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The present study was proposed to investigate the brain injury under acute hypobaric hypoxia following alteration in mRNA expression and stress markers in a time-dependent manner. SD clean graded male rats were randomly divided into four groups for this experimental brain injury, the control group at Xining (altitude, 2270m) and hypoxia treatment groups with different time exposure day1, day2, and day3 at (altitude, 7000m) in a hypobaric chamber. After day3 exposure, the brain tissues were collected. The level of mRNA expression of VEGF and HIF1-α was assessed using qRT-PCR. The oxidative stress level of superoxide dismutase (SOD) and malondialdehyde (MDA) were determined with commercial kits. AHH with time duration significantly increased the MDA level and decreased in the activity of SOD was seen in all hypoxia treated groups as compared to the control (P< 0.001). The mRNA expression level of HIF1-α and VEGF in day1, day2, and day3 AHH groups was markedly raised when it is compared to control (P< 0.05). Ultimately, in conclusion, such results indicate that AHH stimulates oxidative stress induces brain damage in rats. Keywords: Acute hypobaric hypoxia, Brain injury, HIF-1α, Oxidative stress.

Effects of photoperiodicity caused by both the age and individual physiological reactivity estimated by resistance to hypobaric hypoxia on the levels of lipid peroxidation, protein oxidation (aldehydic and ketonic derivatives), total antioxidant capacity, activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase), and biochemical parameters of aerobic and anaerobic pathways in hepatic tissue depending on the blood melatonin level were studied. The study was carried out on 96 6- and 21-month-old male rats divided into hypoxia resistance groups (LR, low resistance, HR, high resistance). The analyses were conducted at four photoperiods: winter (January), spring (March), summer (July), and autumn (October). Our results indicate a significant effect of melatonin, i.e. over 80%, revealed by the complete statistical model of the studied biomarkers of oxidative stress and oxygen-dependent parameters of metabolism. The effects of melatonin vary with age and between photoperiods, which in turn was determined by individual physiological reactivity. In terms of the photoperiods, the melatonin content in the group of the adult animals with low resistance to hypoxia decreased from winter to summer. In a group of old animals in comparison with adults, the melatonin content in all the studied photoperiods was much lower as well, regardless of their hypoxia resistance. In the group of old animals with low resistance to hypoxia, the melatonin content decreased throughout the photoperiods as follows: winter, autumn, summer, and spring. As can be concluded, spring is a critical period for old animals, particularly those with low hypoxia resistance. The important role of melatonin in these processes was also confirmed by our correlation analysis between oxidative stress biomarkers, energy-related metabolites, and antioxidant enzymes in the hepatic tissue of rats of different ages, with different resistance to hypoxia, and in different photoperiods. The melatonin concentration in the blood of highly resistant rats was higher than in those with low resistance to hypoxia. Melatonin determines the individual constitutional level of resistance to hypoxia and is responsible for individual enzymatic antioxidative responses, depending on the four photoperiods. Our studies have shown that melatonin levels are related to the redox characteristics of antioxidant defenses against lipid peroxidation and oxidative modification of proteins in old rats with low resistance to hypoxia, compared to a group of highly resistant adults. Finally, the melatonin-related mechanisms of antioxidative protection depend on metabolic processes in hepatic tissue and exhibit photoperiodical variability in adult and old rats.

2021.—Many previous studies have examined hypoxia-induced physiological responses using various conditions, e.g., artificially reduced atmospheric oxygen concentration [normobaric hypoxia (NH) condition] or low barometric pressure at a mountain [hypobaric hypoxia (HH) condition]. However, when comparing the results from these previous studies conducted in artificial NH and HH including real high altitude, we must consider the possibility that environmental factors, such as temperature, humidity, and fraction of inspired carbon dioxide, might affect the physiological responses. Therefore, we examined cardiorespiratory responses and exercise performances during low- to high-intensity exercise at a fixed heart rate (HR) in both NH and HH using a specific chamber where atmospheric oxygen concentration and barometric pressure as well as the abovementioned environmental factors were precisely controlled. Ten well-trained university students (eight males and two females) performed the exercise test consisting of two 20-minute submaximal pedaling at the intensity corresponding to 50% (low) and 70% (high) of their HR reserve, under three conditions [NH (fraction of inspired oxygen, 0.135; barometric pressure, 754 mmHg), HH (fraction of inspired oxygen, 0.209; barometric pressure, 504 mmHg), and normobaric normoxia (NN; fraction of inspired oxygen, 0.209; barometric pressure, 754 mmHg)]. Peripheral oxygen saturation (SpO2) to estimate arterial oxygen saturation and partial pressure of end-tidal carbon dioxide (PETCO2) were monitored throughout the experiment. SpO2, PETCO2, and power output at fixed HRs (i.e., pedaling efficiency) in NH and HH were all significantly lower than those in NN. Moreover, high-intensity exercise in HH induced greater decreases in SpO2 and power output than did high-intensity exercise in NH (NH vs. HH; SpO2, 78.2% - 5.0% vs. 75.1% - 7.1%; power output, 120.7 - 24.9 W vs. 112.4 - 23.2 W, both p < 0.05). However, high-intensity exercise in HH induced greater increases in PETCO2 than did high-intensity exercise in NH (NH vs. HH; 54.2 - 5.9mmHg vs. 57.2 - 3.4 mmHg, p < 0.01). These results suggest that physiological responses and power output at a fixed HR during hypoxic exposure might depend on the method used to generate the hypoxic condition.

It is known that the altitude area causes hypoxic conditions due to the low oxygen partial pressure. This study was conducted to estimate oxidative stress indices in the heart tissue after Wister rats exposure to the acute intermittent hypobaric hypoxia. Hypobaric hypoxia exposure was simulated by keeping the rats in a hypobaric chamber for 1 min at 35,000 feet altitude. After that the altitude was gradually reduced to 30,000 and 25,000 feet and maitained for 5 min. 25 male Wistar rats were divided into control group and four treatment groups (I-IV), consisting of rats exposed 1, 2, 3 and 4 times to hypobaric hypoxia with a frequency once a week. The animals were removed from the experiment at the height of 18,000 feet and the heart tissue was obtained. The carbonyl groups and MDA levels and superoxide dismutase and catalase activity were exami­ned in the supernatant of the heart tissue homogenate. In the samples of group I, the decrease in catalase activity with a simultaneous notable increase in carbonyl groups level was observed compared to control. In the samples of groups III and IV, the carbonyl level normalized and the activity of both antioxidant enzymes increased significantly. It was concluded that the increase of antioxidant enzymes activity can contribute to cardiac tissue adaptive response to acute hypobaric hypoxia exposure.

ObjectiveThe aim was to determine the effects of chronic intermittent hypobaric hypoxia (CIHH) on prostate-specific antigen (PSA) levels in Chilean miners who work at different altitudes.MethodsA cross-sectional study was conducted between April and July 2019. Miners from five mines (N=338) at different altitudes were evaluated. We recorded sociodemographic, working and altitude information. Haemoglobin oxygen saturation (SaO2) and haemoglobin (Hb) were measured in situ, while PSA and testosterone were analysed at a low level. Linear mixed-effect models were used to evaluate the association between PSA level and two CIHH exposures: composite CIHH (with four descriptors) and ChileStd-CIHH (CIHH Chilean standard; based on the Chilean technical guide for occupational exposure to CIHH). All models were adjusted by age, body mass index and day of the work the samples were taken.ResultsHighest and lowest PSA levels were found in mines ≥3000 m above sea level (mine 3: median=0.75, IQR=−0.45; mine 4: median=0.46, IQR=−0.35). In the multilevel models, the wider altitude difference between mining operation and camp showed lower PSA levels (model D: βPSA=−0.93 ng/mL, βlogPSA=−0.07, p2, Hb and testosterone. The descriptors of composite CIHH explained better PSA variations than ChileStd-CIHH (model D: marginal R2=0.090 vs model A: marginal R2=0.016).ConclusionsOccupational health regulations and high altitude medicine should consider these results as initial evidence on the inclusion of new descriptors for CIHH and the possible effect of this exposure on PSA levels in this male-dominated occupational sector.

