Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease

Abstract

Peripheral arterial disease (PAD) results in a failure to adequately supply blood and oxygen (O(2)) to working tissues and presents as claudication pain during walking. Nitric oxide (NO) bioavailability is essential for vascular health and function. Plasma nitrite (NO(2)(-)) is a marker of vascular NO production but may also be a protected circulating "source" that can be converted to NO during hypoxic conditions, possibly aiding perfusion. We hypothesized that dietary supplementation of inorganic nitrate in the form of beetroot (BR) juice would increase plasma NO(2)(-) concentration, increase exercise tolerance, and decrease gastrocnemius fractional O(2) extraction, compared with placebo (PL). This was a randomized, open-label, crossover study. At each visit, subjects (n = 8) underwent resting blood draws, followed by consumption of 500 ml BR or PL and subsequent blood draws prior to, during, and following a maximal cardiopulmonary exercise (CPX) test. Gastrocnemius oxygenation during the CPX was measured by near-infrared spectroscopy. There were no changes from rest for [NO(2)(-)] (152 ± 72 nM) following PL. BR increased plasma [NO(2)(-)] after 3 h (943 ± 826 nM; P ≤ 0.01). Subjects walked 18% longer before the onset of claudication pain (183 ± 84 s vs. 215 ± 99 s; P ≤ 0.01) and had a 17% longer peak walking time (467 ± 223 s vs. 533 ± 233 s; P ≤ 0.05) following BR vs. PL. Gastrocnemius tissue fractional O(2) extraction was lower during exercise following BR (7.3 ± 6.2 vs. 10.4 ± 6.1 arbitrary units; P ≤ 0.01). Diastolic blood pressure was lower in the BR group at rest and during CPX testing (P ≤ 0.05). These findings support the hypothesis that NO(2)(-)-related NO signaling increases peripheral tissue oxygenation in areas of hypoxia and increases exercise tolerance in PAD.

Figures

Fig. 1.

Plasma nitrate (NO3−; A) and nitrite (NO2−; B) concentrations prior to (baseline) and following consumption of a high NO3− beetroot (BR; ●) or placebo (PL; ○) beverage. Three hours/cardiopulmonary exercise (CPX) base indicates the time point 3 h following beverage consumption, which was also just prior to commencement of the CPX test. Peak, immediately at time to exhaustion; rec, 10 min after time to exhaustion. Values are group mean ± SE. *significantly different from PL group, P ≤ 0.05; **significantly different from PL group, P ≤ 0.01; #significantly different from baseline, P ≤ 0.05.

Fig. 2.

Absolute change in (A) claudication onset time and (B) peak walk time (PWT) during a maximal CPX following PL and BR beverage. (C) The relationship between change (ch) in plasma [NO2−] from baseline to peak (∼3 h) following BR beverage and change in PWT (ΔPWT). Values are group mean ± SE. *significantly different from PL group, P ≤ 0.05; **significantly different from PL group, P ≤ 0.01.

Fig. 3.

Group mean changes in the parameters of gastrocnemius muscle oxygenation measured by near-infrared spectroscopy during a maximal CPX following PL (○) and BR (●) beverage. The data represent 2 stages of the maximal CPX test (grade increased at 120 s). The average data are only shown up to 200 s, as this is the point at which some subjects reached PWT and had to stop. The dotted lines represent the difference in peak amplitude change for the fitted curve of (A) deoxyhemoglobin concentration [HHb] on data from stage 1 only, (B) oxyhemoglobin concentration [HbO2], and (C) total hemoglobin concentration [tHb]. Error bars are not shown for clarity (see Table 1 for further details). AU, arbitrary units. **significantly different from PL group, P ≤ 0.01.

Fig. 4.

Group mean diastolic (A) and systolic (B) blood pressures, heart rate (HR; C), and oxygen consumption (VO2; D) prior to and following consumption of a BR (●) or PL (○) beverage. Three hours/CPX base indicates the time point 3 h following beverage consumption, which was also at rest just prior to commencement of the CPX. The dashed vertical lines represent the start and end of exercise. CPX stages 2 (2 mph/2%) and 4 (2 mph/6%) indicate stages of the CPX when measures were taken. Stages 2 and 4 are measures that are matched for work level. Peak indicates the measure taken immediately prior to test termination (which was at a different intensity for BR or PL). The measures taken at time points after time to exhaustion are 2- and 6-min recovery. Values are group mean ± SE. *significantly different from PL group, P ≤ 0.05; **significantly different from PL group, P ≤ 0.01.

Fig. 5.

Resting brachial artery diameters (Rest Diam; mm) and endothelial function (% dilation) to a hyperemic stimulus following consumption of a BR (●) or PL (○) beverage. Resting diameter is millimeters on the left y-axis; peak is maximal percent change in artery diameter from baseline regardless of time point; and 60 s and 120 s are the percent changes in artery diameter from baseline at specific time points on the right y-axis. Values are group mean ± SE.