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Aims: Many studies demonstrated reproductive damage in men residing in plains who are exposed to hypoxia at high altitudes. However, little is known about mechanisms between male reproductive impairment and hypobaric hypoxia. Hypoxia is one of the reasons for the imbalance of cellular redox system. Ferroptosis, involved in many pathophysiological progresses, is an oxidative damage-related, iron-dependent regulated cell death, which needs exogenous inducer. In our study, we explored the mechanism between hypoxia and male reproductive dysfunction., Materials and Methods: Here, we established animal model simulating hypobaric hypoxia at an altitude of 5000 m and used ELISA, WB, qPCR, flow cytometry and etc. to obtain different results., Key Findings: The results demonstrated decrease of plasma testosterone (T) and free testosterone (FT) levels under hypoxia, meanwhile there's decline in sperm counts and sperm motility, coupled with increase in sperm malformation rates. Flow cytometry confirmed significant reduction in Leydig cell numbers. Prussian blue staining showed iron depositions in interstitial testis. Features of ferroptosis such as increased MDA (malondialdehyde) levels, reduced solute carrier family 7 member 11 (SLC7A11, xCT) and glutathione peroxidase 4 (GPX4) expression were observed in testis after hypoxic exposure. Further in vitro experiments, we observed that hypoxia suppressed xCT-GPX4 pathway and enhanced cellular ROS accumulation to lead Leydig cell proliferation activity decline., Significance: Our findings firstly indicated that hypoxia leads to male reproductive dysfunction via inducing Leydig cell ferroptosis. This discovery may offer a potential intervention target for addressing male reproductive injuries under hypoxic conditions., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The environment has long been considered a crucial factor influencing the onset and progression of pulmonary diseases. Environmental therapy is also a practical treatment approach for many conditions. While research has explored the effects of factors like air pressure and oxygen concentration on pulmonary arterial hypertension (PAH), the impact of air humidity on PAH has not been investigated. In this study, we examined the role of different air humidity levels in a mouse model of PAH by controlling relative humidity. We induced PAH in mice using 10 % hypoxia, which led to significant thickening of the pulmonary vasculature, elevated right ventricular systolic pressure, and an increased right ventricular hypertrophy index (RVHI). However, when exposed to an environment with 80-95 % relative humidity, there was a marked reduction in the extent of pulmonary vascular remodeling, decreased vascular thickening, and lower RVHI, effectively preserving right heart function. Notably, changes in the Bmpr2/Tgf-β signaling pathway were significant and may play a pivotal role in this protective effect. In summary, our findings indicate that high relative humidity confers a protective effect on hypoxia-induced PAH in mice, providing novel insights into potential treatments for PAH., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Hypoxia-Induced Neonatal Seizure (HINS) is a prevalent type of seizure in infants caused by hypoxic conditions, which can lead to an increased risk of epilepsy, learning disabilities, and cognitive impairments later in life. This study focuses on examining the effects of dimethyl itaconate (DMI) on cognition, motor coordination, and anxiety-like behavior in male rats that have experienced HINS. 42 male Wistar newborn rats (PND10) were randomly divided into six groups (n = 7). 1) Control (Vehicle only); received DMI solvent (0.1ml) without applying hypoxia. 2-3) DMI; receiving (20 and 50 mg/kg; i.p). 4) HINS; they were placed in a hypoxia chamber with 7% oxygen and 93% nitrogen concentration for 15 minutes. 5-6) DMI+HINS; received DMI (20 and 50 mg/kg; i.p) 24h before hypoxia. Behavioral tests including; Novel object recognition test, Rotarod, Parallel bar, Open field and elevated plus maze (EPM); started at age 45 after birth. After behavioral tests, the hippocampal CA1 region local EEG was recorded in all groups. Then the brain hippocampus tissue was isolated and the amount of MDA, SOD, NO, and Thiol was measured by ELISA method. Data showed that the administration of DMI improved motor symptoms, anxiety-like behaviors, and cognition in HINS rats (p<0.05). EEG power in the HINS group decreased significantly compared to other experimental groups (p<0.05). Biochemical observations showed that DMI significantly reduced oxidative stress and inflammation in the hippocampal tissue of HINS rats (p<0.05). Increased hippocampal oxidative stress and inflammation can be effective in the occurrence of behavioral disorders observed in HINS rats. While DMI improved these behavioral impairments by reducing oxidative stress and inflammation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Nazarizadeh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Acute mountain sickness (AMS) represents a considerable issue for individuals sojourning to high altitudes with systemic hypoxemia known to be intimately involved in its development. Based on recent evidence that ketone ester (KE) intake attenuates hypoxemia, we investigated whether exogenous ketosis might mitigate AMS development and identified underlying physiological mechanisms. Fourteen healthy, male participants were enrolled in two 29-h protocols (simulated altitude of 4,000-4,500 m) receiving either KE or a placebo (CON) at regular timepoints throughout the protocol in a randomized, crossover manner. Physiological responses were characterized after 15 min and 4 h in hypoxia, and the protocol was terminated prematurely upon development of severe AMS (Lake Louise Score ≥ 10). KE ingestion induced a consistent diurnal ketosis (d-β-hydroxybutyrate, [βHB] of ∼3 mM), whereas blood [βHB] remained low (<0.6 mM) in CON. Each participant tolerated the protocol equally long or longer ( n = 6 or n = 8, respectively) in KE. Protocol duration increased by 32% on average with KE, and doubled upon KE for severe AMS-developing participants ( n = 9). Relative to CON, KE induced a mild metabolic acidosis, hyperventilation, and relative sympathetic dominance. KE also inhibited the progressive hypoxemia that was observed between 15 min and 4 h in hypoxia in CON, while concomitantly increasing cerebral oxygenation and capillary Po 2 within this timeframe despite a KE-induced reduction in cerebral oxygen supply. These data indicate that exogenous ketosis attenuates AMS development. The key underlying mechanisms include improved arterial and cerebral oxygenation, in combination with lowered cerebral blood flow and oxygen delivery, and increased sympathetic dominance. NEW & NOTEWORTHY Ketone ester intake attenuated the development of acute mountain sickness at a simulated altitude of 4,000-4,500 m. This likely resulted from a mitigation of arterial and cerebral hypoxemia, reduced cerebral blood flow, and increased sympathetic drive.

Introduction: The apnea-hypopnea index (AHI) is the current diagnostic parameter for diagnosing and estimating the severity of obstructive sleep apnea (OSA). It is, however, poorly associated with the main clinical symptom of OSA, excessive daytime sleepiness, and with the often-seen cognitive decline among OSA patients. To better evaluate OSA severity, novel hypoxic load parameters have been introduced that consider the duration and depth of oxygen saturation drops associated with apneas or hypopneas. The aim of this paper was to compare novel hypoxic load parameters and traditional OSA parameters to verbal memory and executive function in OSA patients., Method: A total of 207 adults completed a one-night polysomnography at sleep laboratory and two neuropsychological assessments, the Rey Auditory Verbal Learning Test and Stroop test., Results: Simple linear regression analyses were used to evaluate independent associations between each OSA parameter and cognitive performance. Associations were found between immediate recall and arousal index, hypoxia <90 %, average SpO 2 during sleep, and DesSev100+RevSev100. Total recall was associated with all OSA parameters, and no associations were found with the Stroop test. Subsequently, sex, age, and education were included as covariates in multiple linear regression analyses for each OSA parameter and cognitive performance. The main findings of the study were that average SpO 2 during sleep was a significant predictor of total recall (p < .007, β = -.188) with the regression model explaining 21.2 % of performance variation. Average SpO 2 during sleep was also a significant predictor of immediate recall (p < .022, β = -.171) with the regression model explaining 11.4 % of performance variation. Neither traditional OSA parameters nor novel hypoxic load parameters predicted cognitive performance after adjustment for sex, age, and education., Conclusion: The findings validate that the AHI is not an effective indicator of cognitive performance in OSA and suggest that average oxygen saturation during sleep may be the strongest PSG predictor of cognitive decline seen in OSA. The results also underline the importance of considering age when choosing neurocognitive tests, the importance of including more than one test for each cognitive domain as most tests are not pure measures of a single cognitive factor, and the importance of including tests that cover all cognitive domains as OSA is likely to have diffuse cognitive effects., Competing Interests: Declaration of competing interest KTH: no conflict of interest. HH: no conflict of interest. TK: no conflict of interest. SN: no conflict of interest. TD: no conflict of interest. IHN: no conflict of interest. TL: no conflict of interest. ESA: honoraria from Nox Medical, Philips, ResMed, Jazz Pharmaceuticals, Linde Healthcare, Alcoa – Fjardaral, WinkSleep, ApniMed and Vistor. She is also a member of the Philips Sleep Medicine & Innovation Medical Advisory Board. MKJ: no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

For often unclear reasons, the survival times of critically buried avalanche victims vary widely from minutes to hours. Individuals can survive and sustain organ function if they can breathe under the snow and maintain sufficient delivery of oxygen and efflux of carbon dioxide. We review the physiological responses of humans to critical avalanche burial, a model which shares similarities and differences with apnoea and accidental hypothermia. Within a few minutes of burial, an avalanche victim is exposed to hypoxaemia and hypercapnia, which have important effects on the respiratory and cardiovascular systems and pose a major threat to the central nervous system. As burial time increases, an avalanche victim also develops hypothermia. Despite progressively reduced metabolism, reduced oxygen and increased carbon dioxide tensions may exacerbate the pathophysiological consequences of hypothermia. Hypercapnia seems to be the main cause of cardiovascular instability, which, in turn, is the major reason for reduced cerebral oxygenation despite reductions in cerebral metabolic activity caused by hypothermia. 'Triple H syndrome' refers to the interaction of hypoxia, hypercapnia and hypothermia in a buried avalanche victim. Future studies should investigate how the respiratory gases entrapped in the porous snow structure influence the physiological responses of buried individuals and how haemoconcentration, blood viscosity and cell deformability affect blood flow and oxygen delivery. Attention should also be devoted to identifying strategies to prolong avalanche survival by either mitigating hypoxia and hypercapnia or reducing core temperature so that neuroprotection occurs before the onset of cerebral hypoxia., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

