L-Citrulline Supplementation Improves Arterial Blood Flow and Muscle Oxygenation during Handgrip Exercise in Hypertensive Postmenopausal Women.

Endothelial dysfunction decreases exercise limb blood flow (BF) and muscle oxygenation. Acute L-Citrulline supplementation (CIT) improves muscle tissue oxygen saturation index (TSI) and deoxygenated hemoglobin (HHb) during exercise. Although CIT improves endothelial function (flow-mediated dilation [FMD]) in hypertensive women, the impact of CIT on exercise BF and muscle oxygenation (TSI) and extraction (HHb) are unknown. We examined the effects of CIT (10 g/day) and a placebo for 4 weeks on blood pressure (BP), arterial vasodilation (FMD, BF, and vascular conductance [VC]), and forearm muscle oxygenation (TSI and HHb) at rest and during exercise in 22 hypertensive postmenopausal women. Compared to the placebo, CIT significantly (p < 0.05) increased FMD (Δ-0.7 ± 0.6% vs. Δ1.6 ± 0.7%) and reduced aortic systolic BP (Δ3 ± 5 vs. Δ-4 ± 6 mmHg) at rest and improved exercise BF (Δ17 ± 12 vs. Δ48 ± 16 mL/min), VC (Δ-21 ± 9 vs. Δ41 ± 14 mL/mmHg/min), TSI (Δ-0.84 ± 0.58% vs. Δ1.61 ± 0.46%), and HHb (Δ1.03 ± 0.69 vs. Δ-2.76 ± 0.77 µM). Exercise BF and VC were positively correlated with improved FMD and TSI during exercise (all p < 0.05). CIT improved exercise artery vasodilation and muscle oxygenation via increased endothelial function in hypertensive postmenopausal women.

Elevated sympathetic-mediated vasoconstriction at rest but intact functional sympatholysis during exercise in heart failure with reduced ejection fraction.

Patients with heart failure with reduced ejection fraction (HFrEF) have exaggerated sympathoexcitation and impaired peripheral vascular conductance. Evidence demonstrating consequent impaired functional sympatholysis is limited in HFrEF. This study aimed to determine the magnitude of reduced limb vascular conductance during sympathoexcitation and whether functional sympatholysis would abolish such reductions in HFrEF. Twenty patients with HFrEF and 22 age-matched controls performed the cold pressor test (CPT) [left foot 2-min in -0.5 (1)°C water] alone and with right handgrip exercise (EX + CPT). Right forearm vascular conductance (FVC), forearm blood flow (FBF), and mean arterial pressure (MAP) were measured. Patients with HFrEF had greater decreases in %ΔFVC and %ΔFBF during CPT (both P < 0.0001) but not EX + CPT (P = 0.449, P = 0.199) compared with controls, respectively. %ΔFVC and %ΔFBF decreased from CPT to EX + CPT in patients with HFrEF (both P < 0.0001) and controls (P = 0.018, P = 0.015), respectively. MAP increased during CPT and EX + CPT in both groups (all P < 0.0001). MAP was greater in controls than in patients with HFrEF during EX + CPT (P = 0.025) but not CPT (P = 0.209). In conclusion, acute sympathoexcitation caused exaggerated peripheral vasoconstriction and reduced peripheral blood flow in patients with HFrEF. Handgrip exercise abolished sympathoexcitatory-mediated peripheral vasoconstriction and normalized peripheral blood flow in patients with HFrEF. These novel data reveal intact functional sympatholysis in the upper limb and suggest that exercise-mediated, local control of blood flow is preserved when cardiac limitations that are cardinal to HFrEF are evaded with dynamic handgrip exercise.NEW & NOTEWORTHY Patients with HFrEF demonstrate impaired peripheral blood flow regulation, evidenced by heightened peripheral vasoconstriction that reduces limb blood flow in response to physiological sympathoexcitation (cold pressor test). Despite evidence of exaggerated sympathetic vasoconstriction, patients with HFrEF demonstrate a normal hyperemic response to moderate-intensity handgrip exercise. Most importantly, acute, simultaneous handgrip exercise restores normal limb vasomotor control and vascular conductance during acute sympathoexcitation (cold pressor test), suggesting intact functional sympatholysis in patients with HFrEF.

Mechanistic involvement of noradrenergic neuronal neurotransmitter release in cutaneous vasoconstriction during autonomic dysreflexia in persons with spinal cord injury.

