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This study quantified performance, physiological, and perceptual responses during resistance exercise to task failure with blood flow restriction (BFR), in systemic hypoxia, and with these stimuli combined.Fourteen young men were tested for 1-repetition maximum (1RM) in the barbell biceps curl and lying triceps extension exercises. On separate visits, subjects performed exercise trials (4 sets to failure at 70% 1RM with 90 s between sets) in six separate randomized conditions, i.e., in normoxia or hypoxia (fraction of inspired oxygen = 20.9% and 12.9%, respectively) combined with three different levels of BFR (0%, 45%, or 60% of resting arterial occlusion pressure). Muscle activation and oxygenation were monitored via surface electromyography and near-infrared spectroscopy, respectively. Arterial oxygen saturation, heart rate, and perceptual responses were assessed following each set.Compared to set 1, the number of repetitions before failure decreased in sets 2, 3, and 4 for both exercises (all P 0.001), independently of the condition (P 0.065). Arterial oxygen saturation was lower with systemic hypoxia (P 0.001), but not BFR, while heart rate did not differ between conditions (P 0.341). Muscle oxygenation and activation during exercise trials remained unaffected by the different conditions (all P ≥ 0.206). A significant main effect of time, but not condition, was observed for overall perceived discomfort, difficulty breathing, and limb discomfort (all P 0.001).Local and systemic hypoxic stimuli, or a combination of both, did not modify the fatigue-induced change in performance, trends of muscle activation or oxygenation, nor exercise-related sensations during a multi-set resistance exercise to task failure.

Induction of hypothermia and consequent hypometabolism by pharmacological downmodulation of the internal thermostat could be protective in various medical situations such as ischemia/reperfusion. Systemic hypoxia is a trigger of thermostat downregulation in some mammals, which is sensed though carotid chemoreceptors (carotid bodies, CBs). Using non-invasive thermographic imaging in mice, we demonstrated that surgical bilateral CB denervation does not hamper hypoxia-induced hypothermia. However, the recovery from a protective and reversible hypothermic state after restoration to normoxic conditions was impaired in CB-resected mice versus control animals. Therefore, the carotid chemoreceptors play an important role in the central regulation of hypoxia-driven hypothermia in mice, but only in the rewarming phase.

Purpose: The authors compared the effects of active preconditioning with local and systemic hypoxia during submaximal cycling. Methods: On separate visits, 14 active participants completed 4 trials. Each visit was composed of 1 preconditioning phase followed, after 40 minutes of rest, by 3 × 6-minute cycling bouts (intensity = 85% of critical power; rest = 6 min). The preconditioning phase consisted of 4 × 5-minute cycling bouts at 1.5 W·kg−1 (rest = 5 min) in 4 conditions: control (no occlusion and normoxia), blood flow restriction (60% of total occlusion), HYP (systemic hypoxia; inspired fraction of oxygen = 13.6%), and blood flow restriction + HYP (local and systemic hypoxia combined). Results: During the preconditioning phase, there were main effects of both systemic (all P P ≤ .001) on heart rate, arterial oxygen saturation, leg discomfort, difficulty of breathing, and blood lactate concentration. Cardiorespiratory variables, gross efficiency, energy cost, and energy expenditure during the last minute of 6-minute cycling bouts did not differ between conditions (all P > .105). Conclusion: Local and systemic hypoxic stimuli, or a combination of both, during active preconditioning did not improve physiological responses such as cycling efficiency during subsequent submaximal cycling.

This chapter reviews the effects of systemic hypoxia and blood flow restriction on cellular adaptations to training. Strategies for implementing hypoxic training and the efficacy of performing different exercise modalities under hypoxic conditions is discussed. Along with differentiating systemic hypoxia from blood flow restricted exercise, this chapter provides an overview on how to safely administer blood flow restricted exercise, as well as detailing some of the adaptations that occur in response to blood flow restriction administered at res, and in combination with different exercise modalities. Current limitations and future directions for both systemic hypoxia and blood flow restricted exercise are also discussed.

Experimental hypoxia has been used for decades to examine the adaptive response to low-oxygen environments. Various models have been studied, including flies, worms, fish, rodents, and humans. Our lab has recently used this technology to examine the effect of environmental hypoxia on mammalian heart regeneration. In this chapter, we describe studies of systemic hypoxia in mice. We found that systemic hypoxia can blunt oxidative DNA damage and induce cardiomyocyte proliferation. While our primary interests are focused on cardiovascular research, these hypoxia protocols are applicable to any other organ system.

International audience; With minimal costs and travel constraints for athletes, the "living low-training high" (LLTH) approach is becoming an important intervention for modern sport. The popularity of the LLTH model of altitude training is also associated with the fact that it only causes a slight disturbance to athletes' usual daily routine, allowing them to maintain their regular lifestyle in their home environment. In this perspective article, we discuss the evolving boundaries of the LLTH paradigm and its practical applications for athletes. Passive modalities include intermittent hypoxic exposure at rest (IHE) and Ischemic preconditioning (IPC). Active modalities use either local [blood flow restricted (BFR) exercise] and/or systemic hypoxia [continuous low-intensity training in hypoxia (CHT), interval hypoxic training (IHT), repeated-sprint training in hypoxia (RSH), sprint interval training in hypoxia (SIH) and resistance training in hypoxia (RTH)]. A combination of hypoxic methods targeting different attributes also represents an attractive solution. In conclusion, a growing number of LLTH altitude training methods exists that include the application of systemic and local hypoxia stimuli, or a combination of both, for performance enhancement in many disciplines.

Aim: Deviation of the nasal septum, which can cause upper respiratory tract obstruction and systemic hypoxia, may also affect the eye. The aim of this study was to detect changes in posterior segment parameters of the eye in patients with nasal septal deviation. Material and Methods: The study included 50 patients with nasal septal deviation, and a control group of 30 healthy subjects with no nasal septal deviation. Choroidal thickness, central macular thickness and retinal nerve fiber layer thickness were measured with Optical Coherence Tomography. Results: Choroidal thickness was significantly lower in patients with severe nasal septal deviation compared to the control group. (p=0.001) There is no statistically significant change in other measurements. Conclusion: The study results suggest that marked nasal septal deviation may lead to significant hypoxia and sympathetic activation, resulting in deterioration of the choroidal blood flow and consequent choroidal thickening.

