Hypoxic Trials Research Articles

Effect of Prenatal Nicotine Exposure and Serotonin Deficiency on Arousal to Hypoxia in Rat Pups

Smoking during pregnancy increases the risk for the Sudden Infant Death Syndrome (SIDS) and 70% of SIDS infants have a deficiency in brainstem serotonin (5HT). Arousal in response to hypoxia may be impaired by repeated exposures to hypoxia. We hypothesized that prenatal nicotine exposure (PNE) associated with a 5HT deficiency would increase arousal latency to successive bouts of hypoxia in pups. Dams were fed either a control (CONT) or a tryptophan deficient (TD) diet associated with ~50% less medullary 5HT, throughout gestation. From E4 to P10, a subcutaneously implanted osmotic pump continuously delivered saline (NS) or nicotine (NIC) (6mg/kg/day) corresponding to about 0.5-1 pack of cigarettes a day in human smokers. Four groups of litters were studied: CONT/NS, CONT/NIC, TD/NS and TD/NIC. P7 and P13 rat pups from each litter were exposed to 4 successive bouts of 10% oxygen and the time to arousal (latency) from the onset of hypoxia was determined behaviorally. Measurements of blood cotinine concentrations confirmed that nicotine continued to be present in the blood until P13. The results showed a main effect for age (p=0.015), experimental group (p=0.045), hypoxia trial (p<0.001) and interactions between age and group (p=0.021) and age and trial (p=0.003). At P13, but not at P7, mean arousal latency was longer in the CON/NIC group compared to the CON/NS (p=0.003) and the TD/NS (p=0.005) groups. Mean latency for the TD/NIC group fell between the latency for the CON/NIC group and the CON/NS group but was not significantly different from either group. We conclude that PNE impairs arousal in response to hypoxia whereas arousal is not affected by a mild 5HT deficiency. NIH PO1 HD36379

Hypoxic Cerebral Vasodilation in Healthy and Metabolic Syndrome Adults: Distinct Interactions between Cyclooxygenase and Reactive Oxygen Species Signaling

Excess reactive oxygen species (ROS) limit hypoxia‐mediated cerebral vasodilation in animal models of metabolic syndrome (MetSyn). Cyclooxygenase (COX) may be a source of ROS, but data are lacking in humans. We hypothesized ROS limit hypoxic cerebral vasodilation in human MetSyn, but COX is not the source. We measured middle cerebral artery velocity (MCAv) with transcranial Doppler ultrasound in 12 MetSyn adults (34±2 yr) and 12 healthy adults (28±1 yr) during baseline and steady‐state hypoxia (SPo2=80%). Intravenous ascorbic acid suppressed ROS during the first steady‐state hypoxia. Oral indomethacin was administered to inhibit COX prior to a second hypoxia trial to investigate the combined roles of ROS and COX during hypoxia. MCAv was normalized for MABP as cerebrovascular conductance index [CVCi = (MCAv ÷ MABP) * 100], and a change in CVCi from baseline (ΔCVCi) indicated hypoxic dilation. ΔCVCi was ~50% lower in adults with MetSyn during control hypoxia (p&lt;0.05). Ascorbic acid infusion increased ΔCVCi in MetSyn adults (p&lt;0.05), but not healthy adults. Combined ascorbic acid and indomethacin increased ΔCVCi in MetSyn adults (p&lt;0.05) similar to ascorbic acid alone. Surprisingly in healthy adults, combined ascorbic acid and indomethacin reduced ΔCVCi by ~75% (p&lt;0.05). This contrasts previous data in healthy adults that indicated no effect of indomethacin alone. In summary, healthy adults express a ROS‐COX redundancy, whereby ROS suppression increased reliance on COX products to achieve hypoxic cerebral vasodilation. MetSyn disrupts this complementary role of ROS, such that COX‐derived ROS restrain hypoxic cerebral vasodilation.

Endurance exercise performance in acute hypoxia is influenced by expiratory flow limitation.

