Heat-related changes in the velocity and kinetic energy of flowing blood influence the human heart's output during hyperthermia.

Passive whole-body hyperthermia increases limb blood flow and cardiac output ( Q ̇ $\dot Q$ ), but the interplay between peripheral and central thermo-haemodynamic mechanisms remains unclear. Here we tested the hypothesis that local hyperthermia-induced alterations in peripheral blood flow and blood kinetic energy modulate flow to the heart and Q ̇ $\dot Q$ . Body temperatures, regional (leg, arm, head) and systemic haemodynamics, and left ventricular (LV) volumes and functions were assessed in eight healthy males during: (1) 3 h control (normothermic condition); (2) 3 h of single-leg heating; (3) 3 h of two-leg heating; and (4) 2.5 h of whole-body heating. Leg, forearm, and extracranial blood flow increased in close association with local rises in temperature while brain perfusion remained unchanged. Increases in blood velocity with small to no changes in the conduit artery diameter underpinned the augmented limb and extracranial perfusion. In all heating conditions, Q ̇ $\dot Q$ increased in association with proportional elevations in systemic vascular conductance, related to enhanced blood flow, blood velocity, vascular conductance and kinetic energy in the limbs and head (all R2 ≥ 0.803; P < 0.001), but not in the brain. LV systolic (end-systolic elastance and twist) and diastolic functional profiles (untwisting rate), pulmonary ventilation and systemic aerobic metabolism were only altered in whole-body heating. These findings substantiate the idea that local hyperthermia-induced selective alterations in peripheral blood flow modulate the magnitude of flow to the heart and Q ̇ $\dot Q$ through changes in blood velocity and kinetic energy. Localised heat-activated events in the peripheral circulation therefore affect the human heart's output. KEY POINTS: Local and whole-body hyperthermia increases limb and systemic perfusion, but the underlying peripheral and central heat-sensitive mechanisms are not fully established. Here we investigated the regional (leg, arm and head) and systemic haemodynamics (cardiac output: Q ̇ $\dot Q$ ) during passive single-leg, two-leg and whole-body hyperthermia to determine the contribution of peripheral and central thermosensitive factors in the control of human circulation. Single-leg, two-leg, and whole-body hyperthermia induced graded increases in leg blood flow and Q ̇ $\dot Q$ . Brain blood flow, however, remained unchanged in all conditions. Ventilation, extracranial blood flow and cardiac systolic and diastolic functions only increased during whole-body hyperthermia. The augmented Q ̇ $\dot Q$ with hyperthermia was tightly related to increased limb and head blood velocity, flow and kinetic energy. The findings indicate that local thermosensitive mechanisms modulate regional blood velocity, flow and kinetic energy, thereby controlling the magnitude of flow to the heart and thus the coupling of peripheral and central circulation during hyperthermia.

Thermo-haemodynamic coupling during regional thigh heating: Insight into the importance of local thermosensitive mechanisms in blood circulation.

A positive relationship between local tissue temperature and perfusion exists, with isolated limb-segment hyperthermia stimulating hyperaemia in the heated region without affecting the adjacent, non-heated limb segment. However, whether partial-limb segment heating evokes a heightened tissue perfusion in the heated region without directly or reflexly affecting the non-heated tissues of the same limb segment remains unknown. This study investigated, in 11 healthy young adults, the lower limb temperature and haemodynamic responses to three levels of 1 h upper-leg heating, none of which alter core temperature: (1) whole-thigh (WTH; water-perfused garment), (2) quadriceps (QH; water-perfused garment) and (3) partial-quadriceps (PQH; pulsed shortwave diathermy) heating. It was hypothesised that perfusion would only increase in the heated regions. WTH, QH and PQH increased local heated tissue temperature by 2.9 ± 0.6, 2.0 ± 0.7 and 2.9 ± 1.3°C (P < 0.0001), respectively, whilst remaining unchanged in the non-heated hamstrings and quadriceps tissues during QH and PQH. WTH induced a two-fold increase in common femoral artery blood flow (P < 0.0001) whereas QH and PQH evoked a similar ∼1.4-fold elevation (P ≤ 0.0018). During QH and PQH, however, tissue oxygen saturation and laser-Doppler skin blood flow in the adjacent non-heated hamstrings or quadriceps tissues remained stable (P > 0.5000). These findings in healthy young humans demonstrate a tight thermo-haemodynamic coupling during regional thigh heating, providing further evidence of the importance of local heat-activated mechanisms on the control of blood circulation.