INTRODUCTION: Autonomic dysreflexia (AD) is a potentially life-threatening consequence in high (above T6) spinal cord injury that involves multiple incompletely understood mechanisms. While peripheral arteriolar vasoconstriction, which controls systemic vascular resistance, is documented to be pronounced during AD, the pathophysiological neurovascular junction mechanisms of this vasoconstriction are undefined. One hypothesized mechanism is increased neuronal release of norepinephrine and co-transmitters. We tested this by examining the effects of blockade of pre-synaptic neural release of norepinephrine and co-transmitters on cutaneous vasoconstriction during AD, using a novel non-invasive technique; bretylium (BT) iontophoresis followed by skin blood flow measurements via laser doppler flowmetry (LDF). METHODS: Bretylium, a sympathetic neuronal blocking agent (blocks release of norepinephrine and co-transmitters) was applied iontophoretically to the skin of a sensate (arm) and insensate (leg) area in 8 males with motor complete tetraplegia. An nearby untreated site served as control (CON). Cutaneous vascular conductance (CVC) was measured (CVC = LDF/mean arterial pressure) at normotension before AD was elicited by bladder stimulation. The percent drop in CVC values from pre-AD vs. AD was compared among BT and CON sites in sensate and insensate areas. RESULTS: There was a significant effect of treatment but no significant effect of limb/sensation or interaction of limb x treatment on CVC. The percent drop in CVC between BT and CON treated sites was 25.7±1.75 vs. 39.4±0.87, respectively (P = 0.004). CONCLUSION: Bretylium attenuates, but does not fully abolish vasoconstriction during AD. This suggests release of norepinephrine and cotransmitters from cutaneous sympathetic nerves is involved in cutaneous vasoconstriction during AD.

Altered locomotor muscle metaboreflex control of ventilation in patients with COPD.

We investigated the locomotor muscle metaboreflex control of ventilation, circulation, and dyspnea in patients with chronic obstructive pulmonary disease (COPD). Ten patients [forced expiratory volume in 1 second (FEV1; means ± SD) = 43 ± 17% predicted] and nine age- and sex-matched controls underwent 1) cycling exercise followed by postexercise circulatory occlusion (PECO) to activate the metaboreflex or free circulatory flow to inactivate it, 2) cold pressor test to interpret whether any altered reflex response was specific to the metaboreflex arc, and 3) muscle biopsy to explore the metaboreflex arc afferent side. We measured airflow, dyspnea, heart rate, arterial pressure, muscle blood flow, and vascular conductance during reflexes activation. In addition, we measured fiber types, glutathione redox balance, and metaboreceptor-related mRNAs in the vastus lateralis. Metaboreflex activation increased ventilation versus free flow in patients (∼15%, P < 0.020) but not in controls (P > 0.450). In contrast, metaboreflex activation did not change dyspnea in patients (P = 1.000) but increased it in controls (∼100%, P < 0.001). Other metaboreflex-induced responses were similar between groups. Cold receptor activation increased ventilation similarly in both groups (P = 0.46). Patients had greater type II skeletal myocyte percentage (14%, P = 0.010), lower glutathione ratio (-34%, P = 0.015), and lower nerve growth factor (NGF) mRNA expression (-60%, P = 0.031) than controls. Therefore, COPD altered the locomotor muscle metaboreflex control of ventilation. It increased type II myocyte percentage and elicited redox imbalance, potentially producing more muscle metaboreceptor stimuli. Moreover, it decreased NGF expression, suggesting a downregulation of metabolically sensitive muscle afferents.NEW & NOTEWORTHY This study's integrative physiology approach provides evidence for a specific alteration in locomotor muscle metaboreflex control of ventilation in patients with COPD. Furthermore, molecular analyses of a skeletal muscle biopsy suggest that the amount of muscle metaboreceptor stimuli derived from type II skeletal myocytes and redox imbalance overcame a downregulation of metabolically sensitive muscle afferents.

Greater post-exercise hypotension in healthy young untrained men after exercising in a hot compared to a temperate environment.

This research examined the effects of exercising in a hot compared to a temperate environment on post-exercise hemodynamics in untrained men. We hypothesized exercise in a hot compared to a temperate environment would elicit greater post-exercise hypotension, and this would be attributable to higher cutaneous vascular conductance and sweat loss, and lower heart rate variability (HRV) and cardiac baroreflex sensitivity (cBRS). In a randomized counterbalanced order, 12 untrained healthy men completed two trials involving 40-min leg-cycling exercise at either 23 °C (CON) or 35 °C (HOT). Post-exercise participants rested supine for 60 min at 23 °C whilst hemodynamic and thermoregulatory measurements were assessed. Post-exercise hypotension was greater after exercising in a hot than a temperate environment as indicated by a lower mean arterial pressure at 60 min recovery (CON 83 ± 5 mmHg, HOT 78 ± 5 mmHg, Mean difference [95% confidence interval], -5 [-8, -3] mmHg). Throughout recovery, cutaneous vascular conductance was higher, and cBRS and HRV were lower after exercising in a hot than in a temperate environment (P < 0.05). Sweat loss was greater on HOT than on CON (P < 0.001). Post-exercise hypotension after exercising in the hot environment was associated with sweat loss (r = 0.66, P = 0.02), and changes in cutaneous vascular conductance (r = 0.64, P = 0.03), and HRV (Root mean square of the successive difference in R-R interval [RMSSD]) r=0.75, P = 0.01 and and log high frequency [HF] r=0.66, P = 0.02), but not cBRS (all, r ≤ 0.2, P > 0.05). Post-exercise hypotension was greater after exercise in a hot compared to a temperate environment and may be partially explained by greater sweat loss and cutaneous vascular conductance, and lower HRV.

