Leena Ali

Supraspinal fatigue after normoxic and hypoxic exercise in humans

•  Processes leading to fatigue occur within the exercising muscle (peripheral fatigue) and the nervous system (central fatigue). •  We asked whether central processes of fatigue would be increased after strenuous exercise in environments where oxygen availability is reduced (hypoxia) compared to the same absolute exercise intensity at sea‐level. •  Our main finding was that the contribution of central processes to fatigue was increased after exercise in hypoxia (equivalent to ∼3800 m above sea‐level). •  The greater amount of central fatigue in hypoxia was due to suboptimal neural output from the brain and was associated with reductions in oxygen availability. •  The findings provide a plausible mechanism for why exercise performance is impaired at high altitude, and might help our understanding of exercise limitation in patients with reduced oxygen delivery to the brain.

Hemodynamic responses to heat stress in the resting and exercising human leg: Insight into the effect of temperature on skeletal muscle blood flow

Heat stress increases limb blood flow and cardiac output (Q) in humans, presumably in sole response to an augmented thermoregulatory demand of the skin circulation. Here we tested the hypothesis that local hyperthermia also increases skeletal muscle blood flow at rest and during exercise. Hemodynamics, blood and tissue oxygenation, and muscle, skin, and core temperatures were measured at rest and during exercise in 11 males across four conditions of progressive whole body heat stress and at rest during isolated leg heat stress. During whole body heat stress, leg blood flow (LBF), Q, and leg (LVC) and systemic vascular conductance increased gradually with elevations in muscle temperature both at rest and during exercise (r(2) = 0.86-0.99; P < 0.05). Enhanced LBF and LVC were accompanied by reductions in leg arteriovenous oxygen (a-vO(2)) difference and increases in deep femoral venous O(2) content and quadriceps tissue oxygenation, reflecting elevations in muscle and skin perfusion. The increase in LVC occurred despite an augmented plasma norepinephrine (P < 0.05) and was associated with elevations in muscle temperature (r(2) = 0.85; P = 0.001) and arterial plasma ATP (r(2) = 0.87; P < 0.001). Isolated leg heat stress accounted for one-half of the increase in LBF with severe whole body heat stress. Our findings suggest that local hyperthermia also induces vasodilatation of the skeletal muscle microvasculature, thereby contributing to heat stress and exercise hyperemia. The increased limb muscle vasodilatation in these conditions of elevated muscle sympathetic vasoconstrictor activity is closely related to the rise in arterial plasma ATP and local tissue temperature.

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.

Erythrocyte-dependent regulation of human skeletal muscle blood flow: role of varied oxyhemoglobin and exercise on nitrite, S-nitrosohemoglobin, and ATP

The erythrocyte is proposed to play a key role in the control of local tissue perfusion via three O(2)-dependent signaling mechanisms: 1) reduction of circulating nitrite to vasoactive NO, 2) S-nitrosohemoglobin (SNO-Hb)-dependent vasodilatation, and 3) release of the vasodilator and sympatholytic ATP; however, their relative roles in vivo remain unclear. Here we evaluated each mechanism to gain insight into their roles in the regulation of human skeletal muscle blood flow during hypoxia and hyperoxia at rest and during exercise. Arterial and femoral venous hemoglobin O(2) saturation (O(2)Hb), plasma and erythrocyte NO and ATP metabolites, and leg and systemic hemodynamics were measured in 10 healthy males exposed to graded hypoxia, normoxia, and graded hyperoxia both at rest and during submaximal one-legged knee-extensor exercise. At rest, leg blood flow and NO and ATP metabolites in plasma and erythrocytes remained unchanged despite large alterations in O(2)Hb. During exercise, however, leg and systemic perfusion and vascular conductance increased in direct proportion to decreases in arterial and venous O(2)Hb (r(2) = 0.86-0.98; P = 0.01), decreases in venous plasma nitrite (r(2) = 0.93; P < 0.01), increases in venous erythrocyte nitroso species (r(2) = 0.74; P < 0.05), and to a lesser extent increases in erythrocyte SNO (r(2) = 0.59; P = 0.07). No relationship was observed with plasma ATP (r(2) = 0.01; P = 0.99) or its degradation compounds. These in vivo data indicate that, during low-intensity exercise and hypoxic stress, but not hypoxic stress alone, plasma nitrite consumption and formation of erythrocyte nitroso species are associated with limb vasodilatation and increased blood flow in the human skeletal muscle vasculature.

Effects of graded heat stress on global left ventricular function and twist mechanics at rest and during exercise in healthy humans

Increased left ventricular (LV) twist and untwisting (LV twist mechanics) contribute to the maintenance of stroke volume during passive heat stress. However, it remains unknown whether changes in LV twist mechanics are related to the magnitude of heat stress and whether performing exercise during heat stress alters this response. We examined global LV function and LV twist mechanics in 10 healthy men at baseline and three progressive levels of heat stress, at rest and during knee‐extensor exercise. At rest, heat stress increased cardiac output and reduced end‐diastolic volume and end‐systolic volume, whilst stroke volume and mean arterial pressure (MAP) were maintained. Left ventricular twist and untwisting velocity also increased from baseline to severe heat stress (from 10.6 ± 3.3 to 15.1 ± 5.2 deg and from −123 ± 55 to −210 ± 49 deg s−1, respectively, both P < 0.01) and correlated significantly with body temperature, heart rate and LV volumes (P < 0.05). Similar to resting conditions, progressive heat stress during exercise increased cardiac output and reduced end‐diastolic volume and end‐systolic volume with a maintained stroke volume. However, MAP declined (P < 0.01) and there was no significant change in LV twist and untwisting velocity, resulting in non‐significant relationships between twist mechanics and systemic responses. In conclusion, LV twist mechanics increase proportionally with the magnitude of heat stress at rest. However, there is no increase in LV twist and untwisting velocity from control exercise to severe heat stress during exercise despite a significant increase in body temperatures and cardiac output. We, therefore, suggest that the maintenance of stroke volume in the combined conditions of heat stress and small muscle mass exercise may be further facilitated by other peripheral factors, such as the continuous decline in MAP.

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 (R2 = 0.50; P < 0.01), which is partly attributed to increases in tissue V̇O2 (R2 = 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 (R2 = 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.

Urinary CC16 after challenge with dry air hyperpnoea and mannitol in recreational summer athletes

Airway epithelial injury is regarded as a key contributing factor to the pathogenesis of exercise-induced bronchoconstriction (EIB) in athletes. The concentration of the pneumoprotein club cell (Clara cell) CC16 in urine has been found to be a non-invasive marker for hyperpnoea-induced airway epithelial perturbation. Exercise-hyperpnoea induces mechanical, thermal and osmotic stress to the airways. We investigated whether osmotic stress alone causes airway epithelial perturbation in athletes with suspected EIB. Twenty-four recreational summer sports athletes who reported respiratory symptoms on exertion performed a standard eucapnic voluntary hyperpnoea test with dry air and a mannitol test (osmotic challenge) on separate days. Median urinary CC16 increased from 120 to 310 ρg μmol creatinine(-1) after dry air hyperpnoea (P = 0.002) and from 90 to 191 ρg μmol creatinine(-1) after mannitol (P = 0.021). There was no difference in urinary CC16 concentration between athletes who did or did not bronchoconstrict after dry air hyperpnoea or mannitol. We conclude that, in recreational summer sports athletes with respiratory symptoms, osmotic stress per se to the airway epithelium induces a rise in urinary excretion of CC16. This suggests that hyperosmolarity of the airway surface lining perturbs the airway epithelium in symptomatic athletes.

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

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.