The effect of dietary nitrate supplementation on the oxygen cost of cycling, walking performance and resting blood pressure in individuals with chronic obstructive pulmonary disease: A double blind placebo controlled, randomised control trial
Introduction
Exercise in individuals with COPD is limited by multiple factors which can result in hypoxemia. These include loss of normal lung architecture, impaired cardiac function [1], abnormal pulmonary blood flow distribution [2] and peripheral muscle de-conditioning [3]. Oxygen uptake in the lungs and delivery of oxygen to the working muscle is impaired by increases in pulmonary blood flow which increase shunting through blood vessels resulting in incomplete gas exchange [4] and cor pulmonale later in the disease course. These abnormalities result in feelings of breathlessness and fatigue [5], with individuals often finding that activities of daily living are physically challenging.
The beneficial effects of a diet rich in vegetables upon cardiovascular health [6], risk of morbidity and mortality [7], and COPD development [8], [9] have been well described. These positive effects have, in part, been attributed to inorganic nitrate which is found in particularly high quantities in leafy green vegetables and some root vegetables such as beetroot [10]. Nitrate supplementation in the form of sodium nitrate or nitrate-rich beetroot juice has been shown to have remarkable effects in healthy young individuals and athletes, including reductions in the oxygen cost of exercise [11], enhanced exercise tolerance/performance and reduced blood pressure (BP) [11], [12]. Some of these effects have subsequently been observed in individuals with peripheral artery disease following dietary nitrate supplementation [13]. These findings have been attributed to an increase in the bioavailability of nitric oxide (NO).
NO is a signalling molecule with multiple functions including regulation of vascular tone, mitochondrial respiration and skeletal muscle function [14], [15], [16]. These factors are important in the physiological response to exercise. NO is produced in two distinct ways in man. The best known is the classical L-arginine nitric oxide synthase (NOS) pathway which is oxygen dependent [17]. The second is the entero-salivary pathway and is oxygen independent. Briefly, nitrate from the diet is rapidly and extensively absorbed in the stomach and proximal small intestine with bioavailability approaching 100% [18]. Nitrate is then concentrated in the salivary glands, with concentrations 10 fold greater in saliva than in plasma. Nitrate secreted in saliva is reduced to nitrite by facultative anaerobic bacteria on the dorsum of the tongue [19]. On swallowing, the acidic environment of the stomach results in NO formation with important local effects on gastric function and host defence [6], [20]. Some nitrite is absorbed into the circulation where it acts as a storage pool for subsequent NO production [14]. The conversion of nitrite to NO is expedited in conditions of acidosis [21] or hypoxemia [14] which often occur in the exercising muscle of individuals with COPD [22].
In many individuals with COPD, functional capacity is reduced to a level where activities of daily living may impose a challenge due to an energy requirement representing a high fraction of their maximal oxygen uptake. Whilst a number of cardiovascular and physiological benefits have been shown as a result of dietary nitrate supplementation in healthy populations, little is known about possible effects in clinical populations. We aimed to determine whether dietary nitrate supplementation has a beneficial impact upon the oxygen cost of sub-maximal cycling exercise, walking performance and BP in individuals with COPD.
The aim of this study was to assess the effects of 2.5 days of dietary nitrate supplementation on the oxygen cost of sub-maximal cycling, walking performance, and resting BP in individuals with mild–moderate COPD.
Section snippets
Patients
Fourteen individuals with mild–moderate COPD (see Table 1 for patient characteristics) gave written informed consent to participate in this double-blind, placebo-controlled, cross-over design study between April 2013 and January 2014. The study was registered as a clinical trial at ClinicalTrials.gov (NCT01712386). The Exeter NRES Committee gave ethical approval (12//SW//0327). Patients were recruited if lung function was between 30 and 80% of predicted FEV1 values, aged 40–75 years old and
Results
14 individuals with COPD provided written informed consent. Following screening, one individual was withdrawn due to FEV1 < 30%. 13 participants were randomised to start in either the beetroot juice or placebo condition of the study. All participants reported 100% adherence to the supplementation regime. Participants reported similar dietary patterns and physical activity during both study arms. Dietary nitrate supplementation was well tolerated with no adverse events apart from red stools and
Discussion
Beetroot juice supplementation (nitrate; 6.77 mmol) twice daily, for 2.5 days did not reduce the oxygen cost of cycle ergometer exercise, improve functional capacity or reduce resting BP in individuals with COPD. There was no difference between conditions for these variables despite a statistically significant and physiologically meaningful rise in plasma nitrate concentration following nitrate supplementation. Possible explanations for the lack of effect in this study include nitrate dosage,
Conclusion
In contrast to findings in healthy young individuals, and despite a statistically significant and physiologically meaningful rise in plasma nitrate concentration, 2.5 days of beetroot supplementation with 6.77 mmol of nitrate twice daily did not reduce the oxygen cost of cycling exercise, improve functional capacity or reduce resting blood pressure. Potential explanations for the lack of effect include a reduced P/O ratio due to systemic ROS generation associated with oxidative stress, or a
Contributorship statement
DW, LD, JK, PW, AJ, NB, MG were involved in the conception or design of the work. AIS, DW, LD were involved in the acquisition of data. AIS, DW, AJ, NB, PW, ACS, MG were involved in the analysis or interpretation of data. All authors have been involved in drafting of the work and revision for intellectually important content. MG acts as guarantor.
Acknowledgments
This project was funded by Torbay Medical Research Fund and supported by the NIHR Exeter Clinical Research Facility. The views and opinions shown within this paper are those of the authors and do not necessarily represent those of the NIHR, NHS or the DoH. We would also like to thank the research nurses and technicians involved in the study and importantly the volunteers.
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