The effect of increasing work rate amplitudes from a common metabolic baseline on the kinetic response of V̇o2p, blood flow, and muscle deoxygenation.

A step-transition in external work rate (WR) increases pulmonary O2 uptake (V̇o2p) in a monoexponential fashion. Although the rate of this increase, quantified by the time constant (τ), has frequently been shown to be similar between multiple different WR amplitudes (ΔWR), the adjustment of O2 delivery to the muscle (via blood flow; BF), a potential regulator of V̇o2p kinetics, has not been extensively studied. To investigate the role of BF on V̇o2p kinetics, 10 participants performed step-transitions on a knee-extension ergometer from a common baseline WR (3 W) to: 24, 33, 45, 54, and 66 W. Each transition lasted 8 min and was repeated four to six times. Volume turbinometry and mass spectrometry, Doppler ultrasound, and near-infrared spectroscopy were used to measure V̇o2p, BF, and muscle deoxygenation (deoxy[Hb + Mb]), respectively. Similar transitions were ensemble-averaged, and phase II V̇o2p, BF, and deoxy[Hb + Mb] were fit with a monoexponential nonlinear least squares regression equation. With increasing ΔWR, τV̇o2p became larger at the higher ΔWRs (P < 0.05), while τBF did not change significantly, and the mean response time (MRT) of deoxy[Hb + Mb] became smaller. These findings that V̇o2p kinetics become slower with increasing ΔWR, while BF kinetics are not influenced by ΔWR, suggest that O2 delivery could not limit V̇o2p in this situation. However, the speeding of deoxy[Hb + Mb] kinetics with increasing ΔWR does imply that the O2 delivery-to-O2 utilization of the microvasculature decreases at higher ΔWRs. This suggests that the contribution of O2 delivery and O2 extraction to V̇O2 in the muscle changes with increasing ΔWR.NEW & NOTEWORTHY A step increase in work rate produces a monoexponential increase in V̇o2p and blood flow to a new steady-state. We found that step transitions from a common metabolic baseline to increasing work rate amplitudes produced a slowing of V̇o2p kinetics, no change in blood flow kinetics, and a speeding of muscle deoxygenation kinetics. As work rate amplitude increased, the ratio of blood flow to V̇o2p became smaller, while the amplitude of muscle deoxygenation became greater. The gain in vascular conductance became smaller, while kinetics tended to become slower at higher work rate amplitudes.

Neurovascular and hemodynamic responses to mental stress and exercise in severe COVID-19 survivors.

Previous studies show that COVID-19 survivors have elevated muscle sympathetic nerve activity (MSNA), endothelial dysfunction, and aortic stiffening. However, the neurovascular responses to mental stress and exercise are still unexplored. We hypothesized that COVID-19 survivors, compared with age- and body mass index (BMI)-matched control subjects, exhibit abnormal neurovascular responses to mental stress and physical exercise. Fifteen severe COVID-19 survivors (aged: 49 ± 2 yr, BMI: 30 ± 1 kg/m2) and 15 well-matched control subjects (aged: 46 ± 3 yr, BMI: 29 ± 1 kg/m2) were studied. MSNA (microneurography), forearm blood flow (FBF), and forearm vascular conductance (FVC, venous occlusion plethysmography), mean arterial pressure (MAP, Finometer), and heart rate (HR, ECG) were measured during a 3-min mental stress (Stroop Color-Word Test) and during a 3-min isometric handgrip exercise (30% of maximal voluntary contraction). During mental stress, MSNA (frequency and incidence) responses were higher in COVID-19 survivors than in controls (P < 0.001), and FBF and FVC responses were attenuated (P < 0.05). MAP was similar between the groups (P > 0.05). In contrast, the MSNA (frequency and incidence) and FBF and FVC responses to handgrip exercise were similar between the groups (P > 0.05). MAP was lower in COVID-19 survivors (P < 0.05). COVID-19 survivors exhibit an exaggerated MSNA and blunted vasodilatory response to mental challenge compared with healthy adults. However, the neurovascular response to handgrip exercise is preserved in COVID-19 survivors. Overall, the abnormal neurovascular control in response to mental stress suggests that COVID-19 survivors may have an increased risk to cardiovascular events during mental challenge.