A given dose of hypoxia causes a greater increase in pulmonary ventilation during physical exercise than during rest, representing an exercise-induced potentiation of the acute hypoxic ventilatory response (HVR). This phenomenon occurs independently from hypoxic blood entering the contracting skeletal muscle circulation or metabolic byproducts leaving skeletal muscles, supporting the contention that neural mechanisms per se can mediate the HVR when humoral mechanisms are not at play. However, multiple neural mechanisms might be interacting intricately. First, we discuss the neural mechanisms involved in the ventilatory response to hypoxic exercise and their potential interactions. Current evidence does not support an interaction between the carotid chemoreflex and central command. In contrast, findings from some studies support synergistic interactions between the carotid chemoreflex and the muscle mechano- and metaboreflexes. Second, we propose hypotheses about potential mechanisms underlying neural interactions, including spatial and temporal summation of afferent signals into the medulla, short-term potentiation and sympathetically induced activation of the carotid chemoreceptors. Lastly, we ponder how exercise-induced potentiation of the HVR results in hyperventilation-induced hypocapnia, which influences cerebral blood flow regulation, with multifaceted potential consequences, including deleterious (increased central fatigue and impaired cognitive performance), inert (unchanged exercise) and beneficial effects (protection against excessive cerebral perfusion)., (© 2024 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Neuronal activity requires a large amount of ATP, leading to a rapid collapse of brain function when aerobic respiration fails. Here, we summarize how rhythmic motor circuits in the brain stem of adult frogs, which normally have high metabolic demands, transform to produce proper output during severe hypoxia associated with emergence from hibernation. We suggest that general principles underlying plasticity in brain bioenergetics may be uncovered by studying nonmammalian models that face extreme environments, yielding new insights to combat neurological disorders involving dysfunctional energy metabolism.

Chronic hypoxia (CH) during postnatal development attenuates the hypoxic ventilatory response (HVR) in mammals, but there are conflicting reports on whether this plasticity is permanent or reversible. This study tested the hypothesis that CH-induced respiratory plasticity is reversible in neonatal rats and investigated whether the initial plasticity or recovery differs between sexes. Rat pups were exposed to 3 d of normobaric CH (12 % O 2 ) beginning shortly after birth. Ventilation and metabolic CO 2 production were then measured in normoxia and during an acute hypoxic challenge (12 % O 2 ) immediately following CH and after 1, 4-5, and 7 d in room air. CH pups hyperventilated when returned to normoxia immediately following CH, but normoxic ventilation was similar to age-matched control rats within 7 d after return to room air. The early phase of the HVR (minute 1) was only blunted immediately following the CH exposure, while the late phase of the HVR (minute 15) remained blunted after 1 and 4-5 d in room air; recovery appeared complete by 7 d. However, when normalized to CO 2 production, the late phase of the hypoxic response recovered within only 1 d. The initial blunting of the HVR and subsequent recovery were similar in female and male rats. Carotid body responses to hypoxia (in vitro) were also normal in CH pups after approximately one week in room air. Collectively, these data indicate that ventilatory and metabolic responses to hypoxia recover rapidly in both female and male neonatal rats once normoxia is restored following CH., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aging invariably decreases sensory and motor stimuli and affects several neuronal systems and their connectivity to key brain regions, including those involved in breathing. Nevertheless, further investigation is needed to fully comprehend the link between senescence and respiratory function. Here, we investigate whether a mouse model of accelerated senescence could develop central and peripheral respiratory abnormalities. Adult male Senescence Accelerated Mouse Prone 8 (SAMP8) and the control SAMR1 mice (10 months old) were used. Ventilatory parameters were assessed by whole-body plethysmography, and measurements of respiratory input impedance were performed. SAMP8 mice exhibited a reduction in the density of neurokinin-1 receptor immunoreactivity in the entire ventral respiratory column. Physiological experiments showed that SAMP8 mice exhibited a decreased tachypneic response to hypoxia (FiO2 = 0.08; 10 min) or hypercapnia (FiCO2 = 0.07; 10 min). Additionally, the ventilatory response to hypercapnia increased further due to higher tidal volume. Measurements of respiratory mechanics in SAMP8 mice showed decreased static compliance (Cstat), inspiratory capacity (IC), resistance (Rn), and elastance (H) at different ages (3, 6, and 10 months old). SAMP8 mice also have a decrease in contractile response to methacholine compared to SAMR1. In conclusion, our findings indicate that SAMP8 mice display a loss of the NK1-expressing neurons in the respiratory brainstem centers, along with impairments in both central and peripheral respiratory mechanisms. These observations suggest a potential impact on breathing in a senescence animal model., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hypoxia at high altitude facilitates changes in ventilatory control that can lead to nocturnal periodic breathing (nPB). Here, we introduce a placebo-controlled approach to prevent nPB by increasing inspiratory CO 2 and used it to assess whether nPB contributes to the adverse effects of hypoxia on sleep architecture. In a randomized, single-blinded, crossover design, 12 men underwent two sojourns (three days/nights each, separated by 4 weeks) in hypobaric hypoxia corresponding to 4000 m altitude, with polysomnography during the first and third night of each sojourn. During all nights, subjects' heads were encompassed by a canopy retaining exhaled CO 2 , and CO 2 concentration in the canopy (i.e. inspiratory CO 2 concentration) was controlled by adjustment of fresh air inflow. Throughout the placebo sojourn inspiratory CO 2 was ≤0.2%, whereas throughout the other sojourn it was increased to 1.76% (IQR, 1.07%-2.44%). During the placebo sojourn, total sleep time (TST) with nPB was 54.3% (37.4%-80.8%) and 45.0% (24.5%-56.5%) during the first and the third night, respectively (P = 0.042). Increased inspiratory CO 2 reduced TST with nPB by an absolute 38.1% (28.1%-48.1%), the apnoea-hypopnoea index by 58.1/h (40.1-76.1/h), and oxygen desaturation index ≥3% by 56.0/h (38.9.1-73.2/h) (all P < 0.001), whereas it increased the mean arterial oxygen saturation in TST by 2.0% (0.4%-3.5%, P = 0.035). Increased inspiratory CO 2 slightly increased the percentage of N3 sleep during the third night (P = 0.045), without other effects on sleep architecture. Increasing inspiratory CO 2 effectively prevented hypoxia-induced nPB without affecting sleep macro-architecture, indicating that nPB does not explain the sleep deterioration commonly observed at high altitudes. KEY POINTS: Periodic breathing is common during sleep at high altitude, and it is unclear how this affects sleep architecture. We developed a placebo-controlled approach to prevent nocturnal periodic breathing (nPB) with inspiratory CO 2 administration and used it to assess the effects of nPB on sleep in hypobaric hypoxia. Nocturnal periodic breathing was effectively mitigated by an increased inspiratory CO 2 fraction in a blinded manner. Prevention of nPB did not lead to relevant changes in sleep architecture in hypobaric hypoxia. We conclude that nPB does not explain the deterioration in sleep architecture commonly observed at high altitude., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Migraine, a common neurological disorder, impacts over a billion individuals globally. Its complex aetiology involves various signalling cascades. Hypoxia causes headaches such as high-altitude headache and acute mountain sickness which share phenotypical similarities with migraine. Epidemiological data indicate an increased prevalence of migraine with and without aura in high-altitude populations. Experimental studies have further shown that hypoxia can induce migraine attacks. This review summarizes evidence linking hypoxia to migraine, delves into potential pathophysiological mechanisms and highlights research gaps., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

Obstructive sleep apnoea is characterized by chronic intermittent hypoxaemia and is independently associated with an increased risk of metabolic comorbidities (e.g. type II diabetes and ischaemic heart disease). These comorbidities could be attributable to hypoxaemia-induced alterations in blood lipid profiles. However, it remains unclear whether intermittent hypoxaemia alters triglyceridaemia differently between biological sexes. Therefore, we used a randomized crossover design to examine whether 6 h of moderate intermittent hypoxaemia (15 hypoxaemic cycles/h, 85% oxyhaemoglobin saturation) alters plasma triglyceride levels differently between men and women after a high-fat meal. Relative to men, women displayed lower levels of total triglycerides, in addition to denser triglyceride-rich lipoprotein triglycerides (TRL-TG; mainly very low-density lipoprotein triglycerides and chylomicron remnant triglycerides) and buoyant TRL-TG (mainly chylomicron triglycerides) during normoxia (ambient air) and intermittent hypoxaemia (sex × time: all P ≤ 0.008). Intermittent hypoxaemia led to higher triglyceride levels (condition: all P ≤ 0.016); however, this effect was observed only in men (sex × condition: all P ≤ 0.002). Compared with normoxia, glucose levels were higher in men and lower in women during intermittent hypoxaemia (sex × condition: P < 0.001). The different postprandial responses between biological sexes occurred despite similar reductions in mean oxyhaemoglobin saturation and similar elevations in insulin levels, non-esterified fatty acid levels and mean heart rate (sex × condition: all P ≥ 0.185). These results support growing evidence showing that intermittent hypoxaemia impacts men and women differently, and they might help to explain biological sex-related discrepancies in the rate of certain comorbidities associated with intermittent hypoxaemia. KEY POINTS: Intermittent hypoxaemia is a key characteristic of obstructive sleep apnoea and alters lipid metabolism in multiple tissues, resulting in increased circulating triglyceride levels, an important risk factor for cardiometabolic diseases. Circulating triglyceride levels are regulated differently between biological sexes, with women typically displaying much lower fasting and postprandial triglyceride levels than men, partly explaining why women of all ages experience lower mortality rates from cardiometabolic diseases. In this study, healthy young men and women consumed a high-fat meal and were then exposed to 6 h of intermittent hypoxaemia or ambient air. We show that postprandial triglyceride levels are significantly lower in women compared with men and that intermittent hypoxaemia leads to higher postprandial triglyceride levels in men only. These results might help us to understand better why women living with obstructive sleep apnoea experience lower rates of cardiometabolic diseases (e.g. type II diabetes and ischaemic heart disease) than men living with obstructive sleep apnoea., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Abstract: Segovia, M, Salmon, OF, Ugale, C, and Smith, CM. The effects of cold exposure, hypoxia, and fatigue on pistol marksmanship and target engagement decision making in trained marksmen. J Strength Cond Res 38(11): e686-e694, 2024-This study aimed to examine the effects of cold exposure, hypoxia, and fatigue on pistol marksmanship and target engagement in trained marksmen. Twelve healthy subjects (mean ± SD age: 28.8 ± 4.0 years) performed 3 testing visits under normal/normoxic [Norm 21 ] (24° C; 21% FiO 2 ), cold/normoxic [Cold 21 ] (10° C; 21% FiO 2 ), and cold/hypoxic [Cold 14 ] (10° C; FiO 2 : 14.3) conditions. Pistol marksmanship and target engagement were assessed through draw time (DT) and shoot-no-shoot (SNS) courses of fire. The 2 protocols were performed before (T preF ) and immediately after (T postF ) a sandbag deadlift fatiguing protocol. Significance was set at p < 0.05. Significant condition × time interactions ( p = 0.01-0.03) were found for accuracy SNS (SNS acc ), misses SNS (SNS miss ), and total shots SNS (SNS tot ). Follow-up analyses indicated that SNS acc increased by 14.3% ( p = 0.03), SNS miss decreased by 34.7% ( p = 0.02), and SNS tot decreased by 10.6% ( p = 0.04) from T preF to T postF during the Cold 21 condition alone. No significance was found for these in the Norm 21 ( p = 0.08-0.22) or Cold 14 ( p = 0.18-0.47) conditions. Total time (SNS T ) to completion of the SNS ( p = 0.09) and DT ( p = 0.14) showed no significance across time or condition. Significant difference across time for Cold 14 ( p = 0.03-0.02) for reaction time was found. Exercise likely resulted in increased thermogenesis that improved tactically relevant motor skills including SNS acc , decreased SNS miss , and SNS tot in Cold 21 , but not Cold 14 . The additive effect of hypoxia coupled with exercise in the Cold 14 condition did not improve tactical performance, suggesting multi-stressor environments result in competing physiological responses. Tactical strength and conditioning specialists as well as operators should aim to improve thermoregulation during Cold 21 conditions, with exercise as a possible intervention., (Copyright © 2024 National Strength and Conditioning Association.)

