Dietary nitrate supplementation enhances exercise performance in peripheral arterial disease.

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.

[1]  Jonathan Fulford,et al.  Dietary nitrate supplementation reduces the O2 cost of walking and running: a placebo-controlled study. , 2011, Journal of applied physiology.

[2]  Jason D. Allen,et al.  Plasma nitrite flux predicts exercise performance in peripheral arterial disease after 3months of exercise training. , 2010, Free radical biology & medicine.

[3]  Jamie R. Blackwell,et al.  Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise. , 2010, American journal of physiology. Regulatory, integrative and comparative physiology.

[4]  Amrita Ahluwalia,et al.  Inorganic Nitrate Supplementation Lowers Blood Pressure in Humans: Role for Nitrite-Derived NO , 2010, Hypertension.

[5]  Jonathan Fulford,et al.  Dietary nitrate supplementation enhances muscle contractile efficiency during knee-extensor exercise in humans. , 2010, Journal of applied physiology.

[6]  B. Ekblom,et al.  Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise. , 2010, Free radical biology & medicine.

[7]  Jamie R. Blackwell,et al.  Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans. , 2009, Journal of applied physiology.

[8]  M. Gladwin,et al.  Nitrite as regulator of hypoxic signaling in mammalian physiology , 2009, Medicinal research reviews.

[9]  P E James,et al.  Nitrite directly vasodilates hypoxic vasculature via nitric oxide‐dependent and ‐independent pathways , 2009, British journal of pharmacology.

[10]  N. Bryan,et al.  Food sources of nitrates and nitrites: the physiologic context for potential health benefits. , 2009, The American journal of clinical nutrition.

[11]  Jason D. Allen,et al.  Plasma nitrite response and arterial reactivity differentiate vascular health and performance. , 2009, Nitric oxide : biology and chemistry.

[12]  Takamitsu Nakamura,et al.  Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. , 2009, Journal of the American College of Cardiology.

[13]  E. Weitzberg,et al.  The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash. , 2008, Nitric oxide : biology and chemistry.

[14]  A. Ahluwalia,et al.  Acute Blood Pressure Lowering, Vasoprotective, and Antiplatelet Properties of Dietary Nitrate via Bioconversion to Nitrite , 2008, Hypertension.

[15]  Mark T. Gladwin,et al.  The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics , 2008, Nature Reviews Drug Discovery.

[16]  T. Barstow,et al.  Dynamics of noninvasively estimated microvascular O2 extraction during ramp exercise. , 2007, Journal of applied physiology.

[17]  B. Ekblom,et al.  Effects of dietary nitrate on oxygen cost during exercise , 2007, Acta physiologica.

[18]  D. Paterson,et al.  Prior exercise speeds pulmonary O2 uptake kinetics by increases in both local muscle O2 availability and O2 utilization. , 2007, Journal of applied physiology.

[19]  M. Gladwin,et al.  Deoxymyoglobin Is a Nitrite Reductase That Generates Nitric Oxide and Regulates Mitochondrial Respiration , 2007, Circulation research.

[20]  M. Gladwin,et al.  Unraveling the Reactions of Nitric Oxide, Nitrite, and Hemoglobin in Physiology and Therapeutics , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[21]  Rodney A. White,et al.  ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography , 2006, Circulation.

[22]  R. Casaburi,et al.  Exercise training decreases ventilatory requirements and exercise-induced hyperinflation at submaximal intensities in patients with COPD. , 2006, Chest.

[23]  M. Gladwin,et al.  Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control. , 2005, The Journal of clinical investigation.

[24]  Jason D. Allen,et al.  Regional and whole-body markers of nitric oxide production following hyperemic stimuli. , 2005, Free radical biology & medicine.

[25]  A. Ahluwalia,et al.  Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M. Gladwin,et al.  Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator , 2004, Nature Medicine.

[27]  J. Lundberg,et al.  Inorganic nitrate is a possible source for systemic generation of nitric oxide. , 2004, Free radical biology & medicine.