The Elevation Training Mask (ETM) has been assessed for its impact on exercise performance using acute and training protocols. Although the ETM is widely available to consumers, little research exists for validation of the ETM mask settings. Therefore, the purpose of this study was to compare physiological responses during exercise for the ETM mask settings against moderate hypobaric hypoxia. Nine participants living at moderate altitude (1600–1650 m) rested (10 min) and cycled in hypobaric hypoxia simulating 2743 m (ALT), in hypobaric hypoxia simulating 1829 m with the ETM set to 914 m (ALT + ETM), and with the ETM set to 2743 m (ETM) in a randomized order. Participants cycled for 20 min at 60% VO2max as determined by a maximal exertion test (VO2max) at baseline altitude. Oxygen consumption was measured throughout each test. There were no differences between conditions at rest. Repeated measures ANOVA showed the ALT condition elicited significantly greater VO2 compared to the ETM condition and 60% VO2max at baseline altitude (P

Background Studies have revealed the protective effect of DL-3-n-butylphthalide (NBP) against diseases associated with ischemic hypoxia. However, the role of NBP in animals with hypobaric hypoxia has not been elucidated. This study investigated the effects of NBP on rodents with acute and chronic hypobaric hypoxia. Methods Sprague-Dwaley rats and Kunming mice administered with NBP (0, 60, 120, and 240 mg/kg for rats and 0, 90, 180, and 360 mg/kg for mice) were placed in a hypobaric hypoxia chamber at 10,000 m and the survival percentages at 30 min were determined. Then, the time and distance to exhaustion of drug-treated rodents were evaluated during treadmill running and motor-driven wheel-track treadmill experiments, conducted at 5800 m for 3 days or 20 days, to evaluate changes in physical functions. The frequency of active escapes and duration of active escapes were also determined for rats in a shuttle-box experiment, conducted at 5800 m for 6 days or 27 days, to evaluate changes in learning and memory function. ATP levels were measured in the gastrocnemius muscle and malonaldehyde (MDA), superoxide dismutase (SOD), hydrogen peroxide (H2O2), glutathione peroxidase (GSH-Px), and lactate were detected in sera of rats, and routine blood tests were also performed. Results Survival analysis at 10,000 m indicated NBP could improve hypoxia tolerance ability. The time and distance to exhaustion for mice (NBP, 90 mg/kg) and time to exhaustion for rats (NBP, 120 and 240 mg/kg) significantly increased under conditions of acute hypoxia compared with control group. NBP treatment also significantly increased the time to exhaustion for rats when exposed to chronic hypoxia. Moreover, 240 mg/kg NBP significantly increased the frequency of active escapes under conditions of acute hypoxia. Furthermore, the levels of MDA and H2O2 decreased but those of SOD and GSH-Px in the sera of rats increased under conditions of acute and chronic hypoxia. Additionally, ATP levels in the gastrocnemius muscle significantly increased, while lactate levels in sera significantly decreased. Conclusion NBP improved physical and learning and memory functions in rodents exposed to acute or chronic hypobaric hypoxia by increasing their anti-oxidative capacity and energy supply.

Background The thermoregulatory responses during simultaneous exposure to hypoxia and cold are not well understood owing to the opposite reactions of vasomotor tone in these two environments. Therefore, the purpose of this study was to investigate the influences of hypobaric hypoxia on various thermoregulatory responses, including skin blood flow (SkBF) during cold exposure. Methods Ten subjects participated in two experimental conditions: normobaric normoxia with cold (NC, barometric pressure (PB) = 760 mmHg) and hypobaric hypoxia with cold (HC, PB = 493 mmHg). The air temperature was maintained at 28 °C for 65 min and gradually decreased to 19 °C for both conditions. The total duration of the experiment was 135 min. Results The saturation of percutaneous oxygen (SpO2) was maintained at 98–99% in NC condition, but decreased to around 84% in HC condition. The rectal and mean skin temperatures showed no significant differences between the conditions; however, the forehead temperature was higher in HC condition than in NC condition. The pulse rate increased in HC condition, and there was a strong negative relationship between SpO2 and pulse rate (r = − 0.860, p = 0.013). SkBF and blood pressure showed no significant differences between the two conditions. Conclusion These results suggest that hypobaric hypoxia during cold exposure did not alter the overall thermoregulatory responses. However, hypobaric hypoxia did affect pulse rate regardless of cold exposure.

Hypoxia-induced pulmonary vascular constriction and structure remodeling are the main causes of hypoxic pulmonary hypertension. In the present study, an adeno-associated virus vector, containing Tie2 promoter and hypoxia response elements, was designed and named HTSFcAng(1-7). Its targeting, hypoxic inducibility, and vascular relaxation were examined in vitro, and its therapeutic effects on hypobaric hypoxia-induced pulmonary hypertension were examined in rats. Transfection of HTSFcAng(1-7) specifically increased the expression of angiotensin-(1-7) in endothelial cells in normoxia. Hypoxia increased the expression of angiotensin-(1-7) in HTSFcAng(1-7)-transfected endothelial cells. The condition medium from HTSFcAng(1-7)-transfected endothelial cells inhibited the hypoxia-induced proliferation of pulmonary artery smooth muscle cells, relaxed the pulmonary artery rings, totally inhibited hypoxia-induced early contraction, enhanced maximum relaxation, and reversed phase II constriction to sustained relaxation. In hypoxic pulmonary hypertension rats, treatment with HTSFcAng(1-7) by nasal drip adeno-associated virus significantly reversed hypoxia-induced hemodynamic changes and pulmonary artery-wall remodeling, accompanied by the concomitant overexpression of angiotensin-(1-7), mainly in the endothelial cells in the lung. Therefore, hypoxia-inducible overexpression of angiotensin-(1-7) in pulmonary endothelial cells may be a potential strategy for the gene therapy of hypoxic pulmonary hypertension., Graphical Abstract, A novel adeno-associated virus vector for the gene therapy of hypoxic pulmonary hypertension is reported that contains the Tie2 promoter, hypoxia response elements, and target gene angiotensin-(1-7). The vector exhibited hypoxia-inducible overexpression of angiotensin-(1-7), mainly in pulmonary endothelial cells, and significantly reversed hypoxic pulmonary hypertension in rats.

Objective: The objective was to investigate the anti-inflammatory effects of salidroside through the PI3K/Akt signaling pathway and its protective effects on acute hypoxia-induced myocardial injury in rats. Methods: A total of 24 healthy Sprague-Dawley male rats were selected as the experimental subjects. All rats were divided into 4 groups by using the random number table method, with 6 rats in each group. The groups included the normal control group, the salidroside group, the hypobaric hypoxia group, and the hypobaric hypoxia + salidroside group. Rats in the salidroside group were fed in the original animal laboratory and were intragastrically administered with salidroside every morning at a dosage of 35 mg/kg. Rats in the normal control group were intragastrically administered with an equal dosage of saline. Rats in the hypobaric hypoxia + salidroside group were intragastrically administered with salidroside every morning at a dosage of 35 mg/kg, who were fed in the hypoxic experiment module for animals. The altitude was increased to 4000 m, and the rats were kept in the module for 24 h. Rats in the hypobaric hypoxia group were intragastrically administered with an equal dosage of saline in the same environment, and the altitude was increased to 4000 m after administration. Parameters of blood gas analysis, histopathological changes in cardiac tissues, cardiac indexes, and inflammatory factors IL-6 and TNF-α levels of rats in groups were compared. Results: 1. The cardiac indexes of rats in groups were compared. The differences between the hypobaric hypoxia group and the hypobaric hypoxia + salidroside group were statistically significant (P

Forty broilers maintained under natural hypobaric hypoxia (2,638 m above sea level) and 20 maintained under relative normoxia (460 m above sea level) were selected as pulmonary hypertensive (PHB) and nonpulmonary hypertensive (NPHB), to estimate the degree of the adventitial vascular thickness in lung arterioles and connective tissue growth factor (CTGF) expression in lung. In each group, the adventitial thickness (%AT) of 20 arterioles with 100 to 250 μm of external diameter was measured in lung samples of 24 and 42-day-old broilers. Also, mRNA extraction and real-time reverse transcription-PCR analysis were used to measure lung CTGF expression. The %AT was higher in PHB at 42 D as compared to NPHB at both ages and PHB at 24 D; however, the same differences were not evidenced at 24 D. In the 2 ages evaluated, differences were observed in the %AT between broilers under hypobaric hypoxia (PHB and NPHB) and under relative normoxia (P < 0.01). In broilers subjected to relative normoxia, no significant differences were found at any of the 2 ages. The expression levels of CTGF mRNA were higher in PHB compared to NPHB at the 2 ages. The %AT was higher in PHB with high levels of expression of CTGF mRNA than those NPHB with low expression of CTGF mRNA. This study showed that adventitial thickening is part of the pulmonary hypertension (PH) physiopathology in broilers exposed to hypobaric hypoxia, in which CTGF appears to be a fibrosis enhancer. Although present data suggest that adventitial engrossment could be a time-dependent process, individual susceptibility and the variable time-course of PH pathophysiology have to be considered.

Simulated flight in a hypobaric chamber is a fundamental component in the physiological training of aviators. Although rare, there is always a risk of decompression sickness (DCS) in trainees during hypobaric hypoxia training. In this study we aimed to determine the incidence of altitude-induced DCS and the symptoms manifested in trainees and inside chamber observers (ICOs) during the training sessions. We retrospectively reviewed the records of DCS cases during the period of January 1, 2011, and October 1, 2018. The records of 6,657 trainees and 615 ICOs were evaluated. The gender distribution in 6,657 trainees was 6,578 (98.81%) male and 79 (1.19%) female. The numbers of DCS cases in trainees and ICOs were six (0.09%) and two (0.33%), respectively [(ICOs versus trainees – odds ratio (OR): 3.574; 95% CI 0.720–17.744; (p > 0.05)]. All ICOs were male; no DCS incident was observed among female trainees. Recompression treatments were applied on site, and complete recovery was achieved in all cases. Overall DCS incidence was found to be 0.11% among the 7,193 male subjects, which included trainees and ICOs. The higher incidence of DCS in ICOs was attributed to the physical activities performed at altitudes by ICOs. In such training, established instructions have to be strictly followed by physicians, ICOs and trainees. All trainees and ICOs should be aware of the symptoms and signs of DCS, and medical support including a recompression facility, should be provided on site during hypobaric hypoxia training.

