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.

INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction)

“…40-45 Inorganic nitrate and nitrite improve skeletal muscle microvascular conductance during exercise 46 and increase capillary O 2 tension facilitating O 2 diffusion into muscle cells. 47 Nitrite increases mitochondrial efficiency in skeletal muscle 48 and improves insulin sensitivity and glucose uptake.…”

“…1, 2, 34, 60, 61 In contrast, inorganic nitrate and nitrite have been shown to improve endothelium-dependent vasodilation in humans. 43, 45 …”

Nutrition and other lifestyle influences on arterial aging

“…Indeed, short-term supplementation with nitrite restores endothelial function and reverses arterial stiffening in old mice by increasing NO bioavailability, reducing oxidative stress and normalizing structural proteins (Sindler et al, 2011). Moreover, recent reports show that supplementation with nitrite (DeVan et al, 2016) and nitrate (Rammos et al, 2014) improves endothelial function in middle-aged/older adults without clinical CVD. Nitrite seems particularly promising, as it also is reported to improve motor (neuromuscular) and cognitive functions (Justice et al, 2015), and larger trials to establish efficacy and broader mechanisms are underway (clinicaltrials.gov/ct2/show/NCT02393742).…”

Effect of sodium nitrite on local control of contracting skeletal muscle microvascular oxygen pressure in healthy rats

“…However, elevating circulating [NO 2 Ϫ ] via dietary means takes 2-3 h, which may constitute too great a delay for an effective therapeutic outcome. A potential alternative is oral administration of NaNO 2 , which elevates circulating [NO 2 Ϫ ] within 30 min in older adults (16) and diabetic patients (26). More direct routes of NaNO 2 (i.e., intravascular infusion or oral administration) can bypass the need for bacterial breakdown of NO 3 Ϫ and absorption in the gut and increase vascular [NO 2 Ϫ ] rapidly.…”

“…Ϫ on systemic blood pressure have been inconclusive with adults and CHF patients reporting no change (7,16,25) while a modest, transient decrease in MAP has been reported in diabetic patients and during L-NAME induced NOS blockade (20,26).…”