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Sex differences in physiological responses to various stressors, including exercise, have been well documented. However, the specific impact of these differences on exposure to hypoxia, both at rest and during exercise, has remained underexplored. Many studies on the physiological responses to hypoxia have either excluded women or included only a limited number without analyzing sex-related differences. To address this gap, this comprehensive review conducted an extensive literature search to examine changes in physiological functions related to oxygen transport and consumption in hypoxic conditions. The review encompasses various aspects, including ventilatory responses, cardiovascular adjustments, hematological alterations, muscle metabolism shifts, and autonomic function modifications. Furthermore, it delves into the influence of sex hormones, which evolve throughout life, encompassing considerations related to the menstrual cycle and menopause. Among these physiological functions, the ventilatory response to exercise emerges as one of the most sex-sensitive factors that may modify reactions to hypoxia. While no significant sex-based differences were observed in cardiac hemodynamic changes during hypoxia, there is evidence of greater vascular reactivity in women, particularly at rest or when combined with exercise. Consequently, a diffusive mechanism appears to be implicated in sex-related variations in responses to hypoxia. Despite well-established sex disparities in hematological parameters, both acute and chronic hematological responses to hypoxia do not seem to differ significantly between sexes. However, it is important to note that these responses are sensitive to fluctuations in sex hormones, and further investigation is needed to elucidate the impact of the menstrual cycle and menopause on physiological responses to hypoxia.

Administering sodium bicarbonate (NaHCO3) to patients with respiratory acidosis breathing spontaneously is contraindicated because it increases carbon dioxide load and depresses pulmonary ventilation. Nonetheless, several studies have reported salutary effects of NaHCO3 in patients with respiratory acidosis but the underlying mechanism remains uncertain. Considering that such reports have been ignored, we examined the ventilatory response of unanesthetized dogs with respiratory acidosis to hypertonic NaHCO3 infusion (1 N, 5 mmol/kg) and compared it with that of animals with normal acid-base status or one of the remaining acid-base disorders. Ventilatory response to NaHCO3 infusion was evaluated by examining the ensuing change in PaCO2 and the linear regression of the PaCO2 vs. pH relationship. Strikingly, PaCO2 failed to increase and the ΔPaCO2 vs. ΔpH slope was negative in respiratory acidosis, whereas PaCO2 increased consistently and the ΔPaCO2 vs. ΔpH slope was positive in the remaining study groups. These results cannot be explained by differences in buffering-induced decomposition of infused bicarbonate or baseline levels of blood pH, PaCO2, and pulmonary ventilation. We propose that NaHCO3 infusion improved the ventilatory efficiency of animals with respiratory acidosis, i.e., it decreased their ratio of total pulmonary ventilation to carbon dioxide excretion (VE/VCO2). Such exclusive effect of NaHCO3 infusion in animals with respiratory acidosis might emanate from baseline increased VD/VT (dead space/tidal volume) caused by bronchoconstriction and likely reduced pulmonary blood flow, defects that are reversed by alkali infusion. Our observations might explain the beneficial effects of NaHCO3 reported in patients with acute respiratory acidosis.

Functional magnetic resonance imaging (fMRI) suggests that the hypoxic ventilatory response is facilitated by the AMP-activated protein kinase (AMPK), not at the carotid bodies, but within a subnucleus (Bregma -7.5 to -7.1 mm) of the nucleus tractus solitarius that exhibits right-sided bilateral asymmetry. Here, we map this subnucleus using cFos expression as a surrogate for neuronal activation and mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic cells by Cre expression via the tyrosine hydroxylase promoter. Comparative analysis of brainstem sections, relative to controls, revealed that AMPK-α1/α2 deletion inhibited, with right-sided bilateral asymmetry, cFos expression in and thus activation of a neuronal cluster that partially spanned three interconnected anatomical nuclei adjacent to the area postrema: SolDL (Bregma -7.44 mm to -7.48 mm), SolDM (Bregma -7.44 mm to -7.48 mm) and SubP (Bregma -7.48 mm to -7.56 mm). This approximates the volume identified by fMRI. Moreover, these nuclei are known to be in receipt of carotid body afferent inputs, and catecholaminergic neurons of SubP and SolDL innervate aspects of the ventrolateral medulla responsible for respiratory rhythmogenesis. Accordingly, AMPK-α1/α2 deletion attenuated hypoxia-evoked increases in minute ventilation (normalised to metabolism), reductions in expiration time, and increases sigh frequency, but increased apnoea frequency during hypoxia. The metabolic response to hypoxia in AMPK-α1/α2 knockout mice and the brainstem and spinal cord catecholamine levels were equivalent to controls. We conclude that within the brainstem an AMPK-dependent, hypoxia-responsive subnucleus partially spans SubP, SolDM and SolDL, namely SubSol-HIe, and is critical to coordination of active expiration, the hypoxic ventilatory response and defence against apnoea.