Systemic hypoxia is a physiological and pathophysiological stress that activates the sympathoadrenal system and, in young adults, leads to peripheral vasodilation. We tested the hypothesis that peripheral vasodilation to graded systemic hypoxia is impaired in older healthy adults and that this age-associated impairment is due to attenuated β-adrenergic mediated vasodilation and elevated α-adrenergic vasoconstriction. Forearm blood flow was measured (Doppler ultrasound), and vascular conductance (FVC) was calculated in 12 young (24 ± 1 yr) and 10 older (63 ± 2 yr) adults to determine the local dilatory responses to graded hypoxia (90, 85, and 80% O2 saturations) in control conditions, following local intra-arterial blockade of β-receptors (propranolol), and combined blockade of α- and β-receptors (phentolamine + propranolol). Under control conditions, older adults exhibited impaired vasodilation to hypoxia compared with young participants at all levels of hypoxia (peak ΔFVC at 80% [Formula: see text] = 4 ± 6 vs. 35 ± 8%; P < 0.01). During β-blockade, older adults actively constricted at 85 and 80% [Formula: see text] (peak ΔFVC at 80% [Formula: see text] = −13 ± 6%; P < 0.05 vs. control), whereas the response in the young was not significantly impacted (peak ΔFVC = 28 ± 8%). Combined α- and β-blockade increased the dilatory response to hypoxia in young adults; however, older adults failed to significantly vasodilate (peak ΔFVC at 80% [Formula: see text]= 12 ± 11% vs. 58 ± 11%; P < 0.05). Our findings indicate that peripheral vasodilation to graded systemic hypoxia is significantly impaired in older adults, which cannot be fully explained by altered sympathoadrenal control of vascular tone. Thus, the impairment in hypoxic vasodilation is likely due to attenuated local vasodilatory and/or augmented vasoconstrictor signaling with age. NEW & NOTEWORTHY We found that the lack of peripheral vasodilation during graded systemic hypoxia with aging is not mediated by the sympathoadrenal system, strongly implicating local vascular control mechanisms in this impairment. Understanding these mechanisms may lead to therapeutic advances for improving tissue blood flow and oxygen delivery in aging and disease.

In humans, the net effect of acute systemic hypoxia in quiescent skeletal muscle is vasodilation despite significant reflex increases in muscle sympathetic vasoconstrictor nerve activity. This vasodilation increases tissue perfusion and oxygen delivery to maintain tissue oxygen consumption. Although several mechanisms may be involved, we recently tested the roles of two endothelial-derived substances during conditions of sympathoadrenal blockade to isolate local vascular control mechanisms: nitric oxide (NO) and prostaglandins (PGs). Our findings indicate that 1) NO normally plays a role in regulating vascular tone during hypoxia independent of the PG pathway; 2) PGs do not normally contribute to vascular tone during hypoxia, however, they do affect vascular tone when NO is inhibited; 3) NO and PGs are not independently obligatory to observe hypoxic vasodilation when assessed as a response from rest to steady-state hypoxia; and 4) combined NO and PG inhibition abolishes hypoxic vasodilation in human skeletal muscle. When the stimulus is exacerbated via combined submaximal rhythmic exercise and systemic hypoxia to cause further red blood cell (RBC) deoxygenation, skeletal muscle blood flow is augmented compared with normoxic exercise via local dilator mechanisms to maintain oxygen delivery to active tissue. Data obtained in a follow-up study indicate that combined NO and PG inhibition during hypoxic exercise blunts augmented vasodilation and hyperemia compared with control (normoxic) conditions by ∼50%; however, in contrast to hypoxia alone, the response is not abolished, suggesting that other local substances are involved. Factors associated with greater RBC deoxygenation such as ATP release, or nitrite reduction to NO, or both likely play a role in regulating this response.

Dipeptidyl peptidase 4 (DPP4) is a transmembrane glycoprotein involved in protein degradation. Due to its action on incretins, which increase insulin secretion, DPP4 is considered a therapeutic target for type 2 diabetes. Here we have studied the role of single and combined effects of hypoxia and inactivity on the expression of DPP4 in human adipose tissue of 12 adult normal-weight males. Fat biopsies were obtained at baseline and after each of three experimental campaigns. The results revealed that in isolated human preadipocytes the expression of DPP4 was significantly increased by exposure of participants to hypoxia. Physical inactivity per se had no apparent effect on the DPP4 expression. It is concluded that DPP4 may be a marker to monitor indirectly tissue hypoxia, as occurs in obese subjects.

Staphylococcal infection and neutrophilic inflammation can act in concert to establish a profoundly hypoxic environment. In this review we summarise how neutrophils and Staphylococcus aureus are adapted to function under hypoxic conditions, with a particular focus on the impaired ability of hypoxic neutrophils to effect Staphylococcus aureus killing.

Profound systemic hypoxemia in a neonate, unresponsive to supplemental oxygen, is usually secondary to structural heart disease or persistent pulmonary hypertension (PPHN). Pulmonary arteriovenous malformations (AVMs) and direct communications from the pulmonary artery (PA) to the atria are other

Adipose tissue metabolism and circulation play an important role in human health. It is well-known that adipose tissue mass is increased in response to excess caloric intake leading to obesity and further to local hypoxia and inflammatory signalling. Acute exercise increases blood supply to adipose tissue and mobilization of fat stores for energy. However, acute exercise during systemic hypoxia reduces subcutaneous blood flow in healthy young subjects, but the response in overweight or obese subjects remains to be investigated. Emerging evidence also indicates that exercise training during hypoxic exposure may provide additive benefits with respect to many traditional cardiovascular risk factors as compared to exercise performed in normoxia, but unfavourable effects of hypoxia have also been documented. These topics will be covered in this brief review dealing with hypoxia and adipose tissue physiology.

Hypoxia and light illumination can both decrease oxygen consumption in the photoreceptor layers. The purpose of the present study was to investigate whether the mutual effects of hypoxia and intense illumination to the photoreceptors are additive. The a-wave of flash electroretinogram (fERG) was recorded to indirectly measure the photoreceptors function under given conditions. Six normal healthy subjects, mean age 34.0 ± 3.8 years, all of whom had high-altitude (3,000 m) mountain hiking experience, were recruited for the study. Flash a-wave electroretinography was examined under four conditions: (1) normal (D/N); (2) systemic hypoxia induced by inhaling a mixture of O(2) and N(2) gases, which caused oxyhemoglobin saturation (SaO(2)) ≈ 80% (D/H); (3) intense light illumination, which resulted in photoreceptor bleaching (B/N); and (4) a combination of conditions b and c (B/H). Thirty light stimuli, each with a 20-ms ON and 1,980-ms OFF cycle, were given and ERG performed to probe the photoreceptor function. The results showed that a-wave at the various conditions did not respond to all stimuli. The average a-wave amplitudes were 91.4 ± 46.5, 22.8 ± 42.5, 15.5 ± 28.9, and 35.2 ± 41.1 μV for D/N, D/H, B/N, and B/H, respectively. Nonparametric Friedman test for a-wave amplitude indicated that significant differences occurred in D/N-D/H, D/N-B/N, D/N-B/H, D/H-B/H, and B/N-B/H (all p values were0.001, but D/H-B/N was 0.264). Thus, systemic hypoxia or strong illumination to the retina can cause an absence of the ERG a-wave or change its response, although individual differences were observed. In this study, systemic hypoxia appeared to reduce photoreceptor bleaching, an interesting finding in itself. The mechanisms underlying the disappearance of the ERG a-wave following hypoxia or intense illumination to the photoreceptors seem to differ.

