Sex differences in endothelial function in chronic kidney disease.

Vascular dysfunction plays an important role in the etiology of chronic kidney disease (CKD) and is associated with cardiovascular diseases. Sex differences in vascular function are common in clinical and nonclinical populations. However, no data exist in individuals with CKD. The present study tested the hypothesis that sex and/or aging differences exist in vascular function in patients with CKD. Endothelium-dependent dilation (EDD; measured via brachial artery flow-mediated dilation) and endothelium-independent dilation (EID; measured via nitroglycerin-mediated dilation) were assessed. Analyses were adjusted for several variables that could influence vascular function (diabetes, cardiovascular disease, and blood pressure). Women, in general, had higher EDD values than men (6.5 ± 4.9% vs. 4.4 ± 3.4%); however, EID did not differ among these groups. In younger men and women (<55 yr old), EDD and EID were higher (P < 0.05) than their older (≥55 yr old) counterparts (EDD: 7.0 ± 4.1% vs. 4.4 ± 3.8% and EID: 24.0 ± 9.6% vs. 18.3 ± 9.2%). Additionally, younger women exhibited higher (P < 0.05) EDD and EID compared with younger men (EDD: 9.5 ± 6.4% vs. 5.1 ± 3.8%, P = 0.01, and EID: 24.0 ± 9.6% vs. 18.3 ± 9.2%). No differences in EDD and EID were present between older men and women with CKD. Diabetes independently predicted lower EID but not EDD in men and women. Blood pressure and cardiovascular disease did not predict EDD or EID. This is the first study to show significant sex differences in vascular function. Moreover, these differences are evident between younger men and women with CKD but are abolished with age. Additional studies are needed to better understand the mechanisms that may underlie sex differences in vascular dysfunction with CKD.

Greater α1-adrenergic-mediated vasoconstriction in contracting skeletal muscle of patients with type 2 diabetes.

Patients with type 2 diabetes mellitus (T2DM) exhibit diminished exercise capacity likely attributable to reduced skeletal muscle blood flow (i.e., exercise hyperemia). A potential underlying mechanism of the impaired hyperemic response to exercise could be inadequate blunting of sympathetic-mediated vasoconstriction (i.e., poor functional sympatholysis). Therefore, we studied the hyperemic and vasodilatory responses to handgrip exercise in patients with T2DM as well as vasoconstriction to selective α-agonist infusion. Forearm blood flow (FBF) and vascular conductance (FVC) were examined in patients with T2DM (n = 30) as well as nondiabetic controls (n = 15) with similar age (59 ± 9 vs. 60 ± 9 yr, P = 0.69) and body mass index (31.4 ± 5.2 vs. 29.5 ± 4.6 kg/m2, P = 0.48). Intra-arterial infusion of phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) were used to induce vasoconstriction: [(FVCwith drug - FVCpredrug)/FVCpredrug × 100%]. Subjects completed rest and dynamic handgrip exercise (20% of maximum) trials per α-agonist. Patients with T2DM had smaller increases (Δ from rest) in FBF (147 ± 71 vs. 199 ± 63 ml/min) and FVC (126 ± 58 vs. 176 ± 50 ml·min-1·100 mmHg-1, P < 0.01 for both) during exercise compared with controls, respectively. During exercise, patients with T2DM had greater α1- (-16.9 ± 5.9 vs. -11.3 ± 3.8%) and α2-mediated vasoconstriction (-23.5 ± 7.1 vs. -19.0 ± 6.5%, P < 0.05 for both) versus controls. The magnitude of sympatholysis (Δ in %vasoconstriction between exercise and rest) for PE was lower (worse) in patients with T2DM versus controls (14.9 ± 12.2 vs. 23.1 ± 8.1%, P < 0.05) whereas groups were similar during DEX trials (24.6 ± 12.3 vs. 27.6 ± 13.4%, P = 0.47). Our data suggest patients with T2DM have attenuated hyperemic and vasodilatory responses to exercise, which could be attributable to greater α1-mediated vasoconstriction in contracting skeletal muscle.NEW & NOTEWORTHY Findings presented in this article are the first to show patients with type 2 diabetes mellitus have blunted hyperemic and vasodilatory responses to dynamic handgrip exercise. Moreover, we illustrate greater α1-adrenergic-mediated vasoconstriction may contribute to our initial observations. Collectively, these data suggest patients with type 2 diabetes may have impaired functional sympatholysis, which can contribute to their reduced exercise capacity.