Skeletal muscle angiogenic, regulatory, and heat shock protein responses to prolonged passive hyperthermia of the human lower limb.

Passive hyperthermia induces a range of physiological responses including augmenting skeletal muscle mRNA expression. This experiment aimed to examine gene and protein responses to prolonged passive leg hyperthermia. Seven young participants underwent 3 h of resting unilateral leg heating (HEAT) followed by a further 3 h of rest, with the contralateral leg serving as an unheated control (CONT). Muscle biopsies were taken at baseline (0 h), and at 1.5, 3, 4, and 6 h in HEAT and 0 and 6 h in CONT to assess changes in selected mRNA expression via qRT-PCR, and HSP72 and VEGFα concentration via ELISA. Muscle temperature (Tm) increased in HEAT plateauing from 1.5 to 3 h (+3.5 ± 1.5°C from 34.2 ± 1.2°C baseline value; P < 0.001), returning to baseline at 6 h. No change occurred in CONT. Endothelial nitric oxide synthase (eNOS), Forkhead box O1 (FOXO-1), Hsp72, and VEGFα mRNA increased in HEAT (P < 0.05); however, post hoc analysis identified that only Hsp72 mRNA statistically increased (at 4 h vs. baseline). When peak change during HEAT was calculated angiopoietin 2 (ANGPT-2) decreased (-0.4 ± 0.2-fold), and C-C motif chemokine ligand 2 (CCL2) (+2.9 ± 1.6-fold), FOXO-1 (+6.2 ± 4.4-fold), Hsp27 (+2.9 ± 1.7-fold), Hsp72 (+8.5 ± 3.5-fold), Hsp90α (+4.6 ± 3.7-fold), and VEGFα (+5.9 ± 3.1-fold) increased from baseline (all P < 0.05). At 6 h Tm were not different between limbs (P = 0.582; CONT = 32.5 ± 1.6°C, HEAT = 34.3 ± 1.2°C), and only ANGPT-2 (P = 0.031; -1.3 ± 1.4-fold) and VEGFα (P = 0.030; 1.1 ± 1.2-fold) differed between HEAT and CONT. No change in VEGFα or HSP72 protein concentration were observed over time; however, peak change in VEGFα did increase (P < 0.05) in HEAT (+140 ± 184 pg·mL-1) versus CONT (+7 ± 86 pg·mL-1). Passive hyperthermia transiently augmented ANGPT-2, CCL2, eNOS, FOXO-1, Hsp27, Hsp72, Hsp90α and VEGFα mRNA, and VEGFα protein.

The heart, a secondary organ in the control of blood circulation.

Circulation of the blood is a fundamental physiological function traditionally ascribed to the pressure-generating function of the heart. However, over the past century the 'cardiocentric' view has been challenged by August Krogh, Ernst Starling, Arthur Guyton and others, based on haemodynamic data obtained from isolated heart preparations and organ perfusion. Their research brought forth experimental evidence and phenomenological observations supporting the concept that cardiac output occurs primarily in response to the metabolic demands of the tissues. The basic tenets of Guyton's venous return model are presented and juxtaposed with their critiques. Developmental biology of the cardiovascular system shows that the blood circulates before the heart has achieved functional integrity and that its movement is intricately connected with the metabolic demands of the tissues. Long discovered, but as yet overlooked, negative interstitial pressure may play a role in assisting the flow returning to the heart. Based on these phenomena, an alternative circulation model has been proposed in which the heart functions like a hydraulic ram and maintains a dynamic equilibrium between the arterial (centrifugal) and venous (centripetal) forces which define the blood's circular movement. In this focused review we introduce some of the salient arguments in support of the proposed circulation model. Finally, we present evidence that exercising muscle blood flow is subject to local metabolic control which upholds optimal perfusion in the face of a substantive rise in muscle vascular conductance, thus lending further support to the permissive role of the heart in the overall control of blood circulation.

Lower limb hyperthermia augments functional hyperaemia during small muscle mass exercise similarly in trained elderly and young humans.