Background: Hypoxia-inducible factor-1α (HIF-1α), heat shock protein-72 (HSP-72), hemeoxygenase-1 (HO-1), and matrix metalloproteinase-9 (MMP-9) have been identified as potential therapeutic targets in the brain for cerebral ischemia. To elucidate their underlying mechanisms, we first aimed to ascertain whether these proteins participate in the pathogenesis of heat-induced ischemic damage to the hypothalamus of rats. Second, we investigated whether hypobaric hypoxia preconditioning (HHP) attenuates heat-induced hypothalamic ischemic/hypoxic injury by modulating these proteins in situ. Methods: Anesthetized rats treated with or without HHP were subjected to heat stress. Hypothalamic ischemic/hypoxic damage was evaluated by measuring hypothalamic levels of cerebral blood flow (CBF), partial oxygen pressure (PO2), and hypothalamic temperature via an implanted probe. Hypothalamic apoptotic neurons were counted by measuring the number of NeuN/caspase-3/DAPI triple-stained cells. Hypothalamic protein expression of HIF-1α, HSP-72, HO-1, and MMP-9 was determined biochemically. Results: Before the start of the thermal experiments, rats were subjected to 5 hours of HHP (0.66 ATA or 18.3% O2) daily for 5 consecutive days per week for 2 weeks, which led to significant loss of body weight, reduced brown adipose tissue (BAT) wet weight and decreased body temperature. The animals were then subjected to thermal studies. Twenty minutes after heat stress, heat-exposed rats not treated with HHP displayed significantly higher core and hypothalamic temperatures, hypothalamic MMP-9 levels, and numbers of hypothalamic apoptotic neurons but significantly lower mean blood pressure, hypothalamic blood flow, and PO2 values than control rats not exposed to heat. In heat-exposed rats, HHP significantly increased the hypothalamic levels of HIF-1α, HSP-72, and HO-1 but significantly alleviated body and hypothalamic hyperthermia, hypotension, hypothalamic ischemia, hypoxia, neuronal apoptosis and degeneration. Conclusions: HHP may protect against hypothalamic ischemic/hypoxic injury and overexpression of MMP-9 by upregulating the hypothalamic expression of HIF-1α, HSP-72, and HO-1 in rats subjected to heatstroke.

Исследовано влияние комбинированного прекондиционирования с помощью комбинации амтизола (3,5-диамино-1,2,4-тиадиазола) и умеренной гипобарической гипоксии, а также их раздельного применения на уровень окислительного фосфорилирования в митохондриях головного мозга крыс в условиях нормоксии и при ишемии, вызванной двусторонней перевязкой общих сонных артерий. Выявлено, что фармакологическое прекондиционирование не влияет на скорость дыхания митохондрий в ткани мозга в различных метаболических состояниях при нормоксии, при этом ослабляет дыхательный контроль как в ранний, так и в поздний периоды прекондиционирования на 8,7 % (p = 0,045) и 4,2 % (p = 0,038), соответственно. Гипоксическое прекондиционирование снижает скорость фосфорилирующего окисления в митохондриях мозга в ранний период прекондиционирования на 13,6 % (p = 0,019), а также дыхательный контроль как в ранний, так и в поздний периоды прекондиционирования в среднем на 17 % (p = 0,002). При комбинированном прекондиционировании показатели окислительного фосфорилирования не отличаются от данных интактного контроля, в поздний период наблюдается увеличение коэффициента фосфорилирования на 10 % (p = 0,005). Через 1 сут после моделирования ишемии головного мозга наблюдаются нарушения окислительной и фосфорилирующей функции митохондрий. В случае использования за 1 и 48 ч до ишемии отдельно фармакологического или гипоксического прекондиционирования наблюдается повышение скорости дыхания V3 и коэффициента АДФ/O в сравнении с контрольной группой с ишемией, но эти показатели остаются значимо ниже в сравнении с группой интактного контроля. Комбинированное прекондиционирование предотвращает вызванное ишемией нарушение митохондриального окислительного фосфорилирования, в частности, повышая скорость фосфорилирующего дыхания V3 на 38,5 % (p = 0,002) в ранний и на 44,9 % (p = 0,006) в поздний периоды прекондиционирования, сопряженность окислительного фосфорилирования (коэффициент АДФ/O) при окислении НАД-зависимого субстрата глутамата на 22 % (p = 0,002) в ранний и на 30 % (p = 0,0008) в поздний периоды прекондиционирования.

BACKGROUND: In the last 10 yr, the number of ultra-haul flights—defined as flights greater than 12 h of flying time—has increased. While the medical complications of these flights are well-known, the underlying cellular effects are less clear. The primary objective of this study was to test the effects of extended mild hypobaric hypoxia on overall well-being and skeletal muscle morphology and macrophage populations.METHODS: A total of 22 male C57BL/6 mice were assigned to a normobaric (NB) or hypobaric (HB) chamber for 14–17 h. Overall mouse well-being and the general morphology and resident macrophage number in hindlimb muscles were compared between the two pressure conditions.RESULTS: During mild hypobaric hypoxia, the mice behaved normally and no changes were observed in general muscle morphology. Regarding resident macrophages, the mean antigen area of CD206 in the hindlimb muscles, lateral gastrocnemius (LG, 33.8 ± 2.0 vs. 35.3 ± 1.6), medial gastrocnemius (MG, 32.4 ± 1.6 vs. 32.6 ± 1.5), and quadriceps femoris (QF, 36.3 ± 1.2 vs. 34.3 ± 1.1) were similar between NB and HB conditions, and the number of CD68-positive cells in the LG and QF were similar between the two conditions. Significantly fewer CD206-positive cells were counted in the LG muscle under the HB condition.CONCLUSION: Our findings indicate that extended exposure to mild hypobaric hypoxia, similar to that of an ultra-long-haul flight, does not adversely affect healthy skeletal muscle.Zhang L, Soulakova J, St. Pierre Schneider B. Mild hypobaric hypoxia effects on murine skeletal muscle morphology and macrophages and well-being. Aerosp Med Hum Perform. 2019; 90(12):1050–1054.

Background: Hypobaric hypoxia (HH) exposure at high altitudes can result in a decline in cognitive function, which may have a serious impact on the daily life of people who migrate to high altitudes. However, the specific HH-induced changes in brain function remain unclear. This study explored changes in brain activity in rats exposed to a sustained HH environment using functional magnetic resonance imaging (fMRI). Methods: Healthy male rats (8 weeks old) were randomly divided into a model group and a control group. A rat model of cognitive impairment induced by sustained HH exposure was established. The control and model groups completed training and testing in the Morris water maze (MWM). A two-sample t-test for between-group difference comparisons was performed. Repeated measures analyses of variance for within-group comparisons were performed and post-hoc comparisons were made using the Tukey test. Between-group differences in spontaneous brain activity were assessed using a voxel-wise analysis of resting-state fMRI (rs-fMRI), combined with analyses of the fractional amplitude of low frequency fluctuations (fALFF) in statistical parametric mapping. Results: In the MWM test, the escape latencies of the model group were significantly longer compared with those of the control group (control group vs. model group, day 1: 21.6 ± 3.3 s vs. 40.5 ± 3.4 s, t = -11.282; day 2: 13.5 ± 2.2 s vs. 28.7 ± 5.3 s, t = -7.492; day 3: 10.5 ± 2.8 s vs. 22.6 ± 6.1 s, t = -5.099; day 4: 9.7 ± 2.5 s vs. 18.6 ± 5.2 s, t = -4.363; day 5: 8.8 ± 2.7 s vs. 16.7 ± 5.0 s, t = -3.932; all P < 0.001). Within both groups, the escape latency at day 5 was significantly shorter than those at other time points (control group: F = 57.317, P < 0.001; model group: F = 50.718, P < 0.001). There was no within-group difference in average swimming speed (control group, F = 1.162, P = 0.956; model group, F = 0.091, P = 0.880). Within the model group, the time spent within the original platform quadrant was significantly shorter (control group vs. model group: 36.1 ± 5.7 s vs. 17.8 ± 4.3 s, t = 7.249, P < 0.001) and the frequency of crossing the original platform quadrant was significantly reduced (control group vs. model group: 6.4 ± 1.9 s vs. 2.0 ± 0.8 s, t = 6.037, P < 0.001) compared with the control group. In the rs-fMRI study, compared with the control group, rats in the model group showed widespread reductions in fALFF values throughout the brain. Conclusions: The abnormalities in spontaneous brain activity indicated by the fALFF measurements may reflect changes in brain function after HH exposure. This widespread abnormal brain activity may help to explain and to provide new insights into the mechanism underlying the impairment of brain function under sustained exposure to high altitudes. Key words: Hypobaric hypoxia; Cognition; Magnetic resonance imaging; Functional; Rat

An increased and more effective microvascular perfusion is postulated to play a key role in the physiological adaptation of Sherpa highlanders to the hypobaric hypoxia encountered at high altitude. To investigate this, we used Lempel-Ziv complexity (LZC) analysis to explore the spatiotemporal dynamics of the variability of the skin microvascular blood flux (BF) signals measured at the forearm and finger, in 32 lowlanders (LL) and 46 Sherpa highlanders (SH) during the Xtreme Everest 2 expedition. Measurements were made at baseline (BL) (LL: London 35 m; SH: Kathmandu 1300 m) and at Everest base camp (LL and SH: EBC 5,300 m). We found that BF signal content increased with ascent to EBC in both SH and LL. At both altitudes, LZC of the BF signals was significantly higher in SH, and was related to local slow-wave flow-motion activity over multiple spatial and temporal scales. In SH, BF LZC was also positively associated with LZC of the simultaneously measured tissue oxygenation signals. These data provide robust mechanistic information of microvascular network functionality and flexibility during hypoxic exposure on ascent to high altitude. They demonstrate the importance of a sustained heterogeneity of network perfusion, associated with local vaso-control mechanisms, to effective tissue oxygenation during hypobaric hypoxia.