We sought to determine if expiratory flow limitation influences intensive aerobic exercise performance in mild hypoxia. Fourteen trained male cyclists were separated into flow-limited (FL, n = 7) and non-FL (n = 7) groups based on the extent of expiratory flow limitation exhibited during maximal exercise in normoxia. Participants performed two self-paced 5-km cycling time trials, one in normoxic (F IO2 = 0.21) and one in mild hypoxic (F IO2 = 0.17) conditions in a randomized, balanced order with the subjects blinded to composition of the inspirate. Percent change from normoxia to hypoxia in average power output (%ΔP TT) and time to completion (%ΔT TT) were used to assess performance. Hypoxia resulted in a significant decline in estimated arterial O2 saturation and decrements in performance in both groups, although FL had a significantly smaller %ΔP TT (-4.0 ± 0.5 vs. -9.0 ± 1.8 %) and %ΔT TT (1.3 ± 0.3 vs. 3.7 ± 0.9 %) compared to non-FL. At the 5th km of the time trial, minute ventilation did not change from normoxia to hypoxia in FL (3.4 ± 3.1 %) or non-FL (2.3 ± 3.7 %), but only the non-FL reported a significantly increased dyspnea rating in hypoxia compared to normoxia (~9 %). Non-FL athletes did not utilize their ventilatory reserve to defend arterial oxygen saturation in hypoxia, which may have been due to an increased measure of dyspnea in the hypoxic trial. FL athletes experience less hypoxia-related aerobic exercise performance impairment as compared to non-FL athletes, despite having less ventilatory reserve.

Appetite and gut hormone responses to moderate-intensity continuous exercise versus high-intensity interval exercise, in normoxic and hypoxic conditions

This study investigated the effects of continuous moderate-intensity exercise (MIE) and high-intensity interval exercise (HIIE) in combination with short exposure to hypoxia on appetite and plasma concentrations of acylated ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Twelve healthy males completed four, 2.6 h trials in a random order: (1) MIE-normoxia, (2) MIE-hypoxia, (3) HIIE-normoxia, and (4) HIIE-hypoxia. Exercise took place in an environmental chamber. During MIE, participants ran for 50 min at 70% of altitude-specific maximal oxygen uptake (V˙O2max) and during HIIE performed 6 × 3 min running at 90% V˙O2max interspersed with 6 × 3 min active recovery at 50% V˙O2max with a 7 min warm-up and cool-down at 70% V˙O2max (50 min total). In hypoxic trials, exercise was performed at a simulated altitude of 2980 m (14.5% O2). Exercise was completed after a standardised breakfast. A second meal standardised to 30% of participants' daily energy requirements was provided 45 min after exercise. Appetite was suppressed more in hypoxia than normoxia during exercise, post-exercise, and for the full 2.6 h trial period (linear mixed modelling, p < 0.05). Plasma acylated ghrelin concentrations were lower in hypoxia than normoxia post-exercise and for the full 2.6 h trial period (p < 0.05). PYY concentrations were higher in HIIE than MIE under hypoxic conditions during exercise (p = 0.042). No differences in GLP-1 were observed between conditions (p > 0.05). These findings demonstrate that short exposure to hypoxia causes suppressions in appetite and plasma acylated ghrelin concentrations. Furthermore, appetite responses to exercise do not appear to be influenced by exercise modality.

Flow-mediated dilation in the inactive limb following acute hypoxic exercise.

