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Aging is associated with vascular endothelial dysfunction observed through a progressive loss of flow-mediated dilation caused partly by a decreased nitric oxide bioavailability. Intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and normoxic air, was reported to either maintain or improve vascular function in young adults. The aim of this study was to determine the impact of age on the vascular response to intermittent hypoxia. Twelve young adults and 11 older adults visited the laboratory on two occasions. Plasma nitrate concentrations and brachial artery flow-mediated dilation were assessed before and after exposure to either intermittent hypoxia or a sham protocol. Intermittent hypoxia consisted of eight 4-min hypoxic cycles at a targeted oxygen saturation of 80% interspersed with breathing room air to resaturation, and the sham protocol consisted of eight 4-min normoxic cycles interspersed with breathing room air. Vascular responses were assessed during intermittent hypoxia and the sham protocol. Intermittent hypoxia elicited a brachial artery vasodilation but did not change brachial artery shear rate in both young and older adults. Plasma nitrate concentrations were not significantly affected by intermittent hypoxia compared with the sham protocol in both groups. Brachial artery flow-mediated dilation was not acutely affected by intermittent hypoxia or the sham protocol in either young or older adults. In conclusion, the brachial artery vasodilatory response to intermittent hypoxia was not influenced by age. Intermittent hypoxia increased brachial artery diameter but did not acutely affect endothelium-dependent vasodilation in young or older adults. NEW & NOTEWORTHY: The objective of this study was to determine the impact of age on the vascular response to intermittent hypoxia. Eight 4-min bouts of hypoxia at a targeted oxygen saturation of 80% induced a brachial artery vasodilation in both young and older adults, indicating that age does not influence the vasodilatory response to intermittent hypoxia. Intermittent hypoxia did not acutely affect brachial artery flow-mediated dilation in young or older adults. [ABSTRACT FROM AUTHOR]

Acute intermittent hypoxia (AIH) can induce sustained facilitation of motor output in people with spinal cord injury (SCI). Most studies of corticospinal tract excitability in humans have used 9% fraction inspired oxygen (F I O 2 ) AIH (AIH-9%), with inconsistent outcomes. We investigated the effect of single sessions of 9% F I O 2 and 12% F I O 2 AIH (AIH-12%) on corticospinal excitability of a hand and leg muscle in able-bodied adults. Ten naïve participants completed three sessions on separate days comprising 15 epochs of 1 min of AIH-9%, AIH-12%, or sham (SHAM-21%) followed by 1 min of room air (21% F I O 2 ) in a randomized crossover design. Motor-evoked potentials (MEPs; n = 30, ∼1 mV) elicited at rest by transcranial magnetic stimulation and maximal M-waves (Mmax) evoked by peripheral nerve stimulation were measured from the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles at baseline and at ∼0, 20, 40, and 60 min post intervention. AIH-9% induced the greatest reduction in peripheral oxygen saturation (to 85% vs. 93% and 100% in AIH-12% and SHAM-21%, respectively; P < 0.001) and the greatest increase in ventilation [by 22% vs. 12% and −3% in AIH-9%, AIH-12%, and SHAM-21%, respectively (P < 0.001)]. There was no difference in MEP amplitudes (%Mmax) after any of the three conditions (AIH-9%, AIH-12%, SHAM-21%) for both the FDI (P = 0.399) and TA (P = 0.582). Despite greater cardiorespiratory changes during AIH-9%, there was no evidence of corticospinal facilitation (tested with MEPs) in this study. Further studies could explore variability in response to AIH between individuals and other methods to measure motor facilitation in people with and without spinal cord injuries. NEW & NOTEWORTHY: This is the first study that tests whether acute intermittent hypoxia (AIH) induces motor output facilitation in humans after two different doses of AIH (9% and 12% F I O 2 ) and the reproducibility of participant responses after a repeat AIH intervention at 9% AIH. There was no motor output facilitation in response to either dose of AIH. The results question the effectiveness of a single 30-min session of AIH in inducing motor output facilitation, tested in this way. [ABSTRACT FROM AUTHOR]

Acute exposure to hypoxia increases postural sway, but the underlying neurophysiological factors are unclear. Golgi tendon organs (GTOs), located within the musculotendinous junction (MTJ), provide inhibitory signals to plantar flexor muscles that are important for balance control; however, it is uncertain if GTO function is influenced by hypoxia. The aim of this study was to determine how normobaric hypoxia influences lower limb tendon-evoked inhibitory reflexes during upright stance. We hypothesized that tendon-evoked reflex area and duration would decrease during hypoxia, indicating less inhibition of postural muscles compared with normoxia. At baseline (BL; 0.21 fraction of inspired oxygen, FIO2) and at ∼2 (H2) and 4 (H4) h of normobaric hypoxia (0.11 FIO2) in a normobaric hypoxic chamber, 16 healthy participants received electrical musculotendinous stimulation (MTstim) to the MTJ of the left Achilles tendon. The MTstim was delivered as two sets of 50 stimuli while the participant stood on a force plate with their feet together. Tendon-evoked inhibitory reflexes were recorded from the surface electromyogram of the ipsilateral medial gastrocnemius, and center of pressure (CoP) variables were recorded from the force plate. Normobaric hypoxia increased CoP velocity (P ≤ 0.002) but not CoP standard deviation (P ≥ 0.12). Compared with BL, normobaric hypoxia reduced tendon-evoked inhibitory reflex area by 45% at H2 and 53% at H4 (P ≤ 0.002). In contrast, reflex duration was unchanged during hypoxia. The reduced inhibitory feedback from the GTO pathway could likely play a role in the increased postural sway observed during acute exposure to hypoxia. NEW & NOTEWORTHY: The Ib pathway arising from the Golgi tendon organ provides inhibitory signals onto motor neuron pools that modifies force and, hence, postural control. Although hypoxia influences standing balance (increases sway), the underlying mechanisms have yet to be unraveled. Our study identified that tendon-evoked inhibition onto a plantar flexor motoneuron pool is reduced by acute exposure to normobaric hypoxia. This reduction of inhibition may contribute to the hypoxia-related increase in postural sway. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that acute moderate normobaric hypoxia augments circulating thyroid hormone concentrations during and following 1 h of cold head-out water immersion (HOWI), compared with when cold HOWI is completed during normobaric normoxia. In a randomized crossover single-blind design, 12 healthy adults (27 ± 2 yr, 2 women) completed 1 h of cold (22.0 ± 0.1°C) HOWI breathing either normobaric normoxia (F I O 2 = 0.21) or normobaric hypoxia (F I O 2 = 0.14). Free and total thyroxine (T3) and triiodothyronine (T4), and thyroid-stimulating hormone (TSH) concentrations were measured in venous blood samples obtained before (baseline), during (15-, 30-, and 60 min), and 15 min following HOWI (post-), and were corrected for changes in plasma volume. Arterial oxyhemoglobin saturation and core (rectal) temperature were measured continuously. Arterial oxyhemoglobin saturation was lower during hypoxia (90 ± 3%) compared with normoxia (98 ± 1%, P < 0.001). Core temperature fell from baseline (normoxia: 37.2 ± 0.4°C, hypoxia: 37.2 ± 0.4°C) to post-cold HOWI (normoxia: 36.4 ± 0.5°C, hypoxia: 36.3 ± 0.5°C, P < 0.001) in both conditions but did not change differently between conditions (condition × time: P = 0.552). Circulating TSH, total T3, free T4, total T3, and free T4 concentrations demonstrated significant main effects of time (all P ≤ 0.024), but these changes did not differ between normoxic and hypoxic conditions (condition × time: all P ≥ 0.163). These data indicate that acute moderate normobaric hypoxia does not modify the circulating thyroid hormone response during 1 h of cold HOWI. NEW & NOTEWORTHY: Acute head-out cold (22°C) water immersion (HOWI) decreased core temperature and increased thermogenesis. This thermogenic response was paralleled by the activation of the hypothalamic-pituitary-thyroid axis, as evidenced by changes in thyroid hormones. However, cold HOWI in combination with moderate normobaric hypoxia did not modify the thermogenic nor the circulating thyroid hormone response. This finding suggests that hypoxia-induced alterations in thyroid hormone concentrations are unlikely to acutely contribute to adaptations resulting from repeated cold-water exposures. [ABSTRACT FROM AUTHOR]

The common pulmonary consequence of SARS-CoV-2 infection is pneumonia, but vascular clot may also contribute to COVID pathogenesis. Imaging and hemodynamic approaches to identifying diffuse pulmonary vascular obstruction (PVO) in COVID (or acute lung injury generally) are problematic particularly when pneumonia is widespread throughout the lung and hemodynamic consequences are buffered by pulmonary vascular recruitment and distention. Although stimulated by COVID-19, we propose a generally applicable bedside gas exchange approach to identifying PVO occurring alone or in combination with pneumonia, addressing both its theoretical and practical aspects. It is based on knowing that poorly (or non) ventilated regions, as occur in pneumonia, affect O2 more than CO2, whereas poorly (or non) perfused regions, as seen in PVO, affect CO2 more than O2. Exhaled O2 and CO2 concentrations at the mouth are measured over several ambient-air breaths, to determine mean alveolar Po2 and Pco2. A single arterial blood sample is taken over several of these breaths for arterial Po2 and Pco2. The resulting alveolar-arterial Po2 and Pco2 differences (AaPo2, aAPco2) are converted to corresponding physiological shunt and deadspace values using the Riley and Cournand 3-compartment model. For example, a 30% shunt (from pneumonia) with no alveolar deadspace produces an AaPO2 of almost 50 torr, but an aAPco2 of only 3 torr. In contrast, a 30% alveolar deadspace (from PVO) without shunt leads to an AaPO2 of only 12 torr, but an aAPco2 of 9 torr. This approach can identify and quantify physiological shunt and deadspace when present singly or in combination.NEW & NOTEWORTHY Identifying pulmonary vascular obstruction in the presence of pneumonia (e.g., in COVID-19) is difficult. We present here conversion of bedside measurements of arterial and alveolar Po2 and Pco2 into values for shunt and deadspace-when both coexist-using Riley and Cournand's 3-compartment gas exchange model. Deadspace values higher than expected from shunt alone indicate high ventilation/perfusion ratio areas likely reflecting (micro)vascular obstruction.