Dietary nitrate does not acutely enhance skeletal muscle blood flow and vasodilation in the lower limbs of older adults during single-limb exercise.

PURPOSE: Blood flow (BF) and vasodilator responses to knee-extension exercise are attenuated in older adults across an exercise transient (onset, kinetics, and steady-state), and reduced nitric oxide bioavailability (NO) has been hypothesized to be a primary mechanism contributing to this attenuation. We tested the hypothesis acute dietary nitrate (NO3-) supplementation (~ 4.03 mmol NO3- and 0.29 mmol NO2-) would improve leg vasodilator responses across an exercise transient during lower limb exercise in older adults. METHODS: Older (n = 10) untrained adults performed single and rhythmic knee-extension contractions at 20% and 40% work-rate maximum (WRmax) prior to and 2-h after consuming a NO3- or placebo beverage in a double-blind, randomized fashion. Femoral artery BF was measured by Doppler ultrasound. Vascular conductance was calculated using BF and mean arterial pressure. RESULTS: Acute ingestion of dietary NO3- enhanced plasma [NO3-] and [NO2-] (P < 0.05). Neither dietary NO3- or placebo enhanced vasodilator responses at the onset of exercise or during steady state at 20% and 40% WRmax (P > 0.05). Leg vasodilator kinetics during rhythmic exercise remained unchanged following NO3- and placebo ingestion (P > 0.05). CONCLUSIONS: The key findings of this study are that despite increasing plasma [NO3-] and [NO2-], acute dietary NO3- intake had no effect on (1) rapid hyperaemic or vasodilator responses at the onset of exercise; (2) hyperaemic and vasodilator responses during steady-state submaximal exercise; or (3) kinetics of vasodilation preceding steady-state responses. Collectively, these findings suggest that low dose dietary NO3- supplementation does not improve hyperaemic and vasodilator responses across an exercise transient in older adults.

Nutraceuticals as a potential adjunct therapy toward improving vascular health in CKD.

Chronic kidney disease (CKD) is a major public health epidemic and increases risk for developing cardiovascular disease (CVD). Vascular dysfunction is a major independent risk factor toward increased risk for CVD in CKD. Several mechanisms have been postulated to result in vascular dysfunction in CKD, including oxidative stress-mediated inflammation by redox imbalance and reduced nitric oxide (NO) bioavailability and synthesis. Therefore, strategies that decrease oxidative stress and/or increase NO bioactivity may have major clinical implications toward improving vascular health and reducing the burden of CVD in CKD. Nutraceutical therapy in the form of polyphenols, dietary nitrates, or selective mitochondria-targeting therapies has recently been shown to improve vascular function by reducing oxidative stress and/or increasing NO bioavailability and synthesis. This review, therefore, highlights these three emerging nutraceuticals recently implicated in pathophysiological improvement of vascular function in CKD. This review also describes those pathophysiological mechanisms thought to be responsible for the beneficial effects on the vasculature and possible experimental considerations that may exist within human CKD populations. It is clear throughout this review that human-based mechanistic preclinical and health-related clinical studies are lacking regarding whether nutraceuticals do indeed improve vascular function in patients with CKD. As such, a comprehensive, detailed, and fully integrated understanding of nutraceuticals and vasculature function is necessary in patients with CKD. Many opportunities exist for original mechanistic and therapeutic discoveries and investigations on select nutraceuticals and their impact on vascular outcomes in patients with CKD, and these will remain exciting avenues of research in the future.

Impaired modulation of postjunctional α1 - but not α2 -adrenergic vasoconstriction in contracting forearm muscle of postmenopausal women.

