It is accepted that regular exercise improves indices of cardiovascular health including resting blood pressure (BP) and blood pressure reactivity. A commonly cited barrier to exercise is time. High-intensity interval training (HIIT) reduces the time demands of exercise compared to moderate-intensity continuous training (MCT), however the effect of HIIT on resting BP and BP reactivity has not been investigated. Objective: To determine the effect of HIIT on resting BP and BP reactivity compared to MCT. Hypothesis: We hypothesized that 8 weeks of HIIT would result in reductions in resting BP and BP reactivity similar to MCT. Methods: Sedentary adults (5M/11F, age: 29 ± 2) were randomly assigned to either 8 weeks (3 sessions/week) of HIIT or MCT. Participants performed a graded exercise test on a cycle ergometer to establish baseline cardiorespiratory fitness and determine maximal heart rate to set training intensities. Resting systolic and diastolic blood pressure (SBP and DBP, respectively) and mean arterial pressure (MAP) were recorded by an oscillometric device. A Finometer was used to measure beat-to-beat BP during the sympatho-excitatory stressors which included 2 minutes of isometric handgrip exercise (HG) at 40% of maximal voluntary contraction, followed immediately by 3 minutes of post-exercise ischemia (PEI). Cardiorespiratory and blood pressure assessments were repeated post-intervention. Results: SBP decreased post-training in both groups (HIIT: 112 ± 4mmHg to 105 ± 3mmHg, p<0.05; MCT: 119 ± 2 to 115 ± 3, p<0.05). There was a main effect for a decrease in DBP following training (HIIT: 69 ± 3 to 67 ± 3; MCT: 73 ± 3 to 69 ± 2, p<0.05). A main effect was also observed for a decrease in MAP following training (HIIT: 83 ± 3 to 80 ± 3; MCT: 88 ± 2 to 85 ± 2, p<0.01). Analysis of BP reactivity during HG revealed a significant interaction (p<0.05) across all measures. BP reactivity was reduced in the MCT group as measured by ΔSBP (24 ± 3 to 18 ± 3, p<0.05), ΔMAP (23 ± 2 to 17 ± 2, p<0.01) and ΔDBP (23 ± 2 to 16 ± 2, p<0.01). No changes in BP reactivity were observed in the HIIT group. Analysis of BP during PEI revealed a significant interaction (p<0.05) across all measures. HIIT augmented ΔSBP (14 ± 3 to 20 ± 4, p<0.05) during PEI and a trend was observed for ΔMAP (p=0.056) whereas MCT resulted in no differences pre to post intervention. Conclusion: These data suggest that both HIIT and MCT interventions can improve resting BP in sedentary individuals; however, there appears to be a divergent effect of HIIT and MCT on BP reactivity in response to HG suggesting a heightened metaboreflex following HIIT which requires further study. NIH Grant P20GM113125 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD). Abnormal arterial hemodynamics contribute to CVD, a relationship that can be mediated by microvascular dysfunction. The purpose of this study was to investigate potential sex differences in arterial hemodynamics and microvascular dysfunction in patients with stages 3 to 4 CKD. Vascular function was assessed in 22 male (mean +/- SD; age, 56 +/- 13 yr) and 10 female (age, 63 +/- 9 yr) patients. Arterial hemodynamics were acquired with combined tonometry and oscillometry. Skin blood flow was used as a model of microvascular function. Participants were instrumented with three microdialysis fibers for the delivery of 1) Ringer's solution; 2) superoxide dismutase mimetic, Tempol; and 3) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, apocynin. Blood flow was measured via laser-Doppler flowmetry during standardized local heating (42 degrees C). Central pulse pressure (mean +/- SE; 62 +/- 9 vs. 46 +/- 3 mmHg; P = 0.01) and augmentation index (36 +/- 3 vs. 26 +/- 3%; P = 0.03) were higher in females. There was a trend for higher central systolic pressures in females (146 +/- 9 vs. 131 +/- 3 mmHg; P = 0.06). Females reported higher forward (39 +/- 4 vs. 29 +/- 2 mmHg; P = 0.004) and reflected (27 +/- 3 vs. 19 +/- 1 mmHg; P < 0.001) wave amplitudes. Cutaneous vascular function was impaired in females compared with males (77 +/- 3 vs. 89 +/- 1%, P = 0.001). Microvascular function was improved following the delivery of Tempol and apocynin in females but not in males. Female patients with CKD had poorer central hemodynamics and reduced microvascular function compared with their male counterparts. Oxidative stress may contribute to lower microvascular function observed in females. NEW & NOTEWORTHY There are limited data regarding the physiological mechanisms of potential sex differences in central hemodynamics and vascular function in chronic kidney disease (CKD). We report that older female patients with nondialysis CKD have higher central pulse pressures compared with male patients with CKD. In addition, older females with CKD have lower microvascular function compared with their male counterparts, and oxidative stress contributes to the lower microvascular function in older female patients with CKD.