Muscle injuries are the leading cause of sports casualties. Because of its high plasticity, skeletal muscle can respond to different stimuli to maintain and improve functionality. Intermittent hypobaric hypoxia (IHH) improves muscle oxygen delivery and utilization. Hypobaria coexists with cold in the biosphere, opening the possibility to consider the combined use of both environmental factors to achieve beneficial physiological adjustments. We studied the effects of IHH and cold exposure, separately and simultaneously, on muscle regeneration. Adult male rats were surgically injured in one gastrocnemius and randomly assigned to the following groups: (1) CTRL: passive recovery; (2) COLD: intermittently exposed to cold (4°C); (3) HYPO: submitted to IHH (4500 m); (4) COHY: exposed to intermittent simultaneous cold and hypoxia. Animals were subjected to these interventions for 4 h/day for 9 or 21 days. COLD and COHY rats showed faster muscle regeneration than CTRL, evidenced after 9 days at histological (dMHC-positive and centrally nucleated fibre reduction) and functional levels after 21 days. HYPO rats showed a full recovery from injury (at histological and functional levels) after 9 days, while COLD and COHY needed more time to induce a total functional recovery. IHH can be postulated as an anti-fibrotic treatment since it reduces collagen I deposition. The increase in the pSer473Akt/total Akt ratio observed after 9 days in COLD, HYPO and COHY, together with the increase in the pThr172AMPKα/total AMPKα ratio observed in the gastrocnemius of HYPO, provides clues to the molecular mechanisms involved in the improved muscle regeneration. KEY POINTS: Only intermittent hypobaric exposure accelerated muscle recovery as early as 9 days following injury at histological and functional levels. Injured muscles from animals treated with intermittent (4 h/day) cold, hypobaric hypoxia or a simultaneous combination of both stimuli regenerated histological structure and recovered muscle function 21 days after injury. The combination of cold and hypoxia showed a blunting effect as compared to hypoxia alone in the time course of the muscle recovery. The increased expression of the phosphorylated forms of Akt observed in all experimental groups could participate in the molecular cascade of events leading to a faster regeneration. The elevated levels of phosphorylated AMPKα in the HYPO group could play a key role in the modulation of the inflammatory response during the first steps of the muscle regeneration process., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Abstract: Allsopp, GL, Britto, FA, Wright, CR, and Deldicque, L. The effects of normobaric hypoxia on the acute physiological responses to resistance training: a narrative review. J Strength Cond Res 38(11): 2001-2011, 2024-Athletes have used altitude training for many years as a strategy to improve endurance performance. The use of resistance training in simulated altitude (normobaric hypoxia) is a growing strategy that aims to improve the hypertrophy and strength adaptations to training. An increasing breadth of research has characterized the acute physiological responses to resistance training in hypoxia, often with the goal to elucidate the mechanisms by which hypoxia may improve the training adaptations. There is currently no consensus on the overall effectiveness of hypoxic resistance training for strength and hypertrophy adaptations, nor the underlying biochemical pathways involved. There are, however, numerous interesting physiological responses that are amplified by performing resistance training in hypoxia. These include potential changes to the energy system contribution to exercise and alterations to the level of metabolic stress, hormone and cytokine production, autonomic regulation, and other hypoxia-induced cellular pathways. This review describes the foundational exercise physiology underpinning the acute responses to resistance training in normobaric hypoxia, potential applications to clinical populations, including training considerations for athletic populations. The review also presents a summary of the ideal training parameters to promote metabolic stress and associated training adaptations. There are currently many gaps in our understanding of the physiological responses to hypoxic resistance training, partly caused by the infancy of the research field and diversity of hypoxic and training parameters., (Copyright © 2024 National Strength and Conditioning Association.)

There is no study that has investigated the impact of exercise in a combined hypoxic and hot environment on endothelial function. Therefore, we tested whether aerobic exercise in a combined hypoxic and hot conditions induces further enhancement of endothelial function. Twelve healthy males cycled at a constant workload (50% of their maximal oxygen uptake under normoxic/thermoneutral conditions) for 30 min in four different environments: exercise under normoxic condition (NOR: fraction of inspiratory oxygen or FiO 2  = 20.9%, 20°C), exercise under hypoxic condition (HYP: FiO 2  = 14.5%, 20°C), exercise under hot condition (HOT: FiO 2  = 20.9%, 30°C), and exercise under combined hypoxia and hot conditions (HH: FiO 2  = 14.5%, 30°C). Before, during, and after exercise, cardiovascular variables (e.g., heart rate, blood flow, and shear rate), blood variables, and endothelial function evaluated by flow-mediated dilation (FMD) were assessed. Heart rates were significantly higher throughout the HH trial's experimental period than the other trials (p < 0.05). However, in the HH trial, brachial artery blood flow and shear rate did not differ from those in other trials after exercise. Plasma catecholamines (epinephrine, norepinephrine, and dopamine) elevations in response to exercise were significantly higher in the HH trial than in the other three trials (p < 0.05). No considerable differences were observed in FMD responses among trials before and after the exercise. In conclusion, aerobic exercise in a combined hot and hypoxic environment further activated sympathetic nervous activity but did not considerably enhance blood flow, shear rate, or endothelial function., (© 2024 The Author(s). Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Objectives: This study aimed to determine the effects of chronic intermittent hypoxia (CIH) and stress change (SC) on the development of the condyle in mouth breathing rats., Design: A total of 120 4-week-old rats were randomly assigned to one of five groups. The control (Ctrl) group was the blank control and the intermittent nasal obstruction (INO) group was the positive control. Mild CIH (mCIH) and severe CIH (sCIH) groups were developed by adjusting environmental oxygen concentration and monitoring real-time blood oxygen saturation (SpO 2 ). The SC group was developed using INO, increased environmental oxygen concentration, and real-time SpO 2 monitoring. Six rats from each group were sacrificed for analysis at 0, 1, 2, or 4 weeks., Results: Similar to the INO group, condyle and mandibular body development in the sCIH group, but not in the mCIH group, was significantly inhibited compared with the Ctrl group. The SC group had inhibited development of the condyle, especially of the posterior zone, but had minimal impact on the growth of the mandible., Conclusion: The inhibitory effects of CIH on the development of the condyle and mandibular body were SpO 2 -dose-dependent. When SC occurred, inhibited development was observed in the posterior zone of condyle but not the whole mandible. These findings provide important insights for targeted interventions that address the consequences of mouth breathing in children., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest with respect to the authorship and publication of this article., (Copyright © 2024. Published by Elsevier Ltd.)

