Ellen A. Dawson

Shear Stress Mediates Endothelial Adaptations to Exercise Training in Humans

Although episodic changes in shear stress have been proposed as the mechanism responsible for the effects of exercise training on the vasculature, this hypothesis has not been directly addressed in humans. We examined brachial artery flow-mediated dilation, an index of NO-mediated endothelial function, in healthy men in response to an acute bout of handgrip exercise and across an 8-week period of bilateral handgrip training. Shear stress responses were attenuated in one arm by cuff inflation to 60 mm Hg. Similar increases were observed in grip strength and forearm volume and girth in both limbs. Acute bouts of handgrip exercise increased shear rate (P<0.005) and flow-mediated dilation percentage (P<0.05) in the uncuffed limb, whereas no changes were evident in the cuffed arm. Handgrip training increased flow-mediated dilation percentage in the noncuffed limb at weeks 2, 4, and 6 (P<0.001), whereas no changes were observed in the cuffed arm. Brachial artery peak reactive hyperemia, an index of resistance artery remodeling, progressively increased with training in the noncuffed limb (P<0.001 and 0.004); no changes were evident in the cuffed arm. Neither acute nor chronic shear manipulation during exercise influenced endothelium-independent glyceryl trinitrate responses. These results demonstrate that exercise-induced changes in shear provide the principal physiological stimulus to adaptation in flow-mediated endothelial function and vascular remodeling in response to exercise training in healthy humans.

Brain and central haemodynamics and oxygenation during maximal exercise in humans

During maximal exercise in humans, fatigue is preceded by reductions in systemic and skeletal muscle blood flow, O2 delivery and uptake. Here, we examined whether the uptake of O2 and substrates by the human brain is compromised and whether the fall in stroke volume of the heart underlying the decline in systemic O2 delivery is related to declining venous return. We measured brain and central haemodynamics and oxygenation in healthy males (n= 13 in 2 studies) performing intense cycling exercise (360 ± 10 W; mean ±s.e.m.) to exhaustion starting with either high (H) or normal (control, C) body temperature. Time to exhaustion was shorter in H than in C (5.8 ± 0.2 versus 7.5 ± 0.4 min, P < 0.05), despite heart rate reaching similar maximal values. During the first 90 s of both trials, frontal cortex tissue oxygenation and the arterial–internal jugular venous differences (a‐v diff) for O2 and glucose did not change, whereas middle cerebral artery mean flow velocity (MCA Vmean) and cardiac output increased by ∼22 and ∼115%, respectively. Thereafter, brain extraction of O2, glucose and lactate increased by ∼45, ∼55 and ∼95%, respectively, while frontal cortex tissue oxygenation, MCA Vmean and cardiac output declined ∼40, ∼15 and ∼10%, respectively. At exhaustion in both trials, systemic declined in parallel with a similar fall in stroke volume and central venous pressure; yet the brain uptake of O2, glucose and lactate increased. In conclusion, the reduction in stroke volume, which underlies the fall in systemic O2 delivery and uptake before exhaustion, is partly related to reductions in venous return to the heart. Furthermore, fatigue during maximal exercise, with or without heat stress, in healthy humans is associated with an enhanced rather than impaired brain uptake of O2 and substrates.

Retrograde Flow and Shear Rate Acutely Impair Endothelial Function in Humans

Changes in arterial shear stress induce functional and structural vasculature adaptations. Recent studies indicate that substantial retrograde flow and shear can occur through human conduit arteries. In animals, retrograde shear is associated with atherogenic effects. The aim of this study was to examine the impact of incremental levels of retrograde shear on endothelial function in vivo. On 3 separate days, we examined bilateral brachial artery flow-mediated dilation, an index of NO-mediated endothelial function, in healthy men (24±3 years) before and after a 30-minute intervention consisting of cuff inflation to 25, 50, or 75 mm Hg. Cuff inflations resulted in “dose”-dependent increases in retrograde shear rate, compared with the noncuffed arm, within subjects (P<0.001). Flow-mediated dilation in the cuffed arm did not change in response to the 25-mm Hg stimulus but decreased significantly after both the 50- and 75-mm Hg interventions (P<0.05). The decrease in flow-mediated dilation after the 75-mm Hg intervention was significantly larger than that observed after a 50-mm Hg intervention (P=0.03). In the noncuffed arm, no changes in shear rate or flow-mediated dilation were observed. These results demonstrate that an increase in retrograde shear rate induces a dose-dependent attenuation of endothelial function in humans. This finding contributes to our understanding regarding the possible detrimental effects of retrograde shear rate in vivo.