Endogenous opioid release has been linked to exercise. We investigated if opioid blockade following forced swimming, a common model of rodent exercise, influenced cerebral glucose metabolism in mice. PET scan was used to assess the uptake of Fludeoxyglucose (FDG-18), a marker of cerebral glucose metabolism in 19 regions of the interest in the brain following: forced swimming, an acute dose of the opioid receptor blocker naltrexone or a combination of both. Forced swimming increased glucose uptake in the cerebellum, while naltrexone + forced swimming increased glucose uptake in the hypothalamus, forebrain, septum and amygdala. This suggests that opioid blockade alters the typical pattern of cerebral glucose uptake following forced swimming in mice in certain areas of the brain

Background: Patients with chronic kidney disease have reduced cardiorespiratory fitness levels that contribute to mortality. Objectives: The purpose of this study was to investigate the effects of aerobic exercise on cardiopulmonary function in patients with chronic kidney disease. Methods: A total of 36 patients (mean [SD] estimated glomerular filtration rate 44 [12] ml/min/1.73 m(2)) were randomly allocated to an exercise training or a control arm over 12 weeks. The exercise training group performed aerobic exercise for 45 min 3 times/week at 65% to 80% heart rate reserve. The control group received routine care. Outcome measures were assessed at baseline and 12 weeks. Cardiopulmonary exercise testing was performed on a cycle ergometer with workload increased by 15 W/min. A battery of physical function tests were administered. Habitual physical activity levels were recorded via accelerometry. Data are mean [SD]. Results: Exercise training improved VO2peak as compared with the control group (exercise: 17.89 [4.18] vs 19.98 [5.49]; control: 18.29 [6.49] vs 17.36 [5.99] ml/kg/min; P < 0.01). Relative O-2 pulse improved following exercise, suggestive of improved left ventricular function (exercise: 0.12 [0.02] vs 0.14 [0.04]; control: 0.14 [0.05] vs 0.14 [0.04] ml/beat/kg; P = 0.03). Ventilation perfusion mismatching (V-E/VCO2) remained evident after exercise (exercise: 32 [5] vs 33 [5]; control: 32 [7] vs 34 [5] AU; P = 0.1). Exercise did not affect the ventilatory cost of oxygen uptake (V-E/VO2; exercise: 40 [7] vs 42 [8]; control: 3 [7] vs 41 [8] AU; P = 0.5) and had no effect on autonomic function assessed by maximal and recovery heart rates. We found no changes in physical function or habitual physical activity levels. Conclusions: Cardiopulmonary adaptations appeared to be attenuated in patients with chronic kidney disease and were not fully restored to levels observed in healthy individuals. Improvements in exercise capacity did not confer benefits to physical function. Interventions coupled with exercise may be required to enhance adaptations in chronic kidney disease. Performed according to CONSORT guidelines; (C) 2020 Elsevier Masson SAS. All rights reserved.

Introduction: Aberrant vascular function contributes to the substantially high cardiovascular burden of chronic kidney disease (CKD). Mitochondrial derived oxidative stress is a potential therapeutic target to ameliorate CKD related vascular dysfunction. Hypothesis: We hypothesized that a mitochondrial targeted antioxidant (MitoQ) would improve vascular function in Stage 3-5 CKD patients without overt cardiovascular disease. Methods: In this controlled, double-blind trial, 18 CKD patients (Mean±SEM: Age, 62±3 years; eGFR, 45±3 ml•min•1.73 2 ) were randomized to receive an oral dose of MitoQ (20mg/day; MTQ) or a Placebo (PLB) for 4 weeks. Outcome measures were assessed at week 0 and week 4. Aortic pressure waves were synthesized from brachial artery waveforms acquired by oscillometry and the use of a generalized transfer function. The central pressure waveform was separated into forward and reflected waves using a triangular flow waveform. Conduit artery vascular function was assessed via brachial artery flow mediated dilation (FMD). Results: MitoQ was well tolerated and patient compliance was high (MTQ, 99.6±0.4%; PLB, 97.8±2.2%). Independent of peripheral (Baseline vs. Follow Up: MTQ, 140±6 vs. 137±6 mmHg; PLB, 136±4 vs. 134±6 mmHg; interaction p=0.7) and central (MTQ, 128±5 vs. 123±6 mmHg; PLB, 124±3 vs. 123±5 mmHg; interaction p=0.8) systolic blood pressures, MitoQ maintained forward wave amplitudes (MTQ, 31±3 vs. 29±1 mmHg; PLB, 29±3 vs. 36±3 mmHg; interaction p=0.05) and tended to reduce reflected wave amplitudes (MTQ, 18±2 vs. 16±1 mmHg; PLB, 19±2 vs. 21±2 mmHg; interaction p=0.04). MitoQ administration favored improvements in FMD (MTQ, 2.4±0.3 vs. 4.0±0.9%; PLB, 4.2±1.0 vs. 2.5±1.0%; interaction p=0.04). Conclusions: These results suggest that targeting mitochondrial derived reactive oxygen species holds promise as a potential therapeutic strategy to improve CKD related vascular dysfunction. Whether MitoQ related improvements in arterial hemodynamics are a result of augmented cardiac function or a reduction in vascular resistance warrants future investigation in larger studies.