Effect of Combined Grape Seed Extract and L-Citrulline Supplementation on Hemodynamic Responses to Exercise in Young Males.

Grape seed extract (GSE) or L-citrulline supplement has been known to increase nitric oxide (NO) bioavailability and enhance endothelial-mediated vasodilation. Accordingly, to examine the additive benefits of combination of the two supplementations on hemodynamic responses to dynamic exercise, young, healthy males were recruited for this study. Effects of 7 days of 1) GSE + L-citrulline, 2) GSE, 3) L-citrulline, and 4) placebo supplementation on systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), cardiac output, total vascular conductance (TVC), and oxygen (O2) consumption were examined at rest and during cycling exercise. Compared with placebo, GSE, L-citrulline, and combined supplementations did not reduce SBP, DBP, and MAP, while cardiac output (placebo; 23.6 ± 1.3 L/min, GSE; 25.7 ± 1.1 L/min; L-citrulline, 25.2 ± 1.2 L/min; GSE + L-citrulline; 25.3 ± 0.9 L/min) and TVC (placebo; 234.7 ± 11.3 ml/min/mmHg, GSE; 258.3 ± 10.6 ml/min/mmHg; L-citrulline, 255.2 ± 10.6 ml/min/mmHg; GSE + L-citrulline; 260.4 ± 8.9 ml/min/mmHg) were increased at only the 80% workload (p < 0.05). Compared with placebo and L-citrulline, GSE and combined supplementations had a reduction in VO2 across workloads (p < 0.05). However, there was no additive benefits on these variables. We conclude that supplementation with GSE, L-citrulline, and combined supplementations increased cardiac output due partially to decreased vascular resistance. Our findings suggest that GSE may act as an ergogenic aid that can improve O2 delivery to exercising muscles.

Point/counterpoint: Cerebrovascular resistance is a flawed concept.

The relationship between cerebral blood flow and blood pressure is a critical part of investigation of cerebral autoregulation. Conventionally, cerebrovascular resistance (CVR) has been used to describe this relationship, but the underlying principles used for this method is flawed in real-world application for several reasons. Despite this, the use of CVR remains entrenched within current literature. This 'Point/Counterpoint' review provides a summary of the flaws in using CVR and explains the benefits of calculating the more accurate critical closing pressure (CrCP) and resistance-area product (RAP) parameters, with support of real-world data.

Aging increases metabolic capacity and reduces work efficiency during handgrip exercise in males.

Maximal oxygen uptake and exercise performance typically decline with age. However, there are indications of preserved vascular function and blood flow regulation during arm exercise. Yet, it is unknown if this potential physiological preservation with age is mirrored in peripheral metabolic capacity and V̇o2/W ratio. Thus, to investigate the effects of aging in the arms, we measured metabolic and vascular responses to 6-min bouts of dynamic handgrip exercise at 40% and 80% of maximal work rate (WRmax) in 11 young (26 ± 2 yr) and 12 old (80 ± 6 yr) males, applying Doppler-ultrasound combined with blood samples from a deep forearm vein. At baseline, the old had a larger arterial diameter compared with young (P < 0.001). During exercise, the two groups reached the same WRmax. V̇o2, blood flow, and oxygen supply were higher (40%WRmax; 80%WRmax, all P < 0.01), and arteriovenous oxygen difference was lower (80%WRmax, P < 0.02), in old compared with young. Old also had a higher oxygen excess at 80%WRmax (P < 0.01) than young, whereas no difference in muscle diffusion or oxygen extraction was detected. Only young exhibited an increase in intensity-induced arterial dilation (P < 0.05), and they had a lower mean arterial pressure than old at 80%WRmax (P < 0.001). V̇o2/W (40%WRmax; 80%WRmax) was reduced in old compared with young (both P < 0.05). In conclusion, in old and young males with a similar handgrip WRmax, old had a higher V̇o2 during 80%WRmax intensity, achieved by an increased blood flow. This may be a result of the available cardiac output reserve, compensating for reduced work efficiency and attenuated vascular response observed in old.NEW & NOTEWORTHY Contrasting the typically observed decline in V̇o2max with age, the current study reveals an age-related increase in forearm metabolic capacity during handgrip exercise in old, mediated by an increased forearm blood flow. Exercise with a small muscle mass in arms, where central components of the oxygen transport are not limiting, allows old to attain a similar maximal work rate as young despite their increased V̇o2/W ratio.

Effects of comorbid type II diabetes mellitus and heart failure on rat hindlimb and respiratory muscle blood flow during treadmill exercise.

