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.

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WR, Annex BH. Relationship between leg muscle capillary density and peak hyperemic blood flow with endurance capacity in peripheral artery disease. J Appl Physiol 111: 81-86, 2011. First published April 21, 2011 doi:10.1152/japplphysiol.00141.2011.-The aim of this study was to determine if skeletal muscle capillary density is lower in patients with peripheral artery disease (PAD) and if capillary density relates to functional limitations. PAD patients with intermittent claudication (IC) have a decreased exercise tolerance due to exerciseinduced muscle ischemia. Despite the apparent role diminished arterial flow has in this population, the degree of walking pain and functional limitation is not entirely explained by altered hemodynamics of the affected limbs. We hypothesized that skeletal muscle capillary density is lower in PAD and is related to the functional impairment observed in this population. Sixty-four patients with PAD and 56 controls underwent cardiopulmonary exercise testing and a gastrocnemius muscle biopsy. A subset of these patients (48 PAD and 47 controls) underwent peak hyperemic flow testing via plethysmography. Capillary density in PAD patients was lower compared with controls (P Ͻ 0.001). After adjustment for several baseline demographic imbalances the model relating capillary density to peak oxygen consumption (V O2) remained significant (P Ͻ 0.001). In PAD subjects, capillary density correlated with peak V O2, peak walking time (PWT), and claudication onset time (COT). Peak hyperemic blood flow related to peak V O2 in both PAD and control subjects. PAD is associated with lower capillary density, and capillary density is related to the functional impairment as defined by a reduced peak V O2, PWT, and COT. These findings suggest that alterations in microcirculation may contribute to functional impairment capacity in PAD.claudication; skeletal muscle PERIPHERAL ARTERY DISEASE (PAD) is a major health problem that affects over eight million people in the United States (42). PAD is caused by atherosclerosis, which leads to arterial obstruction and decreased blood flow to the lower extremities. The most frequent clinical symptomatic manifestation of PAD is intermittent claudication (IC), which is defined as ischemic leg pain that occurs with walking and improves with rest (21). Patients with IC are known to have impaired exercise capacity and decreased ability to perform activities of daily living (31).Despite the role diminished arterial flow has in claudication, altered hemodynamics of the affected limbs do not entirely explain the degree of functional limitation in patients with IC (6,7,11,29,41). Surgical revascularization does not completely normalize exercise performance (31), and exercise training, which does not modify hemodynamics, has been shown to improve walking capacity in patients with PAD (40). These observations have prompted investigations of a mechanism distal to the arterial occlusion to explain these phenomena.A potential mechanistic target for study is the microcirculation as ...