KEY POINTS: Contraction-mediated blunting of postjunctional α-adrenergic vasoconstriction (functional sympatholysis) is attenuated in skeletal muscle of ageing males, brought on by altered postjunctional α1 - and α2 -adrenergic receptor sensitivity. The extent to which postjunctional α-adrenergic vasoconstriction occurs in the forearms at rest and during exercise in postmenopausal women remains unknown. The novel findings indicate that contraction-mediated blunting of α1 - (via intra-arterial infusion of phenylephrine) but not α2 -adrenergic (via intra-arterial infusion of dexmedetomidine) vasoconstriction was attenuated in postmenopausal women compared to young women. Additional important findings revealed that postjunctional α-adrenergic vasoconstrictor responsiveness at rest does not appear to be affected by age in women. Collectively, these results contribute to our understanding of local neurovascular control at rest and during exercise with age in women. ABSTRACT: Contraction-mediated blunting of postjunctional α-adrenergic vasoconstriction (functional sympatholysis) is attenuated in older males; however, direct confirmation of this effect remains unknown in postmenopausal women (PMW). The present study examined whether PMW exhibit augmented postjunctional α-adrenergic receptor vasoconstriction at rest and during forearm exercise compared to young women (YW). Eight YW (24 ± 1 years) and eight PMW (65 ± 1 years) completed a series of randomized experimental trials: (1) at rest, (2) under high flow (adenosine infusion) conditions and (3) during 6 min of forearm exercise at relative (20% of maximum) and absolute (7 kg) intensities. Phenylephrine (α1 -agonist) or dexmedetomidine (α2 -agonist) was administered during the last 3 min of each trial to elicit α-adrenergic vasoconstriction. Forearm vascular conductance (FVC) was calculated from blood flow and blood pressure. Vasoconstrictor responsiveness was identified as the change in FVC (%) during α-adrenergic agonist infusions from baseline (resting trial) or from steady-state conditions (high flow and exercise trials). During resting and high flow trials, the %FVC during α1 - and α2 -agonist stimulation was similar between YW and PMW. During exercise, α1 -mediated vasoconstriction was blunted in YW vs. PMW at relative (-6 ± 2% vs. -15 ± 3%) and absolute (-4 ± 2% vs. -14 ± 5%) workloads, such that blood flow and FVC were lower in PMW (P < 0.05 for all). Conversely, α2 -mediated vasoconstriction was similar between YW and PMW at relative (-22 ± 3% vs. -22 ± 4%; P > 0.05) and absolute (-19 ± 3% vs. -18 ± 4%; P > 0.05) workloads. Collectively, these findings demonstrate that despite similar α-adrenergic vasoconstrictor responsiveness at rest, PMW have a decreased ability to attenuate α1 -adrenergic vasoconstriction in contracting skeletal muscle.

Eight weeks of nitrate supplementation improves blood flow and reduces the exaggerated pressor response during forearm exercise in peripheral artery disease.

Peripheral artery disease (PAD) is characterized by a reduced blood flow (BF) and an elevated blood pressure (pressor) response during lower extremity exercise. Although PAD is evident in the upper extremities, no studies have determined BF and pressor responses during upper extremity exercise in PAD. Emerging evidence suggests that inorganic nitrate supplementation may serve as an alternative dietary strategy to boost nitric oxide bioavailability, improving exercising BF and pressor responses during exercise. The present study investigated 1) BF and pressor responses to forearm exercise in patients with PAD ( n = 21) relative to healthy age-matched control subjects ( n = 16) and 2) whether 8 wk of NaNO3 supplementation influenced BF and pressor responses to forearm exercise in patients with PAD. Patients with moderate to severe PAD were randomly assigned to a NaNO3 (1 g/day, n = 13)-treated group or a placebo (microcrystalline cellulose, n = 8)-treated group. Brachial artery forearm BF (FBF; via Doppler) and blood pressure (via finger plethysmography) were measured during mild-intensity (~3.5-kg) and moderate-intensity (~7-kg) handgrip exercise. The absolute change (from baseline) in FBF was reduced (except in the 3.5-kg condition) and BP responses were increased in patients with PAD compared with healthy control subjects in 3.5- and 7-kg conditions (all P < 0.05). Plasma nitrate and nitrite were elevated, exercising (7-kg) ΔFBF was improved (from 141 ± 17 to 172 ± 20 ml/min), and mean arterial pressure response was reduced (from 13 ± 1 to 9 ± 1 mmHg, P < 0.05) in patients with PAD that received NaNO3 supplementation for 8 wk relative to those that received placebo. These results suggest that the BF limitation and exaggerated pressor response to moderate-intensity forearm exercise in patients with PAD are improved with 8 wk of NaNO3 supplementation. NEW & NOTEWORTHY Peripheral artery disease (PAD) results in an exaggerated pressor response and reduced blood flow during lower limb exercise; however, the effect of PAD in the upper limbs has remained unknown. These results suggest that 8 wk of inorganic nitrate supplementation improves the blood flow limitation and exaggerated pressor response to moderate-intensity forearm exercise in PAD.