In rats with type II diabetes mellitus (T2DM) compared with nondiabetic healthy controls, muscle blood flow (Q̇m) to primarily glycolytic hindlimb muscles and the diaphragm muscle are elevated during submaximal treadmill running consequent to lower skeletal muscle mass, a finding that held even when muscle mass was normalized to body mass. In rats with heart failure with reduced ejection fraction (HF-rEF) compared with healthy controls, hindlimb Q̇m was lower, whereas diaphragm Q̇m is elevated during submaximal treadmill running. Importantly, T2DM is the most common comorbidity present in patients with HF-rEF, but the effect of concurrent T2DM and HF-rEF on limb and respiratory Q̇m during exercise is unknown. We hypothesized that during treadmill running (20 m·min-1; 10% incline), hindlimb and diaphragm Q̇m would be higher in T2DM Goto-Kakizaki rats with HF-rEF (i.e., HF-rEF + T2DM) compared with nondiabetic Wistar rats with HF-rEF. Ejection fractions were not different between groups (HF-rEF: 30 ± 5; HF-rEF + T2DM: 28 ± 8%; P = 0.617), whereas blood glucose was higher in HF-rEF + T2DM (209 ± 150 mg/dL) compared with HF-rEF rats (113 ± 28 mg/dL; P = 0.040). Hindlimb muscle mass normalized to body mass was lower in rats with HF-rEF + T2DM (36.3 ± 1.6 mg/g) than in nondiabetic HF-rEF counterparts (40.3 ± 2.7 mg/g; P < 0.001). During exercise, Q̇m was elevated in rats with HF-rEF + T2DM compared with nondiabetic counterparts to the hindlimb (HF-rEF: 100 ± 28; HF-rEF + T2DM: 139 ± 23 mL·min-1·100 g-1; P < 0.001) and diaphragm (HF-rEF: 177 ± 66; HF-rEF + T2DM: 215 ± 93 mL·min-1·100g-1; P = 0.035). These data suggest that the pathophysiological consequences of T2DM on hindlimb and diaphragm Q̇m during treadmill running in the GK rat persist even in the presence of HF-rEF.NEW & NOTEWORTHY Herein, we demonstrate that rats comorbid with heart failure with reduced ejection fraction (HF-rEF) and type II diabetes mellitus (T2DM) have a higher hindlimb and respiratory muscle blood flow during submaximal treadmill running (20 m·min-1; 10% incline) compared with nondiabetic HF-rEF counterparts. These data may carry important clinical implications for roughly half of all patients with HF-rEF who present with T2DM.

Sympathetic transduction to blood pressure during euglycemic-hyperinsulinemia in young healthy adults: role of burst amplitude.

Insulin acts centrally to stimulate sympathetic vasoconstrictor outflow to skeletal muscle and peripherally to promote vasodilation. Given these divergent actions, the "net effect" of insulin on the transduction of muscle sympathetic nerve activity (MSNA) into vasoconstriction and thus, blood pressure (BP) remains unclear. We hypothesized that sympathetic transduction to BP would be attenuated during hyperinsulinemia compared with baseline. In 22 young healthy adults, MSNA (microneurography), and beat-to-beat BP (Finometer or arterial catheter) were continuously recorded, and signal-averaging was performed to quantify the mean arterial pressure (MAP) and total vascular conductance (TVC; Modelflow) responses following spontaneous bursts of MSNA at baseline and during a euglycemic-hyperinsulinemic clamp. Hyperinsulinemia significantly increased MSNA burst frequency and mean burst amplitude (baseline: 46 ± 6 au; insulin: 65 ± 16 au, P < 0.001) but did not alter MAP. The peak MAP (baseline: 3.2 ± 1.5 mmHg; insulin: 3.0 ± 1.9 mmHg, P = 0.67) and nadir TVC (P = 0.45) responses following all MSNA bursts were not different between conditions indicating preserved sympathetic transduction. However, when MSNA bursts were segregated into quartiles based on their amplitudes at baseline and compared with similar amplitude bursts during hyperinsulinemia, the peak MAP and TVC responses were blunted (e.g., largest burst quartile: MAP, baseline: Δ4.4 ± 1.7 mmHg; hyperinsulinemia: Δ3.0 ± 0.8 mmHg, P = 0.02). Notably, ∼15% of bursts during hyperinsulinemia exceeded the size of any burst at baseline, yet the MAP/TVC responses to these larger bursts (MAP, Δ4.9 ± 1.4 mmHg) did not differ from the largest baseline bursts (P = 0.47). These findings indicate that increases in MSNA burst amplitude contribute to the overall maintenance of sympathetic transduction during hyperinsulinemia.

Exaggerated pressor responses, but unaltered blood flow regulation and functional sympatholysis during lower limb exercise in young, non-Hispanic black males.