NEW FINDINGS: What is the central question of the study? Ageing is postulated to lead to underperfusion of human limb tissues during passive and exertional hyperthermia, but findings to date have been equivocal. Thus, does age have an independent adverse effect on local haemodynamics during passive single-leg hyperthermia, single-leg knee-extensor exercise and their combination? What is the main finding and its importance? Local hyperthermia increased leg blood flow over three-fold and had an additive effect during knee-extensor exercise with no absolute differences in leg perfusion between the healthy, exercise-trained elderly and the young groups. Our findings indicate that age per se does not compromise lower limb hyperaemia during local hyperthermia and/or small muscle mass exercise. ABSTRACT: Heat and exercise therapies are recommended to improve vascular health across the lifespan. However, the haemodynamic effects of hyperthermia, exercise and their combination are inconsistent in young and elderly people. Here we investigated the acute effects of local-limb hyperthermia and exercise on limb haemodynamics in nine healthy, trained elderly (69 ± 5 years) and 10 young (26 ± 7 years) adults, hypothesising that the combination of local hyperthermia and exercise interact to increase leg perfusion, albeit to a lesser extent in the elderly. Participants underwent 90 min of single whole-leg heating, with the contralateral leg remaining as control, followed by 10 min of low-intensity incremental single-leg knee-extensor exercise with both the heated and control legs. Temperature profiles and leg haemodynamics at the femoral and popliteal arteries were measured. In both groups, heating increased whole-leg skin temperature and blood flow by 9.5 ± 1.2°C and 0.7 ± 0.2 L min-1 (>3-fold), respectively (P < 0.0001). Blood flow in the heated leg remained 0.7 ± 0.6 and 1.0 ± 0.8 L min-1 higher during exercise at 6 and 12 W, respectively (P < 0.0001). However, there were no differences in limb haemodynamics between cohorts, other than the elderly group exhibiting a 16 ± 6% larger arterial diameter and a 51 ± 6% lower blood velocity following heating (P < 0.0001). In conclusion, local hyperthermia-induced limb hyperperfusion and/or small muscle mass exercise hyperaemia are preserved in trained older people despite evident age-related structural and functional alterations in their leg conduit arteries.

Pulmonary ventilation and gas exchange during prolonged exercise in humans: Influence of dehydration, hyperthermia and sympathoadrenal activity.

NEW FINDINGS: What is the central question of the study? Ventilation increases during prolonged intense exercise, but the impact of dehydration and hyperthermia, with associated blunting of pulmonary circulation, and independent influences of dehydration, hyperthermia and sympathoadrenal discharge on ventilatory and pulmonary gas exchange responses remain unclear. What is the main finding and its importance? Dehydration and hyperthermia led to hyperventilation and compensatory adjustments in pulmonary CO2 and O2 exchange, such that CO2 output increased and O2 uptake remained unchanged despite the blunted circulation. Isolated hyperthermia and adrenaline infusion, but not isolated dehydration, increased ventilation to levels similar to combined dehydration and hyperthermia. Hyperthermia is the main stimulus increasing ventilation during prolonged intense exercise, partly via sympathoadrenal activation. ABSTRACT: The mechanisms driving hyperthermic hyperventilation during exercise are unclear. In a series of retrospective analyses, we evaluated the impact of combined versus isolated dehydration and hyperthermia and the effects of sympathoadrenal discharge on ventilation and pulmonary gas exchange during prolonged intense exercise. In the first study, endurance-trained males performed two submaximal cycling exercise trials in the heat. On day 1, participants cycled until volitional exhaustion (135 ± 11 min) while experiencing progressive dehydration and hyperthermia. On day 2, participants maintained euhydration and core temperature (Tc ) during a time-matched exercise (control). At rest and during the first 20 min of exercise, pulmonary ventilation ( V ̇ E ${\skew2\dot V_{\rm{E}}}$ ), arterial blood gases, CO2 output and O2 uptake were similar in both trials. At 135 ± 11 min, however, V ̇ E ${\skew2\dot V_{\rm{E}}}$ was elevated with dehydration and hyperthermia, and this was accompanied by lower arterial partial pressure of CO2 , higher breathing frequency, arterial partial pressure of O2 , arteriovenous CO2 and O2 differences, and elevated CO2 output and unchanged O2 uptake despite a reduced pulmonary circulation. The increased V ̇ E ${\skew2\dot V_{\rm{E}}}$ was closely related to the rise in Tc and circulating catecholamines (R2  ≥ 0.818, P ≤ 0.034). In three additional studies in different participants, hyperthermia independently increased V ̇ E ${\skew2\dot V_{\rm{E}}}$ to an extent similar to combined dehydration and hyperthermia, whereas prevention of hyperthermia in dehydrated individuals restored V ̇ E ${\skew2\dot V_{\rm{E}}}$ to control levels. Furthermore, adrenaline infusion during exercise elevated both Tc and V ̇ E ${\skew2\dot V_{\rm{E}}}$ . These findings indicate that: (1) adjustments in pulmonary gas exchange limit homeostatic disturbances in the face of a blunted pulmonary circulation; (2) hyperthermia is the main stimulus increasing ventilation during prolonged intense exercise; and (3) sympathoadrenal activation might partly mediate the hyperthermic hyperventilation.

