Effects of sodium nitrite supplementation on vascular function and related small metabolite signatures in middle-aged and older adults

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.