Weight loss medications are emerging candidates for pharmacotherapy of sleep-disordered breathing (SDB). A melanocortin 4 receptor (MC4R) agonist, setmelanotide (Set), is used to treat obesity caused by abnormal melanocortin and leptin signaling. We hypothesized that Set can treat SDB in mice with diet-induced obesity. We performed a proof-of-concept randomized crossover trial of a single dose of Set versus vehicle and a 2-week daily Set versus vehicle trial, examined colocalization of Mc4r mRNAs with the markers of CO,-sensing neurons Phox2b and neuromedin B in the brainstem, and expressed Credependent designer receptors exclusively activated by designer drugs (DREADDs) or caspase in obese Mc4r-Cre mice. Set increased minute ventilation across sleep/wake states, enhanced the hypercapnic ventilatory response (HCVR), and abolished apneas during sleep. Phox2b· neurons in the nucleus of the solitary tract (NTS) and the parafacial region expressed Mc4r. Chemogenetic stimulation of the MC4R· neurons in the parafacial region, but not in the NTS, augmented HCVR without any changes in metabolism. Caspase elimination of the parafacial MC4R· neurons abolished effects of Set on HCVR. Parafacial MCAR· neurons projected to the respiratory premotor neurons retrogradely labeled from C3-C4. In conclusion, MC4R agonists enhance the HCVR and treat SDB by acting on the parafacial MC4R· neurons.

New Findings What is the central question of this study? What is the effect of peripheral chemoreflex and muscle metaboreflex integration on ventilation regulation, and what is the effect of integration on breathing‐related sensations and emotions? What is the main finding and its importance? Peripheral chemoreflex and muscle metaboreflex coactivation during isocapnic static handgrip exercise appeared to elicit a hyperadditive effect with regard to ventilation and an additive effect with regard to breathing‐related sensations and emotions. These findings reveal the nature of the integration between two neural mechanisms that operate during small‐muscle static exercise performed under hypoxia. Exercise augments the hypoxia‐induced ventilatory response in an exercise intensity‐dependent manner. A mutual influence of hypoxia‐induced peripheral chemoreflex activation and exercise‐induced muscle metaboreflex activation might mediate the augmentation phenomenon. However, the nature of these reflexes' integration (i.e., hyperadditive, additive or hypoadditive) remains unclear, and the coactivation effect on breathing‐related sensations and emotions has not been explored. Accordingly, we investigated the effect of peripheral chemoreflex and muscle metaboreflex coactivation on ventilatory variables and breathing‐related sensations and emotions during exercise. Fourteen healthy adults performed 2‐min isocapnic static handgrip, first with the non‐dominant hand and immediately after with the dominant hand. During the dominant hand exercise, we (a) did not manipulate either reflex (control); (b) activated the peripheral chemoreflex by hypoxia; (c) activated the muscle metaboreflex in the non‐dominant arm by post‐exercise circulatory occlusion (PECO); or (d) coactivated both reflexes by simultaneous hypoxia and PECO use. Ventilation response to coactivation of reflexes (mean ± SD, 13 ± 6 l/min) was greater than the sum of responses to separated activations of reflexes (mean ± SD, 8 ± 8 l/min, P = 0.005). Breathing‐related sensory and emotional responses were similar between coactivation of reflexes and the sum of separate activations of reflexes. Thus, the peripheral chemoreflex and muscle metaboreflex integration during exercise appeared to be hyperadditive with regard to ventilation and additive with regard to breathing‐related sensations and emotions in healthy adults.