BACKGROUND:Chronic Kidney Disease (CKD) patients exhibit a reduced exercise capacity that impacts quality of life. Dietary nitrate supplementation has been shown to have favorable effects on exercise capacity in disease populations by reducing the oxygen cost of exercise. This study investigated whether dietary nitrates would acutely improve exercise capacity in CKD patients. METHODS AND RESULTS:In this randomized, double-blinded crossover study, 12 Stage 3-4 CKD patients (Mean ± SEM: Age, 60 ± 5yrs; eGFR, 50.3 ± 4.6 ml/min/1.73 m2) received an acute dose of 12.6 mmol of dietary nitrate in the form of concentrated beetroot juice (BRJ) and a nitrate depleted placebo (PLA). Skeletal muscle mitochondrial oxidative function was assessed using near-infrared spectroscopy. Cardiopulmonary exercise testing was performed on a cycle ergometer, with intensity increased by 25 W every 3 min until volitional fatigue. Plasma nitric oxide (NO) metabolites (NOm; nitrate, nitrite, low molecular weight S-nitrosothiols, and metal bound NO) were determined by gas-phase chemiluminescence. Plasma NOm values were significantly increased following BRJ (BRJ vs. PLA: 1074.4 ± 120.4 μM vs. 28.4 ± 6.6 μM, p < 0.001). Total work performed (44.4 ± 10.6 vs 39.6 ± 9.9 kJ, p = 0.03) and total exercise time (674 ± 85 vs 627 ± 86s, p = 0.04) were significantly greater following BRJ. Oxygen consumption at the ventilatory threshold was also improved by BRJ (0.90 ± 0.08 vs. 0.74 ± 0.06 L/min, p = 0.04). These changes occurred in the absence of improved skeletal muscle mitochondrial oxidative capacity (p = 0.52) and VO2peak (p = 0.35). CONCLUSIONS:Our findings demonstrate that inorganic nitrate can acutely improve exercise capacity in CKD patients. The effects of chronic nitrate supplementation on CKD related exercise intolerance should be investigated in future studies.

Endothelial dysfunction and arterial stiffness are nontraditional risk factors of chronic kidney disease (CKD)-related cardiovascular disease (CVD) that could be targeted with exercise. This study investigated the effect of moderate to vigorous aerobic exercise on vascular function in nondialysis CKD. In this randomized, controlled trial, 36 nondialysis patients with CKD (means ± SE, age: 58 ± 2 yr, estimated glomerular filtration rate: 44 ± 2 ml·min−1·1.73 m−2) were allocated to an exercise training (EXT) or control (CON) arm. The EXT group performed 3 × 45 min of supervised exercise per week at 60–85% heart rate reserve for 12 wk, whereas the CON group received routine care. Outcomes were assessed at 0 and 12 wk. The primary outcome, microvascular function, was assessed via cutaneous vasodilation during local heating measured by laser-Doppler flowmetry coupled with microdialysis. Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution and 2) the superoxide scavenger tempol. Conduit artery function was assessed via brachial artery flow-mediated dilation. Aortic pressure waveforms and pulse wave velocity were acquired with tonometry and oscillometry. Microvascular function improved after EXT ( week 0 vs . week 12, EXT: 87 ± 2% vs. 91 ± 2% and CON: 86 ± 2% vs. 84 ± 3%, P = 0.03). At baseline, pharmacological delivery of tempol improved microvascular function (Ringer solution vs. tempol: 86 ± 1% vs. 90 ± 1%, P = 0.02) but was no longer effective after EXT (91 ± 2% vs. 87 ± 1%, P = 0.2), suggesting that an improved redox balance plays a role in EXT-related improvements. Brachial artery flow-mediated dilation was maintained after EXT (EXT: 2.6 ± 0.4% vs. 3.8 ± 0.8% and CON: 3.5 ± 0.6% vs. 2.3 ± 0.4%, P = 0.02). Central arterial hemodynamics and arterial stiffness were unchanged after EXT. Aerobic exercise improved microvascular function and maintained conduit artery function and should be considered as an adjunct therapy to reduce CVD risk in CKD.