Heinonen IH, Kemppainen J, Kaskinoro K, Peltonen JE, Borra R, Lindroos M, Oikonen V, Nuutila P, Knuuti J, Boushel R, Kalliokoski KK. Regulation of human skeletal muscle perfusion and its heterogeneity during exercise in moderate hypoxia. Am J Physiol Regul Integr Comp Physiol 299: R72-R79, 2010. First published April 28, 2010; doi:10.1152/ajpregu.00056.2010.-Although many effects of both acute and chronic hypoxia on the circulation are well characterized, the distribution and regulation of blood flow (BF) heterogeneity in skeletal muscle during systemic hypoxia is not well understood in humans. We measured muscle BF within the thigh muscles of nine healthy young men using positron emission tomography during one-leg dynamic knee extension exercise in normoxia and moderate physiological systemic hypoxia (14% O(2) corresponding to similar to 3,400 m of altitude) without and with local adenosine receptor inhibition with femoral artery infusion of aminophylline. Systemic hypoxia reduced oxygen extraction of the limb but increased muscle BF, and this flow increment was confined solely to the exercising quadriceps femoris muscle. Exercising muscle BF heterogeneity was reduced from rest (P = 0.055) but was not affected by hypoxia. Adenosine receptor inhibition had no effect on capillary BF during exercise in either normoxia or hypoxia. Finally, one-leg exercise increased muscle BF heterogeneity both in the resting posterior hamstring part of the exercising leg and in the resting contralateral leg, whereas mean BF was unchanged. In conclusion, the results show that increased BF during one-leg exercise in moderate hypoxia is confined only to the contracting muscles, and the working muscle hyperemia appears not to be directly mediated by adenosine. Increased flow heterogeneity in noncontracting muscles likely reflects sympathetic nervous constraints to curtail BF increments in areas other than working skeletal muscles, but this effect is not potentiated in moderate systemic hypoxia during small muscle mass exercise.

Recently, Kon et al. (5) published in this journal an interesting paper entitled “Effects of systemic hypoxia on human muscular adaptations to resistance exercise training “ which determined the effect of 8 weeks of resistance training (5 sets of 10 reps at 70% of 1 RM of free weight bench‐press and bilateral leg‐press using a weight‐stack machine) under hypoxia (HRT, 14.4% O2) or normoxia, on muscle cross‐sectorial area, 1 RM, muscular endurance and markers of mitochondrial biogenesis and angiogenesis. Their conclusion suggested two important findings: (1) an increased muscular endurance and, (2) the promotion of angiogenesis in skeletal muscle in the hypoxic‐trained subjects compared to the normoxic‐trained subjects. However, in our opinion, a number of the comments in the Kon et al. (5) publication need clarification, moreover, the author's conclusions may only partially explain the benefits of resistance training in hypoxia for endurance athletes. In the discussion section, the author's state: “For the first time, we demonstrate a significant resistance‐training‐induced increase in muscular endurance in the …

Hypoxia is an important modulator of endurance exercise‐induced oxidative adaptations in skeletal muscle. However, whether hypoxia affects resistance exercise‐induced muscle adaptations remains unknown. Here, we determined the effect of resistance exercise training under systemic hypoxia on muscular adaptations known to occur following both resistance and endurance exercise training, including muscle cross‐sectional area (CSA), one‐repetition maximum (1RM), muscular endurance, and makers of mitochondrial biogenesis and angiogenesis, such as peroxisome proliferator‐activated receptor‐γ coactivator‐1α (PGC‐1α), citrate synthase (CS) activity, nitric oxide synthase (NOS), vascular endothelial growth factor (VEGF), hypoxia‐inducible factor‐1 (HIF‐1), and capillary‐to‐fiber ratio. Sixteen healthy male subjects were randomly assigned to either a normoxic resistance training group (NRT, n =7) or a hypoxic (14.4% oxygen) resistance training group (HRT, n =9) and performed 8 weeks of resistance training. Blood and muscle biopsy samples were obtained before and after training. After training muscle CSA of the femoral region, 1RM for bench‐press and leg‐press, muscular endurance, and skeletal muscle VEGF protein levels significantly increased in both groups. The increase in muscular endurance was significantly higher in the HRT group. Plasma VEGF concentration and skeletal muscle capillary‐to‐fiber ratio were significantly higher in the HRT group than the NRT group following training. Our results suggest that, in addition to increases in muscle size and strength, HRT may also lead to increased muscular endurance and the promotion of angiogenesis in skeletal muscle., This study investigated the effect of resistance exercise training performed under systemic hypoxia or normoxia on biochemical and molecular muscular adaptations in healthy male subjects. Our findings demonstrate that resistance training under systemic hypoxia led not only muscle hypertrophy, but most interestingly, to a greater increase in muscular endurance. This increase in muscular endurance was potentially caused by the increased angiogenesis as determined by capillary‐to‐fiber ratio.

Adenosine A2A receptors and ATP-activated K+ (KATP) channels contribute to part of the cerebral vasodilatory response to systemic hypoxia, but other mediators are likely involved. Epoxyeicosatrienoic acids (EETs) are cerebral vasodilators and are released from astrocytes exposed to hypoxia. Moreover, stimulation of metabotropic glutamate receptors (mGluR) produces vasodilation by an EET-dependent mechanism. Here, we tested the hypothesis that EET signaling and mGluR activation contribute to hypoxic vasodilation. Laser-Doppler flow was measured over cerebral cortex of anesthetized rats subjected to stepwise reductions in arterial oxygen saturation to 50-70%. Hypoxic reactivity was calculated as the slope of the change in laser-Doppler flow vs. the reciprocal of arterial oxygen content. Hypoxic reactivity significantly decreased from 9.2 ± 1.9 (±95% confidence interval) in controls with vehicle treatment to 2.6 ± 1.4 with the EET antagonist 14,15-epoxyeicosa-5(Z)-enoic acid, to 3.0 ± 1.5 with the EET synthesis inhibitor MS-PPOH, to 1.9 ± 2.3 with the combined mGluR subtype 1 and 5 antagonists 2-methyl-6-(phenylethynyl)pyridine and LY367385 , to 5.6 ± 1.2 with the KATP channel inhibitor glibenclamide, and to 5.8 ± 2.3 with the A2A receptor antagonist SCH58261. However, reactivity was not significantly altered by the A2B receptor antagonist MRS1754 (6.7 ± 1.8; P = 0.28 Dunnett's test) or by the 20-hydroxyeicosatetraenoic acid synthesis inhibitor HET0016 (7.5 ± 2.3; P = 0.6). These data indicate that, in addition to the known contributions of A2A receptors and KATP channels to the increase in cerebral blood flow during hypoxia, EETs and mGluRs make a major contribution, possibly by mGluR stimulation and hypoxia-induced release of EETs. In contrast, A2B receptors do not make a major contribution, and 20-hydroxyeicosatetraenoic acid does not significantly limit hypoxic vasodilation.

