterial stiffness in mice, but effects on humans, including the metabolic pathways altered, are unknown. The purpose of this study was to determine the safety, feasibility, and efficacy of oral sodium nitrite supplementation for improving vascular function in middle-aged and older adults and to identify related circulating metabolites. Ten weeks of sodium nitrite (80 or 160 mg/day, capsules, TheraVasc; randomized, placebo control, double blind) increased plasma nitrite acutely (5- to 15-fold, P < 0.001 vs. placebo) and chronically (P < 0.10) and was well tolerated without symptomatic hypotension or clinically relevant elevations in blood methemoglobin. Endothelial function, measured by brachial artery flow-mediated dilation, increased 45-60% vs. baseline (P < 0.10) without changes in body mass or blood lipids. Measures of carotid artery elasticity (ultrasound and applanation tonometry) improved (decreased β-stiffness index, increased cross-sectional compliance, P < 0.05) without changes in brachial or carotid artery blood pressure. Aortic pulse wave velocity was unchanged. Nitrite-induced changes in vascular measures were significantly related to 11 plasma metabolites identified by untargeted analysis. Baseline abundance of multiple metabolites, including glycerophospholipids and fatty acyls, predicted vascular changes with nitrite. This study provides evidence that sodium nitrite supplementation is well tolerated, increases plasma nitrite concentrations, improves endothelial function, and lessens carotid artery stiffening in middle-aged and older adults, perhaps by altering multiple metabolic pathways, thereby warranting a larger clinical trial.
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado; adevan@mcw.edu.
authors.forename: Allison E
authors.initials: AE
authors.lastname: DeVan
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Johnson
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Forrest A
authors.initials: FA
authors.lastname: Brooks
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Trent D
authors.initials: TD
authors.lastname: Evans
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Justice
authors.affiliation: Integrated Department of Immunology, National Jewish Health, Denver, Colorado;
authors.forename: Charmion
authors.initials: C
authors.lastname: Cruickshank-Quinn
authors.affiliation: Integrated Department of Immunology, National Jewish Health, Denver, Colorado;
authors.forename: Nichole
authors.initials: N
authors.lastname: Reisdorph
authors.affiliation: Baylor College of Medicine, Houston, Texas;
authors.forename: Nathan S
authors.initials: NS
authors.lastname: Bryan
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Matthew B
authors.initials: MB
authors.lastname: McQueen
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Santos-Parker
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado;
authors.forename: Michel B
authors.initials: MB
authors.lastname: Chonchol
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Candace J
authors.initials: CJ
authors.lastname: Bassett
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Amy L
authors.initials: AL
authors.lastname: Sindler
authors.affiliation: TheraVasc, Cleveland, Ohio.
authors.forename: Tony
authors.initials: T
authors.lastname: Giordano
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado;
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Seals
mesh_terms: D000368:Aged; D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015992:Body Mass Index; D001916:Brachial Artery / Q000187:drug effects / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism; D019587:Dietary Supplements; D004311:Double-Blind Method; D004548:Elasticity / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008706:Methemoglobin / Q000378:metabolism; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D063177:Pulse Wave Analysis / Q000379:methods; D012977:Sodium Nitrite / Q000494:pharmacology*; D059289:Vascular Stiffness / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D009569:Nitric Oxide; D008706:Methemoglobin; D012977:Sodium Nitrite
keywords: arterial stiffness; endothelial dysfunction; metabolomics