Age-associated impairments in contraction-induced rapid-onset vasodilatation within the forearm are independent of mechanical factors.

NEW FINDINGS: What is the central question of this study? We examined whether the mechanical contribution to contraction-induced rapid-onset vasodilatation (ROV) differed with age and whether ROV is associated with peripheral artery stiffness. Furthermore, we examined how manipulation of perfusion pressure modulates ROV in young and older adults. What is the main finding and its importance? The mechanical contribution to ROV is similar in young and older adults. Conversely, peripheral arterial stiffness is not associated with ROV. Enhancing perfusion pressure augments ROV to a similar extent in young and older adults. These results suggest that age-related attenuations in ROV are not attributable to a mechanical component and that ROV responses are independent of peripheral artery stiffness. ABSTRACT: Contraction-induced rapid-onset vasodilatation (ROV) is modulated by perfusion and transmural pressure in young adults; however, this effect remains unknown in older adults. The present study examined the mechanical contribution to ROV in young versus older adults, the influence of perfusion pressure and whether these responses are associated with arterial stiffness. Forearm vascular conductance (in millilitres per minute per 100 mmHg) was measured in 12 healthy young (24 ± 4 years old) and 12 older (67 ± 3 years old) adults during: (i) single dynamic contractions at 20% of maximal voluntary contraction; and (ii) single external mechanical compression of the forearm (200 mmHg) positioned above, at and below heart level. Carotid-radial pulse-wave velocity characterized upper limb arterial stiffness. Total ROV responses to single muscle contractions and single external mechanical compressions were attenuated in older adults at heart level (P < 0.05); however, the relative mechanical contribution to contraction-induced peak (46 ± 14 versus 40 ± 18%; P = 0.21) and total (37 ± 21 versus 32 ± 18%; P = 0.27) responses were not different between young and older adults. Reducing or enhancing perfusion pressure altered ROV responses to a similar extent between young and older adults (P < 0.05). Upper limb arterial stiffness was not associated with peak (r = 0.02; P = 0.93) or total vascular conductance (r = -0.01; P = 0.96) in the group as a whole. Our data suggest that: (i) age-associated attenuations in ROV are not attributable to a mechanical component; (ii) enhancing perfusion pressure augments ROV to a similar extent between young and older adults; and (iii) basal upper limb arterial stiffness is not associated with the vasodilator responses after a single skeletal muscle contraction in young and older adults.

Vasoconstrictor responsiveness in contracting human muscle: influence of contraction frequency, contractile work, and metabolic rate.

