Rasmus Damsgaard

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.

Inhibition of nitric oxide and prostaglandins, but not endothelial-derived hyperpolarizing factors, reduces blood flow and aerobic energy turnover in the exercising human leg

Prostaglandins, nitric oxide (NO) and endothelial‐derived hyperpolarizing factors (EDHFs) are substances that have been proposed to be involved in the regulation of skeletal muscle blood flow during physical activity. We measured haemodynamics, plasma ATP and at rest and during one‐legged knee‐extensor exercise (19 ± 1 W) in nine healthy subjects with and without intra‐arterial infusion of indomethacin (Indo; 621 ± 17 μg min−1), Indo +NG‐monomethyl‐l‐arginine (l‐NMMA; 12.4 ± 0.3 mg min−1) (double blockade) and Indo +l‐NMMA + tetraethylammonium chloride (TEA; 12.4 ± 0.3 mg min−1) (triple blockade). Double and triple blockade lowered leg blood flow (LBF) at rest (P < 0.05), while it remained unchanged with Indo. During exercise, LBF and vascular conductance were 2.54 ± 0.10 l min−1 and 25 ± 1 mmHg, respectively, in control and they were lower with double (33 ± 3 and 36 ± 4%, respectively) and triple (26 ± 4 and 28 ± 3%, respectively) blockade (P < 0.05), while there was no difference with Indo. The lower LBF and vascular conductance with double and triple blockade occurred in parallel with a lower O2 delivery, cardiac output, heart rate and plasma [noradrenaline] (P < 0.05), while blood pressure remained unchanged and O2 extraction and femoral venous plasma [ATP] increased. Despite the increased O2 extraction, leg was 13 and 17% (triple and double blockade, respectively) lower than control in parallel to a lower femoral venous temperature and lactate release (P < 0.05). These results suggest that NO and prostaglandins play important roles in skeletal muscle blood flow regulation during moderate intensity exercise and that EDHFs do not compensate for the impaired formation of NO and prostaglandins. Moreover, inhibition of NO and prostaglandin formation is associated with a lower aerobic energy turnover and increased concentration of vasoactive ATP in plasma.

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.

Restrictions in systemic and locomotor skeletal muscle perfusion, oxygen supply and VO2 during high-intensity whole-body exercise in humans.

Perfusion to exercising skeletal muscle is regulated to match O2 delivery to the O2 demand, but this regulation might be compromised during or approaching maximal whole‐body exercise as muscle blood flow for a given work rate is blunted. Whether muscle perfusion is restricted when there is an extreme metabolic stimulus to vasodilate during supramaximal exercise remains unknown. To examine the regulatory limits of systemic and muscle perfusion in exercising humans, we measured systemic and leg haemodynamics, O2 transport, and , and estimated non‐locomotor tissue perfusion during constant load supramaximal cycling (498 ± 16 W; 110% of peak power; mean ±s.e.m.) in addition to both incremental cycling and knee‐extensor exercise to exhaustion in 13 trained males. During supramaximal cycling, cardiac output (), leg blood flow (LBF), and systemic and leg O2 delivery and reached peak values after 60–90 s and thereafter levelled off at values similar to or ∼6% (P < 0.05) below maximal cycling, while upper body blood flow remained unchanged (∼5.5 l min−1). In contrast, and LBF increased linearly until exhaustion during one‐legged knee‐extensor exercise accompanying increases in non‐locomotor tissue blood flow to ∼12 l min−1. At exhaustion during cycling compared to knee‐extensor exercise, , LBF, leg vascular conductance, leg O2 delivery and leg for a given power were reduced by 32–47% (P < 0.05). In conclusion, locomotor skeletal muscle perfusion is restricted during maximal and supramaximal whole–body exercise in association with a plateau in and limb vascular conductance. These observations suggest that limits of cardiac function and muscle vasoconstriction underlie the inability of the circulatory system to meet the increasing metabolic demand of skeletal muscles and other tissues during whole‐body exercise.

Haemodynamic responses to exercise, ATP infusion and thigh compression in humans: insight into the role of muscle mechanisms on cardiovascular function

The muscle pump and muscle vasodilatory mechanims are thought to play important roles in increasing and maintaining muscle perfusion and cardiac output during exercise, but their actual contributions remain uncertain. To evaluate the role of the skeletal muscle pump and vasodilatation on cardiovascular function during exercise, we determined leg and systemic haemodynamic responses in healthy men during (1) incremental one‐legged knee‐extensor exercise, (2) step‐wise femoral artery ATP infusion at rest, (3) passive exercise (n= 10), (4) femoral vein or artery ATP infusion (n= 6), and (5) cyclic thigh compressions at rest and during passive and voluntary exercise (n= 7). Incremental exercise resulted in progressive increases in leg blood flow (ΔLBF 7.4 ± 0.7 l min−1), cardiac output ( 8.7 ± 0.7 l min−1), mean arterial pressure (ΔMAP 51 ± 5 mmHg), and leg and systemic oxygen delivery and . Arterial ATP infusion resulted in similar increases in , LBF, and systemic and leg oxygen delivery, but central venous pressure and muscle metabolism remained unchanged and MAP was reduced. In contrast, femoral vein ATP infusion did not alter LBF, or MAP. Passive exercise also increased blood flow (ΔLBF 0.7 ± 0.1 l min−1), yet the increase in muscle and systemic perfusion, unrelated to elevations in aerobic metabolism, accounted only for ∼5% of peak exercise hyperaemia. Likewise, thigh compressions alone or in combination with passive exercise increased blood flow (ΔLBF 0.5–0.7 l min−1) without altering , MAP or . These findings suggest that the skeletal muscle pump is not obligatory for sustaining venous return, central venous pressure, stroke volume and or maintaining muscle blood flow during one‐legged exercise in humans. Further, its contribution to muscle and systemic peak exercise hyperaemia appears to be minimal in comparison to the effects of muscle vasodilatation.