Acute intermittent hypoxia (AIH) is an emerging technique for enhancing neuroplasticity and motor function in respiratory and limb musculature. Thus far, AIH-induced improvements in strength have been reported for upper and lower limb muscles after chronic incomplete cervical spinal cord injury (iSCI), but the underlying mechanisms have been elusive. We used high-density surface EMG (HDsEMG) to determine if motor unit discharge behaviour is altered after 15 × 60 s exposures to 9% inspired oxygen, interspersed with 21% inspired oxygen (AIH), compared to breathing only 21% air (SHAM). We recorded HDsEMG from the biceps and triceps brachii of seven individuals with iSCI during maximal elbow flexion and extension contractions, and motor unit spike trains were identified using convolutive blind source separation. After AIH, elbow flexion and extension torque increased by 54% and 59% from baseline (P = 0.003), respectively, whereas there was no change after SHAM. Across muscles, motor unit discharge rates increased by ∼4 pulses per second (P = 0.002) during maximal efforts, from before to after AIH. These results suggest that excitability and/or activation of spinal motoneurons is augmented after AIH, providing a mechanism to explain AIH-induced increases in voluntary strength. Pending validation, AIH may be helpful in conjunction with other therapies to enhance rehabilitation outcomes after incomplete spinal cord injury, due to these enhancements in motor unit function and strength. KEY POINTS: Acute intermittent hypoxia (AIH) causes increases in muscular strength and neuroplasticity in people living with chronic incomplete spinal cord injury (SCI), but how it affects motor unit discharge rates is unknown. Motor unit spike times were identified from high-density surface electromyograms during maximal voluntary contractions and tracked from before to after AIH. Motor unit discharge rates were increased following AIH. These findings suggest that AIH can facilitate motoneuron function in people with incomplete SCI., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

The present study investigated the maintenance/repeatability of expiratory flow limitation (EFL) between normoxia and hypoxia. Fifty-one healthy active individuals (27 men and 24 women) performed a lung function test and a maximal incremental cycling test in both normoxia and hypoxia (inspired oxygen fraction = 0.14) on two separate visits. During exercise in normoxia, 28 participants exhibited EFL (55 %). In hypoxia, another cohort of 28 participants exhibited EFL. The two groups only partly overlapped. Individuals with EFL only in normoxia reported lower maximal ventilation values in hypoxia than in normoxia (n=5; -13.5 ± 7.8 %) compared to their counterparts with EFL only in hypoxia (n=5; +6.7 ± 6.3 %) or without EFL (n=18; +5.1 ± 10.3 %) (p=0.004 and p<0.001, respectively). EFL development may be induced by different mechanisms in hypoxia vs. normoxia since the individuals who exhibited flow limitation were not the same between the two environmental conditions. This change seems influenced by the magnitude of the maximal ventilation change., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To quantify the magnitude and recovery of central and limbal corneal oedema induced by short-term unilateral eyelid closure without contact lens wear., Methods: The left eye of 10 adults with healthy corneas was patched using a folded eye pad for 30 min. High-resolution optical coherence tomography images (which captured the limbal and central corneal regions simultaneously) were obtained before patching, immediately after eye opening and again at 1, 2, 5, 6, 9, 10, 14 and 15 mins after eyelid opening. Oedema was measured from the limbus (scleral spur) to the central cornea (thinnest corneal location) along the horizontal meridian., Results: A greater amount of limbal oedema was noted (mean [SD] 3.84 [1.79] %) compared to the central cornea (2.48 [0.61] %; p = 0.04) after 30 mins of unilateral eyelid closure. Both central and limbal corneal oedema recovered rapidly following eyelid opening, with no significant differences in the rate of corneal recovery between corneal locations (p = 0.90)., Conclusions: Short-term unilateral eyelid closure resulted in ~55% more relative oedema in the limbal region compared to the central cornea. Rapid recovery of oedema and corneal overshoot (thinning beyond the baseline corneal thickness) was observed within 1-2 min of eyelid opening for both central and peripheral regions., (© 2024 The Author(s). Ophthalmic and Physiological Optics published by John Wiley & Sons Ltd on behalf of College of Optometrists.)

This Symposium Review examines challenges to surviving birth and infancy at high altitudes. Chronic exposure to the environmental hypoxia of high altitudes increases the incidence of maternal vascular disorders of pregnancy characterized by placental insufficiency, restricted fetal growth and preterm delivery, and impairs pulmonary vascular health during infancy. While each condition independently contributes to excess morbidity and mortality in early life, evidence indicates vascular disorders of pregnancy and infantile pulmonary vascular dysfunction are intertwined. By integrating our recent scientific and clinical observations in Bolivia with existing literature, we propose potential avenues to reduce the infant mortality burden at high altitudes and reduce pulmonary vascular disease in highland neonates, and emphasize the need for further research to address unresolved questions., (© 2024 The Authors. The Journal of Physiology © 2024 The Physiological Society.)

During acute hypoxic exposure, cerebral blood flow (CBF) increases to compensate for the reduced arterial oxygen content (CaO 2 ). Nevertheless, as exposure extends, both CaO 2 and CBF progressively normalize. Haemoconcentration is the primary mechanism underlying the CaO 2 restoration and may therefore explain, at least in part, the CBF normalization. Accordingly, we tested the hypothesis that reversing the haemoconcentration associated with extended hypoxic exposure returns CBF towards the values observed in acute hypoxia. Twenty-three healthy lowlanders (12 females) completed two identical 4-day sojourns in a hypobaric chamber, one in normoxia (NX) and one in hypobaric hypoxia (HH, 3500 m). CBF was measured by ultrasound after 1, 6, 12, 48 and 96 h and compared between sojourns to assess the time course of changes in CBF. In addition, CBF was measured at the end of the HH sojourn after hypervolaemic haemodilution. Compared with NX, CBF was increased in HH after 1 h (P = 0.001) but similar at all later time points (all P > 0.199). Haemoglobin concentration was higher in HH than NX from 12 h to 96 h (all P < 0.001). While haemodilution reduced haemoglobin concentration from 14.8 ± 1.0 to 13.9 ± 1.2 g·dl -1 (P < 0.001), it did not increase CBF (974 ± 282 to 872 ± 200 ml·min -1 ; P = 0.135). We thus conclude that, at least at this moderate altitude, haemoconcentration is not the primary mechanism underlying CBF normalization with acclimatization. These data ostensibly reflect the fact that CBF regulation at high altitude is a complex process that integrates physiological variables beyond CaO 2 . KEY POINTS: Acute hypoxia causes an increase in cerebral blood flow (CBF). However, as exposure extends, CBF progressively normalizes. We investigated whether hypoxia-induced haemoconcentration contributes to the normalization of CBF during extended hypoxia. Following 4 days of hypobaric hypoxic exposure (corresponding to 3500 m altitude), we measured CBF before and after abolishing hypoxia-induced haemoconcentration by hypervolaemic haemodilution. Contrary to our hypothesis, the haemodilution did not increase CBF in hypoxia. Our findings do not support haemoconcentration as a stimulus for the CBF normalization during extended hypoxia., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The present investigation aimed to study the cardiovascular responses and the cerebral oxygenation (Cox) during exercise in acute hypoxia and with contemporary mental stress. Fifteen physically active, healthy males (age 29.0 ± 5.9 years) completed a cardiopulmonary test on a cycle ergometer to determine the workload at their gas exchange threshold (GET). On a separate day, participants performed two randomly assigned exercise tests pedaling for 6 min at a workload corresponding to 80% of the GET: (1) during normoxia (NORMO), and (2) during acute, normobaric hypoxia at 13.5% inspired oxygen (HYPO). During the last 3 min of the exercise, they also performed a mental task (MT). Hemodynamics were assessed with impedance cardiography, and peripheral arterial oxygen saturation and Cox were continuously measured by near-infrared spectroscopy. The main results were that both in NORMO and HYPO conditions, the MT caused a significant increase in the heart rate and ventricular filling rate. Moreover, MT significantly reduced (74.8 ± 5.5 vs. 62.0 ± 5.2 A.U.) Cox, while the reaction time (RT) increased (813.3 ± 110.2 vs. 868.2 ± 118.1 ms) during the HYPO test without affecting the correctness of the answers. We conclude that in young, healthy males, adding an MT during mild intensity exercise in both normoxia and acute moderate (normobaric) hypoxia induces a similar hemodynamic response. However, MT and exercise in HYPO cause a decrease in Cox and an impairment in RT., Competing Interests: The authors have no conflicts of interest that are directly relevant to the content of this manuscript.

We examined the extent to which apnoea-induced extremes of oxygen demand/carbon dioxide production impact redox regulation of cerebral bioenergetic function. Ten ultra-elite apnoeists (six men and four women) performed two maximal dry apnoeas preceded by normoxic normoventilation, resulting in severe end-apnoea hypoxaemic hypercapnia, and hyperoxic hyperventilation designed to ablate hypoxaemia, resulting in hyperoxaemic hypercapnia. Transcerebral exchange of ascorbate radicals (by electron paramagnetic resonance spectroscopy) and nitric oxide metabolites (by tri-iodide chemiluminescence) were calculated as the product of global cerebral blood flow (by duplex ultrasound) and radial arterial (a) to internal jugular venous (v) concentration gradients. Apnoea duration increased from 306 ± 62 s during hypoxaemic hypercapnia to 959 ± 201 s in hyperoxaemic hypercapnia (P ≤ 0.001). Apnoea generally increased global cerebral blood flow (all P ≤ 0.001) but was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose (P = 0.015-0.044). This was associated with a general net cerebral output (v > a) of ascorbate radicals that was greater in hypoxaemic hypercapnia (P = 0.046 vs. hyperoxaemic hypercapnia) and coincided with a selective suppression in plasma nitrite uptake (a > v) and global cerebral blood flow (P = 0.034 to <0.001 vs. hyperoxaemic hypercapnia), implying reduced consumption and delivery of nitric oxide consistent with elevated cerebral oxidative-nitrosative stress. In contrast, we failed to observe equidirectional gradients consistent with S-nitrosohaemoglobin consumption and plasma S-nitrosothiol delivery during apnoea (all P ≥ 0.05). Collectively, these findings highlight a key catalytic role for hypoxaemic hypercapnia in cerebral oxidative-nitrosative stress. KEY POINTS: Local sampling of blood across the cerebral circulation in ultra-elite apnoeists determined the extent to which severe end-apnoea hypoxaemic hypercapnia (prior normoxic normoventilation) and hyperoxaemic hypercapnia (prior hyperoxic hyperventilation) impact free radical-mediated nitric oxide bioavailability and global cerebral bioenergetic function. Apnoea generally increased the net cerebral output of free radicals and suppressed plasma nitrite consumption, thereby reducing delivery of nitric oxide consistent with elevated oxidative-nitrosative stress. The apnoea-induced elevation in global cerebral blood flow was insufficient to prevent a reduction in the cerebral metabolic rates of oxygen and glucose. Cerebral oxidative-nitrosative stress was greater during hypoxaemic hypercapnia compared with hyperoxaemic hypercapnia and coincided with a lower apnoea-induced elevation in global cerebral blood flow, highlighting a key catalytic role for hypoxaemia. This applied model of voluntary human asphyxia might have broader implications for the management and treatment of neurological diseases characterized by extremes of oxygen demand and carbon dioxide production., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The cerebral vasculature manages oxygen delivery by adjusting arterial blood in-flow in the face of reductions in oxygen availability. Hypoxic cerebral vasodilatation, and the associated hypoxic cerebral blood flow reactivity, involve many vascular, erythrocytic and cerebral tissue mechanisms that mediate elevations in cerebral blood flow via micro- and macrovascular dilatation. This contemporary review focuses on in vivo human work - with reference to seminal preclinical work where necessary - on hypoxic cerebrovascular reactivity, particularly where recent advancements have been made. We provide updates with the following information: in humans, hypoxic cerebral vasodilatation is partially mediated via a - likely non-obligatory - combination of: (1) nitric oxide synthases, (2) deoxygenation-coupled S-nitrosothiols, (3) potassium channel-related vascular smooth muscle hyperpolarization, and (4) prostaglandin mechanisms with some contribution from an interrelationship with reactive oxygen species. And finally, we discuss the fact that, due to the engagement of deoxyhaemoglobin-related mechanisms, reductions in O 2 content via haemoglobin per se seem to account for ∼50% of that seen with hypoxic cerebral vasodilatation during hypoxaemia. We further highlight the issue that methodological impediments challenge the complete elucidation of hypoxic cerebral reactivity mechanisms in vivo in healthy humans. Future research is needed to confirm recent advancements and to reconcile human and animal findings. Further investigations are also required to extend these findings to address questions of sex-, heredity-, age-, and disease-related differences. The final step is to then ultimately translate understanding of these mechanisms into actionable, targetable pathways for the prevention and treatment of cerebral vascular dysfunction and cerebral hypoxic brain injury., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Intermittent hypoxia (IH) is commonly associated with pathological conditions, particularly obstructive sleep apnoea. However, IH is also increasingly used to enhance health and performance and is emerging as a potent non-pharmacological intervention against numerous diseases. Whether IH is detrimental or beneficial for health is largely determined by the intensity, duration, number and frequency of the hypoxic exposures and by the specific responses they engender. Adaptive responses to hypoxia protect from future hypoxic or ischaemic insults, improve cellular resilience and functions, and boost mental and physical performance. The cellular and systemic mechanisms producing these benefits are highly complex, and the failure of different components can shift long-term adaptation to maladaptation and the development of pathologies. Rather than discussing in detail the well-characterized individual responses and adaptations to IH, we here aim to summarize and integrate hypoxia-activated mechanisms into a holistic picture of the body's adaptive responses to hypoxia and specifically IH, and demonstrate how these mechanisms might be mobilized for their health benefits while minimizing the risks of hypoxia exposure., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