PURPOSE: The aim of this study was to examine whether independent effects exist between contractile work and metabolic demand (VO2m) on vasoconstrictor responsiveness (i.e., functional sympatholysis) under different contraction durations matched for total contractile work in exercising human skeletal muscle. METHODS: Ten young men performed rhythmic forearm contractions at 10 and 15% of maximum voluntary contraction (MVC) which consisted of muscle contractions using the same duty cycle but altering the duration of the contraction-relaxation cycles of exercise and included: 1) fast frequency contractions at 10% MVC (FFC10%) using a contraction relaxation cycle at 1:2 s; 2) slow frequency contractions at 10% MVC (SFC10%) at 2:4 s; and 3) SFC at 15% MVC (SFC15%) at 2:4 s. Lower body negative pressure (LBNP) was applied to increase sympathetic vasoconstriction during forearm exercise. Brachial artery diameter and blood velocities (measured via Doppler ultrasound) determined forearm blood flow (FBF), and forearm vascular conductance (FVC) was calculated from FBF (ml min-1) and mean arterial blood pressure. RESULTS: Results revealed that steady-state indices of FBF, FVC, and VO2m were greater (P < 0.05) in FFC10% and SFC15% vs. SFC10%. In addition, the magnitude of vasoconstriction (percent reduction in FVC) in response to reflex increases in sympathetic activity during LBNP was greater with SFC10% vs. FFC10% (-20.6 ± 3.0 vs. -11.1 ± 2.0%; P < 0.05), whereas there was no difference with FFC10% vs. SFC15% (-11.1 ± 2.0 vs. -11.8 ± 1.8%; P = 0.91). CONCLUSIONS: Our data indicate that faster work-matched muscle contractions increase blood flow and metabolism, leading to improved functional sympatholysis as compared to slower work-matched muscle contractions in humans.

Influence of passive stretch on muscle blood flow, oxygenation and central cardiovascular responses in healthy young males.

The aim of this study was to examine the effect of skeletal muscle stretching on peripheral, central, and autonomic cardiovascular responses in humans. Twelve healthy males completed a controlled passive stretch of the plantar flexors for 4 min at three different intensities. Doppler ultrasound velocimetry and imaging techniques assessed mean leg blood flow (MLBF), antegrade blood flow, and retrograde blood flow of the popliteal artery. Near-infrared spectroscopy assessed the concentration of deoxygenated hemoglobin + myoglobin ([HHb]) and the sum of its deoxygenated and oxygenated forms [i.e., blood volume ([Hbtot])]. Heart rate (HR) and mean arterial pressure were measured simultaneously to peripheral hemodynamic responses. During stretch there was an increase (P < 0.05) in antegrade and retrograde blood flow along with [HHb] and [Hbtot] relative to baseline, whereas MLBF was not altered. HR increased (P < 0.01) in a stretch intensity- and time-dependent manner, suggesting a threshold tension must be met that results in a mechanoreflex-mediated increase in HR. After stretch there was an increase (P < 0.05) in [Hbtot] and MLBF in each condition, suggesting that stretch creates a poststretch hyperemic response. Furthermore, retrograde blood flow was decreased (P < 0.05) after stretch in each stretch condition. Mean arterial pressure was decreased (P < 0.05) after moderate-intensity stretching. Collectively, our data provide novel mechanistic evidence on cardiovascular responses to skeletal muscle stretching in humans. Moreover, the reductions in MAP and retrograde blood flow suggest that stretch transiently reduces myogenic vascular tone in a poststretch resting period.

Curcumin Supplementation and Vascular and Cognitive Function in Chronic Kidney Disease: A Randomized Controlled Trial.

Chronic kidney disease (CKD) increases the risk of cardiovascular disease and cognitive impairment. Curcumin is a polyphenol that improves vascular and cognitive function in older adults; however, its effects on vascular and cognitive function in patients with CKD are unknown. We hypothesized that curcumin supplementation would improve vascular and cognitive function in patients with CKD. Eighty-eight adults diagnosed with stage 3b or 4 CKD (aged 66 ± 8 years, 75% male) participated in a 12-month, randomized, double-blind, placebo-controlled study to test the effects of curcumin (Longvida®, 2000 mg/day) on vascular and cognitive function. Our primary outcome was brachial artery flow-mediated dilation (FMD). Our secondary outcomes were nitroglycerin-mediated dilation, carotid-femoral pulse wave velocity (cfPWV), and cognitive function assessed via the NIH Toolbox Cognition Battery. At baseline, the mean estimated glomerular filtration rate was 34.7 ± 10.8, and the median albumin/creatinine ratio was 81.9 (9.7, 417.3). A total of 44% of participants had diabetes. Compared with placebo, 12 months of curcumin did not improve FMD (median change from baseline was -0.7 (-2.1, 1.1) and -0.1 (-1.5, 1.5) for curcumin and placebo, respectively, with p = 0.69). Similarly, there were no changes in nitroglycerin-mediated dilation, cfPWV, or cognitive outcomes. These results do not support chronic curcumin supplementation to improve vascular and cognitive function in patients with CKD.