The purpose of this study was to elucidate the effect of acute aerobic exercise performed under hypoxic conditions on flow-mediated dilation (FMD) in the inactive limb. Seven males participated in the study. The subjects performed two submaximal leg cycling on a semirecumbent ergometer at the same relative intensity (60% peak oxygen uptake) in normoxia [inspired oxygen fraction (FIO2) = 0·21] and hypoxia (FIO2 = 0·12-0·13) for 30 min. The brachial artery diameter and blood velocity during exercise were measured via ultrasound, and the antegrade and retrograde shear rates were calculated. Before and 5, 30 and 60 min after exercise, brachial artery FMD was measured in normoxia. FMD was estimated as the percentage increase in peak diameter from the baseline diameter at prior occlusion (%FMD) and as the controlling changes in baseline diameter (the corrected-%FMD). No difference in antegrade shear rate during exercise was detected between the normoxic and hypoxic conditions, whereas the retrograde shear rate was larger during hypoxic exercise. The %FMD decreased significantly at 5 min after exercise in both normoxia and hypoxia, and it returned to pre-exercise levels within 60 min of recovery. Significant decreases in FMD at 5 min after exercise had disappeared when the baseline diameter was controlled using an analysis of covariance (the corrected-%FMD). No significant differences were observed between the normoxic and hypoxic trials in the %FMD and corrected-%FMD following exercise. These results suggest that hypoxia has no impact on endothelial function in the inactive limb following acute aerobic exercise.

Successive exposure to moderate hypoxia does not affect glucose metabolism and substrate oxidation in young healthy men.

IntroductionExposure to hypoxia has been suggested to acutely alter glucose regulation. However, the effects of successive exposure to moderate hypoxia on postprandial glucose regulation and substrate oxidation pattern after multiple meals have not been elucidated.PurposeWe examined the effects of successive exposure to moderate hypoxia on metabolic responses and substrate oxidation pattern.MethodsEight healthy men (21.0 ± 0.6 yrs, 173 ± 2.3 cm, 70.6 ± 5.0 kg, 23.4 ± 1.1 kg/m2) completed two experimental trials on separate days: a rest trial under normoxic conditions (FiO2 = 20.9%) and a rest trial under hypoxic conditions (FiO2 = 15.0%). Experimental trials were performed over 7 h in an environmental chamber. Blood and respiratory gas samples were collected over 7 h. Standard meals were provided 1 h (745 kcal) and 4 h (731 kcal) after entering the chamber.ResultsAlthough each meal significantly increased blood glucose and serum insulin concentrations (P < 0.05), these responses did not differ significantly between the trials. There were no significant differences in areas under the curves for glucose or insulin concentrations over 7 h between the trials. No significant differences were observed in blood lactate, serum cortisol, free fatty acid, or glycerol concentrations over 7 h between the trials. The oxygen consumption ( ) and carbon dioxide production ( ) 3 h after entering the chamber were significantly higher in the hypoxic trial than in the normoxic trial (P < 0.05). However, the differences did not affect respiratory exchange ratio (RER). The average values of , , and RER did not differ between the trials.ConclusionSeven hours of moderate hypoxia did not alter postprandial glucose responses or substrate oxidation in young healthy men.

Neocortical pCREB and BDNF expression under different modes of hypobaric hypoxia: Role in brain hypoxic tolerance in rats

Preconditioning with repetitive mild hypobaric hypoxia is known to increase tolerance of susceptible brain neurons to severe hypoxia, whereas a single trial of mild hypoxia has been ineffective. In the present study, the effects of three-trial and one-trial hypobaric preconditioning on the expression of the protective transcription factor phosphorylated CREB (pCREB) and neurotrophin BDNF, before and after severe hypobaric hypoxia, have been comparatively studied in the neocortex of rats. As revealed by quantitative immunocytochemistry, the severe hypobaric hypoxia (180Torr, 3h) substantially down-regulated the levels of pCREB and BDNF in cortical neurons assessed 24h after the treatment. One trial of mild hypoxia (360Torr, 2h) also reduced by half the number of BDNF-expressing cells, but had no effect on pCREB expression in the neocortex. In contrast, the exposure to three trials of mild hypoxia at 24h intervals considerably up-regulated pCREB and BDNF levels in the neocortex of rats. Only preconditioning by three trials of mild hypoxia (360Torr, 2h, 24h intervals), but not a single trial preconditioning, was neuroprotective significantly enhancing the pCREB and BDNF neuronal expression in response to severe hypoxic challenge. The results of the present study indicate that development of the neuronal hypoxic tolerance induced by the three-trial mild hypoxic preconditioning is apparently associated with activation of CREB and BDNF expression.