Exercise heat acclimation has minimal effects on left ventricular volumes, function and systemic hemodynamics in euhydrated and dehydrated trained humans.

Heat acclimation (HA) may improve the regulation of cardiac output (Q̇) through increased blood volume (BV) and left ventricular (LV) diastolic filling and attenuate reductions in Q̇ during exercise-induced dehydration; however, these hypotheses have never been directly tested. Before and following 10-days exercise HA, eight males completed two trials of submaximal exercise in 33°C and 50% relative humidity while maintaining preexercise euhydrated body mass (EUH; -0.6 ± 0.4%) or becoming progressively dehydrated (DEH; -3.6 ± 0.7%). Rectal (Tre) and skin (Tsk) temperatures, heart rate (HR), LV volumes and function, systemic hemodynamics and BV were measured at rest and during bouts of semirecumbent cycling (55% V̇o2max) at 20, 100 and 180 min, interspersed by periods of upright exercise. Tre, BV, HR, LV volumes, LV systolic and diastolic function, and systemic hemodynamics were similar between trials at rest and during the first 20 min of exercise (all P > 0.05). These responses were largely unaffected by HA at 180 min in either hydration state. However, DEH induced higher Tre (0.6 ± 0.3°C) and HR (16 ± 7 beats/min) and lower end-diastolic volume (29 ± 16 mL), stroke volume (26 ± 16 mL), and Q̇ (2.1 ± 0.8 L/min) compared with EUH at 180 min (all P < 0.05), yet LV twist and untwisting rate were increased or maintained (P = 0.028 and 0.52, respectively). Findings indicate HA has minimal effects on LV volumes, LV mechanical function, and systemic hemodynamics during submaximal exercise in moderate heat, where HR and BV are similar. In contrast, DEH evokes greater hyperthermia and tachycardia, reduces BV, and impairs diastolic LV filling, lowering Q̇, regardless of HA state.NEW & NOTEWORTHY This study demonstrates that 10 days of exercise heat acclimation has minimal effects on left ventricular volumes, intrinsic cardiac function, and systemic hemodynamics during prolonged, repeated semirecumbent exercise in moderate heat, where heart rate and blood volume are similar to preacclimation levels. However, progressive dehydration is consistently associated with similar degrees of hyperthermia and tachycardia and reductions in blood volume, diastolic filling of the left ventricle, stroke volume, and cardiac output, regardless of acclimation state.

Out-of-Time-Ordered-Correlator Quasiprobabilities Robustly Witness Scrambling.

Out-of-time-ordered correlators (OTOCs) have received considerable recent attention as qualitative witnesses of information scrambling in many-body quantum systems. Theoretical discussions of OTOCs typically focus on closed systems, raising the question of their suitability as scrambling witnesses in realistic open systems. We demonstrate empirically that the nonclassical negativity of the quasiprobability distribution (QPD) behind the OTOC is a more sensitive witness for scrambling than the OTOC itself. Nonclassical features of the QPD evolve with timescales that are robust with respect to decoherence and are immune to false positives caused by decoherence. To reach this conclusion, we numerically simulate spin-chain dynamics and three measurement protocols (the interferometric, quantum-clock, and weak-measurement schemes) for measuring OTOCs. We target experiments based on quantum-computing hardware such as superconducting qubits and trapped ions.

Mechanisms for the control of local tissue blood flow during thermal interventions: influence of temperature-dependent ATP release from human blood and endothelial cells.

