The effect of dietary nitrates on vascular function and exercise capacity in chronic kidney disease
Date
2017
Authors
Journal Title
Journal ISSN
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Publisher
University of Delaware
Abstract
Chronic kidney disease (CKD) is a major public health concern affecting more than 25 million individuals in the United States (1). Although individuals with CKD risk progressing to end stage renal failure, they are more likely to die of cardiovascular disease (CVD) before ever reaching end stage renal disease (2). Endothelial dysfunction, characterized by a decreased production and/or bioavailability of nitric oxide (NO) (3), is characteristic of CKD (4) and is associated with an increased risk of CVD (5). CKD is also associated with decreased exercise capacity and physical activity that can also contribute to an increased risk of CVD (6). Thus, interventions to improve exercise capacity and cardiovascular mortality in CKD patients are warranted. ☐ Recently, dietary inorganic nitrate (NO3) supplementation has emerged as an alternative pathway to the endogenous production of NO via a reversible, stepwise reduction from nitrate (NO3)→ nitrite (NO2)→ NO (7). Acute and chronic ingestion of nitrate rich beetroot juice (BRJ) has been shown to improve vascular function and exercise capacity in healthy (8-11) as well as various disease states characterized by decreased vascular function and exercise capacity (12-14). Therefore, the aim of this study was to investigate the effects of acute ingestion of 12.6mmol dietary nitrate in the form of concentrated BRJ on conduit and microvascular endothelial function (Aim I) as well as exercise capacity and skeletal muscle mitochondrial function (Aim II) in patients with moderate to severe CKD in a randomized, crossover design. We hypothesized that acute ingestion of 12.6mmol BRJ would improve microvascular and conduit artery function as well as exercise capacity and mitochondrial function in patients with moderate to severe CKD. ☐ 15 individuals with stage 3-5 CKD participated in Aim I and 13 individuals with stage 3-5 CKD participated in Aim II. For Aim I, participants reported to the laboratory and baseline blood, urine, and saliva samples were obtained. Baseline BP was also measured. Participants then ingested 12.6mmol of dietary nitrate in the form of concentrated beetroot juice (BRJ) or a placebo beverage (PLA) over the next 5 minutes. Participants rested comfortably in the lab for 2.5 hours to allow for the reduction of nitrate to nitrite via enterosalivary circulation to take place which correlates with peak plasma nitrite levels occurring 2.5 hours post nitrate ingestion (9). After 2.5 hours, a blood sample was obtained and post ingestion BP measures were recorded. Microvascular function was assessed via the cutaneous response to local heating measured by laser Doppler flowmetry coupled with microdialysis and conduit artery function assessed via flow-mediated dilation (FMD). Central blood pressures, augmentation index, and central pressure waveforms were assessed via pulse wave analysis (PWA) and arterial stiffness measured via carotid femoral pulse wave velocity (PWV). Carotid artery pulsatility index was also assessed. Post ingestion saliva and urine samples were collected at the end of the visit (~4 hours post beverage ingestion). The entire Aim I protocol was repeated in the opposite condition a minimum of 7 days later. ☐ For Aim II, participants reported to the laboratory, and an 18-gauge catheter was inserted for collection of a baseline blood sample. Participants then ingested 12.6mmol of either a BRJ or PLA beverage and rested in the laboratory for 2.5 hours to allow for enterosalivary circulation and the reduction of nitrate to take place. A blood sample was obtained every hour after beverage ingestion with a final sample obtained just prior to exercise testing. After 2.5 hours, skeletal muscle mitochondrial oxidative function was measured via a technique developed by Ryan et al using near infrared spectroscopy which has been validated against 31P-MRS and in situ measures of mitochondrial oxidative capacity (15, 16). Participants then completed a symptom limited graded exercise test on a cycle ergometer for determination of VO2 peak and ventilatory threshold. Resistance started at 25W and increased by 25W every 3 minutes until exhaustion. The entire protocol was repeated in the opposite condition a minimum of 7 days later. ☐ In Aim I, the change in BP from baseline to 2.5 hours post ingestion was significantly decreased in the BRJ condition compared to PLA. We also observed improvements in microvascular function via increases in the plateau phase of the cutaneous response to local heating. We did not observe any improvements in FMD, PWV, pulsatility index, or central pressure measurements after BRJ supplementation. In Aim II, ventilatory threshold, total exercise time, and work performed were significantly increased in the BRJ condition compared to PLA. We also found trends for improvement of VO2 peak in the BRJ condition (p=0.14). Mitochondrial oxidative capacity was not improved after BRJ supplementation. ☐ Together these data suggest that acute dietary nitrate ingestion improves BP and microvascular function as well as ventilatory threshold, total exercise time, and work performed in individuals with moderate to severe CKD. Improvements in microvascular function and BP are most likely due to nitrate-derived NO induced vasodilation and/or decreases in oxidative stress. The improvements in ventilatory threshold, work performed, and total exercise time may be a result of enhanced vasodilation of the muscle microvasculature, thus improving muscle microvascular oxygenation and tissue diffusion capacity to maintain ATP generation via oxidative metabolism.
Description
Keywords
Biological sciences, Capacity, Dietary, Exercise, Kidney, Nitrates, Vascular