Eight 4-min cycles of intermittent hypoxia represent the shortest hypoxic exposure to increase erythropoietin (EPO) levels in young adults. The impact of aging on the EPO response to a hypoxic stimulus remains equivocal. Thus, the objective of this study was to determine the effect of the same intermittent hypoxia protocol on EPO levels in older adults. Twenty-two participants (12 women, age: 53 ± 7 yr) were randomly assigned to an intermittent hypoxia group (IH, n = 11) or an intermittent normoxia group (IN, n = 11). Intermittent hypoxia consisted of eight 4-min cycles at a targeted oxygen saturation of 80% interspersed with normoxic cycles to resaturation. Air was made hypoxic by titrating nitrogen into a breathing circuit. Intermittent normoxia consisted of the same protocol, but nitrogen was not added to the breathing circuit. EPO levels were measured before and 4.5 h after the beginning of each protocol. Intermittent hypoxia lowered oxygen saturation to 82 ± 3%, which corresponded to a fraction of inspired oxygen of 10.9 ± 1.0%. There was a greater increase in EPO levels following intermittent hypoxia than intermittent normoxia (IH: 3.2 ± 2.2 vs. IN: 0.7 ± 0.8 mU/mL, P < 0.01). A single session of eight 4-min cycles of hypoxia increased EPO levels, the glycoprotein stimulating red blood cell production, in older adults. Exposure to intermittent hypoxia has therefore the potential to increase oxygen-carrying capacity in a population with reduced red blood cell volume. [ABSTRACT FROM AUTHOR]

Abstract Repeat exposures to low oxygen (intermittent hypoxia, IH), like that observed in sleep apnea, elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans are unclear. We hypothesized that ETreceptor antagonism would ameliorate any rise in MSNA and BP following acute IH in humans. Twelve healthy men (31 ± 1 yr) completed two visits (control, bosentan) separated by at least 1 wk. MSNA, BP, and baroreflex sensitivity (modified Oxford) were assessed during normoxic rest before and following 30 min of IH. The midpoint (T50) for each individual’s baroreflex curve was calculated. Acute IH increased plasma ET-1 (P < 0.01), MSNA burst frequency (P = 0.03), and mean BP (P < 0.01). There was no effect of IH on baroreflex sensitivity (P = 0.46), although an increase in T50 was observed (P < 0.01). MSNA burst frequency was higher (P = 0.04) and mean BP (P < 0.01) was lower following bosentan treatment compared with control. There was no effect of bosentan on baroreflex sensitivity (P = 0.53), although a lower T50 was observed on the bosentan visit (P < 0.01). There was no effect of bosentan on increases in MSNA (P = 0.81) or mean BP (P = 0.12) following acute IH. Acute IH results in an increase in ET-1, MSNA, and BP in healthy young men. The effect of IH on MSNA and BP is not attenuated following ET-receptor inhibition. Present data suggest that acute IH does not increase MSNA or BP through activation of ETreceptors in healthy young men. NEW & NOTEWORTHY Repeat exposures to low oxygen (intermittent hypoxia, IH) elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans were unclear. We show acute IH results in an increase in ET1, MSNA, and BP in healthy young men; however, the effect of IH on MSNA and BP does not occur through activation of ETreceptors in healthy young men. [ABSTRACT FROM AUTHOR]

The diaphragm is the main skeletal muscle responsible for inspiration and is susceptible to age-associated decline in function and morphology. Satellite cells in diaphragm fuse into unperturbed muscle fibers throughout life, yet their role in adaptations to hypoxia in diaphragm is unknown. Given their continual fusion, we hypothesize that satellite cell depletion will negatively impact adaptations to hypoxia in the diaphragm, particularly with aging. We used the Pax7CreER/CreER:R26RDTA/DTA genetic mouse model of inducible satellite cell depletion to investigate diaphragm responses to hypoxia in adult (6 mo) and aged (22 mo) male mice. The mice were subjected to normobaric hypoxia at 10% FIO2 or normoxia for 4 wk. We showed that satellite cell depletion had no effect on diaphragm muscle fiber cross-sectional area, fiber-type distribution, myonuclear density, or regulation of extracellular matrix in either adult or aged mice. Furthermore, we showed lower muscle fiber cross-sectional area with hypoxia and age (main effects), while extracellular matrix content was higher and satellite cell abundance was lower with age (main effect) in diaphragm. Lastly, a greater number of Pax3-mRNA+ cells was observed in diaphragm muscle of satellite cell-depleted mice independent of hypoxia (main effect), potentially as a compensatory mechanism for the loss of satellite cells. We conclude that satellite cells are not required for diaphragm muscle adaptations to hypoxia in either adult or aged mice. NEW & NOTEWORTHY Satellite cells show consistent fusion into diaphragm muscle fibers throughout life, suggesting a critical role in maintaining homeostasis. Here, we report identical diaphragm adaptations to hypoxia with and without satellite cells in adult and aged mice. In addition, we propose that the higher number of Pax3-positive cells in satellite cell-depleted diaphragm muscle acts as a compensatory mechanism. [ABSTRACT FROM AUTHOR]

The objective of our study was to establish in sedated rats the consequences of high-dose fentanyl-induced acute muscle rigidity on the mechanical properties of the respiratory system and on the metabolic rate. Doses of fentanyl that we have previously shown to produce persistent rigidity of the muscles of the limbs and trunk in the rat (150-300 μg/kg iv), were administered in 23 volume-controlled mechanically ventilated and sedated rats. The effects of a low dose of the FDA-approved central α-2 agonist, dexmedetomidine (3 µg/kg iv), which has been suggested to oppose fentanyl-induced muscle rigidity, were determined after fentanyl administration. Fentanyl produced a significant decrease in compliance of the respiratory system (Crs) in all the rats that were studied. In 13 rats, an abrupt response occurred within 90 s, consisting of rapid rhythmic contractions of most skeletal muscles that were replaced by persistent tonic/tetanic contractions leading to a significant decrease of Crs (from 0.51 ± 0.11 mL/ cmH2O to 0.36 ± 0.08 mL/cmH2O, 3 min after fentanyl injection). In the other 10 animals, Crs progressively decreased to 0.26 ± 0.06 mL/cmH2O at 30 min. There was a significant rise in oxygen consumption ...O2) during these muscle contractions (from 8.48 ± 4.31 to 11.29 ± 2.57 mL/min), which led to a significant hypoxemia, despite ventilation being held constant. Dexmedetomidine provoked a significant and rapid increase in Crs toward baseline levels, whereas decreasing the metabolic rate and restoring normoxemia. We propose that the changes in respiratory mechanics and metabolism produced by opioidinduced muscle rigidity contribute to fentanyl lethality. NEW & NOTEWORTHY The decrease in respiratory compliance and increased metabolism-induced hypoxemia produced by an overdose of fentanyl, in and of themselves, contribute to fentanyl toxicity. [ABSTRACT FROM AUTHOR]

Ventilatory response to sustained isocapnic hypoxia in adult humans and other mammals is characterized by a biphasic pattern, with attenuation of neuromotor output to the diaphragm. However, there is no a priori reason that hypoxia-mediated attenuation of respiratory drive would be a common event among other respiratory muscles. At present, little is known about the function of the chest wall muscles during sustained hypoxia. As an obligatory inspiratory muscle with potential to act as a surrogate for neural drive to the relatively inaccessible costal diaphragm, parasternal intercostal has gained interest clinically: its function during a sustained hypoxic insult, as may occur in respiratory failure, warrants investigation. Therefore, in 11 chronically instrumented awake canines, we simultaneously recorded muscle length and shortening and electromyogram (EMG) activity of the parasternal chest wall inspiratory muscle, along with breathing pattern, during moderate levels of sustained isocapnic hypoxia lasting 20-25 min (mean 80 ± 2% oximeter oxygen saturation). Phasic inspiratory shortening and EMG activity of the parasternal intercostal were observed throughout room air and hypoxic ventilation in all animals. Temporal changes in parasternal intercostal shortening tracked the biphasic changes in ventilation during sustained hypoxia. Mean shortening and EMG activity of parasternal intercostal muscle increased significantly with initial hypoxia (P < 0.01) and then markedly declined with constant hypoxia (P < 0.05). We conclude that attenuation of central neural respiratory drive extends to the primary chest wall inspiratory muscle, the parasternal intercostal, during sustained hypoxia, thus directly contributing to biphasic changes in ventilation. [ABSTRACT FROM AUTHOR]

Proteinuria is a transient physiological phenomenon that occurs with a range of physical activities and during ascent to altitude. Exercise intensity appears to dictate the magnitude of postexercise proteinuria; however, evidence also indicates the possible contributions from exercise-induced hypoxemia or reoxygenation. Using an environmental hypoxic chamber, this cross over designed study aimed to evaluate urinary alpha-1 acid glycoprotein (α1-AGP) excretion pre/postexercise performed in hypoxia (HYP) and normoxia (NOR). Sixteen individuals underwent experimental sessions in normoxia (NOR, 20.9% O2) and hypoxia (HYP, 12.0% O2). Sessions began with α 2-h priming period before completing a graded maximal exercise test (GXT) on a cycle ergometer, which was followed by continuation of exposure for an additional 2 h. Physiological responses (i.e., blood pressure, heart rate, and peripheral oxygenation), Lake Louise Scores (LLSs), and urine specimens (analyzed for albumin and α1-AGP) were collected pre- and postexercise (after 30, 60, and 120 min). Peak power output was significantly reduced in HYP (193 ± 45 W) compared with NOR (249 ± 59 W, P < 0.01). Postexercise urinary α1-AGP was greater in NOR (20.04 ± 14.84 mg·min-1 ) than in HYP (15.08 ± 13.46 mg·min-1 ), albeit the difference was not significant (P > 0.05). Changes in urinary α1-AGP from pre- to post-30 min were not related to physiological responses or performance outcomes observed during GXT in NOR or HYP. Despite profound systemic hypoxemia with maximal exercise in hypoxia, postexercise α1-AGP excretion was not elevated above the levels observed following normoxic exercise. [ABSTRACT FROM AUTHOR]