Exercise is specifically linked to at least three phenomena that are likely to involve opioid release; the ‘athlete’s high’, increased pain tolerance, and addiction to exercise. Exercise studies that have examined the effects of the opiate receptor blocker naltrexone, found that its administration prior to exercise alter these before mentioned phenomena. PURPOSE: The purpose of this study was twofold: 1) to establish an exercise modality that is sufficient to stimulate the release of endogenous opioids and 2) to examine the role endogenous opioids play in post-exercise pain tolerance and depression. METHODS: Following a week of familiarization, mice underwent a 50-minute (min) bout of forced swimming (FS). Mice were injected with either saline (S; 0.9%) or the opioid blocker naltrexone (NTX; 4g/kg) 15 mins prior to exercise. Following exercise mice were challenged with a tail suspension test (TST), pain tolerance test or monitored for post exercise food consumption for 2 hours. RESULTS: NXT injection decreased total FS time (46 ± 1.2 mins. vs. 35 ± 1.6 mins; p<0.05). Forced swimming increased food consumption by 88% ± 11 (p<0.05) two hours following exercise but was abolished by NXT (p<0.05), verifying an increase in opioid mediated hyperphagia. An increase in hot water tail immersion time following exercise (S = 2.72 s ± 0.13 vs. FS = 4.28 ± 0.19; p<0.05) demonstrated an improvement in pain tolerance. Pain tolerance decreased by 20% ± 0.05 with the addition of NXT (P<0.05). Finally, a TST demonstrated that following a bout of exercise, mice spent 49 ± 3.1% less time immobile (p<0.05), signifying lower depression levels. This effect was reversed with the opioid blockade (p<0.05). CONCLUSIONS: Fifty minutes of forced swimming is an effective stimulus for the release of endogenous opioids and modulates behavioral changes specific to the release endogenous opioids in mice.

Exercise has been linked to several opioid mediated phenomena including exercise mediated analgesia, euphoria “runner’s high” and addiction. The role of the endogenous opioid system in these events have all been verified using the opioid receptor blocker naltrexone. Despite this, a full understanding on how the endogenous opioid system influences brain activity under acute exercise conditions is lacking PURPOSE: To investigate the role of the endogenous opioid system on brain glucose uptake following an acute bout of exercise with and without administration of naltrexone. METHODS: To assess cerebral glucose uptake mice were fasted overnight and scanned using positron emission tomography (PET) in one of four assigned conditions: control (CON), exercise (EX), naltrexone injection (NTX) or exercise + naltrexone injection (EX+NTX). Mice were delivered a dose of 18F-fluorodeoxyglucose (FDG) 1 hour prior to scanning. Mice that underwent exercise performed 50 minutes of forced swimming (FS) following a week of familiarization, which consisted of 5-25 minutes of FS. NTX was given via intraperitoneal injection (4 mg/kg) 15 minutes prior to exercise or FDG administration. Data was imaged using VivoQuant software and analyzed using PMOD software by a technician blinded to the experimental conditions. Data was calculated as average standardized uptake values (SUV) for 19 regions of interest (ROI) and made relative to the SUV of the whole brain. RESULTS: Exercise increased the SUV of glucose in the cerebellum (EX=1.27 ± 0.14; P<0.05) relative to mice under CON (0.98 ± 0.07) or NTX (0.85 ± 0.03) conditions. The exercise mediated increase in activity in the cerebellum was abolished (P<0.05) with the addition of NTX (0.88 ± 0.10). The combination of EX+NTX increased the SUV of glucose in the hypothalamus region relative to all groups (P<0.05). CONCLUSIONS: The cerebellum is largely responsible for the regulation of voluntary muscular activity. Exercise appears to have a potent effect on brain activity specific to this region and may be at least partially mediated by endogenous opioids. Further, the endogenous opioid system may play a role in the attenuation of the hypothalamic-pituitary adrenal system during exercise.