As arterial partial pressure of O2 (PaO2) is reduced during systemic hypoxia, right ventricular (RV) work and myocardial O2 consumption (MV̇o2) increase. Mechanisms responsible for maintaining RV O2 demand/supply balance during hypoxia have not been delineated. To address this problem, right coronary (RC) blood flow and RV O2 extraction were measured in nine conscious, instrumented dogs exposed to normobaric hypoxia. Catheters were implanted in the right ventricle for measuring pressure, in the ascending aorta for measuring arterial pressure and for sampling arterial blood, and in an RC vein. A flow transducer was placed around the RC artery. After recovery from surgery, dogs were exposed to hypoxia in a chamber ventilated with N2, and blood samples and hemodynamic data were collected as chamber O2 was reduced progressively to ∼8%. After control measurements were made, the chamber was opened and the dog was allowed to recover. Nω-nitro-l-arginine (l-NNA) was then administered (35 mg/kg, via RV catheter) to inhibit nitric oxide (NO) production, and the hypoxia protocol was repeated. RC blood flow increased during hypoxia due to coronary vasodilation, because RC conductance increased from 0.65 ± 0.05 to 1.32 ± 0.12 ml·min−1·100 g−1. l-NNA blunted the hypoxia-induced increase in RC conductance. RV O2 extraction remained constant at 64 ± 4% as PaO2 was decreased, but after l-NNA, extraction increased to 70 ± 3% during normoxia and then to 78 ± 3% during hypoxia. RV MV̇o2 increased during hypoxia, but after l-NNA, MV̇o2 was lower at any respective PaO2. The relationship between heart rate times RV systolic pressure (rate-pressure product) and RV MV̇o2 was not altered by l-NNA. To account for l-NNA-mediated decreases in RV MV̇o2, O2 demand/supply variables were plotted as functions of MV̇o2. Slope of the conductance-MV̇o2 relationship was depressed by l-NNA ( P = 0.03), whereas the slope of the extraction-MV̇o2 relationship increased ( P = 0.003). In summary, increases in RV MV̇o2 during hypoxia are met normally by increasing RC blood flow. When NO synthesis is blocked, the large RV O2 extraction reserve is mobilized to maintain RV O2 demand/supply balance. We conclude that NO contributes to RC vasodilation during systemic hypoxia.

Animal experiments indicate that the inner retina keeps its oxygen extraction constant despite systemic hypoxia. For the human retina no such data exist. In the present study we hypothesized that systemic hypoxia does not alter inner retinal oxygen extraction. To test this hypothesis we included 30 healthy male and female subjects aged between 18 and 35 years. All subjects were studied at baseline and during breathing 12% O2 in 88% N2 as well as breathing 15% O2 in 85% N2. Oxygen saturation in a retinal artery (SO2art) and an adjacent retinal vein (SO2vein) were measured using spectroscopic fundus reflectometry. Measurements of retinal venous blood velocity using bidirectional laser Doppler velocimetry and retinal venous diameters using a Retinal Vessel Analyzer (RVA) were combined to calculate retinal blood flow. Oxygen and carbon dioxide partial pressure were measured from earlobe arterialized capillary blood. Retinal blood flow was increased by 43.0 ± 23.2% ( P < 0.001) and 30.0 ± 20.9% ( P < 0.001) during 12% and 15% O2 breathing, respectively. SO2art as well as SO2vein decreased during both 12% O2 breathing (SO2art: −11.2 ± 4.3%, P < 0.001; SO2vein: −3.9 ± 8.5%, P = 0.012) and 15% O2 breathing (SO2art: −7.9 ± 3.6%, P < 0.001; SO2vein: −4.0 ± 7.0%, P = 0.010). The arteriovenous oxygen difference decreased during both breathing periods (12% O2: −28.9 ± 18.7%; 15% O2: −19.1 ± 16.7%, P < 0.001 each). Calculated oxygen extraction did, however, not change during our experiments (12% O2: −2.8 ± 18.9%, P = 0.65; 15% O2: 2.4 ± 15.8%, P = 0.26). Our results indicate that in healthy humans, oxygen extraction of the inner retina remains constant during systemic hypoxia.

Introduction. Pulmonary edema, reduced pulmonary gas exchange and systemic hypoxia can be induced or exacerbated by hyperoxia (high FiO2). Systemic hypoxia or prolonged hyperoxia have both been ass...

Methods to enhance the adaptive responses to resistance training are of great interest to clinical and athletic populations alike. Altering the muscular environment by restricting oxygen availability during resistance exercise has been shown to induce favorable physiological adaptations. An acute hypoxic stimulus during exercise essentially increases reliance on anaerobic pathways, augmenting metabolic stress responses, and subsequent hypertrophic processes (Scott et al., 2014). Hypoxic strategies during resistance exercise were originally investigated using blood flow restriction (BFR) methods (Takarada et al., 2000), whereby a cuff is applied proximally to a limb to partially limit arterial inflow while occluding venous outflow from the working muscles. Another method that has been investigated more recently is performing resistance exercise in systemic hypoxia, by means of participants breathing a hypoxic air mixture. The addition of systemic hypoxia to resistance training has previously resulted in significantly enhanced hypertrophic and strength responses to both low-load (20% 1-repetition maximum; 1RM) (Manimmanakorn et al., 2013a,b) and moderate-load (70% 1RM) (Nishimura et al., 2010) resistance training. While research into intermittent hypoxic resistance training (IHRT) is in its infancy, some studies have reported conflicting results, which is likely due to differing research methodologies. In a recent review, it has been suggested that many of the potential mechanisms underpinning muscle adaptations to BFR training and IHRT are linked to the muscular oxygenation status and degree of metabolic stress associated with exercise (Scott et al., 2014). The purpose of this paper is to briefly summarize the adaptive responses that have been reported following both low- and moderate-load IHRT and to highlight key areas of concern for IHRT methodology, including the level of hypoxia used and the degree of metabolic stress imposed during exercise.

This article reviews the clinical manifestations of hypoxia and the important oxygen monitoring considerations for anesthetized patients. The article is divided into two parts: Part 1 reviews the pathophysiology and physiologic compensations to systemic hypoxia, and explores the problem of early diagnosis of hypoxia and available treatment options; Part 2 examines oxygen monitoring modalities, including evaluation (skin and tissue appearance), systemic blood gas monitoring (gold standard for determining blood oxygenation), and pulse oximetry (noninvasive, but a delayed indicator of oxygenation problems when patients are administered a high FIo2). Additionally, available organ-specific monitoring modalities are reviewed. The considerations outlined in this article are of utmost importance to all anesthesiologists striving to provide top quality care to anesthetized patients.