A drop in arterial oxygen content activates fetal chemoreflex including an increase in sympathetic activity leading to peripheral vasoconstriction and redistribution of blood flow to protect the brain, myocardium, and adrenal glands. By using a chronically instrumented fetal sheep model with intact placental circulation at near-term gestation, we investigated the relationship between peripheral chemoreflex activation induced by hypoxemia and central hemodynamics. A total of 17 Åland landrace sheep fetuses at 115-128/145 gestational days were instrumented. Carotid artery was catheterized in 10 fetuses and descending aorta in 7 fetuses. After a 4-day recovery, baseline measurements of fetal arterial blood pressures, blood gas values, and fetal cardiovascular hemodynamics by pulsed Doppler ultrasonography were obtained under isoflurane anesthesia. Comparable data to baseline were collected 10 min (acute hypoxemia) and 60 min (prolonged hypoxemia) after maternal hypo-oxygenation to saturation level of 70%-80% was achieved. During prolonged hypoxemia, pH and base excess (BE) were lower and lactate levels were higher in the descending aorta than in the carotid artery. During hypoxemia mean arterial blood pressure (MAP) in the descending aorta increased, whereas in the carotid artery, MAP decreased. In addition, right pulmonary artery pulsatility index values increased, and the diastolic component in the aortic isthmus blood flow velocity waveform became more retrograde, thus decreasing the aortic isthmus antegrade/retrograde blood flow (AoI Net Flow) ratio. Both fetal ventricular cardiac outputs were maintained even during prolonged hypoxemia when significant fetal metabolic acidemia developed. Fetal chemoreflex activation induced by hypoxemia decreased the perfusion pressure in the cerebral circulation. Fetal weight-indexed left ventricular cardiac output (LVCO) or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure. NEW & NOTEWORTHY During fetal hypoxemia with intact placental circulation, peripheral chemoreflex was activated, as demonstrated by an increase in the descending aorta blood pressure, pulmonary vasoconstriction, and an increase in retrograde diastolic AoI blood flow, while both ventricular cardiac outputs remained stable. However, perfusion pressure in the cerebral circulation decreased. These changes were seen even during prolonged hypoxemia when significant metabolic acidosis developed. Weight-indexed LVCO or AoI Net Flow ratio did not correlate with a drop in carotid artery blood pressure. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of direct creatine infusion on fetal systemic metabolic and cardiovascular responses to mild acute in utero hypoxia. Pregnant ewes (n = 28) were surgically instrumented at 118 days gestation (dGa). A constant intravenous infusion of creatine (6 mg·kg-1·h-1) or isovolumetric saline (1.5 mL·h-1) began at 121 dGa. After 10 days, fetuses were subjected to 10-min umbilical cord occlusion (UCO) to induce mild global hypoxia (saline-UCO, n = 8; creatine-UCO, n = 7) or sham UCO (saline-control, n = 6; creatine-control, n = 7). Cardiovascular, arterial blood gases and metabolites, and plasma creatine were monitored before, during, and then for 72 h following the UCO. Total creatine content in discrete fetal brain regions was also measured. Fetal creatine infusion increased plasma concentrations fivefold but had no significant effects on any measurement pre-UCO. Creatine did not alter fetal physiology during the UCO or in the early recovery stage, up to 24 h after UCO. During the late recovery stage, 24-72 h after UCO, there was a significant reduction in the arterial oxygen pressure and saturation in creatine fetuses (PUCO x TREATMENT = 0.02 and 0.04, respectively). At 72 h after UCO, significant creatine loading was detected in cortical gray matter, hippocampus, thalamus, and striatum (PTREATMENT = 0.01-0.001). In the striatum, the UCO itself increased total creatine content (PUCO = 0.019). Overall, fetal creatine supplementation may alter oxygen flux following an acute hypoxic insult. Increasing total creatine content in the striatum may also be a fetal adaptation to acute oxygen deprivation. [ABSTRACT FROM AUTHOR]

The blood-brain barrier (BBB), blood-cerebrospinal fluid (CSF) barrier (BCSFB), and CSF-brain barriers (CSFBB) are highly regulated barriers in the central nervous system comprising complex multicellular structures that separate nerves and glia from blood and CSF, respectively. Barrier damage has been implicated in the pathophysiology of diverse hypoxia-related neurological conditions, including stroke, multiple sclerosis, hydrocephalus, and high-altitude cerebral edema. Much is known about the damage to the BBB in response to hypoxia, but much less is known about the BCSFB and CSFBB. Yet, it is known that these other barriers are implicated in damage after hypoxia or inflammation. In the 1950s, it was shown that the rate of radionucleated human serum albumin passage from plasma to CSF was five times higher during hypoxic than normoxic conditions in dogs, due to BCSFB disruption. Severe hypoxia due to administration of the bacterial toxin lipopolysaccharide is associated with disruption of the CSFBB. This review discusses the anatomy of the BBB, BCSFB, and CSFBB and the impact of hypoxia and associated inflammation on the regulation of those barriers. [ABSTRACT FROM AUTHOR]

Superior cervical ganglia (SCG) postganglionic neurons receive preganglionic drive via the cervical sympathetic chains (CSC). The SCG projects to structures like the carotid bodies (e.g., vasculature, chemosensitive glomus cells), upper airway (e.g., tongue, nasopharynx), and to the parenchyma and cerebral arteries throughout the brain. We previously reported that a hypoxic gas challenge elicited an array of ventilatory responses in sham-operated (SHAM) freely moving adult male C57BL6 mice and that responses were altered in mice with bilateral transection of the cervical sympathetic chain (CSCX). Since the CSC provides preganglionic innervation to the SCG, we presumed that mice with superior cervical ganglionectomy (SCGX) would respond similarly to hypoxic gas challenge as CSCX mice. However, while SCGX mice had altered responses during hypoxic gas challenge that occurred in CSCX mice (e.g., more rapid occurrence of changes in frequency of breathing and minute ventilation), SCGX mice displayed numerous responses to hypoxic gas challenge that CSCX mice did not, including reduced total increases in frequency of breathing, minute ventilation, inspiratory and expiratory drives, peak inspiratory and expiratory flows, and appearance of noneupneic breaths. In conclusion, hypoxic gas challenge may directly activate subpopulations of SCG cells, including subpopulations of postganglionic neurons and small intensely fluorescent (SIF) cells, independently of CSC drive, and that SCG drive to these structures dampens the initial occurrence of the hypoxic ventilatory response, while promoting the overall magnitude of the response. The multiple effects of SCGX may be due to loss of innervation to peripheral and central structures with differential roles in breathing control. [ABSTRACT FROM AUTHOR]

Diagnosing the cause of hypoxemia and dyspnea can be complicated in complex patients with multiple comorbidities. This "Case Study in Physiology" describes an man with obesity admitted to the hospital for relapse of acute lymphoblastic leukemia, who experienced progressive hypoxemia, shortness of breath, and dyspnea on exertion during his hospitalization. After initial empirical treatment with diuresis and antibiotics failed to improve his symptoms and because an arterial blood gas measurement was not readily available, we applied a novel, recently described physiological method to estimate the arterial partial pressure of oxygen from the peripheral saturation measurement and calculate the alveolar-arterial oxygen difference to discern the source of his hypoxemia and dyspnea. Using basic physiological principles, we describe how hypoventilation, anemia, and the use of a β blocker and furosemide, collaborated to create a "perfect storm" in this patient that impaired oxygen delivery and limited utilization. This case illustrates the application of innovative physiology methodology in medicine and provides a strong rationale for continuing to integrate physiology education in medical education. [ABSTRACT FROM AUTHOR]

Avalanche patients who are completely buried but still able to breathe are exposed to hypothermia, hypoxia, and hypercapnia (triple H syndrome). Little is known about how these pathological changes affect brain physiology. The study aim was to investigate the effect of hypothermia, hypoxia, and hypercapnia on brain oxygenation and systemic and cerebral hemodynamics. Anesthetized pigs were surface cooled to 28° C. Fraction of inspiratory oxygen (FIO2 ) was reduced to 17% and hypercapnia Anesthetized pigs were surface cooled to 28° C. Fraction of inspiratory oxygen (...) was reduced to 17% and hypercapnia induced. Hemodynamic parameters and blood gas values were monitored. Cerebral measurements included cerebral perfusion pressure (CPP), brain tissue oxygen tension (...), cerebral venous oxygen saturation (...), and regional cerebral oxygen saturation (...). Tests were interrupted when hemodynamic instability occurred or 60min after hypercapnia induction. ANOVA for repeated measures was used to compare values across phases. There was no clinically relevant reduction in cerebral oxygenation (...) during hypothermia and initial (...) reduction. Hypercapnia was associated with an increase in pulmonary resistance followed by a decrease in cardiac output and CPP, resulting in hemodynamic instability and cerebral desaturation (decrease in (...). Hypercapnia may be the main cause of cardiovascular instability, which seems to be the major trigger for a decrease in cerebral oxygenation in triple H syndrome despite severe hypothermia. [ABSTRACT FROM AUTHOR]