Background Reductions in exercise capacity associated with exercise intolerance augment cardiovascular disease risk and predict mortality in chronic kidney disease. This study utilized cardiopulmonary exercise testing to (a) investigate mechanisms of exercise intolerance; (b) unmask subclinical abnormalities that may precede cardiovascular disease in chronic kidney disease. Design The design of this study was cross-sectional. Methods Cardiopulmonary exercise testing was carried out in 31 Stage 3–4 chronic kidney disease patients (60 ± 11 years; estimated glomerular filtration rate 43 ± 13 ml/min/1.73 m 2 ) and 21 matched healthy individuals (healthy controls; 56 ± 5 years; estimated glomerular filtration rate>90 ml/min/1.73 m 2 ) on a cycle ergometer with workload increased by 15 W every minute until volitional fatigue. Breath-by-breath respiratory gas analysis was performed with an automated gas analyzer and averaged over 10 s intervals. Results Peak oxygen uptake was reduced in chronic kidney disease compared to healthy controls (17.43 ± 1.03 vs 28 ± 2.05 ml/kg/min; p < 0.01), as was oxygen uptake at the ventilatory threshold (9.44 ± 0.53 vs15.55 ± 1.34 ml/kg/min; p < 0.01). A steeper minute ventilation rate/carbon dioxide production slope (32 ± 0.8 vs 28 ± 1; p < 0.01) and a lower expired carbon dioxide pressure in chronic kidney disease (27 ± 0.6 vs 31 ± 0.9 vs 0.9; p < 0.01) indicated ventilation perfusion mismatching in these patients. The ventilatory cost of oxygen uptake was higher in chronic kidney disease (37 ± 0.8 vs 33 ± 1; p < 0.01). Maximum heart rate (134 ± 5 vs 159 ± 3 bpm) and one-minute heart rate recovery (15 ± 1 vs 20 ± 2 bpm) were reduced in chronic kidney disease ( p < 0.01). Conclusion This study suggests that both central and peripheral limitations likely contribute to reduced exercise capacity in non-dialysis chronic kidney disease. Additionally, cardiopulmonary exercise testing revealed subclinical cardiopulmonary abnormalities in these patients in the absence of overt cardiovascular disease. Cardiopulmonary exercise testing could potentially be a tool for unmasking cardiopulmonary abnormalities preceding cardiovascular disease in chronic kidney disease.

PURPOSE: Subclinical cardiopulmonary abnormalities have been reported in patients with mild-moderate CKD that may predispose these individuals to overt cardiovascular disease (CVD). This randomized controlled trial investigated whether 12 weeks of moderate to vigorous intensity aerobic exercise could improve cardiopulmonary measures in Stage 3-5 non-dialysis CKD patients. METHODS: 36 Stage 3-5 CKD patients (eGFR, 44±2 ml/min/1.73m2) with no CVD history were randomized to an Exercise Training (EXT) or Control (CON) arm. EXT consisted of 3x45 minutes of supervised exercise per week at 60-85% HRR for 12 weeks. CON received routine care. Cardiopulmonary exercise testing (CPX) was carried out at baseline and after 12 weeks. CPX was performed on a cycle ergometer with workload increased by 15W every minute until volitional fatigue. Breath by breath expired respiratory gas analysis was carried out with an automated gas analyzer and averaged over 10 second intervals. RESULTS: EXT significantly improved exercise capacity as shown by an increase in VO2peak compared to CON (EXT: 17.89±1.21 vs. 19.98±1.59; CON: 18.29±1.73 vs. 17.36±1.60 ml/kg/min; p<0.01). Cardiopulmonary reserve improved following EXT as indicated by an increased oxygen uptake efficiency slope (EXT: 1.76±0.13 vs. 1.93 ± 0.12; CON: 1.76±0.14 vs. 1.68±0.15 AU, p<0.01). Relative O2 pulse improved following EXT, suggestive of improved left ventricular function (EXT: 0.12±0.01 vs. 0.14± 0.01; CON: 0.14±0.01 vs. 0.14±0.01 ml/beat/kg; p=0.03). Ventilation perfusion mismatching (VE/VCO2) was still evident following EXT (EXT: 32±2 vs 33±0.9; CON: 32±2 vs 34±1 AU; p=0.1). EXT had no effect on the ventilatory cost of oxygen uptake (VE/VO2; EXT: 40±2 vs. 42±2; CON: 37±2 vs. 41±2 AU; p=0.5). EXT had no effect on autonomic function assessed by maximal heart rate (EXT: 149±8 vs. 143±8; CON: 131±5 vs. 129±5 bpm; p=0.4) and 1 minute heart rate recovery (EXT: 15±1 vs. 16±2; CON: 14±1 vs 13±1 %; p=0.2). CONCLUSION: Aerobic exercise improved exercise capacity, cardiopulmonary reserve and oxygen delivery in CKD patients. Despite these improvements, CPX measures were not fully restored to those observed in matched sedentary healthy individuals. Additional interventions coupled with exercise may be required enhance cardiopulmonary adaptations to exercise training in CKD.