Lifelong physical activity prevents an age-related reduction in arterial and skeletal muscle nitric oxide bioavailability in humans

•  Ageing has been proposed to be associated with increased levels of reactive oxygen species (ROS) that scavenge nitric oxide (NO), thereby decreasing the bioavailability of this potent vasodilator. •  Here we show that NO bioavailability is compromised in the systemic circulation and in skeletal muscle of sedentary older humans as evidenced by an increase in NO metabolites after antioxidant infusion. •  Lifelong physical activity opposes this effect within the trained musculature and in the arterial circulation. •  The reduced blood flow to contracting leg muscles with ageing does not appear to be related to changes in NO bioavailability. •  These findings expand our understanding of the mechanisms underlying the age‐related changes in vascular function and highlight the beneficial effect of exercise training throughout the lifespan.

Low-intensity training increases peak arm VO2 by enhancing both convective and diffusive O2 delivery

It is an ongoing discussion the extent to which oxygen delivery and oxygen extraction contribute to an increased muscle oxygen uptake during dynamic exercise. It has been proposed that local muscle factors including the capillary bed and mitochondrial oxidative capacity play a large role in prolonged low‐intensity training of a small muscle group when the cardiac output capacity is not directly limiting. The purpose of this study was to investigate the relative roles of circulatory and muscle metabolic mechanisms by which prolonged low‐intensity exercise training alters regional muscle VO2.

Maximal heart rate does not limit cardiovascular capacity in healthy humans: insight from right atrial pacing during maximal exercise

During high intensity whole‐body exercise, systemic and contracting skeletal muscle O2 delivery and uptake ( V̇O2 ) are compromised, but the underlying mechanisms remain unclear. We evaluated the effect of a ∼20 beats min−1 increase in heart rate (HR) by right atrial pacing during incremental cycling and knee‐extensor exercise on cardiac output ( Q̇ ) and stroke volume (SV). An increase in HR during both exercise modalities did not alter Q̇ due to a proportional decrease in SV. The lower SV during atrial pacing in the cycling trial was associated with a diminished cardiac filling pressure, but similar arterial pressure. The results demonstrate that the human heart can achieve a higher HR than observed during maximal exercise, suggesting that HRmax and myocardial work capacity do not limit cardiac performance in trained human subjects. Instead, restrictions in ventricular filling appear to compromise cardiac preload, SV and Q̇ at exercise intensities close to V̇O2 max .

Leg oxygen uptake in the initial phase of intense exercise is slowed by a marked reduction in oxygen delivery

The present study examined whether a marked reduction in oxygen delivery, unlike findings in moderate-intensity exercise, would slow leg oxygen uptake (Vo2) kinetics during intense exercise (86 ± 3% of incremental test peak power). Seven healthy males (26 ± 1 years, means ± SE) performed one-legged knee-extensor exercise (60 ± 3 W) for 4 min in a control setting (CON) and with arterial infusion of N(G)-monomethyl-l-arginine and indomethacin in the working leg to reduce blood flow by inhibiting formation of nitric oxide and prostanoids (double blockade; DB). In DB leg blood flow (LBF) and oxygen delivery during the first minute of exercise were 25-50% lower (P < 0.01) compared with CON (LBF after 10 s: 1.1 ± 0.2 vs. 2.5 ± 0.3 l/min and 45 s: 2.7 ± 0.2 vs. 3.8 ± 0.4 l/min) and 15% lower (P < 0.05) after 2 min of exercise. Leg Vo2 in DB was attenuated (P < 0.05) during the first 2 min of exercise (10 s: 161 ± 26 vs. 288 ± 34 ml/min and 45 s: 459 ± 48 vs. 566 ± 81 ml/min) despite a higher (P < 0.01) oxygen extraction in DB. Net leg lactate release was the same in DB and CON. The present study shows that a marked reduction in oxygen delivery can limit the rise in Vo2 during the initial part of intense exercise. This is in contrast to previous observations during moderate-intensity exercise using the same DB procedure, which suggests that fast-twitch muscle fibers are more sensitive to a reduction in oxygen delivery than slow-twitch fibers.

Exercise training improves blood flow to contracting skeletal muscle of older men via enhanced cGMP signaling

Physical activity has the potential to offset age-related impairments in the regulation of blood flow and O2 delivery to the exercising muscles; however, the mechanisms underlying this effect of physical activity remain poorly understood. The present study examined the role of cGMP in training-induced adaptations in the regulation of skeletal muscle blood flow and oxidative metabolism during exercise in aging humans. We measured leg hemodynamics and oxidative metabolism during exercise engaging the knee extensor muscles in young [ n = 15, 25 ± 1 (SE) yr] and older ( n = 15, 72 ± 1 yr) subjects before and after a period of aerobic high-intensity exercise training. To determine the role of cGMP signaling, pharmacological inhibition of phosphodiesterase 5 (PDE5) was performed. Before training, inhibition of PDE5 increased ( P < 0.05) skeletal muscle blood flow and O2 uptake during moderate-intensity exercise in the older group; however, these effects of PDE5 inhibition were not detected after training. These findings suggest a role for enhanced cGMP signaling in the training-induced improvement of regulation of blood flow in contracting skeletal muscle of older men. NEW & NOTEWORTHY The present study provides evidence for enhanced cyclic GMP signaling playing an essential role in the improved regulation of blood flow in contracting skeletal muscle of older men with aerobic exercise training.