Using a practical approach for determining the most effective stretching strategy in female college division I volleyball players.

The purpose of this investigation was to quantify the effects that a practical bout of static stretching (SS) and dynamic stretching (DS) has on maximal countermovement jump (CMJ) height across a time spectrum of 25 minutes in National Collegiate Athletic Association Division I varsity volleyball players. Eleven female varsity volleyball players (mean ± SD; age 20.00 ± 1.55 years; height 1.78 ± 0.08 m; mass 74.55 ± 12.18 kg) volunteered for this investigation. Three days of randomized experimental testing (SS, DS, control) were completed. The SS protocol consisted of stretching 7 muscle groups. The DS protocol consisted of the volleyball team's actual DS routine of equal duration (30 seconds) to SS. Poststretch performance measures of CMJ were determined at 1, 5, 15, and 25 minutes poststretch. Countermovement jump had an acute significant trial-by-time interaction, indicating that DS was found to produce significantly higher scores than the SS and control session at 1 and 5 minutes poststretch, but not at 15 and 25 minutes poststretch. Additionally, there was a timing interaction within trials where SS scores were significantly lower at 1 minute poststretch compared with 5 and 25 minutes poststretch, and DS scores were significantly higher at 1 and 5 minutes poststretch compared with 15 and 25 minutes poststretch. Athletes engaging in competitive power sports should continue to utilize their DS routine but may need to do so within 5 minutes before activity.

Effect of Resveratrol on Endothelial Function in Patients with CKD and Diabetes: A Randomized Controlled Trial.

BACKGROUND: Patients with CKD and diabetes are at higher risk of developing cardiovascular disease, in part, because of impaired endothelial function. Cardioprotective compounds such as resveratrol could improve endothelial function and attenuate the cardiovascular burden in patients with CKD and diabetes. We hypothesized that resveratrol supplementation would improve endothelial function in patients with CKD and diabetes. METHODS: Twenty-eight adults aged 68±7 years (84% men) with stage 3 CKD and diabetes were enrolled in a randomized, double-blind, placebo-controlled, crossover study to investigate the effects of 6-week resveratrol supplementation (400 mg/d) on endothelial function. Endothelial function was determined through brachial artery flow-mediated dilation. RESULTS: The mean values for eGFR and hemoglobin A 1c were 40±9 ml/min per 1.73 m 2 and 7.36%±0.72%, respectively. Compared with placebo, resveratrol supplementation increased flow-mediated dilation (ratio of geometric mean changes and 95% confidence interval for between-group comparisons, 1.43 (1.15 to 1.77); P value = 0.001). eGFR, hemoglobin A 1c , BP, and nitroglycerin-mediated dilation were unchanged with resveratrol or placebo ( P = 0.15), suggesting the observed change in flow-mediated dilation was likely independent of changes in traditional cardiovascular risk factors. CONCLUSIONS: Resveratrol supplementation improved endothelial function in patients with CKD and diabetes. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Resveratrol and Vascular Function in CKD, NCT03597568 .

Association of skeletal muscle mass, kidney disease and mortality in older men and women: the cardiovascular health study.

Low muscle mass (sarcopenia) is a prevalent and major concern in the aging population as well as in patients with chronic kidney disease (CKD). We hypothesized that sarcopenia is an independent predictor of incident and progressive CKD and increased mortality in older men and women (≥65 years) from the Cardiovascular Health Study. Sarcopenia was defined by bioimpedance-estimated skeletal muscle mass index (SMI) as a continuous variable and categorically (normal, class I, and class II). Cox regression hazard ratios (HRs) estimated the risk of incident and prevalent CKD and mortality in individuals with and without CKD. Low SMI was associated with increased prevalence of CKD in men (p<0.001), but lower prevalence of CKD in women (p=0.03). Low muscle mass was not associated with incident CKD or rapid CKD progression (>3 ml/minute/1.73m2/year decline in eGFR) in men, but was associated with lower risk of incident CKD in women ([adjusted RR=0.69, 95% (0.51,0.94)]. Low muscle mass (class II) was independently associated with higher mortality only in men [(adjusted HR=1.26, 95% (1.05,1.50)]. Neither definition of sarcopenia was associated with mortality in men or women with CKD. Further studies are needed to understand the mechanisms by which sarcopenia contributes to higher mortality in aging men.