Although the effects of ischemia-reperfusion have received considerable attention, few studies have directly evaluated the microcirculatory response to systemic hypoxia. The overall objective of this study was to assess the effect of environmental hypoxia on adhesive interactions of circulating leukocytes with rat mesenteric venules by using intravital microscopy. Experiments were designed to 1) characterize the adhesive interactions of circulating leukocytes to venules during acute hypoxia produced by a reduction in inspired[Formula: see text], 2) evaluate the role of nitric oxide in these adhesive interactions, 3) determine whether the effect of hypoxia on leukocyte adhesive interactions differs between acclimatized and nonacclimatized rats, and 4) assess whether compensatory changes in nitric oxide formation contribute to this difference. The results showed that acute hypoxia promotes leukocyte-endothelial adherence in mesenteric venules of nonacclimatized rats. The mechanism of this response is consistent with depletion of nitric oxide within the microcirculation. In contrast, no leukocyte-endothelial adherence occurred during hypoxia in rats acclimatized to hypobaric hypoxia. The results are consistent with increased nitric oxide formation due to expression of inducible nitric oxide synthase during the acclimatization period. Further studies are needed to establish the cause of nitric oxide depletion during acute hypoxia as well as to define the compensatory responses that attenuate hypoxia-induced leukocyte-endothelial adherence in the microvasculature of acclimatized rats.

The three objectives of this study were: 1) to determine whether an initial exposure to systemic hypoxia could affect the ventricular ectopy caused by a second period of hypoxia, 2) to see whether ...

Whole brain radiation therapy (WBRT) is commonly used for treatment of primary and metastatic brain tumors; however, cognitive impairment occurs in 40–50% of brain tumor survivors. The etiology of the cognitive impairment following WBRT remains elusive. We recently reported that radiation-induced cerebrovascular rarefaction within hippocampal subregions could be completely reversed by systemic hypoxia. However, the effects of this intervention on learning and memory have not been reported. In this study, we assessed the time-course for WBRT-induced impairments in contextual and spatial learning and the capacity of systemic hypoxia to reverse WBRT-induced deficits in spatial memory. A clinical fractionated series of 4.5Gy WBRT was administered to mice twice weekly for 4 weeks, and after various periods of recovery, behavioral analyses were performed. To study the effects of systemic hypoxia, mice were subjected to 11% (hypoxia) or 21% oxygen (normoxia) for 28 days, initiated 1 month after the completion of WBRT. Our results indicate that WBRT induces a transient deficit in contextual learning, disruption of working memory, and progressive impairment of spatial learning. Additionally, systemic hypoxia completely reversed WBRT-induced impairments in learning and these behavioral effects as well as increased vessel density persisted for at least 2 months following hypoxia treatment. Our results provide critical support for the hypothesis that cerebrovascular rarefaction is a key component of cognitive impairment post-WBRT and indicate that processes of learning and memory, once thought to be permanently impaired after WBRT, can be restored. Published version

1. In ten spontaneously breathing, Saffan-anaesthetized rats (group I), respiratory and cardiovascular responses evoked by 10 min periods of hypoxia (arterial partial pressure of O2, Pa,O2, 33 mmHg) were recorded before and after the administration of the adenosine receptor antagonist 8-phenyltheophylline (8-PT, 10 mg kg-1 i.v.). Similar experiments were performed on nine constantly ventilated rats (group II; Pa,O2, 29 mmHg) with arterial partial pressure of CO2 (Pa,CO2) held constant. 2. In group I, hypoxia induced an initial increase and a secondary fall in ventilation (VE) with an accompanying secondary fall in heart rate (HR), arterial pressure (ABP) fell and cerebral vascular conductance (CVC) increased progressively. Cerebral blood flow (CBF) tended to fall with time during hypoxia. 8-PT abolished the secondary falls in VE and HR and reduced the fall in ABP and increase in CVC, while CBF was better maintained. 3. In group II, hypoxia induced a similar cardiovascular response to that in group I, but at the 1st minute of hypoxia, the HR was lower and the increase in CVC was greater. 8-PT did not affect the hypoxia-induced changes in HR, ABP, CVC or CBF. 4. These results indicate specific ways in which the ventilatory and cardiovascular responses induced by hypoxia in the spontaneously breathing rat are interdependent. They also indicate that the influences of 8-PT on the cardiovascular changes induced by hypoxia during spontaneous ventilation are mainly a consequence of its ability to block the centrally mediated contribution of adenosine to the secondary fall in ventilation.

Systemic hypoxia (inspired oxygen of 10%) constricts large arterioles (A1) and dilates small arterioles (A3) in striated muscle. The possible role of endothelium-derived relaxing factor (EDRF) or prostaglandins in mediating these responses was examined, as were the arteriolar response to systemic hypoxia in 1K1C (1-kidney, 1-clip) hypertensive rats and EDRF involvement in this response. In the cremaster muscles of anesthetized rats, hypoxia-induced A1 constriction was similar in normotensive and hypertensive animals and was not affected by the blockade of prostaglandin synthesis with mefenamic acid or by EDRF inhibition with hydroquinone (an EDRF inactivator) or L-Nω-nitro-arginine (L-NNA) (an EDRF synthesis inhibitor). A3 dilation in normotensive animals was unaffected by mefenamic acid, but was significantly (p < 0.05) attenuated by hydroquinone and L-NNA. Arteriolar dilation during systemic hypoxia was significantly less (p < 0.05) in the hypertensive compared with the normotensive groups and not alter...

The slope of the relationship between ventilation (VI) and O2 consumption, as derived in progressive-intensity exercise tests, is increased markedly by systemic hypoxia. The mechanisms underlying the hypoxic potentiation of the ventilatory response to exercise have not been established, partly because several factors that can increase respiratory drive (e.g., metabolic rate, cardiac output, circulating catecholamine levels) change significantly and simultaneously under these conditions. In an effort to avoid these confounding changes, we sought to determine whether hypoxia potentiates the ventilatory response to dynamic forearm exercise in humans. Forearm exercise increased the O2 consumption by only 80–90 ml/min; nevertheless, hypoxia resulted in a significant potentiation of VI that was mediated by a marked increase in breathing frequency. These observations led us to hypothesize that the hypoxic potentiation of VI is due to an exaggerated stimulation of chemosensitive afferent nerve endings within the exercising muscles ("muscle chemoreceptors"). We tested this hypothesis in separate experiments under conditions of forearm ischemia so that the stimulus to the muscle chemoreceptors in normoxic and hypoxic exercise would be the same. The magnitude of the change in VI evoked by hypoxic ischemic exercise was significantly greater than the sum of the separate changes evoked by normoxic ischemic exercise and hypoxic ischemic rest. We conclude that the combination of dynamic forearm exercise and hypoxia potentiates VI and that this effect is mediated by neural structures that govern respiratory frequency. Moreover the potentiated ventilatory response cannot be attributed to an exaggerated stimulation of intramuscular chemoreceptors.