Impact of Shear Rate Modulation on Vascular Function in Humans

Shear stress is an important stimulus to arterial adaptation in response to exercise and training in humans. We recently observed significant reverse arterial flow and shear during exercise and different antegrade/retrograde patterns of shear and flow in response to different types of exercise. The purpose of this study was to simultaneously examine flow-mediated dilation, a largely NO-mediated vasodilator response, in both brachial arteries of healthy young men before and after 30-minute interventions consisting of bilateral forearm heating, recumbent leg cycling, and bilateral handgrip exercise. During each intervention, a cuff inflated to 60 mm Hg was placed on 1 arm to unilaterally manipulate the shear rate stimulus. In the noncuffed arm, antegrade flow and shear increased similarly in response to each intervention (ANOVA; P<0.001, no interaction between interventions; P=0.71). Baseline flow-mediated dilation (4.6%, 6.9%, and 6.7%) increased similarly in response to heating, handgrip, and cycling (8.1%, 10.4%, and 8.9%, ANOVA; P<0.001, no interaction; P=0.89). In contrast, cuffed arm antegrade shear rate was lower than in the noncuffed arm for all of the conditions (P<0.05), and the increase in flow-mediated dilation was abolished in this arm (4.7%, 6.7%, and 6.1%; 2-way ANOVA: all conditions interacted P<0.05). These results suggest that differences in the magnitude of antegrade shear rate transduce differences in endothelial vasodilator function in humans, a finding that may have relevance for the impact of different exercise interventions on vascular adaptation in humans.

Capillary-oxygenation-level-dependent near-infrared spectrometry in frontal lobe of humans

Brain function requires oxygen and maintenance of brain capillary oxygenation is important. We evaluated how faithfully frontal lobe near-infrared spectroscopy (NIRS) follows haemoglobin saturation (SCap) and how calculated mitochondrial oxygen tension (PMitoO2) influences motor performance. Twelve healthy subjects (20 to 29 years), supine and seated, inhaled O2 air-mixtures (10% to 100%) with and without added 5% carbon dioxide and during hyperventilation. Two measures of frontal lobe oxygenation by NIRS (NIRO-200 and INVOS) were compared with capillary oxygen saturation (SCap) as calculated from the O2 content of brachial arterial and right internal jugular venous blood. At control SCap (78% ± 4%; mean ± s.d.) was halfway between the arterial (98% ± 1%) and jugular venous oxygenation (SVO2; 61% ± 6%). Both NIRS devices monitored SCap (P < 0.001) within ~5% as SvO2 increased from 39% ± 5% to 79% ± 7% with an increase in the transcranial ultrasound Doppler determined middle cerebral artery flow velocity from 29 ± 8 to 65 ± 15 cm/sec. When SCap fell below ~70% with reduced flow and inspired oxygen tension, PMitoO2 decreased (P < 0.001) and brain lactate release increased concomitantly (P < 0.001). Handgrip strength correlated with the measured (NIRS) and calculated capillary oxygenation values as well as with PMitoO2 (r > 0.74; P < 0.05). These results show that NIRS is an adequate cerebral capillaryoxygenation-level-dependent (COLD) measure during manipulation of cerebral blood flow or inspired oxygen tension, or both, and suggest that motor performance correlates with the frontal lobe COLD signal.

Limitations to systemic and locomotor limb muscle oxygen delivery and uptake during maximal exercise in humans.