PURPOSE: Young non-Hispanic black (BL) males have displayed lower blood flow (BF) and vascular conductance (VC), but intact functional sympatholysis, during upper limb exercise when compared to non-Hispanic white (WH) males. This study sought to explore if similar differences were also present in the lower limbs. METHODS: Thirteen young BL males and thirteen WH males completed one visit comprised of rhythmic lower limb (plantar flexion) exercise as well as upper limb (handgrip) exercise for a limb-specific comparison. Limb BF, mean arterial pressure (MAP), and VC were evaluated at three submaximal workloads (8, 16, and 24 kg). To determine potential limb differences in functional sympatholysis, the impact of sympathetic nervous system activation (via cold-pressor test (CPT)) was evaluated at rest and during steady state exercise (30 % of maximal voluntary contraction) on a subsequent visit. RESULTS: MAP responses to lower and upper limb exercise were elevated in young BL males (vs WH males), resulting in significantly lower VC responses in the upper limb, but not the lower limb. Further, BL males, when compared to WH males, revealed no differences in functional sympatholysis, evident by similar responses in both the exercising leg and arm VC during CPT. CONCLUSION: The findings of the current study indicate that although elevated MAP responses were observed during both lower and upper limb exercise in young BL males, vascular conductance was only hindered in the upper limbs. This may potentially highlight enhanced compensatory mechanisms in the lower limb (vs upper limb) to maintain perfusion in young BL males.

Dietary nitrate supplementation and small muscle mass exercise hemodynamics in patients with essential hypertension.

Exaggerated blood pressure and diminished limb hemodynamics during exercise in patients with hypertension often are not resolved by antihypertensive medications. We hypothesized that, independent of antihypertensive medication status, dietary nitrate supplementation would increase limb blood flow, decrease mean arterial pressure (MAP), and increase limb vascular conductance during exercise in patients with hypertension. Patients with hypertension either abstained from (n = 14, Off-Meds) or continued (n = 12, On-Meds) antihypertensive medications. Within each group, patients consumed (crossover design) nitrate-rich or nitrate-depleted (placebo) beetroot juice for 3 days before performing handgrip (HG) and knee-extensor exercise (KE). Blood flow and MAP were measured using Doppler ultrasound and an automated monitor, respectively. Dietary nitrate increased plasma-[nitrite] Off-Meds and On-Meds. There were no significant effects of dietary nitrate on blood flow, MAP, or vascular conductance during HG in Off-Meds or On-Meds. For KE, dietary nitrate decreased MAP (means ± SD across all 3 exercise intensities, 118 ± 14 vs. 122 ± 14 mmHg, P = 0.024) and increased vascular conductance (26.2 ± 6.1 vs. 24.7 ± 7.0 mL/min/mmHg, P = 0.024), but did not affect blood flow for Off-Meds, with no effects On-Meds. Dietary nitrate-induced changes in blood flow (r = -0.67, P < 0.001), MAP (r = -0.43, P = 0.009), and vascular conductance (r = -0.64, P < 0.001) during KE, but only vascular conductance (r = -0.35, P = 0.039) during HG, were significantly related to the magnitude of placebo values, with no differentiation between groups. Thus, the effects of dietary nitrate on limb hemodynamics and MAP during exercise in patients with hypertension are dependent on the values at baseline, independent of antihypertensive medication status, and dependent on whether exercise was performed by the forearm or quadriceps.NEW & NOTEWORTHY Adverse hemodynamic responses to exercise in patients with hypertension, despite antihypertensive medication, indicate a sustained cardiovascular risk. The efficacy of dietary nitrate to improve limb vascular conductance during exercise was inversely dependent on the magnitude of exercising limb vascular conductance at baseline, rather than antihypertensive medication status. The effects of dietary nitrate on hemodynamics during exercise in patients with hypertension are dependent on the values at baseline and independent of antihypertensive medication status.

Reactive hyperaemia augments local heat-induced skin hyperaemia.

NEW FINDINGS: What is the central question of this study? It is valuable to be able to monitor disease- or treatment-related changes in the microcirculation. Laser Doppler flowmetry with local heating allows non-invasive monitoring of the skin microcirculation and its ability to vasodilate. Does reactive hyperaemia augment the increase in skin blood flow elicited by local heating? What is the main finding and its importance? The addition of reactive hyperaemia to local heating results in greater vasodilatation than heating alone. Thus, reactive hyperaemia can augment local heat-induced hyperaemia in the skin. ABSTRACT: The skin circulation has been proposed as a model of generalized microvascular function that could be monitored non-invasively using laser Doppler flowmetry (LDF). The response to heat hyperaemia (HH) is commonly used to monitor disease- or treatment-related changes in microvascular function. We hypothesized that reactive hyperaemia would augment the increase in skin blood flow elicited by local heating. Fourteen healthy young adults were subjected to three different conditions: reactive hyperaemia (RH; skin temperature controlled at 33°C), heat hyperaemia (HH; 42°C held for 40 min) and HH+RH. Two Peltier-controlled thermomodules with LDF probes were placed on the right forearm to monitor skin blood flow continuously. A cuff was placed on the right upper arm to elicit RH by inflation to 220 mmHg for 5 min. This procedure was performed with the skin temperature at 33°C and again after 40 min of local heating to 42°C. Beat-by-beat mean arterial pressure (MAP) obtained by a photoplethysmographic sensor on the middle finger of the left hand allowed calculation of cutaneous vascular conductance (CVC) as LDF/MAP. Both HH and RH increased LDF (P < 0.0001 and P < 0.0001, respectively) and CVC (P = 0.0001 and P < 0.0001, respectively) above baseline values. The LDF and CVC values were significantly higher during HH+RH when compared with RH or HH alone (P < 0.0001). In summary, HH+RH resulted in greater vasodilatation when compared with HH or RH alone. These results indicate that RH can augment local heat-induced hyperaemia in the skin.