Acute exposure to high altitude perturbs physiological parameters and induces an array of molecular changes in healthy lowlanders. However, activation of compensatory mechanisms and biological processes facilitates high altitude acclimatization. A large number of lowlanders stay at high altitude regions from weeks to months for work and professional commitments, and thus are vulnerable to altitude-associated disorders. Despite this, there is a scarcity of information for molecular changes associated with long-term stay at high altitudes. In the present study, we evaluated oxygen saturation (SpO2), heart rate (HR), and systolic and diastolic blood pressure (SBP and DBP) of lowlanders after short- (7 days, HA-D7) and long-term (3 months, HA-D150) stay at high altitudes, and used TMT-based proteomics studies to decipher plasma proteome alterations. We observed improvements in SpO2 levels after prolonged stay, while HR, SBP, and DBP remained elevated as compared with short-term stay. Plasma proteomics studies revealed higher levels of apolipoproteins APOB, APOCI, APOCIII, APOE, and APOL, and carbonic anhydrases (CA1 and CA2) during hypoxia exposure. Biological network analysis also identified profound alterations in lipoprotein-associated pathways like plasma lipoprotein assembly, VLDL clearance, chylomicron assembly, chylomicron remodeling, plasma lipoprotein clearance, and chylomicron clearance. In corroboration, lipid profiling revealed higher levels of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL) for HA-D150 whereas high density lipoproteins (HDL) levels were lower as compared with HA-D7 and sea-level indicating dyslipidemia. We also observed higher levels of proinflammatory cytokines IL-6, TNFα, and CRP for HA-D150 along with oxidized LDL (oxLDL), suggesting vascular inflammation and proartherogenic propensity. These results demonstrate that long-term stay at high altitudes exacerbates dyslipidemia and associated disorders.

Purpose: The recognition and treatment of high-altitude illness (HAI) is increasingly important in global emergency medicine. High altitude related hypobaric hypoxia can lead to acute mountain sickness (AMS), which may relate to increased expression of vascular endothelial growth factor (VEGF), and subsequent blood-brain barrier (BBB) compromise. This study aimed to establish the relationship between AMS and changes in plasma VEGF levels during a high-altitude ascent. VEGF level changes with dexamethasone, a commonly used AMS medication, may provide additional insight into AMS.Methods: Twelve healthy volunteers ascended Mt Fuji (3,700 m) and blood samples were obtained at distinct altitudes for VEGF analysis. Oxygen saturation (SPO2) measurements were also documented at the same time-point. Six out of the 12 study participants were prescribed dexamethasone for a second ascent performed 48 h later, and blood was again collected to establish VEGF levels.Results: Four key VEGF observations could be made based on the data collected: (i) the baseline VEGF levels between the two ascents trended upwards; (ii) those deemed to have AMS in the first ascent had increased VEGF levels (23.8–30.3 pg/ml), which decreased otherwise (23.8–30.3 pg/ml); (iii) first ascent AMS participants had higher VEGF level variability for the second ascent, and similar to those not treated with dexamethasone; and (iv) for the second ascent dexamethasone participants had similar VEGF levels to non-AMS first ascent participants, and the variability was lower than for first ascent AMS and non-dexamethasone participants. SPO2 changes were unremarkable, other than reducing by around 5% irrespective of whether measurement was taken for the first or second ascent.Conclusion: First ascent findings suggest a hallmark of AMS could be elevated VEGF levels. The lack of an exercise-induced VEGF level change strengthened the notion that elevated plasma VEGF was brain-derived, and related to AMS.

This study aimed to evaluate the protective effect of chronic intermittent hypobaric hypoxia (CIHH) against limb ischemic injury. C57BL/6 mice were randomly divided into three groups: limb ischemic injury group (Ischemia, induced by ligation and excision of the left femoral artery), limb ischemia following CIHH pretreatment group (CIHH+Ischemia, simulated a 5000 m altitude hypoxia, 6 h per day for 28 days, before induction of hind-limb ischemia), and sham group (Sham). The blood flow in the mouse models of hind-limb ischemia was examined using laser doppler imaging. The functional and morphological performance of ischemic muscle was evaluated using contraction force and hematoxylin–eosin and Masson’s trichrome staining. Angiogenesis was determined by immunohistochemistry staining of the endothelial markers CD31 and CD34. The protein expressions of angiogenesis-related genes were detected using Western blot assay. Chronic ischemia resulted in reduced blood perfusion, decreased contraction tension, and morphological destruction in gastrocnemius muscle. CIHH pretreatment increased the contractile force and muscle fiber diameter and decreased necrosis and fibrosis of the ischemic muscle. Also, CIHH significantly increased the density of CD31+ and CD34+ cells and promoted the expression of angiogenesis-related molecules in ischemic muscle. These data demonstrate that CIHH has a protective effect against chronic limb ischemia by promoting angiogenesis.

Oxygen metabolism is closely related to the intestinal homeostasis environment, and the occurrence of many intestinal diseases is as a result of the destruction of oxygen gradients. The hypobaric hypoxic environment of the plateau can cause dysfunction of the intestine for humans, such as inflammation. The compensatory response of the small intestine cells to the harsh environment definitely changes their gene expression. How the small intestine cells response the hypobaric hypoxic environment is still unclear. We studied the rat small intestine under hypobaric hypoxic conditions to explore the transcriptional changes in rats under acute/chronic hypobaric hypoxic conditions. We randomly divided rats into three groups: normal control group (S), acute hypobaric hypoxia group, exposing to hypobaric hypoxic condition for 2 weeks (W2S) and chronic hypobaric hypoxia group, exposing to hypobaric hypoxic condition for 4 weeks (W4S). The RNA sequencing was performed on the small intestine tissues of the three groups of rats. The results of principal component analysis showed that the W4S and W2S groups were quite different from the control group. We identified a total of 636 differentially expressed genes, such as ATP binding cassette, Ace2 and Fabp. KEGG pathway analysis identified several metabolic and digestive pathways, such as PPAR signaling pathway, glycerolipid metabolism, fat metabolism, mineral absorption and vitamin metabolism. Cogena analysis found that up-regulation of digestive and metabolic functions began from the second week of high altitude exposure. Our study highlights the critical role of metabolic and digestive pathways of the intestine in response to the hypobaric hypoxic environment, provides new aspects for the molecular effects of hypobaric hypoxic environment on intestine, and raises further questions about between the lipid metabolism disorders and inflammation.

Jatwani, Arti, and Rajkumar Tulsawani. Ganoderma lucidum induces myogenesis markers to avert damage to skeletal muscles in rats exposed to hypobaric hypoxia. High Alt Med Biol. 16:000–000, 2021. Ba...

Background Aeromedical evacuation of patients with burn trauma is an important transport method in times of peace and war, during which patients are exposed to prolonged periods of hypobaric hypoxia; however, the effects of such exposure on burn injuries, particularly on burn-induced lung injuries, are largely unexplored. This study aimed to determine the effects of hypobaric hypoxia on burn-induced lung injuries and to investigate the underlying mechanism using a rat burn model. Methods A total of 40 male Wistar rats were randomly divided into four groups (10 in each group): sham burn (SB) group, burn in normoxia condition (BN) group, burn in hypoxia condition (BH) group, and burn in hypoxia condition with treatment intervention (BHD) group. Rats with 30% total body surface area burns were exposed to hypobaric hypoxia (2000 m altitude simulation) or normoxia conditions for 4 h. Deoxyribonuclease I (DNase I) was administered systemically as a treatment intervention. Systemic inflammatory mediator and mitochondrial deoxyribonucleic acid (mtDNA) levels were determined. A histopathological evaluation was performed and the acute lung injury (ALI) score was determined. Malonaldehyde (MDA) content, myeloperoxidase (MPO) activity, and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome level were determined in lung tissues. Data among groups were compared using analysis of variance followed by Tukey’s test post hoc analysis. Results Burns resulted in a remarkably higher level of systemic inflammatory cytokines and mtDNA release, which was further heightened by hypobaric hypoxia exposure (P P P P P Conclusions Our results suggested that simulated aeromedical evacuation further increased burn-induced mtDNA release and exacerbated burn-induced inflammation and lung injury. DNase I reduced the release of mtDNA, limited mtDNA-induced systemic inflammation, and ameliorated burn-induced ALI. The intervening mtDNA level is thus a potential target to protect from burn-induced lung injury during aeromedical conditions and provides safer air evacuations for severely burned patients.