Arterial oxygen tension and oxyhemoglobin saturation (...) decrease in parallel during hypoxia. Distinguishing between changes in oxygen tension and oxygen content as the relevant physiological stimulus for cardiorespiratory alterations remains challenging. To overcome this, we recruited nine individuals with hemoglobinopathy manifesting as high-affinity hemoglobin [HAH; partial pressure at 50% ... (P50) = 16 ± 0.4 mmHg] causing greater ... at a given oxygen partial pressure compared with control subjects (n = 12, P50 = 26 ± 0.4 mmHg). We assessed ventilatory and cardiovascular responses to acute isocapnic hypoxia, iso-oxic hypercapnia, and 20 min of isocapnic hypoxia (arterial Po2 = 50 mmHg). Blood gas alterations were achieved with dynamic end-tidal forcing. When expressed as a function of the logarithm of oxygen partial pressure, ventilatory sensitivity to hypoxia was not different between groups. However, there was a significant difference when expressed as a function of .... Conversely, the rise in heart rate was blunted in HAH subjects when expressed as a function of partial pressure but similar when expressed as a function of .... Ventilatory sensitivity to hypercapnia was not different between groups. During sustained isocapnic hypoxia, the rise in minute ventilation was similar between groups; however, heart rate was significantly greater in the controls during 3 to 9 min of exposure. Our results support the notion that oxygen tension, not content, alters cellular Po2 in the chemosensors and drives the hypoxic ventilatory response. Our study suggests that in addition to oxygen partial pressure, oxygen content may also influence the heart rate response to hypoxia. [ABSTRACT FROM AUTHOR]

Elite endurance athletes are used to train under hypoxic/high-altitude conditions, which can elicit certain stress responses in skeletal muscle and helps to improve their physical performance. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates cellular redox homeostasis and metabolism in skeletal muscle, playing important roles in adaptation to various stresses. In this study, Nrf2 knockout (KO) and wild-type (WT) mice were preconditioned to 48 h of hypoxia exposure (11.2% oxygen), and the effects of hypoxia preconditioning (HP) on exercise capacity and exercise-induced changes of antioxidant status, energetic metabolism, and mitochondrial adaptation in skeletal muscle were evaluated. Nrf2 knockout (KO) and wild-type (WT) mice were exposed to normoxia or hypoxia for 48 h before taking incremental treadmill exercise to exhaustion under hypoxia. The skeletal muscles were collected immediately after the incremental treadmill exercise to evaluate the impacts of HP and Nrf2 on the exercise-induced changes. The results indicate the absence of Nrf2 did not affect exercise capacity, although the mRNA expression of certain muscular genes involved in antioxidant, glycogen and fatty acid catabolism was decreased in Nrf2 KO mice. However, 48-h HP enhanced exercise capacity in WT mice but not in Nrf2 KO mice, and the exercise capacity of WT mice was significantly higher than that of Nrf2 KO mice. These findings suggest HP promotes exercise capacity of mice with the participation of the Nrf2 signal in skeletal muscle. [ABSTRACT FROM AUTHOR]

Measuring peripheral oxygen saturation (SpO2) with pulse oximeters at the point of care is widely established. However, since SpO2 is dependent on ambient atmospheric pressure, the distribution of SpO2 values in populations living above 2000 m a.s.l. is largely unknown. Here, we propose and evaluate a computer model to predict SpO2 values for pediatric permanent residents living between 0 and 4,000 m a.s.l. Based on a sensitivity analysis of oxygen transport parameters, we created an altitude-adaptive SpO2 model that takes physiological adaptation of permanent residents into account. From this model, we derived an altitude-adaptive abnormal SpO2 threshold using patient parameters from literature. We compared the obtained model and threshold against a previously proposed threshold derived statistically from data and two empirical data sets independently recorded from Peruvian children living at altitudes up to 4,100 m a.s.l. Our model followed the trends of empirical data, with the empirical data having a narrower healthy SpO2 range below 2,000 m a.s.l. but the medians never differed more than 2.3% across all altitudes. Our threshold estimated abnormal SpO2 in only 17 out of 5,981 (0.3%) healthy recordings, whereas the statistical threshold returned 95 (1.6%) recordings outside the healthy range. The strength of our parametrized model is that it is rooted in physiology-derived equations and enables customization. Furthermore, as it provides a reference SpO2, it could assist practitioners in interpreting SpO2 values for diagnosis, prognosis, and oxygen administration at higher altitudes. NEW & NOTEWORTHY Our model describes the altitude-dependent decrease of SpO2 in healthy pediatric residents based on physiological equations and can be adapted based on measureable clinical parameters. The proposed altitude-specific abnormal SpO2 threshold might be more appropriate than rigid guidelines for administering oxygen that currently are only available for patients at sea level. We see this as a starting point to discuss and adapt oxygen administration guidelines. [ABSTRACT FROM AUTHOR]

Heat and hypobaric hypoxia independently compromise exercise performance; however, their combined impact on exercise performance has yet to be quantified. This study examined the effects of heat, hypobaric hypoxia, and the combination of these environments on self-paced cycling time trial (TT) performance. Twelve subjects [2 female, 10 male; sea level (SL) peak oxygen consumption (VO2peak), 41.5 ± 4.4 mL·kg-1·min-1, mean ± SD] completed 30 min of steady-state cycling exercise (50% SL VO2peak), followed by a 15-min self-paced TT in four environmental conditions: SL thermoneutral [SLTN; 250 m, 20°C, 30-50% relative humidity (rh)], SL hot (SLH; 250 m, 35°C, 30% rh), hypobaric hypoxia thermoneutral (HTN; 3,000 m, 20°C, 30-50% rh), and hypobaric hypoxia hot (HH; 3,000 m, 35°C, 30% rh). Performance was assessed by the total work (kJ) completed. TT performance was lower (P < 0.05) in SLH, HTN, and HH relative to SLTN (-15.4 ± 9.7, <24.1 ± 16.2, and <33.1 ± 13.4 kJ, respectively). Additionally, the total work completed in HTN and HH was lower (P < 0.05) than that in SLH. In SLH, HTN, and HH, work rate was reduced versus SLTN (P < 0.05) within the first 3 min of exercise and was consistent for the remainder of the bout. No differences (P = 0.05) existed for heart rate or Ratings of Perceived Exertion at the end of exercise among conditions. The decrease in self-paced TT performance in the heat and/or hypobaric hypoxia conditions compared with SLTN conditions resulted from a nearly immediate reduction in work rate that may have been regulated by environmentally induced changes in physiological strain and perception of effort in response to TT exercise. [ABSTRACT FROM AUTHOR]

Subjects with a patent foramen ovale (PFO) have blunted ventilatory acclimatization to high altitude compared with subjects without PFO. The blunted response observed could be because of differences in central and/or peripheral respiratory chemoreflexes. We hypothesized that compared with subjects without a PFO (PFO), subjects with a PFO (PFO+) would have blunted ventilatory responses to acute hypoxia and hypercapnia. Sixteen PFO+ subjects (9 female) and 15 PFO- subjects (8 female) completed four 20-min trials on the same day: 1) normoxic hypercapnia (NH), 2) hyperoxic hypercapnia (HH), 3) isocapnic hypoxia (IH), and 4) poikilocapnic hypoxia (PH). Hypercapnic trials were completed before the hypoxic trials, the order of the hypercapnic (NH & HH) and hypoxic (IH & PH) trials were randomized, and trials were separated by ≥40 min. During the NH trials but not the HH trials subjects who were PFO+ had a blunted hypercapnic ventilatory response compared with subjects who were PFO- (1.41 ± 0.46 l·min-1·mmHg-1 vs. 1.98 ± 0.71 l·min-1· mmHg-1, P = 0.02). There were no differences between the PFO+ and PFO- subjects with respect to the acute hypoxic ventilatory response during IH and PH trials. Hypoxic ventilatory depression was similar between subjects who were PFO+ and PFO- during IH. These data suggest that compared with subjects who were PFO-, subjects who were PFO+ have normal ventilatory chemosensitivity to acute hypoxia but blunted ventilatory chemosensitivity to carbon dioxide, possibly because of reduced carbon dioxide sensitivity of either the central and/or the peripheral chemoreceptors. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea is characterized by intermittent hypoxia (IH) during sleep and predisposes to endothelial dysfunction. Obesity is a major risk factor for the occurrence of sleep apnea. The present study compared the functional impact of low- (IH10; 10 hypoxic events/h) and high-frequency (IH60; 60 hypoxic events/h) IH for 4 wk on endothelial function in male C57BL/6 mice with or without high-fat (HF) diet-induced obesity. Mean arterial blood pressure (tail cuff method) was increased in obese mice after IH60 exposure, i.e., HF + IH60 group. The serum levels of the oxidative stress marker malondialdehyde were augmented in lean IH60 and HF groups, with a further increase in HF + IH60 but a reduction in HF + IH10 mice compared with the HF group. Vascular responsiveness was assessed as changes in isometric tension in isolated arteries. Relaxations to the endothelium-dependent vasodilator acetylcholine were impaired in HF + IH60 aortae. Endothelium-dependent contractions (EDC; response to acetylcholine in the presence of the nitric oxide synthase inhibitor L-NAME) in carotid arteries were augmented in the HF group, but this HF-induced augmentation was suppressed by low-frequency IH exposure. The addition of apocynin (antioxidant) reduced EDC in HF and HF + IH60 groups but not in HF + IH10 group. In conclusion, these findings suggest that exposure of obese mice to mild IH exerts preconditioning-like suppression of endothelium-dependent and oxidative stress-mediated contractions. When IH severity increases, this suppression diminishes and endothelial dysfunction accelerates. NEW & NOTEWORTHY The present study demonstrates, for the first time, that low-frequency intermittent hypoxia may exert a preconditioning-like suppression of oxidative stress-induced endothelium-dependent contractions in mice with diet-induced obesity. This relative suppression was diminished as intermittent hypoxia became more severe, and a deleterious effect on endothelial function emerged. [ABSTRACT FROM AUTHOR]