In eukaryotic cells, aerobic energy is produced by mitochondria through oxygen uptake. However, little is known about the early mitochondrial responses to moderate hypobaric hypoxia (MHH) in highly metabolic active tissues. Here, we describe the mitochondrial responses to acute MHH in the heart and skeletal muscle. Rats were randomly allocated into a normoxia control group (n = 10) and a hypoxia group (n = 30), divided into three groups (0, 6, and 24 h post-MHH). The normoxia situation was recapitulated at the University of Granada, at 662 m above sea level. The MHH situation was performed at the High-Performance Altitude Training Centre of Sierra Nevada located in Granada at 2320 m above sea level. We found a significant increase in mitochondrial supercomplex assembly in the heart as soon as the animals reached 2320 m above sea level and their levels are maintained 24 h post-exposure, but not in skeletal muscle. Furthermore, in skeletal muscle, at 0 and 6 h, there was increased dynamin-related protein 1 (Drp1) expression and a significant reduction in Mitofusin 2. In conclusion, mitochondria from the muscle and heart respond differently to MHH: mitochondrial supercomplexes increase in the heart, whereas, in skeletal muscle, the mitochondrial pro-fission response is trigged. Considering that skeletal muscle was not actively involved in the ascent when the heart was beating faster to compensate for the hypobaric, hypoxic conditions, we speculate that the different responses to MHH are a result of the different energetic requirements of the tissues upon MHH. KEY POINTS: The heart and the skeletal muscle showed different mitochondrial responses to moderate hypobaric hypoxia. Moderate hypobaric hypoxia increases the assembly of the electron transport chain complexes into supercomplexes in the heart. Skeletal muscle shows an early mitochondrial pro-fission response following exposure to moderate hypobaric hypoxia., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Breathing mild bouts of low oxygen air (i.e. acute intermittent hypoxia, AIH) has been shown to improve locomotor function in humans after a spinal cord injury. How AIH-induced gains in motor performance are achieved remains unclear. We examined the hypothesis that AIH augments motor learning and motor retention during a locomotor adaptation task. We further hypothesized that gains in motor learning and retention will be associated with reductions in net metabolic power, consistent with the acquisition of energetically favourable mechanics. Thirty healthy individuals were randomly allocated into either a control group or an AIH group. We utilized a split-belt treadmill to characterize adaptations to an unexpected belt speed perturbation of equal magnitude during an initial exposure and a second exposure. Adaptation was characterized by changes in spatiotemporal step asymmetry, anterior-posterior force asymmetry, and net metabolic power. While both groups adapted by reducing spatial asymmetry, only the AIH group achieved significant reductions in double support time asymmetry and propulsive force asymmetry during both the initial and the second exposures to the belt speed perturbation. Net metabolic power was also significantly lower in the AIH group, with significant reductions from the initial perturbation exposure to the second. These results provide the first evidence that AIH mediates improvements in both motor learning and retention. Further, our results suggest that reductions in net metabolic power continue to be optimized upon subsequent learning and are driven by more energetically favourable temporal coordination strategies. Our observation that AIH facilitates motor learning and retention can be leveraged to design rehabilitation interventions that promote functional recovery. KEY POINTS: Brief exposures to low oxygen air, known as acute intermittent hypoxia (AIH), improves locomotor function in humans after a spinal cord injury, but it remains unclear how gains in motor performance are achieved. In this study, we tested the hypothesis that AIH induces enhancements in motor learning and retention by quantifying changes in interlimb coordination, anterior-posterior force symmetry and metabolic cost during a locomotor adaptation task. We show the first evidence that AIH improves both motor learning and savings of newly learned temporal interlimb coordination strategies and force asymmetry compared to untreated individuals. We further demonstrate that AIH elicits greater reductions in metabolic cost during motor learning that continues to be optimized upon subsequent learning. Our findings suggest that AIH-induced gains in locomotor performance are facilitated by enhancements in motor learning and retention of more energetically favourable coordination strategies., (© 2023 The Authors. The Journal of Physiology © 2023 The Physiological Society.)

The unique property of the pulmonary circulation to constrict in response to hypoxia, rather than dilate, brings advantages in both health and disease. Hypoxic pulmonary vasoconstriction (HPV) acts to optimise ventilation-perfusion matching - this is important clinically both in focal disease (such as pneumonia) and in one-lung ventilation during anaesthesia for thoracic surgery. However, during global hypoxia such as that encountered at high altitude, generalised pulmonary vasoconstriction can lead to pulmonary hypertension. There is now a growing body of evidence that links the hypoxia-inducible factor (HIF) pathway and pulmonary vascular tone - in both acute and chronic settings. Genetic and pharmacological alterations to all key components of this pathway (VHL - von Hippel-Lindau ubiquitin E3 ligase; PHD2 - prolyl hydroxylase domain protein 2; HIF1 and HIF2) have clear effects on the pulmonary circulation, particularly in hypoxia. Furthermore, knowledge of the molecular biology of the prolyl hydroxylase enzymes has led to an extensive and ongoing body of research into the importance of iron in both HPV and pulmonary hypertension. This review will explore these relationships in more detail and discuss future avenues of research., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

In recent years, major advances have been made in the understanding of the cellular and molecular mechanisms driving pulmonary vascular remodelling in various forms of pulmonary hypertension, including pulmonary arterial hypertension, pulmonary hypertension associated with left heart disease, pulmonary hypertension associated with chronic lung disease and hypoxia, and chronic thromboembolic pulmonary hypertension. However, the survival rates for these different forms of pulmonary hypertension remain unsatisfactory, underscoring the crucial need to more effectively translate innovative scientific knowledge into healthcare interventions. In these proceedings of the 7th World Symposium on Pulmonary Hypertension, we delve into recent developments in the field of pathology and pathophysiology, prioritising them while questioning their relevance to different subsets of pulmonary hypertension. In addition, we explore how the latest omics and other technological advances can help us better and more rapidly understand the myriad basic mechanisms contributing to the initiation and progression of pulmonary vascular remodelling. Finally, we discuss strategies aimed at improving patient care, optimising drug development, and providing essential support to advance research in this field., Competing Interests: Conflict of interest: C. Guignabert reports grants from Acceleron Pharma, MSD, Corteria Pharmaceuticals, Structure Therapeutics (ex-ShouTi) and Gossamer Bio, payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD, and patents planned, issued or pending (WO/2024/023139, WO/2018/011376). J. Aman has no potential conflicts of interest to disclose. S. Bonnet reports grants from Morphic Therapeutic, Sunshine Bio and Janssen, consultancy fees from Morphic Therapeutic and Chiesi, and participation on a data safety monitoring board or advisory board with Morphic Therapeutic and Allienaire. P. Dorfmüller reports payment or honoraria for lectures, presentations, manuscript writing or educational events from AstraZeneca. A.J. Olschewski reports grants from Austrian Science Fund (FWF) (10.55776/I6299 and 10.55776/KLI1153), payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD, patents pending (PCT/EP2017/055440), and stock (or stock options) with Bayer. S. Pullamsetti reports grants and consultancy fees from Gossamer Bio. M. Rabinovitch reports consultancy fees from Pfizer, Amgen, Merck and Tiakis, payment or honoraria for lectures, presentations, manuscript writing or educational events from NIH, patents planned, issued or pending (FK506: tacrolimus in pulmonary hypertension), participation on a data safety monitoring board or advisory board with Amgen and NIH, is associate editor for JACC BTS, receipt of equipment, materials, drugs, medical writing, gifts or other services from Tiakis (tiprelestat). R.T. Schermuly reports grants from Chiesi and Attgeno, and consultancy fees from Gossamer, Attgeno and Chiesi. M. Humbert reports grants from Gossamer and Merck, consultancy fees from 35 Pharma, Aerovate, AOP Orphan, Chiesi, Ferrer, Gossamer, Janssen, Keros, Liquidia, Merck, Novartis, Respira, Roivant and United Therapeutics, payment or honoraria for lectures, presentations, manuscript writing or educational events from Janssen and Merck, and participation on a data safety monitoring board or advisory board with 35 Pharma, Aerovate, Janssen, Keros, Merck, Novartis and United Therapeutics. K.R. Stenmark reports grants from NIH/NHLBI and DoD, and a leadership role with PVRI., (Copyright ©The authors 2024.)