This study focuses on the investigation of the effects of flight factors, including the hypobaric hypoxia, on physical performance based on the individual psychological profile. The goal of the study was to evaluate the association between the endurability of the flight factors and individual psychological features. Physical performance was assessed using the Ruffier test in three stages: during the recording of the baseline data, when ascending to an altitude of 5000 m in a hypobaric chamber, and after the ascent. The data obtained were analyzed considering the individual psychological features, including the neuroticism, extroversion, and trait anxiety. The levels of neuroticism and extroversion were evaluated using the Eysenck Personality Questionnaire, and trait anxiety was assessed using Spielberger’s tests in the modification of Khanin. It has been found that individuals with a high neuroticism level are characterized by a more significant decrease in myocardial work capacity by 17.3% (p < 0.05) on the 30th minute and by 23.4% (р < 0.01) on the 60th minute of ascent in the hypobaric chamber compared to the subjects with a low neuroticism level. The results of the analysis of the Ruffier test have demonstrated 2.16-fold (р < 0.01) and 2.25-fold (р < 0.01) increase in the Ruffier index by the 30th and 60th minutes of the ascent in the altitude chamber, respectively, in the individuals characterized by an initially 28% lower (р < 0.05) baseline Ruffier index compared to those with high level of trait anxiety. Comparison of the indices of the myocardial work capacity during ascent has shown that heart work capacity in the group of introverts decreased by 20.0% (p < 0.05) by the 30th minute of being in a hypobaric chamber compared to the group of extroverts; by the 60th minute, the difference was 17.8% (р < 0.01). Therefore, it has been demonstrated that the association between the myocardial work capacity and individual psychological characteristics should be considered in the evaluation of the tolerance to moderate hypoxia.

Introduction: The Royal Canadian Air Force (RCAF) imposes a daily 4-hour (h)limit for operating unpressurized aircrafts, including helicopters, between 2,438 and 3,048 m (8,000 [8K] and 10,000 [10K] ft) if supplemental oxygen (O2) is unavailable. This regulation may negatively impact RCAF operations because weight and space restrictions limit sufficient O2 to achieve mission success. The effects of exposure durations beyond the 4-h limit are currently unknown, but extensions have the potential to improve operational effectiveness. This study examined the effects of hypoxic exposures on symptoms, mood and performance as a function of altitude and exposure duration. Methods: Seventeen military helicopter pilots were randomly exposed to two 6-h altitude levels (8K and 9.9K) on 2 separate days in a hypobaric chamber. Daily, participants periodically performed a simulated rotary wing flight task, and completed a cognitive test battery. Cerebral regional and finger pulse oxyheamoglobin saturation levels and heart rate were continuously monitored. Participants indicated their subjective hypoxia signs and symptoms, mood and fatigue. Results: Exposure to altitude significantly decreased cerebral and pulse O2 saturations, but values remained steady during the 6-h exposure. No negative decrements were observed on cognition or simulation performance. Self-reported symptoms of fatigue and headache were reported at altitude with a slight increase with time. Discussion: No clear evidence of significant deficits on performance was observed in participants when exposed to mild levels of hypoxia for up to 6 h without supplemental O2.

Despite its rare occurrence, humans and animals have been prone to getting fast developing severe hypobaric hypoxia. Understanding the redox homeostasis related response of an aging heart to this type of hypoxia are crucially important, since the metabolism of myocardial tissue depends on the redox status of proteins. Rodents can tolerate hypoxic stress better than human subjects. This study was aimed at investigating the effects of fast developing severe hypobaric hypoxia on redox status biomarkers; such as, advanced oxidation protein products (AOPP), lipid hydroperoxides (LHPs), protein carbonyl groups (PCO), protein thiol groups (P-SH), and total thiol groups (T-SH) on the myocardial left ventricles of young and aged Wistar rats. The rats were gradually ascended and exposed to an 8000-meter hypobaric hypoxia. While AOPP levels showed no difference, the TSH and PSH concentrations decreased, and the PCO and LHP increased in both of the hypoxic groups than the controls. The TSH and PSH were lower, and AOPP, PCO and LHP were found to be higher in the elderly hypoxic groups than in the young ones. The significant outcome of the study represents that an 8000-meter hypobaric hypoxia could be considered as a severe hypoxic stress, but not life-treating for the rats and would affect both the young and aged left ventricles similarly in respect to impaired redox status. However, if the percentage increases are taken into consideration, it seems that the higher rate of protein oxidation occurs in young hearts; meanwhile aged hearts are more prone to T-SH oxidation.

Background: The physiological effects of hypoxia may be influenced by how hypoxia is achieved. The purpose of this study was to determine the effects of recovery in hypobaric hypoxia (HH),...

In hypobaric hypoxia (HH) at high altitude, the immune responses are changed probably due to oxidative stress-induced production of free radicals and nonradicals. Vitamin E is an antioxidant and protects the cells from oxidative damage. The present study was carried out to study the antioxidant role of vitamin E on the immune changes induced by oxidative stress in HH at high altitude. Select immune responses (phagocytic activity of white blood cell [WBC], cytotoxic activity of splenic mononuclear cells [MNCs], and delayed type of hypersensitivity [DTH]) and hematological changes (total count and differential count [DC] of WBC) were measured in male rats exposed to intermittent HH (at 5486.4 m in a simulated chamber for 8 hours/d for 6 consecutive days) and in normobaric condition with and without p.o. administration of vitamin E in three different doses (20, 40, and 60 mg/kg body weight). The increase of phagocytic activity of blood WBC, and reduction of cytotoxic activity of splenic MNC and DTH response were observed in rats exposed to HH. After the administration of vitamin E at different doses, the immune changes were blocked in a dose-dependent manner. Exposure to HH also led to the elevation of serum corticosterone (CORT), which was arrested after administration of vitamin E. The results indicate that the immune changes in HH at high altitude are probably mediated by the production of free radicals and nonradicals, and vitamin E can block these immune changes by its reactive oxygen species quenching effects.

We compared the decrease in maximal heart rate (HRmax) from normoxia to normobaric (NH) and hypobaric (HH) hypoxia, respectively, in trained and untrained subjects (n = 187). HRmax data in normoxia and NH (n = 55) or HH (n = 26) were collected from 81 publications. No study directly compared HRmax in NH and HH. Concomitant arterial oxygen saturation (SaO

Olfactory receptor (Olfr) 78 is expressed in the carotid bodies (CB) and participates in CB responses to acute hypoxia. Olfr78 is also expressed in the kidney, which is a major site of erythropoietin (Epo) production by hypoxia. The present study examined the role of Olfr78 in cardiorespiratory and renal Epo gene responses to hypobaric hypoxia (HH), simulating low O(2) condition experienced at high altitude. Studies were performed on adult, male wild-type (WT) and Olfr78 null mice treated with 18 h of HH (0.4 atmospheres). HH-treated WT mice exhibited increased baseline breathing, augmented hypoxic ventilatory response, elevated blood pressure, and plasma norepinephrine (NE) levels. These effects were associated with increased baseline CB sensory nerve activity and augmented CB sensory nerve response to subsequent acute hypoxia. In contrast, HH-treated Olfr78 null mice showed an absence of cardiorespiratory and CB sensory nerve responses, suggesting impaired CB-dependent cardiorespiratory adaptations. WT mice responded to HH with activation of the renal Epo gene expression and elevated plasma Epo levels, and these effects were attenuated or absent in Olfr78 null mice. The attenuated Epo activation by HH was accompanied with markedly reduced hypoxia-inducible factor (HIF)-2α protein and reduced activation of HIF-2 target gene Sod-1 in Olfr78 null mice, suggesting impaired transcriptional activation of HIF-2 contributes to attenuated Epo responses to HH. These results demonstrate a hitherto uncharacterized role for Olfr78 in cardiorespiratory adaptations and renal Epo gene activation by HH such as that experienced at high altitude. NEW & NOTEWORTHY In this study, we delineated a previously uncharacterized role for olfactory receptor 78 (Olfr78), a G-protein-coupled receptor in regulation of erythropoietin and cardiorespiratory responses to hypobaric hypoxia. Our results demonstrate a striking loss of cardiorespiratory adaptations accompanied by an equally striking absence of carotid body sensory nerve responses to hypobaric hypoxia in Olfr78 null mice. We further demonstrate a hitherto uncharacterized role for Olfr78 in erythropoietin activation by hypobaric hypoxia.

The effect of chronic intermittent hypobaric hypoxia (CIHH) on bone fracture healing is not elucidated. The present study aimed to investigate the role of CIHH on bone fracture healing and the mechanism. The Sprague-Dawley rats were randomly divided into the CIHH group and control group and monitored for 2, 4, or 8 weeks after femoral fracture surgery. Bone healing efficiency was significantly increased in the CIHH group as evidenced by higher high-density bone volume fractions, higher bone mineral density, higher maximum force, and higher stiffness. Histologically, the CIHH group exhibited superior bone formation, endochondral ossification, and angiogenic ability compared with the control group. The expression of HIF-1α and its downstream signaling proteins VEGF, SDF-1/CXCR4 axis were increased by the CIHH treatment. Moreover, the expression of RUNX2, osterix, and type I collagen in the callus tissues were also up-regulated in the CIHH group. In conclusion, our study demonstrated that CIHH treatment improves fracture healing, increases bone mineral density, and increases bone strength via the activation of HIF-1α and bone production-related genes.

