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Key Points: Humans suffering from polycythaemia undergo multiple circulatory adaptations including changes in blood rheology and structural and functional vascular adaptations to maintain normal blood pressure and vascular shear stresses, despite high blood viscosity. During exercise, several circulatory adaptations are observed, especially involving adrenergic and non-adrenergic mechanisms within non-active and active skeletal muscle to maintain exercise capacity, which is not observed in animal models. Despite profound circulatory stress, i.e. polycythaemia, several adaptations can occur to maintain exercise capacity, therefore making early identification of the disease difficult without overt symptomology. Pharmacological treatment of the background heightened sympathetic activity may impair the adaptive sympathetic response needed to match local oxygen delivery to active skeletal muscle oxygen demand and therefore inadvertently impair exercise capacity., Abstract: Excessive haematocrit and blood viscosity can increase blood pressure, cardiac work and reduce aerobic capacity. However, past clinical investigations have demonstrated that certain human high-altitude populations suffering from excessive erythrocytosis, Andeans with chronic mountain sickness, appear to have phenotypically adapted to life with polycythaemia, as their exercise capacity is comparable to healthy Andeans and even with sea-level inhabitants residing at high altitude. By studying this unique population, which has adapted through natural selection, this study aimed to describe how humans can adapt to life with polycythaemia. Experimental studies included Andeans with (n = 19) and without (n = 17) chronic mountain sickness, documenting exercise capacity and characterizing the transport of oxygen through blood rheology, including haemoglobin mass, blood and plasma volume and blood viscosity, cardiac output, blood pressure and changes in total and local vascular resistances through pharmacological dissection of α-adrenergic signalling pathways within non-active and active skeletal muscle. At rest, Andeans with chronic mountain sickness had a substantial plasma volume contraction, which alongside a higher red blood cell volume, caused an increase in blood viscosity yet similar total blood volume. Moreover, both morphological and functional alterations in the periphery normalized vascular shear stress and blood pressure despite high sympathetic nerve activity. During exercise, blood pressure, cardiac work and global oxygen delivery increased similar to healthy Andeans but were sustained by modifications in both non-active and active skeletal muscle vascular function. These findings highlight widespread physiological adaptations that can occur in response to polycythaemia, which allow the maintenance of exercise capacity., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

Key Points: Age-related changes in cutaneous microvascular and cardiac functions limit the extent of cutaneous vasodilatation and the increase in cardiac output that healthy older adults can achieve during passive heat stress. However, it is unclear if these age-related changes in microvascular and cardiac functions maximally restrain the levels of cutaneous vasodilatation and cardiac output that healthy older adults can achieve during heat stress. We observed that rapid volume loading, performed during passive heat stress, augments both cutaneous vasodilatation and cardiac output in healthy older humans. These findings demonstrate that the microcirculation of healthy aged skin can further dilate during passive heat exposure, despite peripheral limitations to vasodilatation. Furthermore, healthy older humans can augment cardiac output when cardiac pre-load is increased during heat stress., Abstract: Primary ageing markedly attenuates cutaneous vasodilatation and the increase in cardiac output during passive heating. However, it remains unclear if these responses are maximally restrained by age-related changes in cutaneous microvascular and cardiac functions. We hypothesized that rapid volume loading performed during heat stress would increase cardiac output in older adults without parallel increases in cutaneous vasodilatation. Twelve young (Y: 26 ± 5 years) and ten older (O: 69 ± 3 years) healthy adults were passively heated until core temperature increased by 1.5°C. Cardiac output (thermodilution), forearm vascular conductance (FVC, venous occlusion plethysmography) and cutaneous vascular conductance (CVC, laser-Doppler) were measured before and after rapid infusion of warmed saline (15 mL kg -1 , ∼7 min). While heat stressed, but prior to saline infusion, cardiac output (O: 6.8 ± 0.4 vs. Y: 9.4 ± 0.6 L min -1 ), FVC (O: 0.08 ± 0.01 vs. Y: 0.17 ± 0.02 mL (100 mL min -1  mmHg -1 ) -1 ), and CVC (O: 1.29 ± 0.34 vs. Y: 1.93 ± 0.30 units mmHg -1 ) were lower in older adults (all P < 0.01). Rapid saline infusion increased cardiac output (O: +1.9 ± 0.3, Y: +1.8 ± 0.7 L min -1 ), FVC (O: +0.015 ± 0.007, Y: +0.048 ± 0.013 mL (100 mL min -1  mmHg -1 ) -1 ), and CVC (O: +0.28 ± 0.10, Y: +0.29 ± 0.16 units mmHg -1 ) in both groups (all P < 0.01). The absolute increase in cardiac output and CVC were similar between groups, whereas FVC increased to a greater extent in young adults (P < 0.01). These results demonstrate that healthy older adults can achieve greater levels of cutaneous vasodilatation and cardiac output during passive heating., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Key Points: Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors, in a variety of pathways that probably predate its more recent role in innate and adaptive immunity. Although histamine is normally associated with pathological conditions or allergic and anaphylactic reactions, it may contribute beneficially to the normal changes that occur within skeletal muscle during the recovery from exercise. We show that the human response to exercise includes an altered expression of thousands of protein-coding genes, and much of this response appears to be driven by histamine. Histamine may be an important molecular transducer contributing to many of the adaptations that accompany chronic exercise training., Abstract: Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors. In humans, aerobic exercise is followed by a post-exercise activation of histamine H1 and H2 receptors localized to the previously exercised muscle. This could trigger a broad range of cellular adaptations in response to exercise. Thus, we exploited RNA sequencing to explore the effects of H1 and H2 receptor blockade on the exercise transcriptome in human skeletal muscle tissue harvested from the vastus lateralis. We found that exercise exerts a profound influence on the human transcriptome, causing the differential expression of more than 3000 protein-coding genes. The influence of histamine blockade post-exercise was notable for 795 genes that were differentially expressed between the control and blockade condition, which represents >25% of the number responding to exercise. The broad histamine footprint on the human exercise transcriptome crosses many cellular functions, including inflammation, vascular function, metabolism, and cellular maintenance., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Key Points: Plasma hyperosmolality delays the onset for sweat production and cutaneous vasodilatation during heat stress in humans; however, the mechanism by which hyperosmolality exerts this effect remains unknown. This study examined if plasma hyperosmolality exerts a central and/or peripheral modulation of thermoregulatory function in humans. The main findings are that plasma hyperosmolality delays the increase in skin sympathetic nerve activity during whole-body passive heat stress in humans. In contrast, local intradermal infusion of hyperosmotic saline did not affect sweating or cutaneous vasodilatation. These results suggest that plasma hyperosmolality delays the onset threshold for sweating and cutaneous vasodilatation by inhibiting efferent thermoregulatory activity in humans., Abstract: In humans, plasma hyperosmolality delays the onset of sweating and cutaneous vasodilatation during heat stress. However, it remains unknown if hyperosmolality exerts this effect through a central (i.e. CNS) and/or peripheral (i.e. effector organ) modulation of thermoregulatory activity. We examined if intravenous infusion of hyperosmotic saline affects skin sympathetic nerve activity (SSNA) during whole-body passive heating in healthy humans. Furthermore, we examined if local intradermal infusion of hyperosmotic saline affects sweating and cutaneous vasodilatation during passive heating. Following intravenous infusion of either 0.9% (ISO) or 3.0% (HYPER) NaCl saline, 12 subjects were passively heated until core temperature increased by ∼0.6°C. During each condition, sweating and cutaneous vascular conductance were measured over two intradermal microdialysis probes, one perfused with ISO saline and the other with HYPER saline. Intravenous infusion of HYPER saline increased plasma osmolality (294 ± 3 to 316 ± 5 mOsm kg(-1) H2O, P ≤ 0.01), which remained greater than ISO throughout heating. Plasma hyperosmolality delayed the mean body temperature onset of sweating (+1.24 ± 0.18 vs. +1.60 ± 0.18°C, P ≤ 0.01) and cutaneous vasodilatation (+1.15 ± 0.18 vs. +1.53 ± 0.22°C, P ≤ 0.01), and attenuated the increase in SSNA during heating (+147 ± 178 vs. +427 ± 281%, P ≤ 0.01). Intradermal infusion of HYPER saline increased baseline cutaneous vascular conductance (P ≤ 0.01), which did not increase further during the subsequent heating period (P = 0.11). In contrast, intradermal infusion of HYPER saline did not affect sweating (P = 0.99). These results provide direct evidence that plasma hyperosmolality exerts a central modulatory effect governing efferent thermoregulatory activity in humans., (© 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.)