Reductions in systemic and locomotor limb muscle blood flow and O2 delivery limit aerobic capacity in humans. To examine whether O2 delivery limits both aerobic power and capacity, we first measured systemic haemodynamics, O2 transport and O2 uptake during incremental and constant (372 ± 11 W; 85% of peak power; mean ±s.e.m.) cycling exercise to exhaustion (n= 8) and then measured systemic and leg haemodynamics and during incremental cycling and knee‐extensor exercise in male subjects (n= 10). During incremental cycling, cardiac output and systemic O2 delivery increased linearly to 80% of peak power (r2= 0.998, P < 0.001) and then plateaued in parallel to a decline in stroke volume (SV) and an increase in central venous and mean arterial pressures (P < 0.05). In contrast, heart rate and increased linearly until exhaustion (r2= 0.993; P < 0.001) accompanying a rise in systemic O2 extraction to 84 ± 2%. In the exercising legs, blood flow and O2 delivery levelled off at 73–88% of peak power, blunting leg per unit of work despite increasing O2 extraction. When blood flow increased linearly during one‐legged knee‐extensor exercise, per unit of work was unaltered on fatigue. During constant cycling, , SV, systemic O2 delivery and reached maximal values within ∼5 min, but dropped before exhaustion (P < 0.05) despite increasing or stable central venous and mean arterial pressures. In both types of maximal cycling, the impaired systemic O2 delivery was due to the decline or plateau in because arterial O2 content continued to increase. These results indicate that an inability of the circulatory system to sustain a linear increase in O2 delivery to the locomotor muscles restrains aerobic power. The similar impairment in SV and O2 delivery during incremental and constant load cycling provides evidence for a central limitation to aerobic power and capacity in humans.

Autonomic nervous system influence on arterial baroreflex control of heart rate during exercise in humans

A combination of sympathoexcitation and vagal withdrawal increases heart rate (HR) during exercise, however, their specific contribution to arterial baroreflex sensitivity remains unclear. Eight subjects performed 25 min bouts of exercise at a HR of 90, 120, and 150 beats min−1, respectively, with and without metoprolol (0.16 ± 0.01 mg kg−1; mean ±s.e.m.) or glycopyrrolate (12.6 ± 1.6 μg kg−1). Carotid baroreflex (CBR) function was determined using 5 s pulses of neck pressure (NP) and neck suction (NS) from +40 to −80 Torr, while transfer function gain (GTF) was calculated to assess the linear dynamic relationship between mean arterial pressure and HR. Spontaneous baroreflex sensitivity (SBR) was evaluated as the slope of sequences of three consecutive beats in which systolic blood pressure and the R–R interval of the ECG either increased or decreased, in a linear fashion. The β‐1 adrenergic blockade decreased and vagal cardiac blockade increased HR both at rest and during exercise (P < 0.05). The gain at the operating point of the modelled reflex function curve (GOP) obtained using NP and NS decreased with workload independent of β‐1 adrenergic blockade. In contrast, vagal blockade decreased GOP from −0.40 ± 0.04 to −0.06 ± 0.01 beats min−1 mmHg−1 at rest (P < 0.05). Furthermore, as workload increased both GOP and SBR, and GOP and GTF were correlated (P < 0.001), suggesting that the two dynamic methods applied to evaluate arterial baroreflex (ABR) function provide the same information as the modelled GOP. These findings suggest that during exercise the reduction of arterial baroreceptor reflex sensitivity at the operating point was a result of vagal withdrawal rather than an increase in sympathetic activity.

Brachial Artery Blood Flow Responses to Different Modalities of Lower Limb Exercise

INTRODUCTION/PURPOSE Cycling is associated with a reproducible systolic anterograde and diastolic retrograde flow pattern in the brachial artery (BA) of the inactive upper limb, which results in endothelial nitric oxide (NO) release. The purpose of this study was to examine the impact of different types and intensities of lower limb exercise on the BA flow pattern. METHODS We examined BA blood flow and shear rate patterns during cycling, leg kicking, and walking exercise in 12 young subjects (24 +/- 3 yr). BA diameter, blood flow, and shear rate were assessed at baseline (1 min) and at three incremental intensity levels of cycling (60, 80, and 120 W), bilateral leg kicking (5, 7.5, and 10 kg), and walking (3, 4, and 5 km x h(-1)), performed for 3 min each. Edge detection and wall tracking of high-resolution B-mode arterial ultrasound images, combined with synchronized Doppler waveform envelope analysis, were used to calculate conduit artery diameter and anterograde/retrograde blood flow and shear rate continuously across the cardiac cycle. RESULTS BA mean blood flow and shear rate increased significantly throughout each exercise protocol (P < 0.001), and BA anterograde blood flow and shear rate showed comparable increases throughout each protocol (P < 0.001). Retrograde blood flow and shear rate, however, demonstrated a significant increase during cycling and walking (P < 0.001) but not during leg kicking. CONCLUSION Rhythmic lower limb exercise (cycling and walking) results in an increase in BA systolic anterograde blood flow and shear rate, directly followed by a large retrograde flow and shear rate. This typical pattern, previously linked with endothelial NO release, is not present during a different type of exercise such as leg kicking.