Activation of the carotid chemoreflex secondary to muscle metaboreflex stimulation in men

Recent work has shown that the carotid chemoreceptor (CC) contributes to sympathetic control of cardiovascular function during exercise, despite no evidence of increased circulating CC stimuli, suggesting enhanced CC activity/sensitivity. As interactions between metaboreceptors and chemoreceptors have been previously observed, the purpose of this study was to isolate the metaboreflex while acutely stimulating or inhibiting the CC to determine whether the metaboreflex increased CC activity/sensitivity. Fourteen young healthy men (height: 177.0 ± 2.1 cm, weight: 85.8 ± 5.5 kg, age: 24.6 ± 1.1 yr) performed three trials of 40% maximal voluntary contraction handgrip for 2 min, followed by 3 min of postexercise circulatory occlusion (PECO) to stimulate the metaboreflex. In random order, subjects either breathed room air, hypoxia (target SPo2 = 85%), or hyperoxia (FiO2 = 1.0) during the PECO to modulate the chemoreflex. After these trials, a resting hypoxia trial was conducted without handgrip or PECO. Ventilation (Ve), heart rate (HR), blood pressure, and muscle sympathetic nervous activity (MSNA) data were continuously obtained. Relative to normoxic PECO, inhibition of the CC during hyperoxic PECO resulted in lower MSNA (P = 0.038) and HR (P = 0.021). Relative to normoxic PECO, stimulation of the CC during hypoxic PECO resulted in higher HR (P < 0.001) and Ve (P < 0.001). The ventilatory and MSNA responses to hypoxic PECO were not greater than the sum of the responses to hypoxia and PECO individually, indicating that the CC are not sensitized during metaboreflex activation. These results demonstrate that stimulation of the metaboreflex activates, but does not sensitize the CC, and help explain the enhanced CC activity with exercise.

Peak oxygen uptake and regional oxygenation in response to a 10‐day confinement to normobaric hypoxia

We investigated the effect of hypoxic acclimatization per se, without any concomitant influence of strenuous physical activity on muscle and cerebral oxygenation. Eight healthy male subjects participated in a crossover-designed study. In random order, they conducted a 10-day normoxic (CON) and a 10-day hypoxic (EXP) confinement. Pre and post both CON and EXP confinements, subjects conducted two incremental-load cycling exercises to exhaustion; one under normoxic, and the other under hypoxic (F(I)O(2) = 0.154) conditions. Oxygen uptake (V˙O(2)), ventilation (V˙(E)), and relative changes in regional hemoglobin oxygenation (Δ([HbO(2)]) in the cerebral cortex and in the serratus anterior (SA) and vastus lateralis (VL) muscles were measured. No changes were observed in the CON confinement. Peak work rate and V˙O(2peak) were similar pre and post in the EXP confinement, whereas V˙(E) increased in the EXP post normoxic and hypoxic trials (P < 0.05). The exercise-induced drop in VL Δ[HbO(2)] was less in the post- than pre-EXP trial by 4.0 ± 0.4 and 4.2 ± 0.6 μM during normoxic and hypoxic exercise, respectively. No major changes were observed in cerebral or SA oxygenation. These results demonstrate that a 10-day hypoxic exposure without any concomitant physical activity had no effect on normoxic or hypoxic V˙O(2peak), despite the enhanced VL oxygenation.

Autonomic cardiovascular response to acute hypoxia and passive head-up tilting in humans

