Aging is associated with a pro-oxidant state and a decline in endothelial function. Whether acute, enteral antioxidant treatment can reverse this decrement in vascular function is not well known. Flow-mediated vasodilation and reactive hyperemia were evaluated following consumption of either placebo or an oral antioxidant cocktail (Vitamin C, 1000mg; Vitamin E, 600 I.U.; Alpha-lipoic acid, 600 mg) in 87 healthy volunteers (42 young, 25 ± 1 yrs; 45 older, 71 ± 1 yrs) using a double-blind, crossover design. Blood velocity and brachial artery diameter (ultrasound Doppler) were assessed before and after 5-min forearm circulatory arrest. Serum markers of lipid peroxidation, total antioxidant capacity, endogenous antioxidant activity, and Vitamin C were assayed, and plasma nitrate, nitrite, and 3-nitrotyrosine were determined. In the placebo trial, an age-related reduction in brachial artery vasodilation was evident (young: 7.4 ± 0.6 %; older: 5.2 ± 0.4 %). Following antioxidant consumption, flow-mediated vasodilation improved in older subjects (5.2 ± 0.4 %, placebo: 8.2 ± 0.6 %, antioxidant) but declined in the young (7.4 ± 0.6 %, placebo; 5.8 ± 0.6 %, antioxidant). Reactive hyperemia was reduced with age, but antioxidant administration did not alter the response in either group. Together, these data demonstrate that antioxidant consumption acutely restores endothelial function in the elderly, while disrupting normal endothelium-dependent vasodilation in the young, and suggest that this age-related impairment is due, at least in part, to free radicals.

Limb movement-induced hyperemia has a central hemodynamic component: evidence from a neural blockade study. Am J Physiol Heart Circ Physiol 299: H1693-H1700, 2010. First published August 27, 2010; doi:10.1152/ajpheart.00482.2010.-The purpose of this investigation was to partially remove feedback from type III/IV skeletal muscle afferents and determine how this feedback influences the central and peripheral hemodynamic responses to passive leg movement. Heart rate (HR), stroke volume (SV), cardiac output (CO), mean arterial pressure, leg vascular conductance (LVC), and leg blood flow (LBF) were measured during 2 min of passive knee extension in eight young men before and after intrathecal fentanyl injection. Passive movement increased HR by 14 beats/min from baseline to maximal response during control (CON) (65 Ϯ 4 to 79 Ϯ 5 beats/min, P Ͻ 0.05), whereas HR did not significantly increase with the fentanyl block (BLK). LBF and LVC increased in both conditions; however, these increases were attenuated and delayed during BLK [%change from baseline to maximum, LBF: CON 295 Ϯ 109 vs. BLK 210 Ϯ 86%, (P Ͻ 0.05); LVC: CON 322 Ϯ 40% vs. BLK 231 Ϯ 32%, (P Ͻ 0.04)]. In CON, HR, SV, CO, and LVC increased contributing to the hyperemic response. However, under BLK conditions, statistically insignificant increases in HR and SV combined to yield a small, but significant, increase in CO and an attenuated hyperemic response. Therefore, partially blocking skeletal muscle afferent feedback blunts the central hemodynamic response due to passive limb movement, which then results in an attenuated and delayed movement-induced hyperemia. In combination, these findings provide evidence that limb movement-induced hyperemia has a significant central hemodynamic component induced by peripheral nerve activation. afferent nerve fiber; blood flow; hemodynamics CENTRAL AND PERIPHERAL HEMODYNAMIC factors contribute to the hyperemic response at the onset of exercise. These factors include the muscle pump (24, 38) mechanically induced vasodilation (6,19,41), mechanical deformation of arterioles (37), flow-mediated vasodilation (22, 34), and cardioacceleration (26, 30 -33, 43) due to stimulation of afferent mechanosensitive and metabosensitive fibers in the working muscles (25,36). Isolating the relative importance of these numerous mechanisms is difficult and requires a systematic approach to understand the nature of any single mechanism.One approach to study the movement-induced central and peripheral hemodynamic responses to the onset of exercise is to perform passive movement, thereby minimizing the metabolic contribution of voluntary exercise. Recently, our group (26, 43) and others (30,31,33) have highlighted the role of cardioacceleration in the hyperemic responses to passive movement. Wray et al. (43) reported that passive knee extension resulted in significant tachycardia and increased leg blood flow (LBF) during the first 5 s of movement. However, in this study, stroke volume (SV) was not measured, and cardiac output (CO) was assumed to r...