Uric Acid Lowering and Biomarkers of Kidney Damage in CKD Stage 3: A Post Hoc Analysis of a Randomized Clinical Trial.

RATIONALE & OBJECTIVE: Hyperuricemia is associated with chronic kidney disease (CKD) progression. We evaluated whether lowering serum uric acid levels improves levels of biomarkers of kidney damage. STUDY DESIGN: Post hoc analysis of clinical trial participants. SETTING & PARTICIPANTS: A double-blind randomized placebo-controlled study designed to lower serum uric acid levels. 80 patients with stage 3 CKD and asymptomatic hyperuricemia were randomly assigned to allopurinol treatment or placebo (300 mg/d) for 12 weeks. EXPOSURE/PREDICTOR: Allopurinol treatment versus placebo. OUTCOMES & MEASURES: We evaluated the change from baseline for the following urinary biomarkers of kidney damage: albumin-creatinine ratio (ACR), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and transforming growth factor ß1 (TGF-ß1). Additionally, we evaluated CKD Epidemiology Collaboration (CKD-EPI)-estimated glomerular filtration rate (eGFR) and cystatin C eGFR. ANALYTICAL APPROACH: Generalized linear mixed modeling was used. RESULTS: After 12 weeks, allopurinol (compared to placebo) significantly lowered serum uric acid levels with an estimate of -3.3 mg/dL (95% CI, -4.1 to -2.5 mg/dL; P < 0.001). Estimates for the change for allopurinol versus placebo over time were 1.09 (95% CI, 0.77-1.54) for ACR, 0.77 (95% CI, 0.36-1.63) for NGAL, and 2.36 (95% CI, 0.97-5.70) for TGF-ß1. The model did not converge for KIM-1, but Wilcoxon signed rank test showed no significant difference in change from baseline between study groups. There was no significant change observed in CKD-EPI eGFR or cystatin C eGFR. LIMITATIONS: Post hoc analysis and short duration of the study. CONCLUSIONS: Uric acid-lowering with allopurinol is not associated with improvement in levels of biomarkers of kidney damage in patients with asymptomatic hyperuricemia and stage 3 CKD. FUNDING: The study was funded by the National Institutes of Health through a career development award, K23DK088833, and the Clinical and Translational Science Award UL1TR002537. TRIAL REGISTRATION: NCT01228903.

Mechanistic insights into the modulatory role of the mechanoreflex on central hemodynamics using passive leg movement in humans.

The aim of this study was to examine the independent contributions of joint range of motion (ROM), muscle fascicle length (MFL), and joint angular velocity on mechanoreceptor-mediated central cardiovascular dynamics using passive leg movement (PLM) in humans. Twelve healthy men (age: 23 ± 2 yr, body mass index: 23.7 kg/m2) performed continuous PLM at various randomized joint angle ROMs (0°-50° vs. 50°-100° vs. 0°-100°) and joint angular velocities ("fast": 200°/s vs. "slow": 100°/s). Measures of heart rate (HR), cardiac output (CO), and mean arterial pressure (MAP) were recorded during baseline and during 60 s of PLM. MFL was calculated from muscle architectural measurements of fascicle pennation angle and tissue thickness (Doppler ultrasound). Percent change in MFL increased across the transition of PLM from 0° to 50° (15 ± 3%; P < 0.05) and from 0° to 100° knee flexion (27 ± 4%; P < 0.05). The average peak percent change in HR (increased, approx. +5 ± 2%; P < 0.05), CO (increased, approx. +5 ± 3%; P < 0.05), and MAP (decreased, approx. -2 ± 2%; P < 0.05) were similar between fast versus slow angular velocities when compared against shorter absolute joint ROMs (i.e., 0°-50° and 50°-100°). However, the condition that exhibited the greatest angular velocity in combination with ROM (0°-100° at 200°/s) elicited the greatest increases in HR (+13 ± 2%; P < 0.05) and CO (+12 ± 2%; P < 0.05) compared with all conditions. Additionally, there was a significant relationship between MFL and HR within 0°-100° at 200°/s condition ( r2 = 0.59; P < 0.05). These findings suggest that increasing MFL and joint ROM in combination with increased angular velocity via PLM are important components that activate mechanoreflex-mediated cardioacceleration and increased CO. NEW & NOTEWORTHY The mechanoreflex is an important autonomic feedback mechanism that serves to optimize skeletal muscle perfusion during exercise. The present study sought to explore the mechanistic contributions that initiate the mechanoreflex using passive leg movement (PLM). The novel findings show that progressively increasing joint angle range of motion and muscle fascicle length via PLM, in combination with increased angular velocity, are important components that activate mechanoreflex-mediated cardioacceleration and increase cardiac output in humans.