[28]  Jeff A. Cole,et al.  Nitrate, bacteria and human health , 2004, Nature Reviews Microbiology.

[29]  Andrew M. Jones,et al.  Influence of L-NAME on pulmonary O2 uptake kinetics during heavy-intensity cycle exercise. , 2004, Journal of applied physiology.

[30]  Daniel W. Jones,et al.  Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. , 2003, Hypertension.

[31]  M. Gladwin,et al.  Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation , 2003, Nature Medicine.

[32]  S. Verma,et al.  Endothelial function testing as a biomarker of vascular disease. , 2003, Circulation.

[33]  N. Bryan,et al.  Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. , 2003, Free radical biology & medicine.

[34]  Marco Ferrari,et al.  Muscle oxygenation and pulmonary gas exchange kinetics during cycling exercise on-transitions in humans. , 2003, Journal of applied physiology.

[35]  Daniel W. Jones,et al.  The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. , 2003, JAMA.

[36]  Eric J Topol,et al.  Critical issues in peripheral arterial disease detection and management: a call to action. , 2003, Archives of internal medicine.

[37]  Jason D. Allen,et al.  Stability and reproducibility of brachial artery flow-mediated dilation. , 2002, Medicine and science in sports and exercise.

[38]  E. Benjamin,et al.  Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. , 2002, Journal of the American College of Cardiology.

[39]  T. Rassaf,et al.  Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M. Gladwin,et al.  Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. , 2001, The Journal of clinical investigation.

[41]  Xiaoping Liu,et al.  The biological lifetime of nitric oxide: implications for the perivascular dynamics of NO and O2. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[42]  D. Poole,et al.  Cardiorespiratory impact of the nitric oxide synthase inhibitor L-NAME in the exercising horse. , 2000, Respiration physiology.

[43]  G. Bray,et al.  A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. , 1997, The New England journal of medicine.

[44]  J. Stamler,et al.  S-nitrosohaemoglobin: a dynamic activity of blood involved in vascular control , 1996, Nature.

[45]  J. Zweier,et al.  Enzyme-independent formation of nitric oxide in biological tissues , 1995, Nature Medicine.

[46]  StefanoTaddei,et al.  Aging and Endothelial Function in Normotensive Subjects and Patients With Essential Hypertension , 1995 .

[47]  G. Zhao,et al.  Role of nitric oxide in the regulation of oxygen consumption in conscious dogs. , 1994, Circulation research.

[48]  D. Spiegelhalter,et al.  Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. , 1994, Journal of the American College of Cardiology.

[49]  K. McCully,et al.  Exercise-induced changes in oxygen saturation in the calf muscles of elderly subjects with peripheral vascular disease. , 1994, Journal of gerontology.

[50]  D. Celermajer,et al.  Cigarette Smoking Is Associated With Dose‐Related and Potentially Reversible Impairment of Endothelium‐Dependent Dilation in Healthy Young Adults , 1993, Circulation.

[51]  Marco Ferrari,et al.  Noninvasive measurement of human forearm oxygen consumption by near infrared spectroscopy , 1993, European Journal of Applied Physiology and Occupational Physiology.

[52]  J. Regensteiner,et al.  Functional Benefits of Peripheral Vascular Bypass Surgery for Patients with Intermittent Claudication , 1993, Angiology.

[53]  J. Skinner,et al.  Progressive vs single-stage treadmill tests for evaluation of claudication. , 1991, Medicine and science in sports and exercise.

[54]  M. Gladwin Haldane, hot dogs, halitosis, and hypoxic vasodilation: the emerging biology of the nitrite anion. , 2004, The Journal of clinical investigation.

[55]  C. Cooper Nitric oxide and cytochrome oxidase: substrate, inhibitor or effector? , 2002, Trends in biochemical sciences.

[56]  H. Redl,et al.  Mitochondria Recycle Nitrite Back to the Bioregulator Nitric Monoxide , 2022 .