Objective While vascular dysfunction is well-defined in HF patients with reduced ejection fraction (HFrEF), disease-related alterations in the peripheral vasculature of HF patients with preserved ejection fraction (HFpEF) are not well characterized. Thus, we sought test the hypothesis that HFpEF patients would demonstrate reduced vascular function, at both the conduit artery and microvascular levels, compared to controls. Methods We examined both conduit artery function via brachial artery flow-mediated dilation (FMD) and microvascular function via reactive hyperemia (RH) following 5 min of ischemia in 24 Class II–IV HFpEF patients and 24 healthy controls matched for age, sex, and brachial artery diameter. Results FMD was reduced in HFpEF patients compared to controls (HFpEF: 3.1 ± 0.7%; Controls: 5.1 ± 0.5%; P = 0.03). However, shear rate at time of peak brachial artery dilation was lower in HFpEF patients compared to controls (HFpEF: 42,070 ± 4,018 s−1; Controls: 69,018 ± 9,509 s−1; P = 0.01), and when brachial artery FMD was normalized for the shear stimulus, cumulative area-under-the-curve (AUC) at peak dilation, the between-group differences were eliminated (HFpEF: 0.11 ± 0.03 %/AUC; Controls: 0.09 ± 0.01 %/AUC; P = 0.58). RH, assessed as AUC, was lower in HFpEF patients (HFpEF: 454 ± 35 mL; Controls: 660 ± 63 mL; P < 0.01). Conclusions Collectively, these data suggest that maladaptations at the microvascular level contribute to the pathophysiology of HFpEF, while conduit artery vascular function is not diminished beyond that which occurs with healthy aging.

New findings r What is the central question of this study?The role of histamine-mediated vasodilatation has been studied in the context of whole-body cycling but not small muscle-mass exercise. r What is the main finding and its importance?These data indicate that histamine receptors are activated following dynamic, but not resistance, exercise. Furthermore, these data suggest that local factors associated with aerobic exercise, and not systemic factors, are responsible for activation of histamine receptors in the previously exercised muscle.A sustained postexercise vasodilatation, which is histamine receptor mediated, has been observed following single bouts of whole-body exercise, but the mechanisms that regulate activation of histamine receptors following exercise are undefined. Exploration of vasodilatation after small muscle-mass dynamic or resistance exercise could provide novel insight into the pathways responsible for histamine receptor activation. We hypothesized that there would be a vasodilatation of the previously exercised limb following small muscle-mass dynamic and resistance exercise, which would be mediated by histamine receptors. We studied men and women before and after single-leg dynamic (n = 9) or resistance knee-extension exercise (n = 12) on control and blockade days (combined oral H 1 and H 2 receptor antagonism with fexofenadine and ranitidine). We measured arterial blood pressure (automated brachial oscillometry) and femoral artery blood flow (Doppler ultrasound). Dynamic exercise elevated leg vascular conductance in the active leg by 27.2 ± 8.4% at 60 min postexercise (P < 0.05 versus pre-exercise), but did not alter conductance in the rested leg (change, 4.6 ± 3.5%; P = 0.8 versus pre-exercise). The rise in conductance was abolished on the blockade day (change, 3.7 ± 5.1%; P = 0.8 versus preexercise, P = 0.2 versus control). Resistance exercise did not produce a sustained vasodilatation (change, -4.3 ± 4.7% at 60 min postexercise; P = 0.7 versus pre-exercise). These data indicate that histamine receptors are activated following dynamic, but not resistance, exercise. Furthermore, these data suggest that local factors associated with aerobic exercise, and not systemic factors or factors associated with high muscle force, are responsible for activation of histamine receptors in the previously exercised muscle.

The endothelin-1 vasoconstrictor pathway contributes to age-related elevations in resting peripheral vascular tone primarily through activation of the endothelin subtype A (ET(A)) receptor. However, the regulatory influence of ET(A)-mediated vasoconstriction during exercise in the elderly is unknown. Thus, in 17 healthy volunteers (n = 8 young, 24±2 years; n = 9 old, 70±2 years), we examined leg blood flow, mean arterial pressure, leg arterial-venous oxygen (O2) difference, and leg O2 consumption (VO2) at rest and during knee-extensor exercise before and after intra-arterial administration of the ET(A) antagonist BQ-123. During exercise, BQ-123 administration increased leg blood flow to a greater degree in the old (+29±5 mL/min/W) compared with the young (+16±3 mL/min/W). The increase in leg blood flow with BQ-123 was accompanied by an increase in leg VO2 in both groups, suggesting a reduced efficiency following ET(A) receptor blockade. Together, these findings have identified an age-related increase in ET(A)-mediated vasoconstrictor activity that persists during exercise, suggesting an important role of this pathway in the regulation of exercising skeletal muscle blood flow and maintenance of arterial blood pressure in the elderly.