During exercise in hypoxia, O2 delivery to brain and muscle is compromised, and oxidative stress is elicited. Cocoa flavanols (CF) have antioxidant capacities and can increase blood flow by stimulating endothelial function. We aimed to examine the effects of 7-day CF intake on oxidative stress, nitric oxide production, and tissue oxygenation in response to exercise in normobaric hypoxia (14.3% O2). In a randomized, double-blind, cross-over study, 14 well-trained male cyclists completed four trials: exercise in normoxia or hypoxia, after 7-day CF or placebo intake. Flow-mediated dilation (FMD) was measured before intake of the last dose CF or placebo. One hundred minutes later, 20-min steady-state (SS; 45% VO2max) and 20-min time trial (TT) (cycling) were performed. Blood samples were taken. Prefrontal and muscular oxygenation was assessed by near-infrared spectroscopy. At baseline, FMD was increased by CF. Hypoxia increased exercise-induced elevations in lipid peroxidation and antioxidant capacity. CF suppressed exercise-induced lipid peroxidation but did not influence antioxidant capacity. At rest and during SS, prefrontal and muscular oxygenation was decreased by hypoxia. CF elevated prefrontal oxygenation but did not impact muscular oxygenation. During TT, hypoxia accelerated the exercise-induced decrease in prefrontal oxygenation, but not in muscular oxygenation. During TT, CF did not alter prefrontal and muscular oxygenation. CF did not change plasma nitrite, nitrate, and arginine:citrulline. During high-intensity exercise, CF improved neither tissue oxygenation nor performance in well-trained athletes. At rest and during moderate-intensity exercise, CF reduced exerciseinduced lipid peroxidation and partially restored the hypoxia-induced decline in prefrontal oxygenation. [ABSTRACT FROM AUTHOR]

To determine whether acute exposure to simulated moderate altitude alters locomotor-respiratory coupling (LRC) patterns in runners, 13 trained male distance runners performed a running economy and maximal oxygen uptake (VO2max) test in normoxia (NORM) and hypoxia (HYP) (FIO2= 15.8%; ~2,400 m/8,000 ft) on separate days. Running economy (RE), the degree of LRC, stride frequency-to-breathing frequency quotients (SF/fb), ratings of perceived exertion (RPE), and dyspnea were assessed at three common submaximal speeds and VO2max. SF/fb were significantly lower at each submaximal speed in HYP (12.9 km/h: 2.91 ± 0.20 vs. 2.45 ± 0.17, 14.3 km/h: 2.53 ± 0.17 vs. 2.21 ± 0.14, 16.1 km/h: 2.22 ± 0.14 vs. 1.95 ± 0.09; P < 0.05). The degree of LRC (range: 36-99%) in HYP was not significantly different than NORM at any of the three common submaximal speeds. However, the degree of LRC was significantly higher atVO2max in HYP than NORM (43.8 ± 3.4% vs. 57.1 ± 3.8%; P < 0.05). RE and RPE were similar at all running speeds. Dyspnea was significantly greater in HYP compared with NORM at 16.1 km/h (P < 0.05). Trained distance runners are able to maintain LRC in HYP, despite increases in breathing frequency. Within this unique population, years of training may enhance and optimize the ability to maintain LRC to minimize metabolic costs and dyspnea. [ABSTRACT FROM AUTHOR]

Changes in cerebral blood flow (CBF) subsequent to alterations in the partial pressures of oxygen and carbon dioxide can modify dynamic cerebral autoregulation (CA). While cognitive activity increases CBF, the extent to which it impacts CA remains to be established. In the present study we determined whether dynamic CA would decrease during a cognitive task and whether hypoxia would further compound impairment. Fourteen young healthy subjects performed a simple Go/No-go task during normoxia and hypoxia (inspired O2 fraction =12%), and the corresponding relationship between mean arterial pressure (MAP) and mean middle cerebral artery blood velocity (MCA Vmean) was examined. Dynamic CA and steady-state changes in MCA V in relation to changes in arterial pressure were evaluated with transfer function analysis. While MCA Vmean increased during the cognitive activity (P < 0.001), hypoxia did not cause any additional changes (P < 0.804 vs. normoxia). Cognitive performance was also unaffected by hypoxia (reaction time, P = 0.712; error, P = 0.653). A decrease in the very low- and low-frequency phase shift (VLF and LF; P = 0.021 and P = 0.01) and an increase in LF gain were observed (P = 0.037) during cognitive activity, implying impaired dynamic CA. While hypoxia also increased VLF gain (P < 0.001), it failed to cause any additional modifications in dynamic CA. Collectively, our findings suggest that dynamic CA is impaired during cognitive activity independent of altered systemic O2 availability, although we acknowledge the interpretive complications associated with additional competing, albeit undefined, inputs that could potentially distort the MAP-MCA Vmean relationship. NEW & NOTEWORTHY During normoxia, cognitive activity while increasing cerebral perfusion was shown to attenuate dynamic cerebral autoregulation (CA) yet failed to alter reaction time, thereby questioning its functional significance. No further changes were observed during hypoxia, suggesting that impaired dynamic CA occurs independently of altered systemic O2 availability. However, impaired dynamic CA may reflect a technical artifact, given the confounding influence of additional inputs that could potentially distort the mean arterial pressure-mean middle cerebral artery blood velocity relationship. cerebral blood flow regulation; cognitive function; transfer function analysis [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea (OSA) is common in pregnancy and may compromise fetal and even postnatal development. We developed an animal model to determine if maternal OSA could have lasting effects in offspring. Pregnant Sprague-Dawley rats were exposed to reduced ambient O2 from 21 to 4-5%, approximately once per minute [chronic intermittent hypoxia (CIH)] for 8 h/day during gestation days 3-19. Similarly handled animals exposed to ambient air served as controls (HC). Offspring were studied for body growth and cardiovascular function for 8 postnatal weeks. Compared with HC, prenatal CIH led to growth restriction, indicated by smaller body weight and tibial length, and higher arterial blood pressure in both male and female offspring. Compared with same-sex HC, CIH males showed abdominal obesity (greater ratio of abdominal fat weight to body weight or tibial length), left ventricular (LV) hypertrophy (greater heart weight-to-tibial length ratio and LV posterior wall diastolic thickness), elevated LV contractility (increases in LV ejection fraction, end-systolic pressure-volume relations and preload recruitable stroke work), elevated LV and arterial stiffness (increased end-diastolic pressure-volume relationship and arterial elasticity), and LV oxidative stress (greater lipid peroxide content). Compared with female CIH offspring, male CIH offspring had more profound changes in blood pressure (BP), cardiac function, myocardial lipid peroxidase (LPO) content, and abdominal adiposity. Rodent prenatal CIH exposure, mimicking human maternal OSA, exerts detrimental morphological and cardiovascular effects on developing offspring; the model may provide useful insights of OSA effects in humans. NEW & NOTEWORTHY Obstructive sleep apnea is common in human pregnancy. Following maternal exposure to chronic intermittent hypoxia, a hallmark of sleep apnea, both sexes of rat offspring showed growth retardation, with males being more vulnerable to hypertension and dysfunctional left ventricular changes. This model is useful to study detrimental effects of maternal obstructive sleep apnea on developing offspring in humans. [ABSTRACT FROM AUTHOR]

Exercise reduces the risk of breast cancer development and improves survival in breast cancer patients. However, the underlying mechanisms of this protective effect remain to be fully elucidated and it is unclear whether exercise can attenuate the protumor effects of obesity and related hyperlipidemia on breast cancer growth and development. We hypothesized that exercise attenuates the negative effect of hyperlipidemia through normalization of the tumor microenvironment and improved T cell infiltrate. Hyperlipidemic ApoE-/- mice with orthotopic EO771 breast tumors were randomly assigned to one of two voluntary running groups or sedentary controls and muscular cytochrome c oxidase subunit IV (COX-IV) expression was used as a biomarker for the level of exercise. Tumors from mice with high muscular COX-IV expression took significantly longer to reach 100 mm3 (P < 0.008), but showed no difference in growth rate once the tumor was established. Wheel running appeared to reduce internal metastases, but did not affect T cell infiltrate or the proportion of regulatory and cytotoxic T cells within the tumor. Serum levels of monocyte chemoattractant protein-1 (MCP-1) were significantly increased by tumor burden (P = 0.02) and correlated with spleen weight (P < 0.0001, R = 0.65). Furthermore, tumor hypoxia was significantly decreased in mice with high muscular COX-IV expression (P = 0.01). Taken together, these results indicate that wheel running can slow the establishment of primary and secondary EO771 breast tumors and induce beneficial changes in the breast tumor microenvironment in ApoE-/- mice. NEW & NOTEWORTHY In this first study to investigate the effect of exercise on tumor behavior in a hyperlipidemic model, we hypothesized that wheel running would counteract the protumorigenic environment generated by hyperlipidemia. Wheel running slowed establishment of primary and secondary tumors and reduced tumor hypoxia but did not affect exponential tumor growth in ApoE-/- mice. Overall, voluntary wheel running induced favorable microenvironmental changes in breast tumors. [ABSTRACT FROM AUTHOR]

Cerebral vasodilation and increased cerebral oxygen extraction help maintain cerebral oxygen uptake in the face of hypoxemia. This study examined cerebrovascular responses to intermittent hypoxemia in eight healthy men breathing 10% O2 for 5 cycles, each 6 min, interspersed with 4 min of room air breathing. Hypoxia exposures raised heart rate (P < 0.01) without altering arterial pressure, and increased ventilation (P < 0.01) by expanding tidal volume. Arterial oxygen saturation (SaO2 ) and cerebral tissue oxygenation (ScO2 ) fell (P < 0.01) less appreciably in the first bout (from 97.0 ± 0.3% and 72.8 ± 1.6% to 75.5 ± 0.9% and 54.5 ± 0.9%, respectively) than the fifth bout (from 94.9 ± 0.4% and 70.8 ± 1.0% to 66.7 ± 2.3% and 49.2 ± 1.5%, respectively). Flow velocity in the middle cerebral artery (VMCA) and cerebrovascular conductance increased in a sigmoid fashion with decreases in SaO2 and ScO2 . These stimulusresponse curves shifted leftward and upward from the first to the fifth hypoxia bouts; thus, the centering points fell from 79.2 ± 1.4 to 74.6 ± 1.1% (P < 0.01) and from 59.8 ± 1.0 to 56.6 ± 0.3% (P < 0.002), and the minimum VMCA increased from 54.0 ± 0.5 to 57.2 ± 0.5 cm/s (P < 0.0001) and from 53.9 ± 0.5 to 57.1 ± 0.3 cm/s (P < 0.0001) for the SaO2 -VMCA and ScO2 -VMCA curves, respectively. Cerebral oxygen extraction increased from prehypoxia 0.22 ± 0.01 to 0.25 ± 0.02 in minute 6 of the first hypoxia bout, and remained elevated between 0.25 ± 0.01 and 0.27 ± 0.01 throughout the fifth hypoxia bout. These results demonstrate that cerebral vasodilation combined with enhanced cerebral oxygen extraction fully compensated for decreased oxygen content during acute, cyclic hypoxemia. NEW & NOTEWORTHY Five bouts of 6-min intermittent hypoxia (IH) exposures to 10% O2 progressively reduce arterial oxygen saturation (SaO2 ) to 67% without causing discomfort or distress. Cerebrovascular responses to hypoxemia are dynamically reset over the course of a single IH session, such that threshold and saturation for cerebral vasodilations occurred at lower SaO2 and cerebral tissue oxygenation (ScO2 ) during the fifth vs. first hypoxia bouts. Cerebral oxygen extraction is augmented during acute hypoxemia, which compensates for decreased arterial O2 content. [ABSTRACT FROM AUTHOR]