The relationship between the variations in ovarian hormones (i.e., estrogens and progesterone) and the hypoxic ventilatory response (HVR) remains unclear. HVR is a key adaptive mechanism to high altitude and has been proposed as a predictor for acute mountain sickness (AMS). This study aimed to explore the effects of hormonal changes across the menstrual cycle on HVR. Additionally, it assessed the predictive capacity of HVR for AMS and examined whether a particular menstrual phase could enhance its predictive accuracy. Thirteen eumenorrheic women performed a pure nitrogen breathing test near sea level, measuring HVR and cerebral oxygenation in early follicular, late follicular, and mid-luteal phases. Oxidative stress and ovarian hormone levels were also measured. AMS symptoms were evaluated after spending 14 h, including one overnight, at an altitude of 3,375 m. No differences in HVR, ventilation, peripheral oxygen saturation, or cerebral oxygenation were observed between the three menstrual cycle phases. Moreover, these parameters and the oxidative stress markers did not differ between the women with or without AMS (31% vs 69%), regardless of the menstrual cycle phase. In conclusion, ventilatory responses and cerebral oxygenation in normobaric hypoxia were consistent across the menstrual cycle. Furthermore, these parameters did not differentiate women with or without AMS., (© 2024. The Author(s).)

Obstructive sleep apnea (OSA) affects quality of life and health in nearly 1 billion patients all over the world. With aging society, OSA increases the risk of Alzheimer's disease and leads to severe cognitive impairment. Chronic intermittent hypoxia (CIH), the core pathological mechanism of OSA, may induce synaptic plasticity damage and cognitive impairment, and decrease learning and memory and attention ability. However, the molecular mechanism underlying OSA is still not fully understood. And, there is no targeted treatment strategy for cognitive impairment in patients with OSA. Firstly, the correlation between OSA and cognitive dysfunction was summarized in this review. Secondly, the molecular mechanism of CIH-induced cognitive impairment was elucidated from the perspectives of synaptic plasticity damage, oxidative stress, inflammation, endoplasmic reticulum stress, apoptosis, mitochondrial dysfunction and autophagy. Finally, the current treatment strategy for cognitive impairment in patients with OSA was summarized.

Background: Beneficial effects of breathing at [Formula: see text] < 0.21 on disease outcomes have been reported in previous preclinical and clinical studies. However, the safety and intra-hospital feasibility of breathing hypoxic gas for 5 d have not been established. In this study, we examined the physiologic effects of breathing a gas mixture with [Formula: see text] as low as 0.11 in 5 healthy volunteers., Methods: All 5 subjects completed the study, spending 5 consecutive days in a hypoxic tent, where the ambient oxygen level was lowered in a stepwise manner over 5 d, from [Formula: see text] of 0.16 on the first day to [Formula: see text] of 0.11 on the fifth day of the study. All the subjects returned to an environment at room air on the sixth day. The subjects' [Formula: see text], heart rate, and breathing frequency were continuously recorded, along with daily blood sampling, neurologic evaluations, transthoracic echocardiography, and mental status assessments., Results: Breathing hypoxia concentration dependently caused profound physiologic changes, including decreased [Formula: see text] and increased heart rate. At [Formula: see text] of 0.14, the mean [Formula: see text] was 92%; at [Formula: see text] of 0.13, the mean [Formula: see text] was 93%; at [Formula: see text] of 0.12, the mean [Formula: see text] was 88%; at [Formula: see text] of 0.11, the mean [Formula: see text] was 85%; and, finally, at an [Formula: see text] of 0.21, the mean [Formula: see text] was 98%. These changes were accompanied by increased erythropoietin levels and reticulocyte counts in blood. All 5 subjects concluded the study with no adverse events. No subjects exhibited signs of mental status changes or pulmonary hypertension., Conclusions: Results of the current physiologic study suggests that, within a hospital setting, delivering [Formula: see text] as low as 0.11 is feasible and safe in healthy subjects, and provides the foundation for future studies in which therapeutic effects of hypoxia breathing are tested., Competing Interests: Dr Mootha is listed as an inventor on patent applications filed by Massachusetts General Hospital on the therapeutic uses of hypoxia. Dr Berra is listed as the inventor on patent applications filed by Massachusetts General Hospital on the therapeutic uses of inhaled nitric oxide., (Copyright © 2024 by Daedalus Enterprises.)

We describe a protocol to examine neurophysiological (electroencephalography, EEG), cerebrovascular (ultrasound assessments of middle cerebral artery blood velocity, MCAv) and cardiorespiratory (blood pressure, oxygen saturation, end-tidal gases, respiratory rate) responses inside a hypobaric chamber. This procedure aims to standardize the methodology in experiments conducted within a hypobaric chamber such as comparing normobaric and hypobaric hypoxia. This is important because current understanding of relationships between neurophysiological activity, and cerebrovascular and cardiorespiratory responses under varying environmental conditions remains limited. This procedure combines simultaneous neurophysiological, cardiorespiratory and cerebrovascular evaluations, allowing a comprehensive understanding of electro-neurophysiological activity. Our protocol requires an hour and a half of equipment setup, 1-1.5 hours of participant set-up, and 30 minutes of experimental data collection. Since multiple simultaneous physiological recordings, including EEG in this environment, can be fraught with pitfalls, we also provide practical considerations for experimental design and recording setup. Advanced knowledge of hypobaric chamber operation is required, alongside expertise in EEG and transcranial Doppler ultrasonography. Following our procedure one will acquire simultaneous recordings of neurophysiological, cerebrovascular and cardiorespiratory data., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hutcheon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Oxygen deprivation during embryonic development can permanently remodel the vertebrate heart, often causing cardiovascular abnormalities in adulthood. While this phenomenon is mostly damaging, recent evidence suggests developmental hypoxia produces stress-tolerant phenotypes in some ectothermic vertebrates. Embryonic common snapping turtles (Chelydra serpentina) subjected to chronic hypoxia display improved cardiac anoxia tolerance after hatching, which is associated with altered Ca2+ homeostasis in heart cells (cardiomyocytes). Here, we examined the possibility that changes in Ca2+ cycling, through the sarcoplasmic reticulum (SR), underlie the developmentally programmed cardiac phenotype of snapping turtles. We investigated this hypothesis by isolating cardiomyocytes from juvenile turtles that developed in either normoxia (21% O2; 'N21') or chronic hypoxia (10% O2; 'H10') and subjected the cells to anoxia/reoxygenation, in either the presence or absence of SR Ca2+-cycling inhibitors. We simultaneously measured cellular shortening, intracellular Ca2+ concentration ([Ca2+]i), and intracellular pH (pHi). Under normoxic conditions, N21 and H10 cardiomyocytes shortened equally, but H10 Ca2+ transients (Δ[Ca2+]i) were twofold smaller than those of N21 cells, and SR inhibition only decreased N21 shortening and Δ[Ca2+]i. Anoxia subsequently depressed shortening, Δ[Ca2+]i and pHi in control N21 and H10 cardiomyocytes, yet H10 shortening and Δ[Ca2+]i recovered to pre-anoxic levels, partly due to enhanced myofilament Ca2+ sensitivity. SR blockade abolished the recovery of anoxic H10 cardiomyocytes and potentiated decreases in shortening, Δ[Ca2+]i and pHi. Our novel results provide the first evidence of developmental programming of SR function and demonstrate that developmental hypoxia confers a long-lasting, superior anoxia-tolerant cardiac phenotype in snapping turtles, by modifying SR function and enhancing myofilament Ca2+ sensitivity., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Animals at early life stages are generally more sensitive to environmental stress than adults. This is especially true of oviparous vertebrates that develop in variable environments with little or no parental care. These organisms regularly experience environmental fluctuations as part of their natural development, but climate change is increasing the frequency and intensity of these events. The developmental plasticity of oviparous vertebrates will therefore play a critical role in determining their future fitness and survival. In this Review, we discuss and compare the phenotypic consequences of chronic developmental hypoxia on the cardiovascular system of oviparous vertebrates. In particular, we focus on species-specific responses, critical windows, thresholds for responses and the interactive effects of other stressors, such as temperature and hypercapnia. Although important progress has been made, our Review identifies knowledge gaps that need to be addressed if we are to fully understand the impact of climate change on the developmental plasticity of the oviparous vertebrate cardiovascular system., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Traditional heart failure research often uses daytime population parameter estimates to assess hypoxia and arrhythmias. This approach might not accurately represent heart failure patients as nighttime cardiac behaviors offer crucial insights into their health, especially regarding oxygen levels and heart rhythms. We conducted a prospective study on nocturnal oxygen saturation and heart rate in home-dwelling heart failure patients over 6 nights. Patients were recruited from the Walter Reed National Military Medical Center heart failure clinic. Criteria included a clinical diagnosis of heart failure, a New York Heart Association (NYHA) classification of I to III, ages between 21 to 90, cognitive intactness, capability to use the wearable device, and willingness to use the device for 6 consecutive nights. Average oxygen saturation was 92% with individual readings ranging from 40% to 100%. The mean heart rate was 72 beats per minute (bpm), but individual rates ranged from 18 bpm to a high of 296 bpm. A significant drop in oxygen levels and sleep arrhythmias were consistently observed among participants. Heart failure patients demonstrate notable and variable desaturations and arrhythmias across multiple nights. A single-night sleep study or a 24-hour heart rate monitor may not comprehensively depict patients' oxygenation and heart rate irregularities. Our research highlights wearable devices' potency in medical research for capturing essential nocturnal data. In only 6 nights, we gleaned invaluable clinical insights for optimizing patient care. This study is pioneering, being the first to intensively examine nighttime oxygen levels and heart rates in home-based heart failure patients., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

