Inorganic Nitrate Supplementation Increases Skeletal Muscle Perfusion And Metabolism During Exercise In Peripheral Arterial Disease

Individuals with symptomatic peripheral artery disease (PAD) experience claudication pain when walking and have a markedly impaired quality of life. A primary goal of therapy is to increase pain-free ambulation. Current evidence suggests uncoupling of skeletal muscle metabolism from tissue perfusion impairs exercise tolerance, partly due to reduced levels of bioavailable nitric oxide (NO). Oral inorganic nitrate (NO3-) supplementation restores NO bioavailability in individuals with PAD resulting in improved claudication symptoms and walking capacity. The underlying mechanisms have not been fully elucidated. PURPOSE: To determine the effects of oral NO3- supplementation on skeletal muscle perfusion and oxidative capacity in individuals with PAD. METHODS: In a double-blind, randomized, crossover design, five male patients (72.2 ± 5.2 years) with symptomatic PAD underwent a treadmill and magnetic resonance imaging (MRI) test after consuming ~5 days of 13 mmol NO3- supplementation (BRJ) or identical NO3--depleted placebo (PL) and again 2-hours prior to testing. On one day, resting blood draw and a cardiopulmonary treadmill exercise test were completed. At least 48 hours later, plantar flexion exercise was performed until claudication symptoms within an MRI-compatible ergometer. Skeletal muscle perfusion using Arterial Spin Labelling (ASL-MRI) and oxidative capacity using Chemical Exchange Saturation Transfer (CEST) were measured immediately at the cessation of exercise. RESULTS: Following BRJ, plasma nitrite (NO2-) concentration increased significantly compared to PL (410.5 ± 237.5 v 156.3 ± 45.4 nM; p < 0.01, respectively). There was a trend towards longer pain-free walking (+30%) after BRJ supplementation (312.8 ± 207.3 v 238.5 ± 197.8 sec; Cohens d = 0.37) with no change in peak walking time (585.8 ± 56 v 589.5 ± 103.6 sec; p = 0.94). BRJ also tended to demonstrate higher tissue perfusion at peak plantar flexion exercise (+32%; 22.9 ± 17.4 v 17.4 ± 10.5 mL/min/100 g; d = 0.40) and faster CEST asymmetry decay times (196.0 ± 99.4 v 247.6 ± 145.1, d = 0.44). CONCLUSION: These preliminary findings support the hypothesis that oral NO3- supplementation may increase NO2-/NO signaling, improve skeletal muscle perfusion and oxidative capacity, and increase pain-free walking in individuals with symptomatic PAD. Three Cavaliers Award, Office of Vice President for Research, UVA