Ventilation and cerebral blood flow (CBF) are both sensitive to hypoxia and hypercapnia. To compare chemosensitivity in these two systems, we made simultaneous measurements of ventilatory and cerebrovascular responses to hypoxia and hypercapnia in 35 normal human subjects before and after acclimatization to hypoxia. Ventilation and CBF were measured during stepwise changes in isocapnic hypoxia and iso-oxic hypercapnia. We used MRI to quantify actual cerebral perfusion. Measurements were repeated after 2 days of acclimatization to hypoxia at 3,800 m altitude (partial pressure of inspired O2 = 90 Torr) to compare plasticity in the chemosensitivity of these two systems. Potential effects of hypoxic and hypercapnic responses on acute mountain sickness (AMS) were assessed also. The pattern of CBF and ventilatory responses to hypercapnia were almost identical. CO2 responses were augmented to a similar degree in both systems by concomitant acute hypoxia or acclimatization to sustained hypoxia. Conversely, the pattern of CBF and ventilatory responses to hypoxia were markedly different. Ventilation showed the well-known increase with acute hypoxia and a progressive decline in absolute value over 25 min of sustained hypoxia. With acclimatization to hypoxia for 2 days, the absolute values of ventilation and O2 sensitivity increased. By contrast, O2 sensitivity of CBF or its absolute value did not change during sustained hypoxia for up to 2 days. The results suggest a common or integrated control mechanism for CBF and ventilation by CO2 but different mechanisms of O2 sensitivity and plasticity between the systems. Ventilatory and cerebrovascular responses were the same for all subjects irrespective of AMS symptoms. NEW & NOTEWORTHY Ventilatory and cerebrovascular hypercapnic response patterns show similar plasticity in CO2 sensitivity following hypoxic acclimatization, suggesting an integrated control mechanism. Conversely, ventilatory and cerebrovascular hypoxic responses differ. Ventilation initially increases but adapts with prolonged hypoxia (hypoxic ventilatory decline), and ventilatory sensitivity increases following acclimatization. In contrast, cerebral blood flow hypoxic sensitivity remains constant over a range of hypoxic stimuli, with no cerebrovascular acclimatization to sustained hypoxia, suggesting different mechanisms for O2 sensitivity in the two systems. [ABSTRACT FROM AUTHOR]

The underlying cause of systolic heart failure is the inability of the adult mammalian heart to regenerate damaged myocardium. In contrast, some vertebrate species and immature mammals are capable of full cardiac regeneration following multiple types of injury through cardiomyocyte proliferation. Little is known about what distinguishes proliferative cardiomyocytes from terminally differentiated, nonproliferative cardiomyocytes. Recently, several reports have suggested that oxygen metabolism and oxidative stress play a pivotal role in regulating the proliferative capacity of mammalian cardiomyocytes. Moreover, reducing oxygen metabolism in the adult mammalian heart can induce cardiomyocyte cell cycle reentry through blunting oxidative damage, which is sufficient for functional improvement following myocardial infarction. Here we concisely summarize recent findings that highlight the role of oxygen metabolism and oxidative stress in cardiomyocyte cell cycle regulation, and discuss future therapeutic approaches targeting oxidative metabolism to induce cardiac regeneration. [ABSTRACT FROM AUTHOR]

High-Altitude High Opening (HAHO) is a military operational procedure in which parachute jumps are performed at high altitude requiring supplemental oxygen, putting personnel at risk of acute hypoxia in the event of oxygen equipment failure. This study was initiated by the Norwegian Army to evaluate potential outcomes during failure of oxygen supply, and to explore physiology during acute severe hypobaric hypoxia. A simulated HAHO without supplemental oxygen was carried out in a hypobaric chamber with decompression to 30,000 ft (9,144 m) and then recompression to ground level with a descent rate of 1,000 ft/min (305 m/min). Nine subjects were studied. Repeated arterial blood gas samples were drawn throughout the entire hypoxic exposure. Additionally, pulse oximetry, cerebral oximetry, and hemodynamic variables were monitored. Desaturation evolved rapidly and the arterial oxygen tensions are among the lowest ever reported in volunteers during acute hypoxia. PaO2 decreased from baseline 18.4 (17.3-19.1) kPa, 138.0 (133.5-143.3) mmHg, to a minimum value of 3.3 (2.9 -3.7) kPa, 24.8 (21.6 -27.8) mmHg, after 180 (60 -210) s, [median (range)], N = 9. Hyperventilation with ensuing hypocapnia was associated with both increased arterial oxygen saturation and cerebral oximetry values, and potentially improved tolerance to severe hypoxia. One subject had a sharp drop in heart rate and cardiac index and lost consciousness 4 min into the hypoxic exposure. A simulated high-altitude airdrop scenario without supplemental oxygen results in extreme hypoxemia and may result in loss of consciousness in some individuals. NEW & NOTEWORTHY This is the first study to investigate physiology and clinical outcome of oxygen system failure in a simulated HAHO scenario. The acquired knowledge is of great value to make valid risk-benefit analyses during HAHO training or operations. The arterial oxygen tensions reported in this hypobaric chamber study are among the lowest ever reported during acute hypoxia. [ABSTRACT FROM AUTHOR]

Hypoxia increases erythropoiesis mediated by hypoxia-inducible transcription factors (HIF), which regulate erythropoietin transcription. Neocytolysis is a physiological mechanism that corrects polycythemia from chronic sustained hypoxemia by transient, preferential destruction of young RBCs after normoxia is restored. We showed that neocytolysis is caused by excessive mitochondrialderived reactive oxygen species in reticulocytes mediated by downregulation of HIF-controlled BNIP3L regulated mitophagy and a decrease in RBC antioxidant catalase (CAT) in hypoxia-produced erythrocytes. Decreased CAT results from hypoxia-induced miR-21 that downregulates CAT. This correlates with a transient acute decrease of HIF-1 at normoxic return that is associated with normalization of red cell mass. [ABSTRACT FROM AUTHOR]

Hypoxic pulmonary vasoconstriction (HPV) is a physiological reaction, which adapts lung perfusion to regional ventilation and optimizes gas exchange. Impaired HPV may cause systemic hypoxemia, while generalized HPV contributes to the development of pulmonary hypertension. The triggering mechanisms underlying HPV are still not fully elucidated. Several hypotheses are currently under debate, including a possible decrease as well as an increase in reactive oxygen species as a triggering event. Recent findings suggest an increase in the production of reactive oxygen species in pulmonary artery smooth muscle cells by complex III of the mitochondrial electron transport chain and occurrence of oxygen sensing at complex IV. Other essential components are voltage-dependent potassium and possibly L-type, transient receptor potential channel 6, and transient receptor potential vanilloid 4 channels. The release of arachidonic acid metabolites appears also to be involved in HPV regulation. Further investigation of the HPV mechanisms will facilitate the development of novel therapeutic strategies for the treatment of HPV-related disorders. [ABSTRACT FROM AUTHOR]

Intermittent hypoxia (IH) has been implicated in the cardiovascular consequences of obstructive sleep apnea (OSA). However, the lack of suitable experimental systems has precluded assessment as to whether IH is detrimental, protective, or both for the endothelium. The aim of the work was to determine the effects of frequency and amplitude of IH oxygenation swings on aortic endothelial wound healing. Monolayers of human primary endothelial cells were wounded and subjected to constant oxygenation (1%, 4%, 13%, or 20% O2) or IH at different frequencies (0.6, 6, or 60 cycles/h) and magnitude ranges (13-4% O2 or 20-1% O2), using a novel well-controlled system, with wound healing being measured after 24 h. Cell monolayer repair was similar at 20% O2 and 13% O2, but was considerably increased (approximately twofold) in constant hypoxia at 4% O2. The magnitude and frequency of IH considerably modulated wound healing. Cycles ranging 13-4% O2 at the lowest frequency (0.6 cycles/h) accelerated endothelial wound healing by 102%. However, for IH exposures consisting of 20% to 1% O2 oscillations, wound closure was reduced compared with oscillation in the 13-4% range (by 74% and 44% at 6 cycles/h and 0.6 cycles/h, respectively). High-frequency IH patterns simulating severe OSA (60 cycles/h) did not significantly modify endothelial wound closure, regardless of the oxygenation cycle amplitude. In conclusion, the frequency and magnitude of hypoxia cycling in IH markedly alter wound healing responses and emerge as key factors determining how cells will respond in OSA. [ABSTRACT FROM AUTHOR]