Purpose High altitude results in lower barometric pressure and hence partial pressure of O2 decrease can lead to several molecular and cellular changes, such as generation of reactive oxygen species (ROS). Electron Paramagnetic Resonance technique was adopted in the field, to evaluate the effects of acute and sub-acute hypobaric hypoxia (HH) on ROS production by micro-invasive method. Biological biomarkers, indicators of oxidative stress, renal function and inflammation were investigated too. Methods Fourteen lowlander subjects (mean age 27.3 ± 5.9 years) were exposed to HH at 3269 m s.l. ROS production, related oxidative damage to cellular components, systemic inflammatory response and renal function were determined through blood and urine profile performed at 1st, 2nd, 4th, 7th, and 14th days during sojourn. Results Kinetics of changes during HH exposition showed out significant (range p < 0.05-0.0001) increases that at max corresponds to 38% for ROS production rate, 140% for protein carbonyl, 44% for lipid peroxidation, 42% for DNA damage, 200% for inflammatory cytokines and modifications in renal function (assessed by neopterin concentration: 48%). Conversely, antioxidant capacity significantly (p < 0.0001) decreased - 17% at max. Conclusion This 14 days in-field study describes changes of oxidative-stress biomarkers during HH exposure in lowlanders. The results show an overproduction of ROS and consequent oxidative damage to protein, lipids and DNA with a decrease in antioxidant capacity and the involvement of inflammatory status and a transient renal dysfunction. Exposure at high altitude induces a hypoxic condition during acute and sub-acute phases accompanied by molecular adaptation mechanism indicating acclimatization.

We investigated whether low arterial oxygen tension ([Formula: see text]) or hypoxia-induced plasma volume (PV) contraction, which reduces central blood volume (BV) and atrial distension, explain reduction in circulating atrial natriuretic peptide (ANP) after prolonged hypoxic exposure. Ten healthy males were exposed for 4 days to hypobaric hypoxia corresponding to an altitude of 3,500 m. PV changes were determined by carbon monoxide rebreathing. Venous plasma concentrations of midregional proANP (MR-proANP) were measured before and at the end of the exposure. At the latter time point, the measurement was repeated after 1) restoration of [Formula: see text] by breathing a hyperoxic gas mixture for 30 min and 2) restoration of BV by fluid infusion. Correspondingly, left ventricular end-diastolic volume (LVEDV), left atrial area (LAA), and right atrial area (RAA) were determined by ultrasound before exposure and both before and after fluid infusion at the end of the exposure. Hypoxic exposure reduced MR-proANP from 37.9 ± 18.5 to 24.5 ± 10.3 pmol/L ( P = 0.034), LVEDV from 107.4 ± 33.5 to 91.6 ± 26.3 mL ( P = 0.005), LAA from 15.8 ± 4.9 to 13.3 ± 4.2 cm2 ( P = 0.007), and RAA from 16.2 ± 3.1 to 14.3 ± 3.5 cm2 ( P = 0.001). Hyperoxic breathing did not affect MR-proANP (24.8 ± 12.3 pmol/L, P = 0.890). Conversely, fluid infusion restored LVEDV, LAA, and RAA to near-baseline values (108.0 ± 29.3 mL, 17.2 ± 5.7 cm2, and 17.2 ± 3.1 cm2, respectively, P > 0.05 vs. baseline) and increased MR-proANP to 29.5 ± 13.3 pmol/L ( P = 0.010 vs. preinfusion and P = 0.182 vs. baseline). These findings support that ANP reduction in hypoxia is at least partially attributed to plasma volume contraction, whereas reduced [Formula: see text] does not seem to contribute.

INTRODUCTION: Exposure to hypoxia has a deleterious effect on cognitive function; however, the putative effect of hypobaria remains unclear. The present study aimed to evaluate cognitive performance in pilot trainees who were exposed to acute normobaric (NH) and hypobaric hypoxia (HH). Of relevance for military pilots, we also aimed to assess cognitive performance in hypobaric normoxia (HN).METHODS: A total of 16 healthy pilot trainees were exposed to 4 randomized conditions (i.e., normobaric normoxia, NN, altitude level of 440 m; HH at 5500 m; NH, altitude simulation of 5500 m; and HN). Subjects performed a cognitive assessment (KLT-R test). Cerebral oxygen delivery (cDO2) was estimated based middle cerebral artery blood flow velocity (MCAv) and pulse oxygen saturation (Spo2) monitored during cognitive assessment.RESULTS: Percentage of errors increased in NH (14.3 9.1%) and HH (12.9 6.4%) when compared to NN (6.5 4.1%) and HN (6.0 4.0%). Number of calculations accomplished was lower only in HH than in NN and HN. When compared to NN, cDO2 decreased in NH and HH.DISCUSSION: Cognitive performance was decreased similarly in acute NH and HH. The cDO2 reduction in NH and HH implies insufficient MCAv increase to ensure cognitive performance maintenance. The present study suggests negligible hypobaric influence on cognitive performance in hypoxia and normoxia.Aebi MR, Bourdillon N, Noser P, Millet GP, Bron D. Cognitive impairment during combined normobaric vs. hypobaric and normoxic vs. hypoxic acute exposure. Aerosp Med Hum Perform. 2020; 91(11):845851.

Altitude ascending represents an intriguing experimental model reproducing physiological and pathophysiological conditions sharing hypoxemia as the denominator. The aim of the present study was to investigate fractional oxygen extraction and blood dynamics in response to hypobaric hypoxia and to acute resistance exercises, taking into account several factors including different ethnic origin and muscle groups. As part of the “Kanchenjunga Exploration & Physiology” project, six Italian trekkers and six Nepalese porters took part in a high altitude trek in the Himalayas. The measurements were carried out at low (1,450 m) and high altitude (HA; 4,780 m). Near-infrared spectroscopy (NIRS)-derived parameters, i.e., Tot-Hb and tissue saturation index (TSI), were gathered at rest and after bouts of 3-min resistive exercise, both in the quadriceps and in the forearm muscles. TSI decreased with altitude, particularly in forearm muscles (from 66.9 to 57.3%), whereas the decrement was less in the quadriceps (from 62.5 to 57.2%); Nepalese porters were characterized by greater values in thigh TSI than Italian trekkers. Tot-Hb was increased after exercise. At altitude, such increase appeared to be higher in the quadriceps. This effect might be a consequence of the long-term adaptive memory due to the frequent exposures to altitude. Although speculative, we suggest a long-term adaptation of the Nepalese porters due to improved oxygenation of muscles frequently undergoing hypoxic exercise. Muscle structure, individual factors, and altitude exposure time should be taken into account to move on the knowledge of oxygen delivery and utilization at altitude.

High altitude exposure typically reduces endothelial function, and this is modulated by hemoconcentration resulting from plasma volume contraction. However, the specific impact of hypobaric hypoxia, independent of external factors (e.g. cold, varying altitudes, exercise, diet, dehydration) on endothelial function is unknown. We examined the temporal changes in blood viscosity, shear stress and endothelial function and the impact of plasma volume expansion (PVX) during exposure to hypobaric hypoxia while controlling for external factors. Eleven healthy males (25±4 years; mean±SD) completed two four-day chamber visits (normoxia [NX] and hypobaric hypoxia [HH; equivalent altitude: 3500m]) in a cross-over design. Endothelial function was assessed via flow-mediated dilation in response to transient (reactive hyperemia; RH-FMD) and sustained (progressive handgrip exercise; SS-FMD) increases in shear stress prior to entering and after 1h, 6h, 12h, 48h and 96h in the chamber. During HH, endothelial function was also measured on the last day after PVX to pre-exposure levels (1140±320 ml balanced crystalloid solution). Blood viscosity and arterial shear stress increased on the first day during HH compared to NX and remained elevated at 48h and 96h (P

Introduction The present study evaluated the putative effect of hypobaria on resting HRV in normoxia and hypoxia. Methods Fifteen young pilot trainees were exposed to five different conditions in a randomized order: normobaric normoxia (NN, PB = 726 ± 5 mmHg, FIO2 = 20.9%), hypobaric normoxia (HN, PB = 380 ± 6 mmHg, FIO2≅40%), normobaric hypoxia (NH, PB = 725 ± 4 mmHg, FIO2≅11%); and hypobaric hypoxia (HH at 3000 and 5500 m, HH3000 and HH5500, PB = 525 ± 6 and 380 ± 8 mmHg, respectively, FIO2 = 20.9%). HRV and pulse arterial oxygen saturation (SpO2) were measured at rest seated during a 6 min period in each condition. HRV parameters were analyzed (Kubios HVR Standard, V 3.0) for time (RMSSD) and frequency (LF, HF, LF/HF ratio, and total power). Gas exchanges were collected at rest for 10 min following HRV recording. Results SpO2 decreased in HH3000 (95 ± 3) and HH5500 (81 ± 5), when compared to NN (99 ± 0). SpO2 was higher in NH (86 ± 4) than HH5500 but similar between HN (98 ± 2) and NN. Participants showed lower RMSSD and total power values in NH and HH5500 when compared to NN. In hypoxia, LF/HF ratio was greater in HH5500 than NH, whereas in normoxia, LF/HF ratio was lower in HN than NN. Minute ventilation was higher in HH5500 than in all other conditions. Discussion The present study reports a slight hypobaric effect either in normoxia or in hypoxia on some HRV parameters. In hypoxia, with a more prominent sympathetic activation, the hypobaric effect is likely due to the greater ventilation stimulus and larger desaturation. In normoxia, the HRV differences may come from the hyperoxic breathing and slight breathing pattern change due to hypobaria in HN.