Maximal strength training (MST) reduces pulmonary oxygen uptake (V O2) at a given submaximal exercise work rate (i.e., efficiency). However, whether the increase in efficiency originates in the trained skeletal muscle, and therefore the impact of this adaptation on muscle blood flow and arterial-venous oxygen difference (a-vO 2diff), is unknown. Thus five trained subjects partook in an 8-wk MST intervention consisting of half-squats with an emphasis on the rate of force development during the concentric phase of the movement. Pre-and posttraining measurements of pulmonary V O2 (indirect calorimetry), single-leg blood flow (thermodilution), and single-leg a-vO2diff (blood gases) were performed, to allow the assessment of skeletal muscle V O2 during submaximal cycling [237 Ϯ 23 W; ϳ60% of their peak pulmonary V O2 (V O2peak)]. Pulmonary V O2peak (ϳ4.05 l/min) and peak work rate (ϳ355 W), assessed during a graded exercise test, were unaffected by MST. As expected, following MST there was a significant reduction in pulmonary V O2 during steady-state submaximal cycling (ϳ237 W: 3.2 Ϯ 0.1 to 2.9 Ϯ 0.1 l/min). This was accompanied by a significant reduction in single-leg V O2 (1,101 Ϯ 105 to 935 Ϯ 93 ml/min) and single-leg blood flow (6,670 Ϯ 700 to 5,649 Ϯ 641 ml/min), but no change in single-leg a-vO2diff (16.7 Ϯ 0.8 to 16.8 Ϯ0.4 ml/dl). These data confirm an MSTinduced reduction in pulmonary V O2 during submaximal exercise and identify that this change in efficiency originates solely in skeletal muscle, reducing muscle blood flow, but not altering muscle a-vO2diff. oxygen consumption; blood flow; work economy DURING CYCLE EXERCISE, at a given submaximal work rate (WR), pulmonary oxygen uptake (V O 2 ) is similar between individuals of varying aerobic capacities [peak V O 2 (V O 2peak )] (34). This is true despite the complex, systemwide metabolic costs of exercise, such as ventilatory and cardiac muscle work, ion transport, and exercise-induced alterations in thermoregulation and metabolism, each of which may influence the V O 2 /WR relationship (6,39,43). Thus work efficiency, measured as the ratio of pulmonary V O 2 to work accomplished during submaximal steady-state cycling, is a global assessment of metabolic demand and may be influenced by a change in any of these systems. Therefore, a perturbation or stressor, such as maximal strength training (MST), which has been determined to alter work efficiency (22,26,42), may not simply be attributed to a change in efficiency of the exercising muscle.For over a decade, studies have documented that the use of MST, which consists of high loads and few repetitions, with an emphasis on the maximal rate of force development, improves work efficiency in both sedentary (22) and aerobically trained individuals (26,42), and this MST-induced change is even more evident during high-intensity exercise (22). While it is reasonable to expect enhanced intramuscular efficiency to be a major contributor to this documented improvement in work efficiency, an attenuated O 2 cost, external ...

Using flow-mediated vasodilation (FMD), reactive hyperemia (RH), and an acute oral antioxidant cocktail (AOC [Vitamin C, E and α-lipoic acid]), this study aimed to provide greater insight into altered vascular function and the role of oxidative stress in chronic heart failure patients with reduced ejection fraction (HFrEF) and at several time points beyond heart transplantation (HTx). A total of 61 age-matched subjects (12 healthy controls, 14 NYHA Class II and III HFrEF patients, and 35 HTx recipients (< 3 yrs post-HTx, 5-10 yrs post-HTx, and > 14 yrs post-HTx)) ingested either placebo (PL) or an AOC prior to FMD and RH testing of the brachial artery. Vascular function, as measured by FMD, was not different between the controls (6.8 ± 1.9 %), recent < 3 yrs post-HTx group (8.1 ± 1.2%), and the 5-10 yrs post-HTx group (5.5 ± 1.0%). However, PL FMD was lower in the HFrEF patients (4.5 ± 0.7%) and in the > 14 yrs post-HTx group (2.9 ± 0.8%). The AOC increased plasma ascorbate levels in all groups, but only increased FMD in the controls (PL 6.8 ± 1.9%; AOC 9.2 ± 1.0%) and > 14 yrs post-HTx recipients (PL 2.9 ± 0.8%; AOC 4.5 ± 1.3%). There were no differences in RH in any of the groups with PL or AOC. This cross-sectional study reveals that, compared to controls, vascular function is blunted in HFrEF patients, is similar soon after HTx, but is decreased with greater time post-HTx with free radicals implicated in this progression.

No abstract