Our purpose was to determine whether exposure to mild intermittent hypoxia leads to a reduction in the therapeutic continuous positive airway pressure required to eliminate breathing events. Ten male participants were treated with twelve 2-min episodes of hypoxia (PETCO2 ≈50 mmHg) separated by 2-min intervals of normoxia in the presence of PETCO2 that was sustained 3 mmHg above baseline. During recovery from the last episode, the positive airway pressure was reduced in a stepwise fashion until flow limitation was evident. The participants also completed a sham protocol under normocapnic conditions, which mimicked the time frame of the intermittent hypoxia protocol. After exposure to intermittent hypoxia, the therapeutic pressure was significantly reduced (i.e., 5 cmH2O) without evidence of flow limitation (103.4 ± 6.3% of baseline, P = 0.5) or increases in upper airway resistance (95.6 ± 15.0% of baseline, P = 0.6). In contrast, a similar decrease in pressure was accompanied by flow limitation (77.0 ± 1.8% of baseline, P = 0.001) and an increase in upper airway resistance (167.2 ± 17.5% of baseline, P = 0.01) after the sham protocol. Consistent with the initiation of long-term facilitation of upper airway muscle activity, exposure to intermittent hypoxia reduced the therapeutic pressure required to eliminate apneic events that could improve treatment compliance. This possibility, coupled with the potentially beneficial effects of intermittent hypoxia on comorbidities linked to sleep apnea, suggests that mild intermittent hypoxia may have a multipronged therapeutic effect on sleep apnea. NEW & NOTEWORTHY Our new finding is that exposure to mild intermittent hypoxia reduced the therapeutic pressure required to treat sleep apnea. These findings are consistent with previous results, which have shown that long-term facilitation of upper muscle activity can be initiated following exposure to intermittent hypoxia in humans. [ABSTRACT FROM AUTHOR]

Rats breathing 10% O2 show a rapid and widespread systemic microvascular inflammation that results from nitric oxide (NO) depletion secondary to increased reactive O2 species (ROS) generation. The inflammation eventually resolves, and the microcirculation becomes resistant to more severe hypoxia. These experiments were directed to determine the mechanisms underlying this microvascular acclimatization process. Intravital microscopy of the mesentery showed that after 3 wk of hypoxia (barometric pressure ~380 Torr; partial pressure of inspired O2 ~68–70 Torr), rats showed no evidence of inflammation; however, treatment with the inducible NO synthase (iNOS) inhibitor L-N6-(1-iminoethyl) lysine dihydrochloride led to ROS generation, leukocyte-endothelial adherence and emigration, and increased vascular permeability. Mast cells harvested from normoxic rats underwent degranulation when exposed in vitro to monocyte chemoattractant protein-1 (MCP-1), the proximate mediator of mast cell degranulation in acute hypoxia. Mast cell degranulation by MCP-1 was prevented by the NO donor spermine-NONOate. MCP-1 did not induce degranulation of mast cells harvested from 6-day hypoxic rats; however, pretreatment with either the general NOS inhibitor L-NG-monomethyl arginine citrate or the selective iNOS inhibitor N-[3-(aminomethyl) benzyl] acetamidine restored the effect of MCP-1. iNOS was demonstrated in mast cells and alveolar macrophages of acclimatized rats. Nitrate + nitrite plasma levels decreased significantly in acute hypoxia and were restored after 6 days of acclimatization. The results support the hypothesis that the microvascular acclimatization to hypoxia results from the restoration of the ROS/NO balance mediated by iNOS expression at key sites in the inflammatory cascade. NEW & NOTEWORTHY The study shows that the systemic inflammation of acute hypoxia resolves via an inducible nitric oxide (NO) synthase-induced restoration of the reactive O2 species/NO balance in the systemic microcirculation. It is proposed that the acute systemic inflammation may represent the first step of the microvascular acclimatization process. [ABSTRACT FROM AUTHOR]

The article focuses on a study on effect of intermittent hypercapnic hypoxia during sleep on neuroplasticity in humans, and mentions manifestation of hypoglossal long-term facilitation as an increase in genioglossal electromyogram (EMG) phasic burst amplitude in rats.

This study sought to assess the within-subject influence of acute hypoxia on exercise-induced changes in core temperature and sweating. Eight participants [1.75 (0.06) m, 70.2 (6.8) kg, 25 (4) yr, 54 (8) ml·kg−1·min−1] completed 45 min of cycling, once in normoxia (NORM; FIO2 = 0.21) and twice in hypoxia (HYP1/HYP2; FIO2= 0.13) at 34.4(0.2)°C, 46(3)% RH. These trials were designed to elicit 1) two distinctly different %V̇o2peak [NORM: 45 (8)% and HYP1: 62 (7)%] at the same heat production (Hprod) [NORM: 6.7 (0.6) W/kg and HYP1: 7.0 (0.5) W/kg]; and 2) the same %V̇o2peak [NORM: 45 (8)% and HYP2: 48 (5)%] with different Hprod [NORM: 6.7 (0.6) W/kg and HYP2: 5.5 (0.6) W/kg]. At a fixed %V̇o2peak, changes in rectal temperature (ΔTre) and changes in esophageal temperature (ΔTes) were greater at end-exercise in NORM [ΔTre: 0.76 (0.19)°C; ΔTes: 0.64 (0.22)°C] compared with HYP2 [ΔTre: 0.56 (0.22)°C, P < 0.01; ΔTes: 0.42 (0.21)°C, P < 0.01]. As a result of a greater Hprod (P < 0.01) in normoxia, and therefore evaporative heat balance requirements, to maintain a similar %V̇o2peak compared with hypoxia, mean local sweat rates (LSR) from the forearm, upper back, and forehead were greater (all P < 0.01) in NORM [1.10 (0.20) mg·cm−2·min−1] compared with HYP2 [0.71 (0.19) mg·cm−2·min−1]. However, at a fixed Hprod, ΔTre [0.75 (0.24)°C; P = 0.77] and ΔTes [0.63 (0.29)°C; P = 0.69] were not different in HYP1, compared with NORM. Likewise, mean LSR [1.11 (0.20) mg·cm−2·min−1] was not different (P = 0.84) in HYP1 compared with NORM. These data demonstrate, using a within-subjects design, that hypoxia does not independently influence thermoregulatory responses. Additionally, further evidence is provided to support that metabolic heat production, irrespective of %V̇o2peak, determines changes in core temperature and sweating during exercise. NEW & NOTEWORTHY Using a within-subject design, hypoxia does not independently alter core temperature and sweating during exercise at a fixed rate of heat production. These findings also further contribute to the development of a methodological framework for assessing differences in thermoregulatory responses to exercise between various populations and individuals. Using the combined environmental stressors of heat and hypoxia we conclusively demonstrate that exercise intensity relative to aerobic capacity (i.e., %V̇o2max) does not influence changes in thermoregulatory responses. [ABSTRACT FROM AUTHOR]

Although it is well known that chronic hypoxia induces muscle wasting, the effects of intermittent hypoxia on skeletal muscle protein metabolism remain unclear. We hypothesized that acute intermittent hypoxia (AIH), a challenge that activates the hypothalamic-pituitary-adrenal axis, would alter muscle protein homeostasis through a glucocorticoid-dependent mechanism. Three-week-old rats were submitted to adrenalectomy (ADX) and exposed to 8 h of AIH (6%O2 for 40 s at 9-min intervals). Animals were euthanized, and the soleus and extensor digitorum longus (EDL) muscles were harvested and incubated in vitro for measurements of protein turnover. AIH increased plasma levels of corticosterone and induced insulin resistance as estimated by the insulin tolerance test and lower rates of muscle glucose oxidation and the HOMA index. In both soleus and EDL muscles, rates of overall proteolysis increased after AIH. This rise was accompanied by an increased proteolytic activities of the ubiquitin(Ub)-proteasome system (UPS) and lysosomal and Ca2+-dependent pathways. Furthermore, AIH increased Ub-protein conjugates and gene expression of atrogin-1 and MuRF-1, two key Ub-protein ligases involved in muscle atrophy. In parallel, AIH increased the mRNA expression of the autophagy-related genes LC3b and GABARAPl1. In vitro rates of protein synthesis in skeletal muscles did not differ between AIH and control rats. ADX completely blocked the insulin resistance in hypoxic rats and the AIH-induced activation of proteolytic pathways and atrogene expression in both soleus and EDL muscles. These results demonstrate that AIH induces insulin resistance in association with activation of the UPS, the autophagic-lysosomal process, and Ca2+- dependent proteolysis through a glucocorticoid-dependent mechanism. NEW & NOTEWORTHY Since hypoxia is a condition in which the body is deprived of adequate oxygen supply and muscle wasting is induced, the present work provides evidence linking hypoxia to proteolysis through a glucocorticoid-dependent mechanism. We show that the activation of proteolytic pathways, atrophy-related genes, and insulin resistance in rats exposed to acute intermittent hypoxia was abolished by surgical removal of adrenal gland. This finding will be helpful for understanding of the muscle wasting in hypoxemic conditions. [ABSTRACT FROM AUTHOR]

Obstructive sleep apnea is associated with type 2 diabetes. We have previously developed a mouse model of intermittent hypoxia (IH) mimicking oxyhemoglobin desaturations in patients with sleep apnea and have shown that IH increases fasting glucose, hepatic glucose output, and plasma catecholamines. We hypothesize that adrenal medulla modulates glucose responses to IH and that such responses can be prevented by adrenal medullectomy. We performed adrenal medullectomy or sham surgery in lean C57BL/6J mice, which were exposed to IH or intermittent air (control) for 4 wk followed by the frequently sampled intravenous glucose tolerance test (FSIVGTT) in unanesthetized unrestrained animals. IH was administered during the 12-h light phase (9 AM to 9 PM) by decreasing inspired oxygen from 21 to 6.5% 60 cycles/h. Insulin sensitivity (SI), insulin independent glucose disposal [glucose effectiveness (SG)], and the insulin response to glucose (AIRG) were determined using the minimal model method. In contrast to our previous data obtained in restrained mice, IH did not affect fasting blood glucose and plasma insulin levels in shamoperated mice. IH significantly decreased SG but did not affect SI and AIRG. Adrenal medullectomy decreased fasting blood glucose and plasma insulin levels and increased glycogen synthesis in the liver in hypoxic mice but did not have a significant effect on the FSIVGTT metrics. We conclude that, in the absence of restraints, IH has no effect on glucose metabolism in lean mice with exception of decreased SG, whereas adrenal medullectomy decreases fasting glucose and insulin levels in the IH environment. [ABSTRACT FROM AUTHOR]