Betge, Stefan, Stefan Drinda, Thomas Neumann, Laura Bäz, Alexander Pfeil, Christian Schulze, Ralf Mrowka, Christian Jung, and Marcus Franz. Influence of macitentan on the vascular tone and recruitment of finger capillaries under hypobaric hypoxia in high altitude.

The cardiopulmonary system is a physiological cornerstone in the adaptive response to hypobaric hypoxia. Portable devices make it feasible nowadays to precisely assess the response to high altitude (HA) expeditions. In this study, we investigated breathing and arterial blood pressure responses during a Himalayan trek from 665 m to 4,780 m altitude in a white European (Italian) sojourner and a native Nepali (Tamang) guide, both healthy males. Resting diurnal and nocturnal data were acquired by means of ambulatory blood pressure monitoring (ABPM) and sleep apnea monitoring. We found an increase in the mean diurnal arterial blood pressure. Nocturnal blood pressure dipping was confirmed at all altitudes. Oxygen saturation decreased at altitude, with its additional nocturnal fall. Sleep apneic episodes, present in the Italian only, increased with altitude. We conclude that the nocturnal, more than diurnal, cardiorespiratory function is affected by HA hypoxia. Further studies should address the role of ethnicity, medications, and sociodemographic factors in the cardiorespiratory responses to hypobaric hypoxia., In this study, we investigated cardiopulmonary nocturnal and diurnal responses during a Himalayan trek in a white European (Italian) sojourner and a native Nepali (Tamang) guide, by means of ambulatory blood pressure and sleep‐apnea monitoring. We found an increase in the mean BP. Oxygen saturation decreased at altitude, with its additional nocturnal fall. Sleep apneic episodes increased with altitude.

New findings What is the central question of this study? What is the impact of oxygen on the circulatory responses to an isocapnic cold pressor test (CPT) in lowlanders and Andean highlanders? What is the main finding and its importance? Overall, the circulatory responses to an isocapnic CPT were largely unaltered with acute normobaric hypoxia and chronic hypobaric hypoxia exposure in lowlanders. However, the relationship between mean arterial pressure and common carotid artery diameter was dampened under hypoxic conditions. Furthermore, there were no differences in the circulatory responses to the CPT between lowlanders and Andean highlanders with lifelong exposure to high-altitude. Abstract The impact of oxygen on the circulatory responses to a cold pressor test (CPT) in lowlanders and Andean highlanders remains unknown. We hypothesized: 1) in lowlanders, acute normobaric and hypobaric hypoxia would attenuate the common carotid artery (CCA) diameter response to the CPT compared to normobaric normoxia; 2) Andean highlanders would exhibit a greater CCA diameter response compared to lowlanders; and, 3) a positive relationship between CCA diameter and blood pressure in response to the CPT would be present in both lowlanders and highlanders. Healthy lowlanders (n = 13) and Andean highlanders (n = 8) were recruited and conducted an isocapnic CPT, which consisted of a 3-minute foot immersion into 0-1 °C water. Blood pressure (finger photoplethysmography) and CCA diameter and blood flow (Duplex ultrasound) were continuously recorded. The CPT was conducted in lowlanders at sea-level under isocapnic normoxic and hypoxic conditions, and after 10 days of acclimatization to 4300 m (Cerro de Pasco, Peru) under hypoxic and hyperoxic conditions. Andean highlanders were tested at rest at high-altitude. The main findings were: 1) in lowlanders, normobaric, but not hypobaric hypoxia, elevated CCA reactivity to the CPT; 2) no differences in response to CPT was observed between lowlanders and highlanders, and; 3) while hypobaric hypoxemia reduced the relationship between CCA diameter and blood pressure compared to normobaric normoxia (P = 0.132), hypobaric hyperoxia improved this relationship (P = 0.012), and no relationship was observed in Andean highlanders (P = 0.261). These data demonstrate that the circulatory responses to a CPT are modified by oxygen in lowlanders, but unaltered with lifelong hypoxic exposure. This article is protected by copyright. All rights reserved.

High-altitude (HA) natives have evolved some beneficial responses leading to superior work capacity at HA compared to native lowlanders. Our aim was to study two responses potentially protective against hypoxia: the spleen contraction elevating hemoglobin concentration (Hb) and the cardiovascular diving response in Sherpa highlanders, compared to lowlanders. Male participants were recruited from three groups: (1) 21 Sherpa living at HA (SH); (2) seven Sherpa living at low altitude (SL); and (3) ten native Nepalese lowlanders (NL). They performed three apneas spaced by a two-min rest at low altitude (1370 m). Their peripheral oxygen saturation (SpO2), heart rate (HR), and spleen volume were measured across the apnea protocol. Spleen volume at rest was 198 ± 56 mL in SH and 159 ± 35 mL in SL (p = 0.047). The spleen was larger in Sherpa groups compared to the 129 ± 22 mL in NL (p < 0.001 compared to SH; p = 0.046 compared to SL). Spleen contraction occurred in all groups during apnea, but it was greater in Sherpa groups compared to NL (p < 0.001). HR was lower in Sherpa groups compared to NL both during rest (SL: p < 0.001; SH: p = 0.003) and during maximal apneas (SL: p < 0.001; SH: p = 0.06). The apnea-induced HR reduction was 8 ± 8% in SH, 10 ± 4% in SL (NS), and 18 ± 6% in NL (SH: p = 0.005; SL: p = 0.021 compared to NL). Resting SpO2 was similar in all groups. The progressively decreasing baseline spleen size across SH, SL, and NL suggests a role of the spleen at HA and further that both genetic predisposition and environmental exposure determine human spleen size. The similar HR responses of SH and SL suggest that a genetic component is involved in determining the cardiovascular diving response.

Short-term hypoxic states can influence the health and life activities of lowlanders who travel shortly to high altitudes, in transitory situations, such as surgical ischemia-reperfusion (to one or several organs), and in some sporting activities, such as parachuting and extreme skiing, mountain rescue teams, regular commercial flight crews, in which the subject may not even notice the hypoxia. NO is an integral part of the human physiological response to hypoxia. Until recently, the urea cycle (UC) was only considered as an important mechanism for neutralizing ammonia. We are the first to reveal an interrelation in hypoxic states between the activities of NO-synthase and UC enzymes in male rats' liver, kidney and brain. In the presented work, we have shown that during short-term intermittent hypobaric hypoxia (IHH) all enzymes of UC play an important role in the maintenance of NO quantity. The results allow thinking that kidney and brain argininosuccinate synthase (ASS) and argininosuccinate lyase (ASL) and liver ASS and ASL can be different isoenzymes. It is worth mentioning that the results have revealed new sides of l -arginine metabolism in a hypoxic state in male rats.

BACKGROUND: Although the understanding of hypobaric hypoxia is increasing, it remains a hazard in aviation medicine. This study examined the feasibility of detecting voice markers sensitive to acute hypobaric hypoxia in an early presymptomatic (PRE-SYMP) stage.METHOD: Eight subjects qualified with hypobaric training completed a series of standardized speech tests in a hypobaric chamber at 20,000 ft and 25,000 ft (6096 and 7620 m) of altitude. Voice response patterns were analyzed in terms of fundamental frequency (F0), F0 range, and voice onset time (VOT). We hypothesized a PRE-SYMP compensatory stage in voice reactivity.RESULTS: There was a different dose-response reactivity course at 20,000 ft vs. 25,000 ft, nonlinear to altitude. At 20,000 ft, our hypothesis was confirmed. In comparison to sea level, a PRE-SYMP compensatory stage could be distinguished, characterized by a decreased F0 range, decreased VOT, and increased F0. During a transitional (TRANS) stage, in comparison with sea level, the F0-range reset, VOT decreased, and F0 increased. During a symptomatic (SYMP) stage, F0 increased, F0 range increased, and VOT decreased. At 25,000 ft, in comparison to sea level, voice reactivity showed increased F0 and F0 range and decreased VOT in a PRE-SYMP stage and increased F0 and F0 range in the SYMP stage.DISCUSSION: The compensatory PRE-SYMP stage is suggested to be the expression of ongoing bottom-up and top-down regulatory mechanisms, whereas the 25,000-ft results are interpreted as a combination of tonic and phasic voice reactivity. This tonic component needs to be foreseen in sea level baseline measures.Van Puyvelde M, Neyt X, Vanderlinden W, Van den Bossche M, Bucovaz T, De Winne T, Pattyn N. Voice reactivity as a response to acute hypobaric hypoxia at high altitude. Aerosp Med Hum Perform. 2020; 91(6):471–478.