PURPOSEThe purpose of this study was to test the hypothesis that an acute dose of 12.6 mmol dietary nitrate in the form of concentrated beetroot juice (BRJ) would improve measures of microvascular and conduit artery endothelial function in patients with moderate to severe chronic kidney disease (CKD).METHODSFifteen adults with moderate to severe CKD participated in this double blind, randomized, crossover study (61±4 yrs; 11 males; eGFR 49.2±3.4 ml•min−1•1.73 m2). Participants reported to the laboratory and baseline blood pressure (BP) was measured and a baseline blood sample obtained for determination of NO metabolites (NOm; Nitrate, nitrite, s‐nitrosothiols and metal bound NO). Participants were then randomized to ingest 12.6 mmol of BRJ or a nitrate depleted placebo (PLA). Vascular testing began 2.5 hours post beverage ingestion. A second blood sample was obtained and post‐ingestion BP was recorded. Microvascular function was assessed via the cutaneous response to local heating measured by laser Doppler flowmetry coupled with microdialysis, and conduit artery function was assessed via brachial artery flow‐mediated dilation (FMD). Arterial stiffness (via carotid‐femoral pulse wave velocity, PWV) was also measured. The entire protocol was repeated a minimum of 7 days later in the other condition.RESULTSPlasma NOm was not different between conditions at baseline but was significantly increased 2.5 hours post BRJ ingestion compared to pre‐ingestion values, as well as compared to post PLA values (PREPLA 53.0±11.6 POSTPLA 33.2±9.9 mM; PREBRJ 57.3±21.4 vs POSTBRJ1068.0±106.6 mM). Mean arterial pressure (MAP) was not different between conditions at baseline or 2.5 hours post, however the change in MAP from pre‐ingestion baseline to 2.5 hours post ingestion was significantly different between conditions (ΔMAPPLA 2.0±2.1 vs ΔMAPBRJ −3.2±2.6 mmHg, p>0.05). The plateau phase of the cutaneous response to local heating was significantly greater in the BRJ condition compared to PLA (PLA 83.4±2.2 vs BRJ 88.8±1.7%CVCmax; p<0.05). The NOS mediated contribution to the plateau phase as assessed via L‐NAME infusion was not different between conditions. We did not observe any improvements in FMD or PWV.CONCLUSIONAn acute dose of 12.6 mmol dietary nitrate significantly improves microvascular function in patients with moderate to severe CKD.Support or Funding InformationThis research was supported by an ACSM Foundation Research Grant from the American College of Sports Medicine Foundation and NIH grant HL113514.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Mitochondrial dysfunction secondary to CKD is a potential source of oxidative stress that may impair vascular function. This study sought to determine if mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in stage 3-5 CKD. Cutaneous vasodilation in response to local heating was assessed in 20 CKD patients [60 ± 13 yr; estimated glomerular filtration rate (eGFR) 46 ± 13 ml·kg-1·1.73 m-2] and 11 matched healthy participants (58 ± 2 yr; eGFR >90 ml·kg-1·1.73 m-2). Participants were instrumented with two microdialysis fibers for the delivery of 1) Ringer solution, and 2) the mitochondria- specific superoxide scavenger MitoTempo. Skin blood flow was measured via laser Doppler flowmetry during standardized local heating (42°C). Cutaneous vascular conductance (CVC) was calculated as a percentage of the maximum conductance achieved with sodium nitroprusside infusion at 43°C. Urinary isofuran/F2-isoprostane ratios were assessed by gas-chromatography mass spectroscopy. Isofuran-to-F2-isoprostane ratios were increased in CKD patients (3.08 ± 0.32 vs. 1.69 ± 0.12 arbitrary units; P < 0.01) indicative of mitochondria-derived oxidative stress. Cutaneous vasodilation was impaired in CKD compared with healthy controls (87 ± 1 vs. 92 ± 1%CVCmax; P < 0.01). Infusion of MitoTempo significantly increased the plateau phase CVC in CKD patients (CKD Ringer vs. CKD MitoTempo: 87 ± 1 vs. 93 ± 1%CVCmax; P < 0.01) to similar levels observed in healthy controls ( P = 0.9). These data provide in vivo evidence that mitochondria-derived reactive oxygen species contribute to microvascular dysfunction in CKD and suggest that mitochondrial dysfunction may be a potential therapeutic target to improve CKD-related vascular dysfunction.