The developing human fetus is able to cope with the physiological reduction in oxygen supply occurring in utero. However, it is not known if microvascularization of the fetus is augmented when pregnancy occurs at high altitude. Fifty-three healthy term newborns in Puno, Peru (3,840 m) were compared with sea-level controls. Pre- and postductal arterial oxygen saturation (SpO2) was determined. Cerebral and calf muscle regional tissue oxygenation was measured using near infrared spectroscopy (NIRS). Skin microcirculation was noninvasively measured using incident dark field imaging. Pre- and postductal SpO2 in Peruvian babies was 88.1 and 88.4%, respectively, which was 10.4 and 9.7% lower than in newborns at sea level (P < 0.001). Cerebral and regional oxygen saturation was significantly lower in the Peruvian newborns (cerebral: 71.0 vs. 74.9%; regional: 68.5 vs. 76.0%, P < 0.001). Transcutaneously measured total vessel density in the Peruvian newborns was 14% higher than that in the newborns born at sea level (29.7 vs. 26.0 mm/mm2; P ≤ 0.001). This study demonstrates that microvascular vessel density in neonates born to mothers living at high altitude is higher than that in neonates born at sea level. [ABSTRACT FROM AUTHOR]

Recent studies have shown an association between obstructive sleep apnea (OSA) and cognitive impairment. This study was done to investigate whether varied levels of cyclical intermittent hypoxia (CIH) differentially affect the microvasculature in the hippocampus, operating as a mechanistic link between OSA and cognitive impairment. We exposed C57BL/6 mice to sham [continuous air, arterial O2 saturation (SaO2) 97%], severe CIH to inspired O2 fraction (FIO2) < 0.10 (CIH10; SaO2 nadir of 61%), or very severe CIH to FIO2 < 0.05 (CIH5; SaO2 nadir of 37%) for 12 h/day for 2 wk. We quantified capillary length using neurostereology techniques in the dorsal hippocampus and utilized quantitative PCR methods to measure changes in sets of genes related to angiogenesis and to metabolism. Next, we employed immunohistochemistry semiquantification algorithms to quantitate GLUT1 protein on endothelial cells within hippocampal capillaries. Capillary length differed among CIH severity groups (P < 0.013) and demonstrated a linear relationship with CIH severity (P < 0.002). There was a strong association between CIH severity and changes in mRNA for VEGFA (P < 0.0001). Less strong, but nominally significant associations with CIH severity were also observed for ANGPT2 (PANOVA = 0.065, PTREND = 0.040), VEGFR2 (PANOVA = 0.032, PTREND = 0.429), and TIE-2 (PANOVA=0.006, PTREND=0.010). We found that the CIH5 group had increased GLUT1 protein relative to sham (P = 0.006) and CIH10 (P = 0.001). There was variation in GLUT1 protein along the microvasculature in different hippocampal subregions. An effect of CIH5 on GLUT1 mRNA was seen (PANOVA=0.042, PTREND=0.012). Thus CIH affects the microvasculature in the hippocampus, but consequences depend on CIH severity. [ABSTRACT FROM AUTHOR]

5-HT neurons contribute to autoresuscitation and survival during intermittent severe hypoxia (IsH). In adults, catecholaminergic neurons in the ventrolateral medulla (VLM) contribute to the autonomic response to hypoxia. We hypothesized that 1) catecholaminergic neurons in the neonatal VLM are activated following IsH, 2) this activation is compromised following an acute loss of brain stem 5-HT, and 3) IsH induces cellular and/or transcriptomic plasticity within catecholaminergic and serotonergic neurons that are within or project to the VLM, respectively. To test these hypotheses, we treated rat pups with 6-fluorotryptophan, a tryptophan hydroxylase (TPH) inhibitor, and then exposed treated and vehicle controls to IsH or air. Along with immunohistochemistry to detect tyrosine hydroxylase (TH)- or Fos-positive neurons, we used RNA sequencing to resolve the effects of IsH and 5-HT deficiency on the expression of serotonergic and catecholaminergic system genes in the VLM. 5-HT deficiency compromised autoresuscitation and survival. IsH significantly increased the number of identifiable TH-positive VLM neurons, an effect enhanced by 5-HT deficiency (P = 0.003). Contrary to our hypothesis, 5-HT-deficient pups had significantly more Fos-positive neurons following IsH (P = 0.008) and more activated TH-positive neurons following IsH or air (P = 0.04). In both groups the expression of the 5-HT transporter and TPH2 was increased following IsH. In 5-HT-deficient pups, the expression of the inhibitory 5-HT1A receptor was decreased following IsH, while the expression of DOPA decarboxylase was increased. These data show that the serotonergic and catecholaminergic systems in the VLM of the neonatal rat are dynamically upregulated by IsH, potentially adapting cardiorespiratory responses to severe hypoxia. [ABSTRACT FROM AUTHOR]

To gain insights into microgravity-induced ophthalmic changes (microgravity ocular syndrome), and as part of a project investigating effects of future planetary habitats, we investigated the effect of acute hypercapnia following 10-day bed rest and hypoxia on posterior eye structures. Female subjects (N = 7) completed three 10-day experimental interventions: 1) normoxic bed rest [NBR; partial pressure of inspired O2 (PIO2) 132.9 ± 0.3 Torr]; 2) hypoxic ambulatory confinement (HAMB; PIO2 =90.4 ± 0.3 Torr); and 3) hypoxic bed rest (HBR; n = 12; PIO2 = 90.4 ± 0.3 Torr). Before and on the last day of each intervention, optical coherence tomography (OCT) of the optic disk was performed, and the thicknesses of the retinal nerve fiber layer (RNFL), retina, and choroid were measured. OCT examinations were conducted with the subjects breathing the prevailing normocapnic breathing mixture (either normoxic or hypoxic) and then following a 10-min period of breathing the same gas mixture, but with the addition of 1% CO2. Choroidal thickness was greater during both bed-rest conditions (NBR and HBR) compared with the ambulatory (HAMB) condition (ANOVA, P < 0.001). Increases in RNFL thickness compared with baseline were observed in the hypoxic trials (HBR, P < 0.001; and HAMB, P = 0.021), but not the normoxic trial (NBR). A further increase in RNFL thickness (P = 0.019) was observed after the 10-min hypercapnic trial in the NBR condition only. The fact that choroidal thickness was not affected by PO2 or PCO2, but increased by bed rest, suggests a hydrostatic rather than a vasoactive effect. The increments in RNFL thickness were most likely associated with local hypoxia and hypercapnia-induced dilatation of the retinal blood vessels. [ABSTRACT FROM AUTHOR]

We determined the effects of chronic exposure to intermittent hypoxia (CIH) on chemoreflex control of ventilation in conscious animals. Adult male Sprague-Dawley rats were exposed to CIH [nadir oxygen saturation (SpO2), 75%; 15 events/h; 10 h/day] or normoxia (NORM) for 21 days. We assessed the following responses to acute, graded hypoxia before and after exposures: ventilation (VE, via barometric plethysmography), VO2 and VCO2 (analysis of expired air), heart rate (HR), and SpO2 (pulse oximetry via neck collar). We quantified hypoxia-induced chemoreceptor sensitivity by calculating the stimulus-response relationship between SpO2 and the ventilatory equivalent for VCO2 (linear regression). An additional aim was to determine whether CIH causes proliferation of carotid body glomus cells (using bromodeoxyuridine). CIH exposure increased the slope of the VE/VCO2/SpO2 relationship and caused hyperventilation in normoxia. Bromodeoxyuridine staining was comparable in CIH and NORM. Thus our CIH paradigm augmented hypoxic chemosensitivity without causing glomus cell proliferation. [ABSTRACT FROM AUTHOR]

Only very limited information regarding the protective effects of the superoxide anion scavenger on chronic intermittent hypoxia-induced cardiac apoptosis is available. The purpose of this study is to evaluate the effects of the superoxide anion scavenger on cardiac apoptotic and prosurvival pathways in rats with sleep apnea. Forty-two Sprague-Dawley rats were divided into three groups, rats with normoxic exposure (Control, 21% O2, 1 mo), rats with chronic intermittent hypoxia exposure (Hypoxia, 3-7% O2 vs. 21% O2 per 40 s cycle, 8 h per day, 1 mo), and rats with pretreatment of the superoxide anion scavenger and chronic intermittent hypoxia exposure (Hypoxia-O-2 -Scavenger, MnTMPyP pentachloride, 1 mg/kg ip per day; 3-7% O2 vs. 21% O2 per 40 s cycle, 8 h per day, 1 mo) at 5-6 mo of age. After 1 mo, the protein levels and apoptotic cells of excised hearts from three groups were measured by Western blotting and terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assay. The superoxide anion scavenger decreased hypoxia-induced myocardial architecture abnormalities, left ventricular hypertrophy, and TUNELpositive apoptosis. The superoxide anion scavenger decreased hypoxia- induced Fas ligand, Fas death receptors, Fas-associated death domain (FADD), activated caspase-8, and activated caspase-3 (Fasdependent apoptotic pathway) as well as Bad, activated caspase-9 and activated caspase-3 (mitochondria-dependent apoptotic pathway), endonuclease G (EndoG), apoptosis-inducing factor (AIF), and TUNELpositive apoptosis. The superoxide anion scavenger increased IGF-1, IGF-1R, p-PI3k, p-Akt, p-Bad, Bcl-2, and Bcl-xL (survival pathway). Our findings imply that the superoxide anion scavenger might prevent cardiac Fas-mediated and mitochondrial-mediated apoptosis and enhance the IGF-1-related survival pathway in chronic intermittent hypoxia. The superoxide anion scavenger may prevent chronic sleep apnea-enhanced cardiac apoptotic pathways and enhances cardiac survival pathways. [ABSTRACT FROM AUTHOR]