Heinonen I, Kemppainen J, Kaskinoro K, Peltonen JE, Borra R, Lindroos MM, Oikonen V, Nuutila P, Knuuti J, Hellsten Y, Boushel R, Kalliokoski KK. Comparison of exogenous adenosine and voluntary exercise on human skeletal muscle perfusion and perfusion heterogeneity. J Appl Physiol 108: 378-386, 2010. First published November 25, 2009; doi:10.1152/japplphysiol.00745.2009.-Adenosine is a widely used pharmacological agent to induce a "high-flow" control condition to study the mechanisms of exercise hyperemia, but it is not known how well an adenosine infusion depicts exercise-induced hyperemia, especially in terms of blood flow distribution at the capillary level in human muscle. Additionally, it remains to be determined what proportion of the adenosine-induced flow elevation is specifically directed to muscle only. In the present study, we measured thigh muscle capillary nutritive blood flow in nine healthy young men using PET at rest and during the femoral artery infusion of adenosine (1 mgmin(-1)1 thigh volume(-1)), which has previously been shown to induce a maximal whole thigh blood flow of similar to 8 1/min. This response was compared with the blood flow induced by moderate- to high-intensity one-leg dynamic knee extension exercise. Adenosine increased muscle blood flow on average to 40 +/- 7 ml.min(-1).100 g muscle(-1) with an aggregate value of 2.3 +/- 0.6 1/min for the whole thigh musculature. Adenosine also induced a substantial change in blood flow distribution within individuals. Muscle blood flow during the adenosine infusion was comparable with blood flow in moderate- to high-intensity exercise (36 +/- 9 ml.min(-1).100 g muscle(-1)), but flow heterogeneity was significantly higher during the adenosine infusion than during voluntary exercise. In conclusion, a substantial part of the flow increase in the whole limb blood flow induced by a high-dose adenosine infusion is conducted through the physiological non-nutritive shunt in muscle and/or also through tissues of the limb other than muscle. Additionally, an intra-arterial adenosine infusion does not mimic exercise hyperemia, especially in terms of muscle capillary flow heterogeneity, while the often-observed exercise-induced changes in capillary blood flow heterogeneity likely reflect true changes in nutritive flow linked to muscle fiber and vascular unit recruitment.

Natural killer cells (NKs) are important to the clearance of transformed cells. This investigation elucidates how systemic hypoxia influences mobilization of the NK subsets and cytotoxicity of NKs to nasopharyngeal carcinoma cells (NPCs) during exercise. Sixteen sedentary men performed six distinct experimental tests in an air-conditioned normobaric hypoxia chamber: high-intensity exercise [HE; up to maximal O2 consumption (V̇o2 max)] under 21% O2; moderate-intensity exercise (ME; 50% V̇o2 max for 30 min) under 12%, 15%, and 21% O2; and breathing 12% and 15% O2 for 30 min at rest. The results demonstrated that 21% O2 HE, but not ME, increased cellular perforin/granzyme B/interferon-γ levels in NKs and interferon-γ concentration in NK-NPC coincubation, and also promoted capacity of NKs to bind to NPCs and NK-induced CD95 expression and phosphatidylserine exposure of NPCs. However, the HE simultaneously increased percentages of the replicative senescent (CD57+ and CD28−) NKs and the NKs with inhibitory receptors (KLRG1+) that entered the bloodstream from peripheral tissues. Breathing 12% and 15% O2 at rest did not influence mobilization of NK subsets and cytotoxicity of NKs to NPCs. Although both 12% and 15% O2 ME increased NK count, perforin/granzyme B/interferon-γ levels, NK-NPC binding, and NK-induced CD95 expression and apoptosis of NPC, only 12% O2 ME increased percentages of the NKs with CD57+/CD28−/KLRG1+ in blood. Therefore, we conclude that systemic hypoxic exposure affects redistribution of NK subsets and anti-NPC cytotoxicity of NKs during exercise in a concentration-dependent manner. Moreover, exposure to 12% O2 promotes the NK cytotoxicity with mobilizing the replicative senescent/inhibitory NKs into the bloodstream during ME.

Phagocytosis and oxidative burst are critical host defense mechanisms in which neutrophils clear invading pathogens. Clearing phagocytic neutrophils by triggering apoptosis is an essential process for controlling inflammation. This study elucidates how various exercise bouts with/without hypoxia affected neutrophil bactericidal activity and subsequent apoptosis in humans. Fifteen sedentary males performed six distinct experimental tests in an air-conditioned normobaric hypoxia chamber: two normoxic exercises [strenuous exercise (SE; up to maximal O2consumption) and moderate exercise (ME; 50% maximal O2consumption for 30 min) while exposed to 21% O2], two hypoxic exercises (ME for 30 min while exposed to 12% and 15% O2), and two hypoxic exposures (resting for 30 min while exposed to 12% and 15% O2). The results showed that 1) plasma complement-C3a desArg/C4a desArg/C5a concentrations were increased, 2) expressions of L-selectin/lymphocyte functin-associated antigen-1/Mac-1/C5aR on neutrophils were enhanced, 3) phagocytosis of neutrophils to Esherichia coli and release of neutrophil oxidant products by E. coli were elevated, and 4) E. coli -induced phosphotidylserine exposure or caspase-3 activation of neutrophils were promoted immediately and 2 h after both 12% O2exposure at rest and with ME as well as normoxic SE. Although neither normoxic ME nor breathing 15% O2at rest influenced these complement- and neutrophil-related immune responses, ME at both 12% and 15% O2resulted in enhanced complement activation in the blood, expressions of opsonic/complement receptors on neutrophils, or the bactericidal activity and apoptosis of neutrophils. Moreover, the increased neutrophil oxidant production and apoptosis by normoxic SE and hypoxic ME were ameliorated by treating neutrophils with diphenylene iodonium (a NADPH oxidase inhibitor). Therefore, we conclude that ME at 12–15% O2enhances bactericidal capacity and facilitates the subsequent apoptosis of neutrophils.

Acute systemic hypoxia (Hx) promotes leukocyte adherence in post-capillary venules of rats. When animals are chronically hypoxic, the initial microvascular inflammation resolves in part due to upre...