NEW FINDINGS: What is the central question of this study? Skin and muscle blood flow increases with heating and decreases with cooling, but the temperature-sensitive mechanisms underlying these responses are not fully elucidated. What is the main finding and its importance? We found that local tissue hyperaemia was related to elevations in ATP release from erythrocytes. Increasing intravascular ATP augmented skin and tissue perfusion to levels equal or above thermal hyperaemia. ATP release from isolated erythrocytes was altered by heating and cooling. Our findings suggest that erythrocytes are involved in thermal regulation of blood flow via modulation of ATP release. Local tissue perfusion changes with alterations in temperature during heating and cooling, but the thermosensitivity of the vascular ATP signalling mechanisms for control of blood flow during thermal interventions remains unknown. Here, we tested the hypotheses that the release of the vasodilator mediator ATP from human erythrocytes, but not from endothelial cells or other blood constituents, is sensitive to both increases and reductions in temperature and that increasing intravascular ATP availability with ATP infusion would potentiate thermal hyperaemia in limb tissues. We first measured blood temperature, brachial artery blood flow and plasma [ATP] during passive arm heating and cooling in healthy men and found that they increased by 3.0 ± 1.2°C, 105 ± 25 ml min-1  °C-1 and twofold, respectively, (all P < 0.05) with heating, but decreased or remained unchanged with cooling. In additional men, infusion of ATP into the brachial artery increased skin and deep tissue perfusion to levels equal or above thermal hyperaemia. In isolated erythrocyte samples exposed to different temperatures, ATP release increased 1.9-fold from 33 to 39°C (P < 0.05) and declined by ∼50% at 20°C (P < 0.05), but no changes were observed in cultured human endothelial cells, plasma or serum samples. In conclusion, increases in plasma [ATP] and skin and deep tissue perfusion with limb heating are associated with elevations in ATP release from erythrocytes, but not from endothelial cells or other blood constituents. Erythrocyte ATP release is also sensitive to temperature reductions, suggesting that erythrocytes may function as thermal sensors and ATP signalling generators for control of tissue perfusion during thermal interventions.

New Insights Into the Impact of Dehydration on Blood Flow and Metabolism During Exercise.

Exercise-induced dehydration can lead to impaired perfusion to multiple regional tissues and organs. We propose that the impact of dehydration on regional blood flow and metabolism is dependent on the extent of the cardiovascular demand imposed by exercise, with the greatest physiological strain seen when approaching cardiovascular and aerobic capacities.

Exercise intensity modulates the appearance of circulating microvesicles with proangiogenic potential upon endothelial cells.

The effect of endurance exercise on circulating microvesicle dynamics and their impact on surrounding endothelial cells is unclear. Here we tested the hypothesis that exercise intensity modulates the time course of platelet (PMV) and endothelial-derived (EMV) microvesicle appearance in the circulation through hemodynamic and biochemical-related mechanisms, and that microvesicles formed during exercise would stimulate endothelial angiogenesis in vitro. Nine healthy young men had venous blood samples taken before, during, and throughout the recovery period after 1 h of moderate [46 ± 2% maximal oxygen uptake (V̇o2max)] or heavy (67 ± 2% V̇o2max) intensity semirecumbent cycling and a time-matched resting control trial. In vitro experiments were performed by incubating endothelial cells with rest and exercise-derived microvesicles to examine their effects on cell angiogenic capacities. PMVs (CD41+) increased from baseline only during heavy exercise (from 21 ± 1 × 103 to 55 ± 8 × 103 and 48 ± 6 × 103 PMV/µl at 30 and 60 min, respectively; P < 0.05), returning to baseline early in postexercise recovery (P > 0.05), whereas EMVs (CD62E+) were unchanged (P > 0.05). PMVs were related to brachial artery shear rate (r2 = 0.43) and plasma norepinephrine concentrations (r2 = 0.21) during exercise (P < 0.05). Exercise-derived microvesicles enhanced endothelial proliferation, migration, and tubule formation compared with rest microvesicles (P < 0.05). These results demonstrate substantial increases in circulating PMVs during heavy exercise and that exercise-derived microvesicles stimulate human endothelial cells by enhancing angiogenesis and proliferation. This involvement of microvesicles may be considered a novel mechanism through which exercise mediates vascular healing and adaptation.

Dehydration accelerates reductions in cerebral blood flow during prolonged exercise in the heat without compromising brain metabolism.

Dehydration hastens the decline in cerebral blood flow (CBF) during incremental exercise, whereas the cerebral metabolic rate for O2 (CMRO2 ) is preserved. It remains unknown whether CMRO2 is also maintained during prolonged exercise in the heat and whether an eventual decline in CBF is coupled to fatigue. Two studies were undertaken. In study 1, 10 male cyclists cycled in the heat for ∼2 h with (control) and without fluid replacement (dehydration) while internal and external carotid artery blood flow and core and blood temperature were obtained. Arterial and internal jugular venous blood samples were assessed with dehydration to evaluate CMRO2 . In study 2, in 8 male subjects, middle cerebral artery blood velocity was measured during prolonged exercise to exhaustion in both dehydrated and euhydrated states. After a rise at the onset of exercise, internal carotid artery flow declined to baseline with progressive dehydration (P < 0.05). However, cerebral metabolism remained stable through enhanced O2 and glucose extraction (P < 0.05). External carotid artery flow increased for 1 h but declined before exhaustion. Fluid ingestion maintained cerebral and extracranial perfusion throughout nonfatiguing exercise. During exhaustive exercise, however, euhydration delayed but did not prevent the decline in cerebral perfusion. In conclusion, during prolonged exercise in the heat, dehydration accelerates the decline in CBF without affecting CMRO2 and also restricts extracranial perfusion. Thus, fatigue is related to a reduction in CBF and extracranial perfusion rather than CMRO2 .

