Inorganic nitrate supplementation improves exercise tolerance and calf vascular function in patients with peripheral artery disease

Abstract

Peripheral artery disease (PAD) is characterized by widespread atherosclerotic development and endothelial dysfunction in the vasculature. This pathological process leads to hypoperfusion of local tissues, increases dependence on anaerobic metabolism, and induces the hallmark symptom of PAD; ischemic claudication. Additionally, PAD is associated with reductions in the bioavailability of nitric oxide (NO), a known regulator of vasodilator function. Together, ischemic claudication and reduced NO bioavailability attenuate exercise tolerance in PAD patients. Inorganic nitrate (NO3−) supplementation boosts NO bioavailability independent of NO‐synthase enzymes, subsequently improving vasodilator function and enhancing skeletal muscle oxygenation. Thus, inorganic NO3− supplementation may improve exercise tolerance in PAD patients. We therefore investigated if eight weeks of sodium NO3− (NaNO3) supplementation would improve exercise tolerance (six‐minute walk test, 6MWT) as well as calf blood flow or vasodilation in response to reactive hyperemia (strain gauge plethysmography) in patients with PAD. Twenty‐one patients diagnosed with moderate‐to‐severe PAD (ankle‐brachial index 0.80±0.07) were randomly assigned to NaNO3 (1g/day; n=13) or placebo (microcrystalline cellulose; n=8) supplementation groups. Eight weeks of NaNO3 supplementation elevated plasma NO3− (32.3±5.6 to 379.8±56.7μmol/L) and nitrite (192.2±15.0 to 353.1±38.7 nmol/L), improved 6MWT distance (387±26 to 425±24 m), peak calf blood flow (BFPeak, 11.6±1.5 to 14.1±1.5 mL/100 mL tissue/min), and peak calf vascular conductance (VCPeak, 11.1±1.3 to 14.2±1.5 mL/dL tissue/min/mmHg, P<0.05 for all). Moreover, improvements in 6MWT distance correlated with calf BFPeak (r=0.70) and VCPeak (r=0.61, P<0.05 for both). Placebo supplementation did not change any of the outcome measures (P=0.22 to 0.92). Neither NaNO3 nor placebo supplementation changed total calf blood flow (P=0.11) or conductance (P=0.18). These data demonstrate that eight weeks of inorganic NO3− supplementation elicits a clinically‐significant improvement in exercise tolerance which correlated to improvements in blood flow and vasodilator function in the lower limbs of patients with PAD.Support or Funding InformationThis study was supported by the American Heart Association 13GRNT16490002 (D.P.C.) and National Institutes of Health Clinical and Translational Science Award U54TR001356.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.