PURPOSE The purpose of this study was to test the hypothesis that an acute dose of 12.6mmol dietary nitrate in the form of concentrated beetroot juice (BRJ) would improve exercise capacity and skeletal muscle mitochondria function in adults with moderate to severe chronic kidney disease (CKD). METHODS 12 individuals with moderate to severe CKD participated in this study (61±4 yrs; 9 males; eGFR 47.8ml•min-1•1.73m2). Participants reported to the laboratory and a baseline blood sample was obtained for determination of NO metabolites (NOm; Nitrate, nitrite, s-nitrosothiols and metal bound NO). Participants were then randomized to ingest 12.6mmol of BRJ or a nitrate depleted placebo (PLA). Exercise testing began 2.5 hours post beverage ingestion to coincide with peak plasma nitrite levels. Skeletal muscle mitochondrial oxidative function testing was performed using near infrared spectroscopy (NIRS) followed by a symptom limited graded exercise test (GXT) on a cycle ergometer for determination of peak oxygen consumption (VO2 peak). Participants repeated the entire protocol in the other condition a minimum of 7 days later. RESULTS Plasma NOm values were significantly increased in the BRJ condition 2.5 hours post ingestion compared to BRJ baseline as well as PLA at 2.5 hr (2.5 hr: PLA 30.2±6.6uM vs BRJ 973±261uM, p>0.05). We did not observe an improvement in mitochondrial oxidative capacity or VO2 peak in the BRJ condition compared to PLA (p>0.05). The amount of work performed and total exercise time was significantly increased after BRJ compared to PLA (Work: PLA 39.5±9.9 vs BRJ 44.7±10.7kJ; Exercise Time: PLA 627±86 vs BRJ 674±85 seconds; p<0.05 for both). VO2 at the ventilatory threshold (VT) was significantly greater in the BRJ condition compared to PLA (PLA 0.79±0.08L/min vs BRJ 0.95±0.09 L/min; p<0.05). CONCLUSION An acute dose of 12.6mmol dietary nitrate significantly improved VO2 at VT, work performed, and total exercise time in adults with moderate to severe CKD. This research was supported by an ACSM Foundation Research Grant from the American College of Sports Medicine Foundation and NIH grant HL113514.

High dietary sodium intake can lead to hypertension and increased incidence of cardiovascular disease. We sought to determine the effect of short-term dietary sodium loading on central blood pressure and arterial stiffness in young (YG; 22-40 years) and middle-aged (MA; 41-60 years) noimotensive adults. YG (n = 49; age: 27 +/- 1 years) and MA (n = 36; age: 52 +/- 1 years) subjects were randomized, in a cross-over design, to 7 days of low-sodium (LS; 20 mmol/d) or high sodium (HS; 300 mmol/d) diet. On the last day of each diet, central pressures, forward and reflected wave amplitudes (via radial artery applanation tonometry), and carotid-femoral pulse wave velocity were assessed. Central systolic blood pressure (cSBP) was greater after HS in both YG (LS: 96 +/- 1 vs. HS: 99 +/- 1 mm Hg; P = .012) and MA (LS: 106 +/- 2 vs. HS: 115 +/- 3 mm Hg; P < .001). However, the increase in cSBP was greater in MA (YG: 4 + 1 vs. MA: 9 2; P = .02). In MA subjects, HS elicited greater forward (LS: 25 +/- 1 vs. HS: 29 +/- 1 mm Hg; P < .001) and reflected (LS: 19 +/- 1 vs. HS: 23 +/- 1 mm Hg; P < .001) wave amplitudes. Carotid-femoral pulse wave velocity was also greater in MA on HS but after adjustment for mean arterial pressure, the difference was no longer significant. Our data indicate that HS intake leads to a greater increase in cSBP in MA adults, which may be the result of increased forward and reflected wave amplitudes. (C) 2017 American Society of Hypertension. All rights reserved.