Acute hypoxia may alter autonomic cardiovascular reflexes during orthostasis. Heart rate variability (HRV), arterial blood pressure (MAP), and respiratory sinus arrhythmia (RSA) were recorded during supine (SUP) and passive head up tilt (HUT) in eight healthy humans, spontaneously breathing either room air or 10% O₂ in N₂. In the time domain, heart rate increased and variability decreased with HUT in both trials, with no difference between trials. In the frequency domain, normalized low frequency HRV increased, and normalized high frequency HRV decreased with HUT in both trials, with no difference between trials. MAP was 74.9 (8.6) and 77.5 (11.7) mmHg when SUP in the room air and hypoxia trials, respectively. A significant increase in MAP occurred with HUT in the room air trial but not in the hypoxia trial. In both trials, end tidal CO₂ decreased with HUT, with no difference between trials. In the room air trial, end tidal O₂ increased with HUT, whereas during the hypoxia trial, end tidal O₂ decreased with HUT. The distribution of heart beats relative to the phase of ventilation (%HBIN and %HBOUT) was similar in both trials: the %HBIN was 43.5 (3.3) % and %HBOUT was 56.5 (4.2) % breathing room air when SUP, and 45.5 (3.0) and 54.5 (3.2) when hypoxic and SUP. For both trials, this distribution did not change with HUT. As both HRV and RSA showed similar responses to HUT when spontaneously breathing either room air or 10% O₂ in N₂, we suggest that autonomic cardiovascular reflexes are preserved during acute hypoxia.

The effect of acute exercise in hypoxia on flow-mediated vasodilation

The purpose of this study was to clarify the effect of acute exercise in hypoxia on flow-mediated vasodilation (FMD). Eight males participated in this study. Two maximal exercise tests were performed using arm cycle ergometry to estimate peak oxygen uptake [Formula: see text] while breathing normoxic [inspired O(2) fraction (FIO(2))=0.21] or hypoxic (FIO(2)=0.12) gas mixtures. Next, subjects performed submaximal exercise at the same relative exercise intensity [Formula: see text] in normoxia or hypoxia for 30min. Before (Pre) and after exercise (Post 5, 30, and 60min), brachial artery FMD was measured during reactive hyperemia by ultrasound under normoxic conditions. FMD was estimated as the percent (%) rise in the peak diameter from the baseline value at prior occlusion at each FMD measurement (%FMD). The area under the curve for the shear rate stimulus (SR(AUC)) was calculated in each measurement, and each %FMD value was normalized to SR(AUC) (normalized FMD). %FMD and normalized FMD decreased significantly (P<0.05) immediately after exercise in both condition (mean±SE, FMD, normoxic trial, Pre: 8.85±0.58%, Post 5: -0.01±1.30%, hypoxic trial, Pre: 8.84±0.63%, Post 5: 2.56±0.83%). At Post 30 and 60, %FMD and normalized FMD returned gradually to pre-exercise levels in both trials (FMD, normoxic trial, Post 30: 1.51±0.68%, Post 60: 2.99±0.79%; hypoxic trial, Post 30: 4.57±0.78%, Post 60: 6.15±1.20%). %FMD and normalized FMD following hypoxic exercise (at Post 5, 30, and 60) were significantly (P<0.05) higher than after normoxic exercise. These results suggest that aerobic exercise in hypoxia has a significant impact on endothelial-mediated vasodilation.

Influence of rest and exercise at a simulated altitude of 4,000 m on appetite, energy intake, and plasma concentrations of acylated ghrelin and peptide YY

The reason for high altitude anorexia is unclear but could involve alterations in the appetite hormones ghrelin and peptide YY (PYY). This study examined the effect of resting and exercising in hypoxia (12.7% O(2); ∼4,000 m) on appetite, energy intake, and plasma concentrations of acylated ghrelin and PYY. Ten healthy males completed four, 7-h trials in an environmental chamber in a random order. The four trials were control-normoxia, control-hypoxia, exercise-normoxia, and exercise-hypoxia. During exercise trials, participants ran for 60 min at 70% of altitude-specific maximal oxygen consumption (Vo(2max)) and then rested. Participants rested throughout control trials. A standardized meal was consumed at 2 h and an ad libitum buffet meal at 5.5 h. Area under the curve values for hunger (assessed using visual analog scales) tended to be lower during hypoxic trials than normoxic trials (repeated-measures ANOVA, P = 0.07). Ad libitum energy intake was lower (P = 0.001) in hypoxia (5,291 ± 2,189 kJ) than normoxia (7,718 ± 2,356 kJ; means ± SD). Mean plasma acylated ghrelin concentrations were lower in hypoxia than normoxia (82 ± 66 vs. 100 ± 69 pg/ml; P = 0.005) while PYY concentrations tended to be higher in normoxia (32 ± 4 vs. 30 ± 3 pmol/l; P = 0.059). Exercise suppressed hunger and acylated ghrelin and increased PYY but did not influence ad libitum energy intake. These findings confirm that hypoxia suppresses hunger and food intake. Further research is required to determine if decreased concentrations of acylated ghrelin orchestrate this suppression.