Dietary nitrate supplementation effect on dynamic cerebral autoregulation in normoxia and acute hypoxia.

We tested the hypothesis that increasing the nitric oxide (NO) bioavailability by dietary nitrate would recover the hypoxia-induced reduction in dynamic cerebral autoregulation (CA). Twelve healthy males (age 21 ± 2 years) completed four days of dietary supplementation with a placebo or inorganic nitrate drink (140-ml beetroot juice per day) followed by 60-min of normoxia or hypoxia (fraction of inspired oxygen [FiO2] = 13%). Duplex ultrasonography was used to perform volumetric change-based assessment of dynamic CA in the internal carotid artery (ICA). Dynamic CA was assessed by rate of regulation (RoR) of vascular conductance using the thigh-cuff method. Four days of beetroot supplementation increased circulating nitrate by 208 [171,245] µM (mean difference [95% confidence interval]) compared with placebo. Dynamic CA was lower in hypoxia than normoxia (RoR Δ-0.085 [-0.116, -0.054]). Compared with placebo, nitrate did not alter dynamic CA in normoxia (RoR Δ-0.022 [-0.060, 0.016]) or hypoxia (RoR Δ0.017 [-0.019, 0.053]). Further, nitrate did not affect ICA vessel diameter, blood velocity or flow in either normoxia or hypoxia. Increased bioavailability of NO through dietary nitrate supplementation did not recover the hypoxia-induced reduction in dynamic CA. This suggests the mechanism of hypoxia-induced reduction in dynamic CA does not relate to the availability of NO.

Effects of cooling or warming of the distal upper limb on skin vascular conductance and brachial artery shear profiles during cycling exercise.

The relative influence of skin vascular conductance in glabrous (G; palm) and non-glabrous (NG; dorsal and forearm) regions to upstream brachial artery-shear stress (BA-SS) profile are unknown. This study aimed to elucidate the effects of G and/or NG skin vascular conductance (VC), which were modulated by warming or cooling manipulation, on BA-shear rate (SR, an estimate of SS) during cycling exercise. Seven healthy subjects performed 60-min exercise. Between 20 and 50 min of the exercise, the NG+G or G skin region were warmed to 42°C or cooled to 15°C using a water bath. Throughout the protocol, diameter and blood velocity in BA and skin VCs in forearm and palm were measured. All measurements showed that a steady-state response was reached after 20 min of exercise. Subsequently, during cooling manipulation, forearm VC was significantly decreased, and the concomitant BA-SR profile was revealed (primarily characterized by decreased antegrade SR and increased retrograde SR) in the NG+G. Such changes were not observed in G alone. During warming manipulation, forearm VC and mean BA-SR significantly increased only in the NG+G. In conclusion, vascular response in NG skin possibly plays a major role in the modulation of BA-SS profile during cycling exercise.

Cerebral vascular function following the acute consumption of caffeinated artificially- and sugar sweetened soft drinks in healthy adults.

