Reductions in systemic and skeletal muscle blood flow and oxygen delivery limit maximal aerobic capacity in humans

[EN] BACKGROUND: A classic, unresolved physiological question is whether central cardiorespiratory and/or local skeletal muscle circulatory factors limit maximal aerobic capacity (VO2max) in humans. Severe heat stress drastically reduces VO2max, but the mechanisms have never been studied. METHODS AND RESULTS: To determine the main contributing factor that limits VO2max with and without heat stress, we measured hemodynamics in 8 healthy males performing intense upright cycling exercise until exhaustion starting with either high or normal skin and core temperatures (+10 degrees C and +1 degrees C). Heat stress reduced VO2max, 2-legged VO2, and time to fatigue by 0.4+/-0.1 L/min (8%), 0.5+/-0.2 L/min (11%), and 2.2+/-0.4 minutes (28%), respectively (all P<0.05), despite heart rate and core temperature reaching similar peak values. However, before exhaustion in both heat stress and normal conditions, cardiac output, leg blood flow, mean arterial pressure, and systemic and leg O2 delivery declined significantly (all 5% to 11%, P<0.05), yet arterial O2 content and leg vascular conductance remained unchanged. Despite increasing leg O2 extraction, leg VO2 declined 5% to 6% before exhaustion in both heat stress and normal conditions, accompanied by enhanced muscle lactate accumulation and ATP and creatine phosphate hydrolysis. CONCLUSIONS: These results demonstrate that in trained humans, severe heat stress reduces VO2max by accelerating the declines in cardiac output and mean arterial pressure that lead to decrements in exercising muscle blood flow, O2 delivery, and O2 uptake. Furthermore, the impaired systemic and skeletal muscle aerobic capacity that precedes fatigue with or without heat stress is largely related to the failure of the heart to maintain cardiac output and O2 delivery to locomotive muscle.

Muscle blood flow is reduced with dehydration during prolonged exercise in humans

[EN] 1. The present study examined whether the blood flow to exercising muscles becomes reduced when cardiac output and systemic vascular conductance decline with dehydration during prolonged exercise in the heat. A secondary aim was to determine whether the upward drift in oxygen consumption (VO2) during prolonged exercise is confined to the active muscles. 2. Seven euhydrated, endurance-trained cyclists performed two bicycle exercise trials in the heat (35 C; 40-50 % relative humidity; 61 +/- 2 % of maximal VO2), separated by 1 week. During the first trial (dehydration trial, DE), they bicycled until volitional exhaustion (135 +/- 4 min, mean +/- s.e.m.), while developing progressive dehydration and hyperthermia (3.9 +/- 0.3 % body weight loss; 39.7 +/- 0.2 C oesophageal temperature, Toes). In the second trial (control trial), they bicycled for the same period of time while maintaining euhydration by ingesting fluids and stabilizing Toes at 38.2 +/- 0.1 C after 30 min exercise. 3. In both trials, cardiac output, leg blood flow (LBF), vascular conductance and VO2 were similar after 20 min exercise. During the 20 min-exhaustion period of DE, cardiac output, LBF and systemic vascular conductance declined significantly (8-14 %; P < 0.05) yet muscle vascular conductance was unaltered. In contrast, during the same period of control, all these cardiovascular variables tended to increase. After 135 +/- 4 min of DE, the 2.0 +/- 0.6 l min-1 lower blood flow to the exercising legs accounted for approximately two-thirds of the reduction in cardiac output. Blood flow to the skin also declined markedly as forearm blood flow was 39 +/- 8 % (P < 0.05) lower in DE vs. control after 135 +/- 4 min. 4. In both trials, whole body VO2 and leg VO2 increased in parallel and were similar throughout exercise. The reduced leg blood flow in DE was accompanied by an even greater increase in femoral arterial-venous O2 (a-vO2) difference. 5. It is concluded that blood flow to the exercising muscles declines significantly with dehydration, due to a lowering in perfusion pressure and systemic blood flow rather than increased vasoconstriction. Furthermore, the progressive increase in oxygen consumption during exercise is confined to the exercising skeletal muscles.

Cardiac output and leg and arm blood flow during incremental exercise to exhaustion on the cycle ergometer

[EN] To determine central and peripheral hemodynamic responses to upright leg cycling exercise, nine physically active men underwent measurements of arterial blood pressure and gases, as well as femoral and subclavian vein blood flows and gases during incremental exercise to exhaustion (Wmax). Cardiac output (CO) and leg blood flow (BF) increased in parallel with exercise intensity. In contrast, arm BF remained at 0.8 l/min during submaximal exercise, increasing to 1.2 +/- 0.2 l/min at maximal exercise (P < 0.05) when arm O(2) extraction reached 73 +/- 3%. The leg received a greater percentage of the CO with exercise intensity, reaching a value close to 70% at 64% of Wmax, which was maintained until exhaustion. The percentage of CO perfusing the trunk decreased with exercise intensity to 21% at Wmax, i.e., to approximately 5.5 l/min. For a given local Vo(2), leg vascular conductance (VC) was five- to sixfold higher than arm VC, despite marked hemoglobin deoxygenation in the subclavian vein. At peak exercise, arm VC was not significantly different than at rest. Leg Vo(2) represented approximately 84% of the whole body Vo(2) at intensities ranging from 38 to 100% of Wmax. Arm Vo(2) contributed between 7 and 10% to the whole body Vo(2). From 20 to 100% of Wmax, the trunk Vo(2) (including the gluteus muscles) represented between 14 and 15% of the whole body Vo(2). In summary, vasoconstrictor signals efficiently oppose the vasodilatory metabolites in the arms, suggesting that during whole body exercise in the upright position blood flow is differentially regulated in the upper and lower extremities.