Mountaineers with a high ventilatory response to hypoxia experience greater cognitive impairment at high altitude, possibly because hyperventilation causes hypocapnia, cerebral vasoconstriction and ultimately cerebral ischaemia. We hypothesised that a high ventilatory response, and consequently a lower arterial partial pressure of carbon dioxide (PaCO 2 ), could increase the risk of delirium in hospitalised patients with acute hypoxia. To test our hypothesis, we conducted a cohort study in which PaCO 2 and arterial oxygen saturation were measured upon hospital admission in 126 patients with COVID-19. After adjusting for oxygen saturation, we found that a lower PaCO 2 was associated with a higher risk of delirium during hospital admission (risk ratio 1.67 [95% confidence interval 1.09–2.54] per 1 kilopascal reduction, P  = 0.017). The association remained statistically significant after adjusting for other well-established risk factors for delirium. This finding supports our hypothesis that a high hypoxic ventilatory response increases the risk of delirium in patients with acute hypoxia.

Background The COVID-19 pandemic resulted in over 7 million reported deaths and over 700.4 million reported infections to-date. Many individuals who recover from COVID-19 report prolonged dyspnea, sometimes persisting for months. Furthermore, COVID-19 has been linked to systemic and neuronal inflammation which may have downstream impacts on the neural control of breathing. Therefore, we hypothesized that individuals recovered from COVID-19 may exhibit changes in their ventilatory chemosensitivity to carbon dioxide and hypoxia, and that these changes may be linked to systemic inflammation. Methods To test this hypothesis, we measured baseline ventilatory patterns and chemoreflex sensitivity in individuals recovered from COVID-19 ( n =  77) and individuals with no prior COVID-19 infection ( n =  41). Peripheral venous blood samples were also collected for inflammatory biomarker expression and profiling. Results Recovered participants demonstrated a small but progressive decrease in the hypercapnic ventilatory response under a co-stimulus with hypoxia (control vs. 24-month post-recovery; p =  0.023). Additionally, we identified several significant correlations between plasma inflammatory markers and ventilatory chemoreflex characteristics, including a positive correlation between SAA and CRP and the ventilatory response to hypoxia ( p <  0.05 within recovered and control cohorts). Finally, expression of six vascular inflammatory markers (Myoglobin, NGAL, MMP-2, OPN, IGFBP-4, and Cystatin C) was unexpectedly decreased in recovered participants compared to the control cohort for up to one-year post recovery. Conclusions Overall, this data indicates that COVID-19 and other acute viral infections may have a modest impact on the chemoreflex control of breathing as well as systemic inflammatory profiles, and that these changes may be linked to each other. These findings may strengthen our understanding of the pathology of long-COVID symptoms.

Obstructive sleep apnoea (OSA) is highly prevalent but approved pharmacological treatment options are missing. Sultiame improves the ventilatory response and upper airway muscle activity by inhibiting carbonic anhydrase. This study aimed to prospectively assess the efficacy and safety of three dosages of sultiame in OSA. This multicentre, randomised, parallel, double-blind, placebo-controlled, dose-finding, phase 2 trial was performed at 28 hospitals and community-based sites in five European countries. Adults (aged 18–75 years) with untreated, moderate to severe OSA and an Apnoea–Hypopnea Index (AHI) of ≥15 to ≤50 events per h were randomly assigned (1:1:1:1), using interactive response technology, to receive placebo or sultiame 100 mg, 200 mg, or 300 mg tablets of identical appearance once per day at bedtime for 15 weeks. Randomisation was stratified by baseline AHI3a. The primary outcome measure for efficacy was the relative change of AHI3a from baseline to week 15 (scheduled treatment end). All participants who were randomly assigned were included in the primary efficacy analysis using an estimands framework and in the safety analysis. This trial is registered with EudraCT (2021–002926–26) and ClinicalTrials.gov (NCT05236842) and is complete. Between Dec 2, 2021, and April 8, 2023, 535 patients were screened and 298 were randomly assigned to placebo (n=75), or sultiame 100 mg (n=74), 200 mg (n=74), or 300 mg (n=75). 240 patients completed 15 weeks of treatment. 220 (74%) of 298 participants were male and 78 (26%) were female. In the full analysis set, placebo-subtracted relative AHI3a adjusted means change at week 15 was –16·4% (95% CI –31·3 to –1·4; p=0·032), –30·2% (–45·4 to –15·1; p<0·0001), and 34·6% (–49·1 to –20·0; p<0·0001) for sultiame 100 mg, 200 mg, and 300 mg, respectively. The incidence of adverse events increased dose-dependently: 46 (61%) of 75 patients in the placebo group, 54 (73%) of 74 in the 100 mg group, 62 (84%) of 74 in the 200 mg group, and 68 (91%) of 75 in the 300 mg group. Events reported in more than 10% of patients in the placebo, 100 mg, 200 mg, or 300 mg groups were paraesthesia (seven [9%] of 75, 16 [22%] of 74, 32 [43%] of 74, 43 [57%] of 75), headache (six [8%], five [7%], 12 [16%], 11 [15%]), COVID-19 (three [4%], three [4%], six [8%], ten [13%]), and nasopharyngitis (nine [12%], three [4%], seven [9%], seven [9%]). Sultiame caused consistent, dose-dependent improvements of OSA, nocturnal hypoxia, sleep quality, and excessive daytime sleepiness. These findings offer perspectives for a pharmaceutical approach to treatment of patients with obstructive sleep apnoea. Desitin Arzneimittel.