Cardiopulmonary exercise testing (CPX) provides a wide range of information related to cardiorespiratory fitness, mechanisms of limitations in exercise capacity and prognosis. Cardiorespiratory fitness is reduced in patients with chronic kidney disease (CKD) however the mechanisms of reduced fitness and additional prognostic information from CPX in these patients are under investigated. PURPOSE: The aim of this cohort study was to test the hypothesis that key CPX variables, in addition to peak oxygen uptake, are abnormal in CKD patients compared to matched healthy individuals (HC). METHODS: CPX was carried out in 25 Stage 3 - 5 CKD patients (60 ± 13 yrs; eGFR 43 ± 14) and 19 matched healthy individuals (56 ± 5 yrs; eGFR > 60) on a cycle ergometer with workload increased by 15W every minute until volitional fatigue. Breath by breath expired respiratory gas analysis was carried out with an automated gas analyzer and averaged over 10 second intervals. RESULTS: Peak oxygen uptake was reduced in CKD compared to HC (18 ± 6 vs. 26 ± 8 ml/kg/min; p < 0.01), as was oxygen uptake at the ventilatory threshold (9 ± 4 vs. 13 ± 6 ml/kg/min; p < 0.05). A steeper VE/VCO2 slope (32 ± 3 vs. 27 ± 4; p < 0.05) in CKD indicates ventilation perfusion mismatching in these patients. A lower PETCO2 (p < 0.05) with a normal PECO2/PETCO2 ratio (p > 0.05) during exercise suggest that this may be due to pulmonary blood flow as opposed to ventilatory defects. The ventilatory cost of oxygen uptake was higher in CKD (36 ± 5 vs. 33 ±5; p > 0.05). Maximum heart rate (135 ± 22 vs. 155 ± 18 bpm) and heart rate recovery after one minute (21 ± 10 vs. 31 ± 11 bpm) were both reduced in CKD (p < 0.05). CONCLUSION: In CKD patients a number of CPX variables were markedly abnormal in comparison to age matched healthy individuals. These findings provide a strong case for the expanded clinical use of CPX in patients with CKD. Future studies should assess the prognostic value of these abnormalities in CKD. Supported by NIH Grant R01 HL113514

Blunted nighttime blood pressure (BP) dipping is related to increased cardiovascular risk. Altered dietary sodium can influence short‐term and long‐term BP, but studies that have assessed nighttime BP dipping have not controlled for sodium intake in normotensives. We therefore measured nighttime BP dipping during a controlled sodium diet in normotensive adults (n=96; age= 38±1 yrs, BP= 119±1 / 75±1 mmHg), and examined sex (women n=48, age= 41±2 yrs, BP= 115±2 / 73±2 mmHg vs. men n=48, age= 35±2 yrs, BP= 123±1 / 76±1 mmHg) and racial differences (Caucasians n=75, age=39±2 yrs, BP= 120±1 / 75±1 mmHg; African American n=13, age= 35±3 yrs, BP= 116±3 / 71±2 mmHg) in subgroup analyses. All subjects consumed a recommended sodium diet (100 mmol/day) for 7 days and 24‐hour ambulatory BP was measured on the 7th day of the diet. BP was assessed every 20 minutes during daytime (wake) and every 30 minutes during nighttime (sleep). Nighttime BP dipping was assessed by measuring the percent (%) difference between mean systolic daytime BP and mean systolic nighttime BP. Twenty‐four‐hour urine sodium excretion was 82.9±4.2 mmol/24 hrs for all subjects; no difference was observed between sex and race (p>0.05). Nighttime BP dipping under a controlled sodium condition was 10.9±0.6% for all subjects. No differences were observed in nighttime BP dipping between sexes (women= 10.9±0.8% vs. men= 10.8±0.9%, p>0.05) or between races (Caucasian= 10.7±0.7% vs. African American= 9.6±1.3% p>0.05). These data suggest that under controlled sodium conditions, there are no sex or race differences in nighttime BP dipping.

Excess dietary sodium intake has been linked to increased incidence of cardiovascular disease and the development of hypertension. We sought to determine the effect of short‐term dietary sodium loading on central blood pressure in young (YG; n=46, 26±1 yrs) and middle‐aged (MA; n=27, 51±1 yrs) normotensive, salt resistant adults. Subjects were randomized to 7 days of low sodium (LS: 20 mmol/d) and 7 days of high sodium (HS: 300 mmol/d). Salt‐resistance was defined as mean 24‐hour MAP change 蠄5 mmHg between diets (LS: 87±1 vs. HS: 86±1 mmHg, p > 0.05). On the last day of each diet, carotid‐femoral pulse wave velocity (PWV) and the synthesis of a central aortic pressure waveform (by radial artery applanation tonometry and generalized transfer function) and wave separation analysis were performed. When compared to the LS diet, the HS diet elicited an increase in central systolic blood pressure (cSBP) in both YG (LS: 95±1 vs. HS: 98±1 mmHg, p < 0.05) and MA (LS: 107±2 vs. HS: 116±3 mmHg, p < 0.05), with a larger increase seen in MA (YG: 3±1 vs. MA: 9±2, p < 0.05). In MA, HS elicited greater central forward wave amplitude (LS: 26±1 vs. HS: 30±1 mmHg, p < 0.05) and central reflected wave amplitude (LS: 18±1 vs. HS: 22±1 mmHg, p < 0.05) but no difference was seen in YG. PWV was not altered by 7 days of HS in either group (p>0.05). These data suggest that higher sodium intake is associated with a greater increase in cSBP in MA compared to YG adults that may be due to increases in forward and reflected wave amplitudes.Supported by NIH Grant R01 HL104106