Local temperature-sensitive mechanisms are important mediators of limb tissue hyperemia in the heat-stressed human at rest and during small muscle mass exercise.

Limb tissue and systemic blood flow increases with heat stress, but the underlying mechanisms remain poorly understood. Here, we tested the hypothesis that heat stress-induced increases in limb tissue perfusion are primarily mediated by local temperature-sensitive mechanisms. Leg and systemic temperatures and hemodynamics were measured at rest and during incremental single-legged knee extensor exercise in 15 males exposed to 1 h of either systemic passive heat-stress with simultaneous cooling of a single leg (n = 8) or isolated leg heating or cooling (n = 7). Systemic heat stress increased core, skin and heated leg blood temperatures (Tb), cardiac output, and heated leg blood flow (LBF; 0.6 ± 0.1 l/min; P < 0.05). In the cooled leg, however, LBF remained unchanged throughout (P > 0.05). Increased heated leg deep tissue blood flow was closely related to Tb (R(2) = 0.50; P < 0.01), which is partly attributed to increases in tissue V̇O2 (R(2) = 0.55; P < 0.01) accompanying elevations in total leg glucose uptake (P < 0.05). During isolated limb heating and cooling, LBFs were equivalent to those found during systemic heat stress (P > 0.05), despite unchanged systemic temperatures and hemodynamics. During incremental exercise, heated LBF was consistently maintained ∼ 0.6 l/min higher than that in the cooled leg (P < 0.01), with LBF and vascular conductance in both legs showing a strong correlation with their respective local Tb (R(2) = 0.85 and 0.95, P < 0.05). We conclude that local temperature-sensitive mechanisms are important mediators in limb tissue perfusion regulation both at rest and during small-muscle mass exercise in hyperthermic humans.

Blood temperature and perfusion to exercising and non-exercising human limbs.

NEW FINDINGS: What is the central question of this study? Temperature-sensitive mechanisms are thought to contribute to blood-flow regulation, but the relationship between exercising and non-exercising limb perfusion and blood temperature is not established. What is the main finding and its importance? The close coupling among perfusion, blood temperature and aerobic metabolism in exercising and non-exercising extremities across different exercise modalities and activity levels and the tight association between limb vasodilatation and increases in plasma ATP suggest that both temperature- and metabolism-sensitive mechanisms are important for the control of human limb perfusion, possibly by activating ATP release from the erythrocytes. Temperature-sensitive mechanisms may contribute to blood-flow regulation, but the influence of temperature on perfusion to exercising and non-exercising human limbs is not established. Blood temperature (TB ), blood flow and oxygen uptake (V̇O2) in the legs and arms were measured in 16 healthy humans during 90 min of leg and arm exercise and during exhaustive incremental leg or arm exercise. During prolonged exercise, leg blood flow (LBF) was fourfold higher than arm blood flow (ABF) in association with higher TB and limb V̇O2. Leg and arm vascular conductance during exercise compared with rest was related closely to TB (r(2) = 0.91; P < 0.05), plasma ATP (r(2) = 0.94; P < 0.05) and limb V̇O2 (r(2) = 0.99; P < 0.05). During incremental leg exercise, LBF increased in association with elevations in TB and limb V̇O2, whereas ABF, arm TB and V̇O2 remained largely unchanged. During incremental arm exercise, both ABF and LBF increased in relationship to similar increases in V̇O2. In 12 trained males, increases in femoral TB and LBF during incremental leg exercise were mirrored by similar pulmonary artery TB and cardiac output dynamics, suggesting that processes in active limbs dominate central temperature and perfusion responses. The present data reveal a close coupling among perfusion, TB and aerobic metabolism in exercising and non-exercising extremities and a tight association between limb vasodilatation and increases in plasma ATP. These findings suggest that temperature and V̇O2 contribute to the regulation of limb perfusion through control of intravascular ATP.

Dehydration affects cerebral blood flow but not its metabolic rate for oxygen during maximal exercise in trained humans.