A fundamental question in evolutionary biology concerns the relative contributions of phenotypic plasticity vs. local adaptation (genotypic specialization) in enabling wide-ranging species to inhabit diverse environmental conditions. Here, we conduct a long-term hypoxia acclimation experiment to assess the relative roles of local adaptation and plasticity in enabling highland and lowland deer mice ( Peromyscus maniculatus ) to sustain aerobic thermogenesis at progressively increasing elevations. We assessed the relative physiological performance capacities of highland and lowland natives as they were exposed to progressive, stepwise increases in hypoxia, simulating the gradual ascent from sea level to an elevation of 6,000 m. The final elevation of 6,000 m far exceeds the highest attainable elevations within the species' range, and therefore tests the animals' ability to tolerate levels of hypoxia that surpass the prevailing conditions within their current distributional limits. Our results demonstrate that highland natives exhibit superior thermogenic capacities at the most severe levels of hypoxia, suggesting that the species' broad fundamental niche and its ability to inhabit such a broad range of elevational zones is attributable to genetically based local adaptation, including evolved changes in plasticity. Transcriptomic and physiological measurements identify evolved changes in the acclimation response to hypoxia that contribute to the enhanced thermogenic capacity of highland natives., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Hypoxia and hyperoxia can affect the acute psycho-physiological response to exercise. Recording various perceptual responses to exercise is of particular importance for investigating behavioral changes to physical activity, given that the perception of exercise-induced pain, discomfort or unpleasure, and a low level of exercise enjoyment are commonly associated with a low adherence to physical activity. Therefore, this study aimed to compare the acute perceptual and physiological responses to aerobic exercise under intermittent hypoxia-hyperoxia (IHHT), hypoxia-normoxia (IHT), and sustained normoxia (NOR) in young, recreational active, healthy males., Methods: Using a randomized, single-blinded, crossover design, 15 males (age: 24.5 ± 4.2 yrs) performed 40 min of submaximal constant-load cycling (at 60% peak oxygen uptake, 80 rpm) under IHHT (5 × 4 min hypoxia and hyperoxia), IHT (5 × 4 min hypoxia and normoxia), and NOR. Inspiratory fraction of oxygen during hypoxia and hyperoxia was set to 14% and 30%, respectively. Heart rate (HR), total hemoglobin (tHb) and muscle oxygen saturation (S m O 2 ) of the right vastus lateralis muscle were continuously recorded during cycling. Participants' peripheral oxygen saturation (S p O 2 ) and perceptual responses ( i.e ., perceived motor fatigue, effort perception, perceived physical strain, affective valence, arousal, motivation to exercise, and conflict to continue exercise) were surveyed prior, during (every 4 min), and after cycling. Prior to and after exercise, peripheral blood lactate concentration (BLC) was determined. Exercise enjoyment was ascertained after cycling. For statistical analysis, repeated measures analyses of variance were conducted., Results: No differences in the acute perceptual responses were found between conditions ( p ≥ 0.059, η p 2 ≤ 0.18), while the physiological responses differed. Accordingly, S p O 2 was higher during the hyperoxic periods during the IHHT compared to the normoxic periods during the IHT ( p < 0.001, η p 2 = 0.91). Moreover, HR ( p = 0.005, η p 2 = 0.33) and BLC ( p = 0.033, η p 2 = 0.28) were higher during IHT compared to NOR. No differences between conditions were found for changes in tHb ( p = 0.684, η p 2 = 0.03) and S m O 2 ( p = 0.093, η p 2 = 0.16)., Conclusion: IHT was associated with a higher physiological response and metabolic stress, while IHHT did not lead to an increase in HR and BLC compared to NOR. In addition, compared to IHT, IHHT seems to improve reoxygenation indicated by a higher S p O 2 during the hyperoxic periods. However, there were no differences in perceptual responses and ratings of exercise enjoyment between conditions. These results suggest that replacing normoxic by hyperoxic reoxygenation-periods during submaximal constant-load cycling under intermittent hypoxia reduced the exercise-related physiological stress but had no effect on perceptual responses and perceived exercise enjoyment in young recreational active healthy males., Competing Interests: The authors declare that they have no competing interests., (© 2024 Behrendt et al.)

Background: Cognitive impairment is prevalent across neuropsychiatric disorders but there is a lack of treatment strategies with robust, enduring effects. Emerging evidence indicates that altitude-like hypoxia cognition training may induce long-lasting neuroplasticity and improve cognition. We will investigate whether repeated cognition training under normobaric hypoxia can improve cognitive functions in healthy individuals and patients with affective disorders and the neurobiological underpinnings of such effects., Methods: In sub-study 1, 120 healthy participants are randomized to one of four treatment arms in a double-blind manner, allowing for examination of separate and combined effects of three-week repeated moderate hypoxia and cognitive training, respectively. In sub-study 2, 60 remitted patients with major depressive disorder or bipolar disorder are randomized to hypoxia with cognition training or treatment as usual. Assessments of cognition, psychosocial functioning, and quality of life are performed at baseline, end-of-treatment, and at 1-month follow-up. Functional magnetic resonance imaging (fMRI) scans are conducted at baseline and 1-month follow-up, and [ 11 C]UCB-J positron emission tomography (PET) scans are performed at end-of-treatment to quantify the synaptic vesicle glycoprotein 2A (SV2A). The primary outcome is a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference with minimum n = 26 per treatment arm. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data is analyzed with the FMRIB Software Library, while PET data is quantified using the simplified reference tissue model (SRTM) with centrum semiovale as reference region., Discussion: The results will provide novel insights into whether repeated hypoxia cognition training increases cognition and brain plasticity, which can aid future treatment development strategies., Trial Registration: ClinicalTrials.gov, NCT06121206 . Registered on 31 October 2023., (© 2024. The Author(s).)

Physical training in heat or hypoxia can improve physical performance. The purpose of this parallel group study was to investigate the concurrent effect of training performed simultaneously in heat (31 °C) and hypoxia (FIO 2  = 14.4%) on anaerobic capacity in young men. For the study, 80 non-trained men were recruited and divided into 5 groups (16 participants per group): control, non-training (CTRL); training in normoxia and thermoneutral conditions (NT: 21 °C, FIO 2  = 20.95%); training in normoxia and heat (H: 31 °C, FIO 2  = 20.95%); training in hypoxia and thermoneutral conditions (IHT: 21 °C, FIO 2  = 14.4%), and training in hypoxia and heat (IHT + H: 31 °C, FIO 2  = 14.4%). Before and after physical training, the participants performed the Wingate Test, in which peak power and mean power were measured. Physical training lasted 4 weeks and the participants exercised 3 times a week for 60 min, performing interval training. Only the IHT and IHT + H groups showed significant increases in absolute peak power (p < 0.001, ES = 0.36 and p = 0.02, ES = 0.26, respectively). There were no significant changes (p = 0.18) after training in mean power. Hypoxia appeared to be an environmental factor that significantly improved peak power, but not mean power. Heat, added to hypoxia, did not increase cycling anaerobic power. Also, training only in heat did not significantly affect anaerobic power. The inclusion of heat and/or hypoxia in training did not induce negative effects, i.e., a reduction in peak and mean power as measured in the Wingate Test., (© 2024. The Author(s).)

The existence of sex-specific differences in phenotypic traits is widely recognized. Yet they are often ignored in studies looking at the impact of global changes on marine organisms, particularly within the context of combined drivers that are known to elicit complex interactions. We tested sex-specific physiological responses of the cosmopolitan and ecologically important marine copepod Acartia tonsa exposed to combined hypoxia and marine heatwave (MHW) conditions, both of which individually strongly affect marine ectotherms. Females and males were acutely exposed for 5 days to a combination of either control (18°C) or a high temperature mimicking a MHW (25°C), and normoxia (100% O 2 sat.) or mild hypoxia (35% O 2 sat.). Life-history traits, as well as sex-specific survival and physiological traits, were measured. Females had overall higher thermal tolerance levels and responded differently than males when exposed to the combined global change drivers investigated. Females also showed lower metabolic thermal sensitivity when compared to males. Additionally, the MHW exerted a dominant effect on the traits investigated, causing a lower survival and higher metabolic rate at 25°C. However, egg production rates appeared unaffected by hypoxia and MHW conditions. Our results showed that MHWs could strongly affect copepods' survival, that combined exposure to hypoxia and MHW exerted an interactive effect only on CT max , and that sex-specific vulnerability to these global change drivers could have major implications for population dynamics. Our results highlight the importance of considering the differences in the responses of females and males to rapid environmental changes to improve the implementation of climate-smart conservation approaches., (© 2024 The Author(s). Global Change Biology published by John Wiley & Sons Ltd.)

Introduction: Hypoxia training is mandatory for military pilots, but variability in hypoxia symptoms challenges the training. In a previous study we showed that 64% of pilots recognized hypoxia faster in their second normobaric hypoxia session conducted 2.4 yr after the first. Our aim here was to evaluate whether a third session conducted 5.0 yr after the first would provide further benefit., Methods: This study was conducted under normobaric conditions in a tactical F/A-18C Hornet simulator in three sessions in which the pilots performed visual identification missions and breathed 21% oxygen in nitrogen. The breathing gas was changed to a hypoxic mixture containing either 8%, 7%, or 6% oxygen in nitrogen without the pilot's knowledge. Data were collected from 102 military pilots. The primary outcome was the time taken for initial identification of hypoxia symptoms., Results: Hypoxia symptoms were recognized on average in the first session in 8% oxygen in 100 s, 7% oxygen in 90 s, and 6% oxygen in 78 s; in the second in 87 s, 80 s, and 71 s, respectively; and in the third in 79 s, 67 s, and 64 s, respectively. In 2 sessions 20 pilots and in each 3 training sessions 3 pilots had slow recognition times., Discussion: Hypoxia symptom recognition improved the further the repeated normobaric hypoxia training went. More emphasis should be put on the 23% group of slow hypoxia symptom recognizers and more customized hypoxia training for them should be offered. Leinonen AM, Varis NO, Kokki HJ, Leino TK. Normobaric hypoxia symptom recognition in three training sessions. Aerosp Med Hum Perform. 2024; 95(10):758-764.