Erythrocytes and the regulation of human skeletal muscle blood flow and oxygen delivery: role of erythrocyte count and oxygenation state of haemoglobin

Blood flow to dynamically contracting myocytes is regulated to match O2 delivery to metabolic demand. The red blood cell (RBC) itself functions as an O2 sensor, contributing to the control of O2 delivery by releasing the vasodilators ATP and S‐nitrosohaemoglobin with the offloading of O2 from the haemoglobin molecule. Whether RBC number is sensed remains unknown. To investigate the role of RBC number, in isolation and in combination with alterations in blood oxygenation, on muscle and systemic perfusion, we measured local and central haemodynamics during one‐legged knee‐extensor exercise (∼50% peak power) in 10 healthy males under conditions of normocythaemia (control), anaemia, anaemia + plasma volume expansion (PVX), anaemia + PVX + hypoxia, polycythaemia, polycythaemia + hyperoxia and polycythaemia + hypoxia, which changed either RBC count alone or both RBC count and oxyhaemoglobin. Leg blood flow (LBF), cardiac output (Q) and vascular conductance did not change with either anaemia or polycythaemia alone. However, LBF increased with anaemia + PVX (28 ± 4%) and anaemia + PVX + hypoxia (46 ± 6%) and decreased with polycythaemia + hyperoxia (18 ± 5%). LBF and Q with anaemia + PVX + hypoxia (8.0 ± 0.5 and 15.8 ± 0.7 l min−1, respectively) equalled those during maximal knee‐extensor exercise. Collectively, LBF and vascular conductance were intimately related to leg arterial–venous (a–v) O2 difference (r2= 0.89–0.93; P < 0.001), suggesting a pivotal role of blood O2 gradients in muscle microcirculatory control. The systemic circulation accommodated to the changes in muscle perfusion. Our results indicate that, when coping with severe haematological challenges, local regulation of skeletal muscle blood flow and O2 delivery primarily senses alterations in the oxygenation state of haemoglobin and, to a lesser extent, alterations in the number of RBCs and haemoglobin molecules.

Changes in vascular and cardiac function after prolonged strenuous exercise in humans

Prolonged exercise has been shown to result in an acute depression in cardiac function. However, little is known about the effect of this type of exercise on vascular function. Therefore, the purpose of the present study was to investigate the impact of an acute bout of prolonged strenuous exercise on vascular and cardiac function and the appearance of biomarkers of cardiomyocyte damage in 15 male (32 +/- 10 yr) nonelite runners. The subjects were tested on two occasions, the day before and within an hour of finishing the London marathon (229 +/- 38 min). Function of the brachial and femoral arteries was determined using flow-mediated dilatation (FMD). Echocardiographic assessment of cardiac strain, strain rate, tissue velocities, and flow velocities during diastole and systole were also obtained. Venous blood samples were taken for later assessment of cardiac troponin I (cTnI), a biomarker of cardiomyocyte damage. Completion of the marathon resulted in a depression in femoral (P = 0.04), but not brachial (P = 0.96), artery FMD. There was no change, pre- vs. postmarathon, in vascular shear, indicating that the impaired femoral artery function was not related to hemodynamic changes. The ratio of peak early to atrial radial strain rate, a measure of left ventricular diastolic function, was reduced postmarathon (P = 0.006). Postrace cTnI was elevated in 12 of 13 runners, with levels above the recognized clinical threshold for damage in 7 of these. In conclusion, when taken together, these data suggest a transient depression in cardiac and leg vascular function following prolonged intensive exercise.