Dietary nitrate reduces muscle metabolic perturbation and improves exercise tolerance in hypoxia

Exercise in hypoxia is associated with reduced muscle oxidative function and impaired exercise tolerance. We hypothesised that dietary nitrate supplementation (which increases plasma [nitrite] and thus NO bioavailability) would ameliorate the adverse effects of hypoxia on muscle metabolism and oxidative function. In a double-blind, randomised crossover study, nine healthy subjects completed knee-extension exercise to the limit of tolerance (T(lim)), once in normoxia (20.9% O(2); CON) and twice in hypoxia (14.5% O(2)). During 24 h prior to the hypoxia trials, subjects consumed 0.75 L of nitrate-rich beetroot juice (9.3 mmol nitrate; H-BR) or 0.75 L of nitrate-depleted beetroot juice as a placebo (0.006 mmol nitrate; H-PL). Muscle metabolism was assessed using calibrated (31)P-MRS. Plasma [nitrite] was elevated (P < 0.01) following BR (194 ± 51 nm) compared to PL (129 ± 23 nm) and CON (142 ± 37 nM). T(lim) was reduced in H-PL compared to CON (393 ± 169 vs. 471 ± 200 s; P < 0.05) but was not different between CON and H-BR (477 ± 200 s). The muscle [PCr], [P(i)] and pH changed at a faster rate in H-PL compared to CON and H-BR. The [PCr] recovery time constant was greater (P < 0.01) in H-PL (29 ± 5 s) compared to CON (23 ± 5 s) and H-BR (24 ± 5 s). Nitrate supplementation reduced muscle metabolic perturbation during exercise in hypoxia and restored exercise tolerance and oxidative function to values observed in normoxia. The results suggest that augmenting the nitrate-nitrite-NO pathway may have important therapeutic applications for improving muscle energetics and functional capacity in hypoxia.

Postnatal loss of brainstem serotonin neurones compromises the ability of neonatal rats to survive episodic severe hypoxia

Pet-1(-/-) mice with a prenatal, genetically induced loss of 5-hydroxytryptamine (5-HT, serotonin) neurones are compromised in their ability to withstand episodic environmental anoxia via autoresuscitation. Given the prenatal role of 5-HT neurones in the development of neural networks, here we ask if a postnatal loss of 5-HT neurones also compromises autoresuscitation. We treated neonatal rat pups at postnatal day (P)2-3 with an intra-cisternal injection of 5,7-dihydroxytryptamine (5,7-DHT; ~40 μg; n = 8) to pharmacologically lesion the 5-HT system, or vehicle (control; n = 14). At P7-10 we exposed unanaesthetized treated and control pups to 15 episodes of environmental anoxia (97% N(2), 3% CO(2)). Medullary 5-HT content was reduced 80% by 5,7-DHT treatment (P < 0.001). Baseline ventilation (V(E)), metabolic rate (V(O(2))), ventilatory equivalent (V(E)/V(O(2))), heart rate (HR), heart rate variability (HRV) and arterial haemoglobin saturation (S(aO(2))) were no different in 5-HT-deficient pups compared to controls. However, only 25% of 5-HT-deficient pups survived all 15 episodes of environmental anoxia, compared to 79% of control littermates (P = 0.007). High mortality of 5,7-DHT-treated pups was associated with delayed onset of gasping (P < 0.001), delayed recovery of HR from hypoxic-induced bradycardia (P < 0.001), and delayed recovery of eupnoea from hypoxic-induced apnoea (P < 0.001). Treatment with 5,7-DHT affected neither the gasping pattern once initiated, nor HR, V(E)/V(O(2)) or S(aO(2)) during the intervening episodes of room air. A significant increase in HRV occurred in all animals with repeated exposure, and in 5-HT-deficient pups this increase occurred immediately prior to death. We conclude that a postnatal loss of brainstem 5-HT content compromises autoresuscitation in response to environmental anoxia. This report provides new evidence in rat pups that 5-HT neurones serve a physiological role in autoresuscitation. Our data may be relevant to understanding the aetiology of the sudden infant death syndrome (SIDS), in which there is medullary 5-HT deficiency and in some cases evidence of severe hypoxia and failed autoresuscitation.