Intense exercise is associated with a reduction in cerebral blood flow (CBF), but regulation of CBF during strenuous exercise in the heat with dehydration is unclear. We assessed internal (ICA) and common carotid artery (CCA) haemodynamics (indicative of CBF and extra-cranial blood flow), middle cerebral artery velocity (MCA Vmean), arterial-venous differences and blood temperature in 10 trained males during incremental cycling to exhaustion in the heat (35°C) in control, dehydrated and rehydrated states. Dehydration reduced body mass (75.8 ± 3 vs. 78.2 ± 3 kg), increased internal temperature (38.3 ± 0.1 vs. 36.8 ± 0.1°C), impaired exercise capacity (269 ± 11 vs. 336 ± 14 W), and lowered ICA and MCA Vmean by 12-23% without compromising CCA blood flow. During euhydrated incremental exercise on a separate day, however, exercise capacity and ICA, MCA Vmean and CCA dynamics were preserved. The fast decline in cerebral perfusion with dehydration was accompanied by increased O2 extraction (P < 0.05), resulting in a maintained cerebral metabolic rate for oxygen (CMRO2). In all conditions, reductions in ICA and MCA Vmean were associated with declining cerebral vascular conductance, increasing jugular venous noradrenaline, and falling arterial carbon dioxide tension (P aCO 2) (R(2) ≥ 0.41, P ≤ 0.01) whereas CCA flow and conductance were related to elevated blood temperature. In conclusion, dehydration accelerated the decline in CBF by decreasing P aCO 2 and enhancing vasoconstrictor activity. However, the circulatory strain on the human brain during maximal exercise does not compromise CMRO2 because of compensatory increases in O2 extraction.

Left ventricular energetics: new insight into the plasticity of regional contributions at rest and during exercise.

Although the human left ventricle (LV) operates as a functional syncytium and previous studies have reported a single value for LV stroke work at rest, more intricate plasticity of regional LV energetics may be required during enhanced cardiovascular demand. We compared kinetic energy of the LV base and apex, respectively, during ventricular contraction and relaxation at rest and during continuous and discontinuous incremental exercise. At rest, prior to both exercise trials, the accumulated kinetic energy during contraction and relaxation was significantly higher at the LV base compared with the apex (P ≤ 0.05). With increasing exercise intensity, kinetic energy during contraction increased significantly more at the LV base (interaction effect: P < 0.0001), while kinetic energy during relaxation increased significantly more at the apex during high-intensity exercise (interaction effect: P < 0.001). Total kinetic energy produced over the entire cardiac cycle was significantly greater at the LV apex during high exercise intensities (P < 0.05). We further show that the region-specific differences in kinetic energy at rest and during exercise are explained by significantly different wall mechanics, showing heterogenic contributions from radial, circumferential, and angular components at the base and apex, respectively. In conclusion, the present findings provide unique insight into human LV function by demonstrating that within this functional syncytium, significant differences in the regional contributions of kinetic energy to overall LV work exist. Importantly, regional contributions are not fixed but highly plastic and the underpinning LV wall energetics adjust according to the prevailing cardiovascular demand.

Haemodynamic responses to dehydration in the resting and exercising human leg.

Dehydration and hyperthermia reduces leg blood flow (LBF), cardiac output ([Formula: see text]) and arterial pressure during whole-body exercise. It is unknown whether the reductions in blood flow are associated with dehydration-induced alterations in arterial blood oxygen content (C aO2) and O2-dependent signalling. This study investigated the impact of dehydration and concomitant alterations in C aO2 upon LBF and [Formula: see text]. Haemodynamics, arterial and femoral venous blood parameters and plasma [ATP] were measured at rest and during one-legged knee-extensor exercise in 7 males in four conditions: (1) control, (2) mild dehydration, (3) moderate dehydration, and (4) rehydration. Relative to control, C aO2 and LBF increased with dehydration at rest and during exercise (C aO2: from 199 ± 1 to 208 ± 2, and 202 ± 2 to 210 ± 2 ml L(-1) and LBF: from 0.38 ± 0.04 to 0.77 ± 0.09, and 1.64 ± 0.09 to 1.88 ± 0.1 L min(-1), respectively). Similarly, [Formula: see text] was unchanged or increased with dehydration at rest and during exercise, whereas arterial and leg perfusion pressures declined. Following rehydration, C aO2 declined (to 193 ± 2 mL L(-1)) but LBF remained elevated. Alterations in LBF were unrelated to C aO2 (r (2) = 0.13-0.27, P = 0.48-0.64) and plasma [ATP]. These findings suggest dehydration and concomitant alterations in C aO2 do not compromise LBF despite reductions in plasma [ATP]. While an additive or synergistic effect cannot be excluded, reductions in LBF during exercise with dehydration may not necessarily be associated with alterations in C aO2 and/or intravascular [ATP].