Chronic hypoxia increases blood pressure and noradrenaline spillover in healthy humans

[EN] Chronic hypoxia is associated with elevated sympathetic activity and hypertension in patients with chronic pulmonary obstructive disease. However, the effect of chronic hypoxia on systemic and regional sympathetic activity in healthy humans remains unknown. To determine if chronic hypoxia in healthy humans is associated with hyperactivity of the sympathetic system, we measured intra-arterial blood pressure, arterial blood gases, systemic and skeletal muscle noradrenaline (norepinephrine) spillover and vascular conductances in nine Danish lowlanders at sea level and after 9 weeks of exposure at 5260 m. Mean blood pressure was 28 % higher at altitude (P < 0.01) due to increases in both systolic (18 % higher, P < 0.05) and diastolic (41 % higher, P < 0.001) blood pressures. Cardiac output and leg blood flow were not altered by chronic hypoxia, but systemic vascular conductance was reduced by 30 % (P < 0.05). Plasma arterial noradrenaline (NA) and adrenaline concentrations were 3.7- and 2.4-fold higher at altitude, respectively (P < 0.05). The elevation of plasma arterial NA concentration was caused by a 3.8-fold higher whole-body NA release (P < 0.001) since whole-body noradrenaline clearance was similar in both conditions. Leg NA spillover was increased similarly (x 3.2, P < 0.05). These changes occurred despite the fact that systemic O2 delivery was greater after altitude acclimatisation than at sea level, due to 37 % higher blood haemoglobin concentration. In summary, this study shows that chronic hypoxia causes marked activation of the sympathetic nervous system in healthy humans and increased systemic arterial pressure, despite normalisation of the arterial O2 content with acclimatisation.

Metabolic and thermodynamic responses to dehydration-induced reductions in muscle blood flow in exercising humans

[EN] 1. The present study examined whether reductions in muscle blood flow with exercise-induced dehydration would reduce substrate delivery and metabolite and heat removal to and from active skeletal muscles during prolonged exercise in the heat. A second aim was to examine the effects of dehydration on fuel utilisation across the exercising leg and identify factors related to fatigue. 2. Seven cyclists performed two cycle ergometer exercise trials in the heat (35 C; 61 +/- 2 % of maximal oxygen consumption rate, VO2,max), separated by 1 week. During the first trial (dehydration, DE), they cycled until volitional exhaustion (135 +/- 4 min, mean +/- s.e.m.), while developing progressive DE and hyperthermia (3.9 +/- 0.3 % body weight loss and 39.7 +/- 0.2 C oesophageal temperature, Toes). On the second trial (control), they cycled for the same period of time maintaining euhydration by ingesting fluids and stabilising Toes at 38.2 +/- 0.1 degrees C. 3. After 20 min of exercise in both trials, leg blood flow (LBF) and leg exchange of lactate, glucose, free fatty acids (FFA) and glycerol were similar. During the 20 to 135 +/- 4 min period of exercise, LBF declined significantly in DE but tended to increase in control. Therefore, after 120 and 135 +/- 4 min of DE, LBF was 0.6 +/- 0.2 and 1.0 +/- 0.3 l min-1 lower (P < 0.05), respectively, compared with control. 4. The lower LBF after 2 h in DE did not alter glucose or FFA delivery compared with control. However, DE resulted in lower (P < 0.05) net FFA uptake and higher (P < 0.05) muscle glycogen utilisation (45 %), muscle lactate accumulation (4.6-fold) and net lactate release (52 %), without altering net glycerol release or net glucose uptake. 5. In both trials, the mean convective heat transfer from the exercising legs to the body core ranged from 6.3 +/- 1.7 to 7.2 +/- 1.3 kJ min-1, thereby accounting for 35-40 % of the estimated rate of heat production ( approximately 18 kJ min-1). 6. At exhaustion in DE, blood lactate values were low whereas blood glucose and muscle glycogen levels were still high. Exhaustion coincided with high body temperature ( approximately 40 C). 7. In conclusion, the present results demonstrate that reductions in exercising muscle blood flow with dehydration do not impair either the delivery of glucose and FFA or the removal of lactate during moderately intense prolonged exercise in the heat. However, dehydration during exercise in the heat elevates carbohydrate oxidation and lactate production. A major finding is that more than one-half of the metabolic heat liberated in the contracting leg muscles is dissipated directly to the surrounding environment. The present results indicate that hyperthermia, rather than altered metabolism, is the main factor underlying the early fatigue with dehydration during prolonged exercise in the heat.