Exercise-heat acclimation (EHA) induces adaptations that improve tolerance to heat exposure. Whether adaptations from EHA can also alter responses to hypobaric hypoxia (HH) conditions remains unclear. This study assessed whether EHA can alter time-trial performance and/or incidence of acute mountain sickness (AMS) during HH exposure. Thirteen sea-level (SL) resident men [SL peak oxygen consumption (V̇o2peak) 3.19 ± 0.43 L/min] completed steady-state exercise, followed by a 15-min cycle time trial and assessment of AMS before (HH1; 3,500 m) and after (HH2) an 8-day EHA protocol [120 min; 5 km/h; 2% incline; 40°C and 40% relative humidity (RH)]. EHA induced lower heart rate (HR) and core temperature and plasma volume expansion. Time-trial performance was not different between HH1 and HH2 after 2 h (106.3 ± 23.8 vs. 101.4 ± 23.0 kJ, P = 0.71) or 24 h (107.3 ± 23.4 vs. 106.3 ± 20.8 kJ, P > 0.9). From HH1 to HH2, HR and oxygen saturation, at the end of steady-state exercise and time-trial tests at 2 h and 24 h, were not different ( P > 0.05). Three of 13 volunteers developed AMS during HH1 but not during HH2, whereas a fourth volunteer only developed AMS during HH2. Heat shock protein 70 was not different from HH1 to HH2 at SL [1.9 ± 0.7 vs. 1.8 ± 0.6 normalized integrated intensities (NII), P = 0.97] or after 23 h (1.8 ± 0.4 vs. 1.7 ± 0.5 NII, P = 0.78) at HH. Our results indicate that this EHA protocol had little to no effect—neither beneficial nor detrimental—on exercise performance in HH. EHA may reduce AMS in those who initially developed AMS; however, studies at higher elevations, having higher incidence rates, are needed to confirm our findings.

Background: Both chronic hypoxia (CH) and long-term chronic intermittent hypoxia (CIH) exposure lead to right ventricular hypertrophy (RVH). Weight loss is an effective intervention to improve cardiac function and energy metabolism in cardiac hypertrophy. Likewise, caloric restriction (CR) also plays an important role in this cardioprotection through AMPK activation. We aimed to determine the influence of body weight (BW) on RVH, AMPK and related variables by comparing rats exposed to both hypoxic conditions. Methods: Sixty male adult rats were separated into two groups (n = 30 per group) according to their previous diet: a caloric restriction (CR) group and an ad libitum (AL) group. Rats in both groups were randomly assigned to 3 groups: a normoxic group (NX, n = 10), a CIH group (2 days hypoxia/2 days normoxia; n = 10) and a CH group (n = 10). The CR group was previously fed 10 g daily, and the other was fed ad libitum. Rats were exposed to simulated hypobaric hypoxia in a hypobaric chamber set to 428 Torr (the equivalent pressure to that at an altitude of 4,600 m above sea level) for 30 days. Measurements included body weight; hematocrit; serum insulin; glycemia; the degree of RVH (Fulton’s index and histology); and AMPK, mTOR, and PP2C expression levels in the right ventricle determined by western blotting. Results: A lower degree of RVH, higher AMPK activation, and no activation of mTOR were found in the CR groups exposed to hypobaric hypoxia compared to the AL groups (p < 0.05). Additionally, decreased glycemia and serum insulin levels were observed. Interestingly, PP2C expression showed an increase in the AL groups but not in the CR groups (p < 0.05). Conclusion: Maintaining a low weight before and during exposure to high-altitude hypoxia, during either CH or CIH, could prevent a major degree of RVH. This cardioprotection would likely be due to the activation of AMPK. Thus, body weight is a factor that might contribute to RVH at high altitudes., This study was supported by grants from projects GORE FIC Tarapacá BIP30477541-0 and Internal Project VRIIP0098

In some subjects, high-altitude hypobaric hypoxia leads to high-altitude pulmonary hypertension. The threshold for the diagnosis of high-altitude pulmonary hypertension is a mean pulmonary artery pressure of 30 mmHg, even though for general pulmonary hypertension is ≥25 mmHg. High-altitude pulmonary hypertension has been associated with high hematocrit findings (chronic mountain sickness), and although these are two separate entities, they have a synergistic effect that should be considered. In recent years, a new condition associated with high altitude was described in South America named long-term chronic intermittent hypoxia and has appeared in individuals who commute to work at high altitude but live and rest at sea level. In this review, we discuss the initial epidemiological pattern from the early studies done in Chile, the clinical presentation and possible molecular mechanism and a discussion of the potential management of this condition.

Reports of VO2 response differences between normoxia and hypoxia during incremental exercise do not agree. In this study VO2 and VE were obtained from 15-s averages at identical work rates during continuous incremental cycle exercise in 8 subjects under ambient pressure (633 mmHg ≈1,600 m) and during duplicate tests in acute hypobaric hypoxia (455 mmHg ≈4,350 m), ranging from 49 to 100% of VO2 peak in hypoxia and 42–87% of VO2 peak in normoxia. The average VO2 was 96 mL/min (619 mL) lower at 455 mmHg (n.s. P = 0.15) during ramp exercises. Individual response points were better described by polynomial than linear equations (mL/min/W). The VE was greater in hypoxia, with marked individual variation in the differences which correlated significantly and directly with the VO2 difference between 455 mmHg and 633 mmHg (P = 0.002), likely related to work of breathing (Wb). The greater VE at 455 mmHg resulted from a greater breathing frequency. When a subject's hypoxic ventilatory response is high, the extra work of breathing reduces mechanical efficiency (E). Mean ∆E calculated from individual linear slopes was 27.7 and 30.3% at 633 and 455 mmHg, respectively (n.s.). Gross efficiency (GE) calculated from mean VO2 and work rate and correcting for Wb from a VE–VO2 relationship reported previously, gave corresponding values of 20.6 and 21.8 (P = 0.05). Individual variation in VE among individuals overshadows average trends, as also apparent from other reports comparing hypoxia and normoxia during progressive exercise and must be considered in such studies.

As a model of extreme conditions, eight healthy women, part of a 40-member Nepal mountain-climbing expedition, were monitored for dynamic endocrine adaptations. Endocrine measurements were made at frequent intervals over a 6–10-h period at four altitudes: 450 m, 4,800 m (base camp), 6,050 m, and again at 4,800 m (on descent) after an acclimatization (A) period (4,800 mA). Quantified hormones were growth hormone (GH), prolactin (PROL), cortisol (Cort), thyroid-stimulating hormone (TSH), and free thyroxine. These hormones are important to the anabolic/catabolic balance of the body, and are vital to growth, homeostasis, hypothalamic inhibition, regulation of stress, and metabolism. A key secondary question was the degree to which acclimatization can stabilize hormonal disruption. On the basis of statistical false discovery rates, the present analyses unveil marked adaptive changes in the thyroid axis at the level of pulsatile secretion of the pituitary hormone TSH and its downstream product, free thyroxine; strong effects on the mass of GH, TSH, Cort, and PROL secretion per burst; and prominent pulsatile frequency disruption and recovery for PROL and Cort. Because pulsatility changes reflect de facto perturbations in hypothalamo-pituitary control mechanisms, the present data introduce the concept of both frequency- and amplitude-dependent adaptive control of brain-pituitary neuroendocrine signals under conditions of extreme altitude exertion and exposure.

It remains unknown whether hypobaria plays a role on cerebrovascular reactivity to CO2 (CVR). The present study evaluated the putative effect of hypobaria on CVR and its influence on cerebral oxygen delivery (cDO2) in five randomized conditions (i.e., normobaric normoxia, NN, altitude level of 440 m; hypobaric hypoxia, HH at altitude levels of 3,000 m and 5,500 m; normobaric hypoxia, NH, altitude simulation of 5,500 m; and hypobaric normoxia, HN). CVR was assessed in nine healthy participants (either students in aviation or pilots) during a hypercapnic test (i.e., 5% CO2). We obtained CVR by plotting middle cerebral artery velocity versus end‐tidal CO2 pressure (PETCO2) using a sigmoid model. Hypobaria induced an increased slope in HH (0.66 ± 0.33) compared to NH (0.35 ± 0.19) with a trend in HN (0.46 ± 0.12) compared to NN (0.23 ± 0.12, p = .069). PETCO2 was decreased (22.3 ± 2.4 vs. 34.5 ± 2.8 mmHg and 19.9 ± 1.3 vs. 30.8 ± 2.2 mmHg, for HN vs. NN and HH vs. NH, respectively, p, The present study was the first one to compare cerebrovascular CO2 reactivity during acute exposure in various normobaric/hypobaric and normoxic/hypoxic conditions. Our results suggest that vascular reserve to dilate may be blunted in hypobaria, either in hypoxic or normoxic conditions, since midpoint was left shifted. This blunt effect in hypobaria could impair cerebral oxygen delivery.

Background: The study investigated submaximal exercise responses during an acute exposure to normobaric hypoxia (NH) versus hypobaric hypoxia (HH) focusing on different exercise intensities. Method...