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.

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.

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.

Regional thermal hyperemia in the human leg: Evidence of the importance of thermosensitive mechanisms in the control of the peripheral circulation.

Hyperthermia is thought to increase limb blood flow through the activation of thermosensitive mechanisms within the limb vasculature, but the precise vascular locus in which hyperthermia modulates perfusion remains elusive. We tested the hypothesis that local temperature-sensitive mechanisms alter limb hemodynamics by regulating microvascular blood flow. Temperature and oxygenation profiles and leg hemodynamics of the common (CFA), superficial (SFA) and profunda (PFA) femoral arteries, and popliteal artery (POA) of the experimental and control legs were measured in healthy participants during: (1) 3 h of whole leg heating (WLH) followed by 3 h of recovery (n = 9); (2) 1 h of upper leg heating (ULH) followed by 30 min of cooling and 1 h ULH bout (n = 8); and (3) 1 h of lower leg heating (LLH) (n = 8). WLH increased experimental leg temperature by 4.2 ± 1.2ºC and blood flow in CFA, SFA, PFA, and POA by ≥3-fold, while the core temperature essentially remained stable. Upper and lower leg blood flow increased exponentially in response to leg temperature and then declined during recovery. ULH and LLH similarly increased the corresponding segmental leg temperature, blood flow, and tissue oxygenation without affecting these responses in the non-heated leg segment, or perfusion pressure and conduit artery diameter across all vessels. Findings demonstrate that whole leg hyperthermia induces profound and sustained elevations in upper and lower limb blood flow and that segmental hyperthermia matches the regional thermal hyperemia without causing thermal or hemodynamic alterations in the non-heated limb segment. These observations support the notion that heat-activated thermosensitive mechanisms in microcirculation regulate limb tissue perfusion during hyperthermia.

Temperature and blood flow distribution in the human leg during passive heat stress.

The influence of temperature on the hemodynamic adjustments to direct passive heat stress within the leg's major arterial and venous vessels and compartments remains unclear. Fifteen healthy young males were tested during exposure to either passive whole body heat stress to levels approaching thermal tolerance [core temperature (Tc) + 2°C; study 1; n = 8] or single leg heat stress (Tc + 0°C; study 2; n = 7). Whole body heat stress increased perfusion and decreased oscillatory shear index in relation to the rise in leg temperature (Tleg) in all three major arteries supplying the leg, plateauing in the common and superficial femoral arteries before reaching severe heat stress levels. Isolated leg heat stress increased arterial blood flows and shear patterns to a level similar to that obtained during moderate core hyperthermia (Tc + 1°C). Despite modest increases in great saphenous venous (GSV) blood flow (0.2 l/min), the deep venous system accounted for the majority of returning flow (common femoral vein 0.7 l/min) during intense to severe levels of heat stress. Rapid cooling of a single leg during severe whole body heat stress resulted in an equivalent blood flow reduction in the major artery supplying the thigh deep tissues only, suggesting central temperature-sensitive mechanisms contribute to skin blood flow alone. These findings further our knowledge of leg hemodynamic responses during direct heat stress and provide evidence of potentially beneficial vascular alterations during isolated limb heat stress that are equivalent to those experienced during exposure to moderate levels of whole body hyperthermia.

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.

Effects of blood withdrawal and reinfusion on biomarkers of erythropoiesis in humans: Implications for anti-doping strategies.

To discriminate autologous blood doping procedures from normal conditions, we examined the hematological response to blood withdrawal and reinfusion. We found that biomarkers of erythropoiesis are primarily affected in the anemic period. Therefore, individual variations in [Hb] exceeding 15% between samples obtained shortly before any major competition would be indicative of autologous blood manipulation.

Enhanced pyruvate dehydrogenase activity does not affect muscle O2 uptake at onset of intense exercise in humans.

It has been proposed that the activation state of pyruvate dehydrogenase (PDH) may influence the rate of skeletal muscle O2 uptake during the initial phase of exercise; however, this has not been directly tested in humans. To remedy this, we used dichloroacetate (DCA) infusion to increase the active form of PDH (PDH(a)) and, subsequently, measured leg O2 uptake and markers of anaerobic ATP provision during conditions of intense dynamic exercise, when the rate of muscle O2 uptake would be very high. Six subjects performed brief bouts of one-legged knee-extensor exercise at approximately 110% of thigh peak O2 uptake (65.3 +/- 3.7 W) on several occasions: under noninfused control (Con) and DCA-supplemented conditions. Needle biopsy samples from the vastus lateralis muscle were obtained at rest and after 5 s, 15 s, and 3 min of exercise during both experimental conditions. In addition, thigh blood flow and femoral arteriovenous differences for O2 and lactate were measured repeatedly during the 3-min work bouts (Con and DCA) to calculate thigh O2 uptake and lactate release. After DCA administration, PDH(a) was four- to eightfold higher (P < 0.05) than Con at rest, and PDH(a) remained approximately 130% and 100% higher (P < 0.05) after 5 and 15 s of exercise, respectively. There was no difference between trials after 3 min. Despite the marked difference in PDH(a) between trials at rest and during the initial phase of exercise, thigh O2 uptake was the same. In addition, muscle phosphocreatine utilization and lactate production were similar after 5 s, 15 s, and 3 min of exercise in DCA and Con. The present findings demonstrate that increasing PDH(a) does not alter muscle O2 uptake and anaerobic ATP provision during the initial phase of intense dynamic knee-extensor exercise in humans.