ATP as a mediator of erythrocyte-dependent regulation of skeletal muscle blood flow and oxygen delivery in humans.

In healthy human beings, blood flow to dynamically contracting skeletal muscle is regulated primarily to match oxygen (O(2)) delivery closely with utilisation. This occurs across a wide range of exercise intensities, as well as when exercise is combined with conditions that modify blood O(2) content. The red blood cells (RBCs), the primary O(2) carriers in the blood, contribute to the regulation of the local processes matching O(2) supply and demand. This is made possible by the ability of RBCs to release the vasoactive substance adenosine triphosphate (ATP) in response to reductions in erythrocyte and plasma O(2), as well as to other adjuvant metabolic and mechanical stimuli. The regulatory role of RBCs in human beings is supported by the observations that, i) exercising skeletal muscle blood flow responds primarily to changes in the amount of O(2) bound to the erythrocyte haemoglobin molecules, rather than the amount of O(2) in plasma, and ii) exercising muscle blood flow can almost double (from 260 to 460 ml min(-1) 100 g(-1)) with alterations in blood O(2) content, such that O(2) delivery and are kept constant. Besides falling blood O(2) content, RBCs release ATP when exposed to increased temperature, reduced pH, hypercapnia, elevated shear stress and augmented mechanical deformation, i.e. conditions that exist in the microcirculation of active skeletal muscle. ATP is an attractive mediator signal for skeletal muscle blood flow regulation, not only because it can act as a potent vasodilator, but also because of its sympatholytic properties in the human limb circulations. These properties are essential to counteract the vasoconstrictor effects of concurrent increases in muscle sympathetic nerve activity and circulating vasoconstrictor substances during exercise. Comparison of the relative vasoactive potencies and sympatholytic properties of ATP, other nucleotides, and adenosine in human limbs, suggests that intravascular ATP exerts its vasodilator and sympatholytic effects directly, and not via its degradation compounds. In conclusion, current evidence clearly indicates that RBCs are involved directly in the regulation of O(2) supply to human skeletal muscle during dynamic exercise. Further, intravascular ATP might be an important mediator in local metabolic sensing and signal transduction between the RBCs and the endothelial and smooth muscle cells in the vascular beds of skeletal muscle.

Supraspinal fatigue after normoxic and hypoxic exercise in humans.

Inadequate cerebral O2 availability has been proposed to be an important contributing factor to the development of central fatigue during strenuous exercise. Here we tested the hypothesis that supraspinal processes of fatigue would be increased after locomotor exercise in acute hypoxia compared to normoxia, and that such change would be related to reductions in cerebral O2 delivery and tissue oxygenation. Nine endurance-trained cyclists completed three constant-load cycling exercise trials at ∼80% of maximal work rate: (1) to the limit of tolerance in acute hypoxia; (2) for the same duration but in normoxia (control); and (3) to the limit of tolerance in normoxia. Throughout each trial, prefrontal cortex tissue oxygenation and middle cerebral artery blood velocity (MCAV) were assessed using near-infrared spectroscopy and trans-cranial Doppler sonography, respectively. Cerebral O2 delivery was calculated as the product of arterial O2 content and MCAV. Before and immediately after each trial, twitch responses to supramaximal femoral nerve stimulation and transcranial magnetic stimulation were obtained to assess neuromuscular and cortical function, respectively. Exercise time was reduced by 54%in hypoxia compared to normoxia (3.6 ± 1.3 vs. 8.1 ± 2.9 min; P<0.001). Cerebral O2 delivery,cerebral oxygenation and maximum O2 uptake were reduced whereas muscle electromyographic activity was increased in hypoxia compared to control (P <0.05).Maximum voluntary force and potentiated quadriceps twitch force were decreased below baseline after exercise in each trial;the decreases were greater in hypoxia compared to control (P<0.001), but were not different in the exhaustive trials (P>0.05). Cortical voluntary activation was also decreased after exercise in all trials, but the decline in hypoxia (Δ18%) was greater than in the normoxic trials (Δ5-9%)(P <0.05). The reductions in cortical voluntary activation were paralleled by reductions in cerebral O2 delivery. The results suggest that curtailment of exercise performance in acute severe hypoxia is due, in part, to failure of drive from the motor cortex, possibly as a consequence of diminished O2 availability in the brain.