Purpose. To measure the effect of acute, mild, systemic hypoxia on neuroretinal function in two different age groups.Methods. The slow-flash paradigm of the multifocal electroreti-nogram (mfERG) was measured in two different oxygenation levels. Twelve participants of two age groups (28 ± 4 and 55 ±5 years) breathed room air (normoxia) or 12% oxygen (hyp-oxia).Results. During normoxia (SaO = 98%) there was a significantly different effect between the younger and older participants on the mfERG positive waveform components (N1P1amplitudes and P1 implicit times; P < 0.001). Hypoxia (SaO =90%) significantly decreased N1P1 response density amplitudes in the central retinal field in both groups, with a larger effect in the older group (P < 0.001). There was no significant change in function of the cellular generators of oscillatory potentials (OPs).Conclusion. The results extend recent findings by showing a greater effect of hypoxia on ON- and OFF-bipolar cell function in healthy older persons than in younger persons, but no effect on OPs during moderate acute hypoxia in either age group. (Invest Ophthalmol Vis Sci. 2008;49:807-813) DOI:10.1167/iovs.07- 0994

Systemic hypoxia in mammals is sensed and transduced by the carotid body into increased action potential (AP) frequency on the sinus nerve, resulting in increased ventilation. The mechanism of hypoxia transduction is not resolved, but previous work suggested that fast Na+channels play an important role in determining the rate and timing of APs (Donnelly, DF, Panisello JM, and Boggs D. J Physiol. 511: 301–311, 1998). We speculated that Na+channel activity between APs, termed persistent Na+current ( INaP), is responsible for AP generation that and riluzole and phenytoin, which inhibit this current, would impair organ function. Using whole cell patch clamp recording of intact petrosal neurons with projections to the carotid body, we demonstrated that INaPis present in chemoreceptor afferent neurons and is inhibited by riluzole. Furthermore, discharge frequencies of single-unit, chemoreceptor activity, in vitro, during normoxia (Po2150 Torr) and during acute hypoxia (Po290 Torr) were significantly reduced by riluzole concentrations at or above 5 μM, and by phenytoin at 100 μM, without significant affect on nerve conduction time, AP magnitude (inferred from extracellular field), and AP duration. The effect of both drugs appeared solely postsynaptic because hypoxia-induced catecholamine release in the carotid body was not altered by either drug. The respiratory response of unanesthetized, unrestrained 2-wk-old rats to acute hypoxia (12% inspired O2fraction), which was measured with whole body plethysmography, was significantly reduced after treatment with riluzole (2 mg/kg ip) and phenytoin (20 mg/kg ip). We conclude that INaPis present in chemoreceptor afferent neurons and serves an important role in peripheral chemoreceptor function and, hence, in the ventilatory response to hypoxia.

In functional atudy of the cardiac pump during systemic hypoxia, noninvasive measurement of the cardiac left ventricular pressure (LVP) during hypoxia is a tempting problem. The authors found from point of view of systems physiology that there existed correlation between brachial arterial blood pressure (BP1 and LVP. Using method of normalization and stepwise regression, models were establiahed for estimating LVP upon BP. For the LVP estimated with single hypoxia condition models the average relative area errors P

We present the case of a 6-month-old infant born premature at 29 weeks with perinatal stroke and postnatal hypoxia. Echocardiogram was suspicious for partial anomalous pulmonary venous return (PAPVR). Cardiac CT showed an unusual variant of PAPVR, with a vertical vein having a dual connection superiorly to the left innominate vein and inferiorly to the morphologic left atrium. This unusual variant has the potential for right-to-left flow with a possibility of systemic hypoxia and paradoxical embolism.

It has been reported by many authors that the carotid bodies become enlarged several fold in rats exposed to long term hypoxia. As a result of enlargement, the carotid body takes on a spongy appearance with increased vascularization. In early studies, experimental animals were exposed to hypoxia equivalent to that of high altitudes (3800-7500m) in a hypobaric chamber (Blessing and Wolff, 1973; Heath et ai 1973; Moller et al 1974; Laidler and Kay, 1975a, b, 1978; Barer et al 1976), and in later studies, the animals were also exposed to hypoxia in a normobaric hypoxic chamber (10% O2) (Pequignot and Hellstrom, 1983; Dhillon et al 1984; McGregor et al 1984; Pequignot et al 1984; Kusakabe et al 1998a, b; 2000, 2002). In some studies the animals were exposed to hypoxia for short periods of 1-2 weeks, and in other studies for long periods of 2-3 months.However, most authors use the term “chronic hypoxia” in their publications.Thus, the condition and duration of experimental hypoxic exposure have been various, and it is difficult to compare these results.

The rebound tachycardia, transient increase in heart rate (HR) that was observed immediately after the cessation of hypoxia was investigated. Whether the cardiovascular responses induced by hypoxia depend on species difference is also discussed. Wistar rats were chronically instrumented for measurements of arterial blood pressure (ABP), HR and renal sympathetic nerve activity (RSNA), and then subjected to hypocapnic (Hypo), isocapnic (Iso) or hypercapnic (Hyper) hypoxia. Iso did not affect mean ABP (MAP) or HR, whereas Hypo decreased MAP and increased HR, and Hyper increased MAP and decreased HR. RSNA increased in each hypoxia. After the cessation of Iso and Hyper, HR transiently increased and then returned to that of the control. This HR response did not parallel the changes in RSNA, suggesting that "rebound" tachycardia is not due to a sympathetic but rather a parasympathetic mechanism. Although it has been generally believed that cardiovascular responses to systemic hypoxia depend on the species, there was little difference between the results observed in this study and those in previous studies under similar experimental conditions. Accordingly, we suggest that the cardiovascular responses to systemic hypoxia do not depend on species difference but rather on differences in experimental design.

It has been suggested that the cardiovascular responses to hypoxia are produced as integrated interactions between the effects of the autonomic nervous system and the direct effect of hypoxia on the central nervous system (CNS) and the cardiovascular system (Daly, 1986; Marshall, 1994). However, hypoxic exposure has been delivered for relatively short periods of time before attaining a steady state in many works. Therefore, such responses may have resulted before integrated interactions began operating. There is also no information on the behavior of the autonomic nervous activities during hypoxia in conscious animals, which may be relevant to the study of an integrated function. In this study, the autonomic nervous activities are examined during the cardiovascular responses of the chemoreceptor-intact and of denervated conscious rats to systemic hypoxia, in order to determine the contribution of the arterial chemoreceptors to these responses.