The Sugen 5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) demonstrates most of the distinguishing features of PAH in humans, including increased wall thickness and obstruction of the small pulmonary arteries along with plexiform lesion formation. Recently, significant advancement has been made describing the epidemiology, genomics, biochemistry, physiology, and pharmacology in Su/Hx challenge in rats. For example, there are differences in the overall reactivity to Su/Hx challenge in different rat strains and only female rats respond to estrogen treatments. These conditions are also encountered in human subjects with PAH. Also, there is a good translation in both the biochemical and metabolic pathways in the pulmonary vasculature and right heart between Su/Hx rats and humans, particularly during the transition from the adaptive to the nonadaptive phase of right heart failure. Noninvasive techniques such as echocardiography and magnetic resonance imaging have recently been used to evaluate the progression of the pulmonary vascular and cardiac hemodynamics, which are important parameters to monitor the efficacy of drug treatment over time. From a pharmacological perspective, most of the compounds approved clinically for the treatment of PAH are efficacious in Su/Hx rats. Several compounds that show efficacy in Su/Hx rats have advanced into phase II/phase III studies in humans with positive results. Results from these drug trials, if successful, will provide additional treatment options for patients with PAH and will also further validate the excellent translation that currently exists between Su/Hx rats and the human PAH condition.

Background: Sympathetic hyperactivity plays an important role in the initiation and maintenance of pulmonary hypertension. Carotid baroreceptor stimulation (CBS) is an effective autonomic neuromodulation therapy. We aim to investigate the effects of CBS on hypoxia-induced pulmonary hypertension and its underlying mechanisms., Methods and Results: Rats were randomly assigned into 4 groups, including a Control-sham group (n=7), a Control-CBS group (n=7), a Hypoxia-sham group (n=10) and a Hypoxia-CBS group (n=10). Echocardiography, ECG, and hemodynamics examination were performed. Samples of blood, lung tissue, pulmonary arteries, and right ventricle were collected for the further analysis. In the in vivo study, CBS reduced wall thickness and muscularization degree in pulmonary arterioles, thereby improving pulmonary hemodynamics. Right ventricle hypertrophy, fibrosis and dysfunction were all improved. CBS rebalanced autonomic tone and reduced the density of sympathetic nerves around pulmonary artery trunks and bifurcations. RNA-seq analysis identified BDNF and periostin ( POSTN ) as key genes involved in hypoxia-induced pulmonary hypertension, and CBS downregulated the mRNA expression of BDNF and POSTN in rat pulmonary arteries. In the in vitro study, norepinephrine was found to promote pulmonary artery smooth muscle cell proliferation while upregulating BDNF and POSTN expression. The proliferative effect was alleviated by silence BDNF or POSTN ., Conclusions: Our results showed that CBS could rebalance autonomic tone, inhibit pulmonary arterial remodeling, and improve pulmonary hemodynamics and right ventricle function, thus delaying hypoxia-induced pulmonary hypertension progression. There may be a reciprocal interaction between POSTN and BDNF that is responsible for the underlying mechanism.

Hypoxia can trigger a sequence of breathing-related behaviors, from augmentation to apneusis to apnea and gasping. Gasping is an autoresuscitative behavior that, via large tidal volumes and altered intrathoracic pressure, can enhance coronary perfusion, carotid blood flow, and sympathetic activity, and thereby coordinate cardiac and respiratory functions. We tested the hypotheses that hypoxia-evoked gasps are amplified through a disinhibitory microcircuit within the inspiratory neuron chain and that this drive is distributed via an efference copy mechanism. This generates coordinated gasplike discharges concurrently in other circuits of the raphe-pontomedullary respiratory network. Data were obtained from six decerebrate, vagotomized, neuromuscularly blocked, and artificially ventilated adult cats. Arterial blood pressure, phrenic nerve activity, end-tidal CO 2 , and other parameters were monitored. Hypoxia was produced by ventilation with a gas mixture of 5% O 2 in nitrogen. Neuron spike trains were recorded at multiple pontomedullary sites simultaneously and evaluated for firing rate modulations and short-timescale correlations indicative of functional connectivity. Experimental perturbations evoked reconfiguration of raphe-pontomedullary circuits during initial augmentation, apneusis and augmented bursts, apnea, and gasping. Functional connectivity, altered firing rates, efference copy of gasp drive, and coordinated incremental blood pressure increases support a distributed brain stem network model for amplification and broadcasting of inspiratory drive during autoresuscitative gasping. Gasping begins with a reduction in inhibition by expiratory neurons and an initial loss of inspiratory drive during hypoxic apnea and culminates in autoresuscitative efforts. NEW & NOTEWORTHY Severe hypoxia evokes a sequence of breathing-related behaviors culminating in gasping. We report firing rate modulations and short-timescale correlations in spike trains recorded simultaneously in the raphe-pontomedullary respiratory network during hypoxia. Our findings support a disinhibitory microcircuit and a distributed efference copy mechanism for amplification of gasping. Coordinated increments in blood pressure lead to a model for autoresuscitative bootstrapping of peripheral chemoreceptor reflexes, breathing, and sympathetic activity, complementing and extending prior work.

There is evidence that astrocytes modulate synaptic transmission in the nucleus tractus solitarius (NTS) interacting with glutamatergic and purinergic mechanisms. Here, using in situ working heart-brainstem preparations, we evaluated the involvement of astrocyte and glutamatergic/purinergic neurotransmission in the processing of autonomic and respiratory pathways in the NTS of control and rats exposed to sustained hypoxia (SH). Baseline autonomic and respiratory activities and the responses to chemoreflex activation (KCN) were evaluated before and after microinjections of fluorocitrate (FCt, an astrocyte metabolic inhibitor), kynurenic acid, and pyridoxalphosphate-6-azophenyl-2',4'-disulfonate (PPADS) (nonselective antagonists of glutamatergic and purinergic receptors) into the rostral aspect of the caudal commissural NTS. FCt had no effects on the baseline parameters evaluated but reduced the bradycardic response to chemoreflex activation in SH rats. FCt combined with kynurenic acid and PPADS in control rats reduced the baseline duration of expiration, which was attenuated after SH. FCt produced a large increase in PN frequency discharge in control rats, which was reduced after SH, indicating a reduction in the astrocyte modulation after SH. The data show that 1 ) the bradycardic component of the peripheral chemoreflex is reduced in SH rats after astrocytes inhibition, 2 ) the inhibition of astrocytes in the presence of double antagonists in the NTS affects the modulation of baseline duration of expiration in control but not in SH rats, and 3 ) the autonomic and respiratory responses to chemoreflex activation are mediated by glutamatergic and purinergic receptors in the rostral aspect of the caudal commissural NTS. NEW & NOTEWORTHY Our findings indicate that the neurotransmission of autonomic and respiratory components of the peripheral chemoreflex in the nucleus tractus solitarius (NTS) is mediated by glutamatergic and purinergic mechanisms and reveal a selective involvement of NTS astrocytes in controlling the chemoreflex parasympathetic response in rats exposed to sustained hypoxia (SH) and the baseline duration of expiration mainly in control rats, indicating a selective role for astrocytes modulation in the NTS of control and SH rats.

Birds are highly dependent on their vision for orientation and navigation. The avian eye differs from the mammalian eye as the retina is avascular, leaving the inner, highly metabolically active layers with a very long diffusion distance to the oxygen supply. During flight at high altitudes, birds face a decrease in environmental oxygen partial pressure, which leads to a decrease in arterial oxygen levels. Since oxygen perfusion to the retina is already limited in birds, we hypothesize that visual function is impaired by low oxygen availability. However, the visual performance of birds exposed to hypoxia has not been evaluated before. Here, we assess the optomotor response (OMR) in zebra finches under simulated high-altitude hypoxia (10%) and show that the OMR is largely maintained under hypoxia with only a modest reduction in OMR, demonstrating that birds can largely maintain visual function at high altitudes. The method of our study does not provide insight into the mechanisms involved, but our findings suggest that birds have evolved physiological mechanisms for retinal function at low tissue oxygen levels., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Chemosensitivity is an essential part of the pathophysiological mechanisms of obstructive sleep apnea (OSA). This study aims to use the rebreathing method to assess hypercapnic ventilatory response (HCVR) and analyze the association between chemosensitivity and certain symptoms in patients with OSA., Methods: A total of 104 male patients with diagnosed OSA were enrolled. The HCVR was assessed using rebreathing methods under hypoxia exposure to reflect the overall chemosensitivity. Univariate and multivariate linear regression were used to explore the association with chemosensitivity. Participants were enrolled in the cluster analysis using certain symptoms, basic characteristics, and polysomnographic indices., Results: At similar baseline values, the high chemosensitivity group (n = 39) demonstrated more severe levels of OSA and nocturnal hypoxia than the low chemosensitivity group (n = 65). After screening the possible associated factors, nocturnal urination, rather than OSA severity, was found to be positively associated with the level of chemosensitivity. Cluster analysis revealed three distinct groups: Cluster 1 (n = 32, 34.0%) held younger, obese individuals with nocturnal urination, elevated chemosensitivity level, and very severe OSA; Cluster 2 (41, 43.6%) included middle-aged overweighted patients with nocturnal urination, increased chemosensitivity level, but moderate-severe OSA; and Cluster 3 (n = 21, 22.3%) contained middle-aged overweighted patients without nocturnal urination, with a lowered chemosensitivity level and only moderate OSA., Conclusion: The presence of nocturnal urination in male patients with OSA may be a sign of higher levels of ventilatory chemosensitivity, requiring early therapy efforts independent of AHI levels., (© 2024. The Author(s).)