Arterial O2 content and tension in regulation of cardiac output and leg blood flow during exercise in humans

[EN] A universal O2 sensor presumes that compensation for impaired O2 delivery is triggered by low O2 tension, but in humans, comparisons of compensatory responses to altered arterial O2 content (CaO2) or tension (PaO2) have not been reported. To directly compare cardiac output (QTOT) and leg blood flow (LBF) responses to a range of CaO2 and PaO2, seven healthy young men were studied during two-legged knee extension exercise with control hemoglobin concentration ([Hb] = 144.4 +/- 4 g/l) and at least 1 wk later after isovolemic hemodilution ([Hb] = 115 +/- 2 g/l). On each study day, subjects exercised twice at 30 W and on to voluntary exhaustion with an FIO2 of 0.21 or 0.11. The interventions resulted in two conditions with matched CaO2 but markedly different PaO2 (hypoxia and anemia) and two conditions with matched PaO2 and different CaO2 (hypoxia and anemia + hypoxia). PaO2 varied from 46 +/- 3 Torr in hypoxia to 95 +/- 3 Torr (range 37 to >100) in anemia (P < 0.001), yet LBF at exercise was nearly identical. However, as CaO2 dropped from 190 +/- 5 ml/l in control to 132 +/- 2 ml/l in anemia + hypoxia (P < 0.001), QTOT and LBF at 30 W rose to 12.8 +/- 0.8 and 7.2 +/- 0.3 l/min, respectively, values 23 and 47% above control (P < 0.01). Thus regulation of QTOT, LBF, and arterial O2 delivery to contracting intact human skeletal muscle is dependent for signaling primarily on CaO2, not PaO2. This finding suggests that factors related to CaO2 or [Hb] may play an important role in the regulation of blood flow during exercise in humans.

Maximal exercise and muscle oxygen extraction in acclimatizing lowlanders and high altitude natives

[EN] The tight relation between arterial oxygen content and maximum oxygen uptake (Vv(o2max)within a given person at sea level is diminished with altitude acclimatization. An explanation often suggested for this mismatch is impairment of the muscle O(2) extraction capacity with chronic hypoxia, and is the focus of the present study. We have studied six lowlanders during maximal exercise at sea level (SL) and with acute (AH) exposure to 4,100 m altitude, and again after 2 (W2) and 8 weeks (W8) of altitude sojourn, where also eight high altitude native (Nat) Aymaras were studied. Fractional arterial muscle O(2) extraction at maximal exercise was 90.0+/-1.0% in the Danish lowlanders at sea level, and remained close to this value in all situations. In contrast to this, fractional arterial O(2) extraction was 83.2+/-2.8% in the high altitude natives, and did not change with the induction of normoxia. The capillary oxygen conductance of the lower extremity, a measure of oxygen diffusing capacity, was decreased in the Danish lowlanders after 8 weeks of acclimatization, but was still higher than the value obtained from the high altitude natives. The values were (in ml min(-1) mmHg(-1)) 55.2+/-3.7 (SL), 48.0+/-1.7 (W2), 37.8+/-0.4 (W8) and 27.7+/-1.5 (Nat). However, when correcting oxygen conductance for the observed reduction in maximal leg blood flow with acclimatization the effect diminished. When calculating a hypothetical leg V(o2max)at altitude using either the leg blood flow or the O(2) conductance values obtained at sea level, the former values were almost completely restored to sea level values. This would suggest that the major determinant V(o2max)for not to increase with acclimatization is the observed reduction in maximal leg blood flow and O(2) conductance.

Disparity in regional and systemic circulatory capacities: do they affect the regulation of the circulation?

[EN] In this review we integrate ideas about regional and systemic circulatory capacities and the balance between skeletal muscle blood flow and cardiac output during heavy exercise in humans. In the first part of the review we discuss issues related to the pumping capacity of the heart and the vasodilator capacity of skeletal muscle. The issue is that skeletal muscle has a vast capacity to vasodilate during exercise [approximately 300 mL (100 g)(-1) min(-1)], but the pumping capacity of the human heart is limited to 20-25 L min(-1) in untrained subjects and approximately 35 L min(-1) in elite endurance athletes. This means that when more than 7-10 kg of muscle is active during heavy exercise, perfusion of the contracting muscles must be limited or mean arterial pressure will fall. In the second part of the review we emphasize that there is an interplay between sympathetic vasoconstriction and metabolic vasodilation that limits blood flow to contracting muscles to maintain mean arterial pressure. Vasoconstriction in larger vessels continues while constriction in smaller vessels is blunted permitting total muscle blood flow to be limited but distributed more optimally. This interplay between sympathetic constriction and metabolic dilation during heavy whole-body exercise is likely responsible for the very high levels of oxygen extraction seen in contracting skeletal muscle. It also explains why infusing vasodilators in the contracting muscles does not increase oxygen uptake in the muscle. Finally, when approximately 80% of cardiac output is directed towards contracting skeletal muscle modest vasoconstriction in the active muscles can evoke marked changes in arterial pressure.