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). What is the topic of this review? What neural mechanisms are involved in the ventilatory response to hypoxic exercise and do they interact? What are the mechanisms underlying neural interactions during hypoxic exercise? What advances does it highlight? 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. Medullary signal summation, short‐term potentiation and sympathetic carotid chemoreceptor activation probably contribute to potentiation of the hypoxic ventilatory response during exercise, impacting cerebral blood flow and oxygenation via hyperventilation‐induced hypocapnia.

Human populations native to high altitude have evolved distinct physiological adaptations to chronic hypoxia. This adaptation is evident in the O 2 transport cascade. In this review, with brief inclusion of the related genetic adaptations, we compare the O 2 cascade across three well‐characterized high‐altitude populations: Andeans (Aymara and Quechua), Tibetans/Sherpa and Ethiopians (Amhara and Oromo). We contrast the steps of the O 2 cascade: (1) ventilation; (2) pulmonary O 2 diffusion; (3) cardiac output and circulation; (4) haematological traits; and (5) tissue O 2 utilization. Tibetans exhibit a robust hypoxic ventilatory response and efficient pulmonary diffusion capacity. They maintain preserved cardiac function with optimized muscle energetics. These adaptations are supported by enhanced tissue blood flow and greater muscle capillary density. Andeans demonstrate a blunted ventilatory response and marked remodelling of the pulmonary circulation, resulting in elevated pulmonary arterial pressure and mild but persistent right ventricular hypertrophy along with lifelong sympathetic overactivity. They also show strong haematological adaptations, with increased haemoglobin concentration. Ethiopians, particularly Amhara highlanders, show ventilatory status close to sea‐level values, with limited pulmonary and cerebral vasoreactivity to hypoxia. Although data remain limited, the Amhara highlanders exhibit higher oxygen saturation and enhanced tissue blood flow in comparison to Oromo counterparts. In conclusion, these physiological (i.e., O 2 cascade) differences provide evidence of the diverse patterns of evolutionarily adaptive responses to the stresses of high‐altitude hypoxia. Further research comparing the O 2 cascade across these Indigenous populations will enhance our understanding of the genetic and physiological adaptations to life at high altitude. What is the topic of this review? This review examines contemporary research findings in the context of the oxygen cascade among the three well‐recognized high‐altitude natives: the Andeans (Aymara, Quechua), Himalayans (Tibetans, Sherpa) and Ethiopian Highlanders (Amhara, Oromo). What advances does it highlight? It highlights the divergent oxygen cascade in native highlanders, probably influenced by geography and evolution. Variability in study sites and limited research in Ethiopian highlanders challenges comparison and underscores the need for nuanced interpretation. For comprehensive understanding of human adaptation to high altitude, integrative approaches across the high‐altitude populations that combine genomic, physiological, anthropological and environmental studies are recommended.