Habitual exercise training in older adults offsets the age-related prolongation in leg vasodilator kinetics during single-limb lower body exercise.

We tested the hypothesis that aging is associated with prolonged leg vasodilator kinetics and habitual exercise training in older adults improves these responses relative to untrained older adults. Additionally, we examined the relationship between contraction-induced rapid onset vasodilation (ROV) and vasodilator kinetics. Young ( n = 10), older untrained ( n = 13), and older trained ( n = 14) adults performed single and rhythmic knee-extension contractions at 20% and 40% work-rate maximum (WRmax). Femoral artery diameter and mean blood velocity were measured by Doppler ultrasound. Vascular conductance (VC; ml·min-1·mmHg-1) was calculated using blood flow (ml/min) and mean arterial pressure (mmHg). The primary outcome was the kinetic response (mean response time; MRT), modeled using an exponential model, expressed as the number of duty cycles to change 63% of the steady-state amplitude. There were no age- or training-related differences in VC MRT between the groups at 20% WRmax. Older untrained adults exhibited prolonged VC MRT at 40% WRmax relative to young (37 ± 16 vs. 24 ± 10 duty-cycles; P < 0.05) and older trained adults (37 ± 16 vs. 23 ± 14 duty-cycles; P < 0.05). There were no differences in VC MRT between young and older trained adults at 40% WRmax ( P = 0.96). There were no associations between peak ROV and VC MRT at 20% or 40% WRmax ( r = -0.08 and 0.22; P = 0.67 and 0.20, respectively) in the group as a whole. Our data suggest 1) advancing age prolongs leg vasodilator kinetics; 2) habitual exercise training in older adults offsets this age-related prolongation; and 3) contraction-induced ROV is not related to vasodilator kinetics within a group of young and older adults. NEW & NOTEWORTHY Aging is associated with reductions in exercise hyperemia and vasodilation at the onset of exercise, as well as during steady-state exercise. Habitual endurance exercise training offsets these age-related reductions. We found that aging prolongs vasodilator kinetics in the leg of older untrained but not older trained adults. Finally, our results demonstrate that contraction-induced rapid vasodilation is not associated with vasodilator kinetics within the leg of young and older adults.

Acute Effects of Interrupting Sitting on Discomfort and Alertness of Office Workers.

OBJECTIVE: The aim of this study was to compare the effect of 4 hours of sitting interrupted with hourly bouts of standing and/or pedaling versus uninterrupted sitting on alertness and discomfort among sedentary office workers. METHODS: Fifteen middle-aged sedentary workers were randomized to three 4-hour conditions: (1) uninterrupted sitting; (2) sitting interrupted with 10 minutes of standing/hour; and (3) sitting interrupted with 10 minutes of pedaling/hour. Self-reported measures of alertness and discomfort were collected. RESULTS: Uninterrupted sitting significantly increased discomfort (P < 0.001). Discomfort was lower in both the standing (P < 0.001) and pedaling (P < 0.001) conditions than the uninterrupted sitting condition. Short-lived improvements in alertness were observed immediately following several standing (50%) and pedaling (100%) interruptions. CONCLUSION: Prolonged sitting increases discomfort while brief standing and pedaling interruptions attenuate impairments in discomfort among sedentary workers.