1. Direct observations were made of responses to systemic hypoxia (breathing 12 or 6% O2 for 3 min) evoked in terminal arterioles (TA, 14-30 microns internal diameter), precapillary arterioles (PCA, 8-18 microns), collecting venules (CV, 12-30 microns) and small veins (SV, 20-50 microns) of the mesenteric circulation of the anaesthetized rat. Changes in vessel diameter were recorded before and after local blockade of alpha-adrenoreceptors with phentolamine when the mesentery was covered with Saran Wrap, which is impermeable to O2, and then after removal of the Saran Wrap, which would have kept local PO2 relatively high even during systemic hypoxia. 2. The majority of TA showed an initial decrease in diameter of 14 +/- 1% (mean +/- S.E.M.). These responses were reversed to increases in diameter (12 +/- 2%) after phentolamine, but virtually abolished after removal of the Saran Wrap (0.3 +/- 2%). 3. Some PCA showed similar behaviour to the TA; others showed an increase in diameter (11 +/- 1%). The increases in diameter were accentuated after phentolamine (16 +/- 1%), but were reduced after removal of the Saran Wrap (6 +/- 2%). 4. CV and SV showed either a decrease in diameter followed by relaxation towards control levels, or an increase in diameter that waned before hypoxia ceased (6 +/- 1% and 1 +/- 1%, respectively). The responses of CV were not altered by phentolamine (8 +/- 1%), but SV showed larger increases in diameter (5 +/- 1%).(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Hypoxia results in an increased generation of ROS. Until now, little is known about the role of MnSOD - a major endogenous antioxidant enzyme - on the cell adaptation response against hypoxia. The aim of this study was to determine the MnSOD mRNA expression and levels of specific activity in blood, heart and brain of rats during induced systemic hypoxia.Methods: Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia in an hypoxic chamber (at 8-10% O2) for 0, 1, 7, 14 and 21 days, respectively. The mRNA relative expression of MnSOD was analyzed using Real Time RT-PCR. MnSOD specific activity was determined using xanthine oxidase inhibition assay.Results: The MnSOD mRNA relative expression in rat blood and heart was decreased during early induced systemic hypoxia (day 1) and increased as hypoxia continued, whereas the mRNA expression in brain was increased since day 1 and reached its maximum level at day 7. The result of MnSOD specific activity during early systemic hypoxia was similar to the mRNA expression. Under very late hypoxic condition (day 21), MnSOD specific activity in blood, heart and brain was significantly decreased. We demonstrate a positive correlation between MnSOD mRNA expression and specific activity in these 3 tissues during day 0-14 of induced systemic hypoxia. Furthermore, mRNA expression and specific activity levels in heart strongly correlate with those in blood.Conclusion: The MnSOD expression at early and late phases of induced systemic hypoxia is distinctly regulated. The MnSOD expression in brain differs from that in blood and heart revealing that brain tissue can possibly survive better from induced systemic hypoxia than heart and blood. The determination of MnSOD expression in blood can be used to describe its expression in heart under systemic hypoxic condition. (Med J Indones 2011; 20:27-33)Keywords: MnSOD, mRNA expression, ROS, specific activity, systemic hypoxia

Summary The concentrations of reduced (GSH) and oxidized glutathione (glutathione disulfide, GSSG) in lung, liver, brain and plasma of newborn rats were investigated under the condition of reversible hypoxia. Brain and lung of newborn rats seem to be susceptible to reversible hypoxia. We found an increase in GSSG concentration after hypoxia in these organs. This alteration of the GSH-GSSG redox system was reversible within 2 hours of reoxygenation. A second increase in cerebral GSSG concentration after 4 hours of reoxygenation was connected with fasting during the experiment. In the liver we found a hypoxia dependent decrease in the GSH level, followed by a decrease in GSSG concentration. The increased GSSG concentrations in lung and brain are accompanied by an enhancement of plasma GSSG concentration.

It is known that systemic hypoxia has marked effects on the cardiovascular system. These are generally attributed to the interaction between reflex, nerve-mediated responses, and the local influences of changes in blood gas tensions. They include the reflex effects of hypoxic stimulation of peripheral chemoreceptors, effects mediated by the actions of hypoxia upon the central nervous system, the local actions of hypoxia upon the heart and vasculature, as well as the reflex and direct effects of any evoked changes in ventilation and in PaCO2 1.

The aim of this critical review was to establish morphologic or biochemical diagnostic markers or indications for the pathogenesis of SIDS in the CNS and to review current literature dealing with CNS changes, especially in the brain stem. The functional disturbances recently discussed as the cause of SIDS, i.e. primary CNS changes in the sense of retardation of neurons in the brain stem, are presented first. Signs of retardation were obtained by quantification of dendritic spines [1, 2] and determination of phenylethanolamine-N-methyltransferase (PNMT), the adrenalin-synthesizing enzyme [3] and disturbances of endorphin immunoreactivity [4, 5]. Dendritic spine density was higher and PNMT activity weaker in the SIDS cases than in the controls, whereas no definitive findings of an increase or decrease in endorphin system activity were found. Signs of secondary CNS changes were established by quantification of the glial cell population in the brain stem [6–8] and determination of Purkinje cell density [9]; some authors found evidence of a brain stem gliosis, but no further indications of chronic systemic hypoxia or chronic hypoperfusion of the CNS could be established in SIDS victims.

METHODS: Macrophages were obtained from C3H/HeOUJ mice by peritoneal lavage. Hypoxia was induced in mice and RAW 264.7 macrophages using a modular hypoxic chamber (1% O2), and phagocytosis was quantified by confocal microscopy after internalization of IgG-opsonized erythrocytes (37degC). p38MAPK and HIF signaling were assessed by SDS-PAGE. HIF-1 alpha was inhibited using specific siRNA, and activated after overexpression with HIF-1 alpha cDNA. Data are mean / SEM.

The effect upon pancreatic blood flow of systemic hypoxia and hypercapnia was examined in 15 anesthetized puppies. Blood flow was measured by the 86 RbCl distribution technique. Reduction in arterial P O 2 and elevation of arterial P CO 2 were each found to effect significant mean reductions in pancreatic blood flow of 47 and 50%, respectively. Simultaneous measurements of duodenal blood flow showed no change from control levels.

Despite the seriousness of pulmonary O2 toxicity, patients can generally withstand 1 atm. of PO2 for at least 24 hours. Also, there is no evidence that clinically relevant pulmonary O2 toxicity occurs in humans at inspired partial pressures below 0.4 to 0.5 ATA, even with prolonged exposures. Neither is there clinical or experimental evidence to indicate that patients with preexisting pulmonary disease are more sensitive to O2 toxicity than are normal volunteers. Although the florid manifestations of pulmonary O2 toxicity may have dire consequences, a lower dosage of O2, though still potentially toxic, may well be acceptable. The lung itself can generate some level of self-protection with prolonged O2 exposure, ultimately healing itself to a significant degree. Therefore, no patient should be exposed to dangerous levels of hypoxia out of fear of causing pulmonary O2 toxicity. Pulmonary hyperoxia and systemic hypoxia can usually be avoided with skillful, titrated management of respiratory insufficiency.

The effects of systemic hypoxia upon liver blood flow and oxygen consumption were studied in a group of six pentobarbitone anaesthetised greyhounds. The effect of systemic hyperoxia upon the same factors were also studied in a further group of six greyhounds.