Chronic consumption of sugar- and artificially-sweetened beverages (SSB and ASB) are associated with an increased risk of stroke but it is unclear how acute consumption influences cerebral vascular function. Purpose: We hypothesized that: (1) acute consumption of SSB and ASB would augment dynamic cerebral autoregulation (dCA) and attenuate cerebral vascular reactivity to hypercapnia (CVRCO2) compared to water; and (2) dCA and CVRCO2 would be attenuated with SSB compared to ASB and water. Methods: Twelve healthy adults (age: 23 ± 2 years, four females) completed three randomized trials where they drank 500 ml of water, SSB (Mountain Dew®), or ASB (Diet Mountain Dew®). We measured mean arterial pressure (MAP), middle and posterior cerebral artery blood velocities (MCAv and PCAv), and end-tidal CO2 tension (PETCO2). Cerebral vascular conductance was calculated as cerebral artery blood velocity/MAP (MCAc and PCAc). Twenty min after consumption, participants completed a 5 min baseline, and in a counterbalanced order, a CVRCO2 test (3%, 5%, and 7% CO2 in 3 min stages) and a dCA test (squat-stand tests at 0.10 Hz and 0.05 Hz for 5 min each) separated by 10 min. CVRCO2 was calculated as the slope of the linear regression lines of MCAv and PCAv vs. PETCO2. dCA was assessed in the MCA using transfer function analysis. Coherence, gain, and phase were determined in the low frequency (LF; 0.07-0.2 Hz) and very low frequency (VLF; 0.02-0.07 Hz). Results: MCAv and MCAc were lower after SSB (54.11 ± 12.28 cm/s, 0.58 ± 0.15 cm/s/mmHg) and ASB (51.07 ± 9.35 cm/s, 0.52 ± 1.0 cm/s/mmHg) vs. water (62.73 ± 12.96 cm/s, 0.67 ± 0.11 cm/s/mmHg; all P < 0.035), respectively. PCAc was also lower with the ASB compared to water (P = 0.007). MCA CVRCO2 was lower following ASB (1.55 ± 0.38 cm/s/mmHg) vs. water (2.00 ± 0.57 cm/s/mmHg; P = 0.011) but not after SSB (1.90 ± 0.67 cm/s/mmHg; P = 0.593). PCA CVRCO2 did not differ between beverages (P > 0.853). There were no differences between beverages for coherence (P ≥ 0.295), gain (P ≥ 0.058), or phase (P ≥ 0.084) for either frequency. Discussion: Acute consumption of caffeinated SSB and ASB resulted in lower intracranial artery blood velocity and conductance but had a minimal effect on cerebral vascular function as only MCA CVRCO2 was altered with the ASB compared to water.

Sympathetic vasoconstriction in skeletal muscle: modulatory effects of aging, exercise training, and sex.

The sympathetic nervous system (SNS) is a critically important regulator of the cardiovascular system. The SNS controls cardiac output and its distribution, as well as peripheral vascular resistance and blood pressure at rest and during exercise. Aging is associated with increased blood pressure and decreased skeletal muscle blood flow at rest and in response to exercise. The mechanisms responsible for the blunted skeletal muscle blood flow response to dynamic exercise with aging have not been fully elucidated; however, increased muscle sympathetic nerve activity (MSNA), elevated vascular resistance, and a decline in endothelium-dependent vasodilation are commonly reported in older adults. In contrast to aging, exercise training has been shown to reduce blood pressure and enhance skeletal muscle vascular function. Exercise training has been shown to enhance nitric oxide-dependent vascular function and may improve the vasodilatory capacity of the skeletal muscle vasculature; however, surprisingly little is known about the effect of exercise training on the neural control of circulation. The control of blood pressure and skeletal muscle blood flow also differs between men and women. Blood pressure and MSNA appear to be lower in young women than in men. However, females experience a larger increase in MSNA with aging compared with males. The mechanism(s) underlying the altered SNS control of vascular function in females remains to be determined. Novelty: This review summarizes our current understanding of the effects of aging, exercise training, and sex on sympathetic vasoconstriction at rest and during exercise. Areas where additional research is needed are also identified.

Thermoregulatory and cardiovascular responses in the elderly towards a broad range of gradual air temperature changes.

This study aimed to determine age-related differences in thermoregulatory and cardiovascular responses to a wide range of gradual ambient temperature (Ta) changes. Morphologically matched normotensive elderly and young males participated. The participants wearing only shorts rested during the 3-h experiment. After 30 min of baseline at 28 °C, Ta increased linearly to 43 °C in 30 min (warming) and then gradually decreased to 13 °C in 60 min (cooling). Ta was rewarmed to 28 °C in 30 min (rewarming), and that temperature was maintained for an additional 30 min (second baseline). During the warming phase, there were no age-related differences in blood pressure (BP) and rectal temperature (Tre), despite a significantly lower cutaneous vascular conductance and heart rate in the elderly (P < 0.05). At the end of the cooling phase, systolic blood pressure (SBP) in the elderly was significantly higher than the young (155.8 ± 16.1 and 125.0 ± 12.5 mmHg, P < 0.01). There was a consistent age group difference in SBP during rewarming. Mean skin temperature was significantly lower in the elderly during rewarming (P < 0.05). Tre decreased more in the elderly and was significantly lower at the end of the experiment than the younger participants (36.78 ± 0.34 and 37.01 ± 0.15 °C, P < 0.05). However, there were no age group differences in thermal sensation. In conclusion, even normotensive elderly participants have a greater and more persistent BP response to cold than younger adults, suggesting that the elderly might be at a higher risk of cardiac events during cooling and subsequent rewarming.