The Effect of Hypoxia and Work Intensity on Insulin Resistance in Type 2 Diabetes

Hypoxia and muscle contraction stimulate glucose transport in vitro. We have previously demonstrated that exercise and hypoxia have an additive effect on insulin sensitivity in type 2 diabetics. Our objective was to examine the effects of three different hypoxic/exercise (Hy Ex) trials on glucose metabolism and insulin resistance in the 48 h after acute hypoxia in type 2 diabetics. Eight male type 2 diabetics completed 60 min of hypoxic [mean (sem) O(2) = ∼14.7 (0.2)%] exercise at 90% of lactate threshold [Hy Ex(60); 49 (1) W]. Patients completed an additional two hypoxic trials of equal work, lasting 40 min [Hy Ex(40); 70 (1) W] and 20 min [Hy Ex(20); 140 (12) W]. Glucose rate of appearance and rate of disappearance were determined using the one-compartment minimal model. Homeostasis models of insulin resistance (HOMA(IR)), fasting insulin resistance index and β-cell function (HOMA(β-cell)) were calculated at 24 and 48 h after trials. Peak glucose rate of appearance was highest during Hy Ex(20) [8.89 (0.56) mg/kg · min, P < 0.05]. HOMA(IR) and fasting insulin resistance index were improved in the 24 and 48 h after Hy Ex(60) and Hy Ex(40) (P < 0.05). HOMA(IR) decreased 24 h after Hy Ex(20) (P < 0.05) and returned to baseline values at 48 h. Moderate-intensity exercise in hypoxia (Hy Ex(60) and Hy Ex(40)) stimulates acute- and moderate-term improvements in insulin sensitivity that were less apparent in Hy Ex(20). Results suggest that exercise duration and not total work completed has a greater influence on acute and moderate-term glucose control in type 2 diabetics.

Acute mountain sickness, inflammation, and permeability: new insights from a blood biomarker study

The pathophysiology of acute mountain sickness (AMS) is unknown. One hypothesis is that hypoxia induces biochemical changes that disrupt the blood-brain barrier (BBB) and, subsequently, lead to the development of cerebral edema and the defining symptoms of AMS. This study explores the relationship between AMS and biomarkers thought to protect against or contribute to BBB disruption. Twenty healthy volunteers participated in a series of hypobaric hypoxia trials distinguished by pretreatment with placebo, acetazolamide (250 mg), or dexamethasone (4 mg), administered using a randomized, double-blind, placebo-controlled, crossover design. Each trial included peripheral blood sampling and AMS assessment before (-15 and 0 h) and during (0.5, 4, and 9 h) a 10-h hypoxic exposure (barometric pressure = 425 mmHg). Anti-inflammatory and/or anti-permeability [interleukin (IL)-1 receptor agonist (IL-1RA), heat shock protein (HSP)-70, and adrenomedullin], proinflammatory (IL-6, IL-8, IL-2, IL-1β, and substance P), angiogenic, or chemotactic biomarkers (macrophage inflammatory protein-1β, VEGF, TNF-α, monocyte chemotactic protein-1, and matrix metalloproteinase-9) were assessed. AMS-resistant subjects had higher IL-1RA (4 and 9 h and overall), HSP-70 (0 h and overall), and adrenomedullin (overall) compared with AMS-susceptible subjects. Acetazolamide raised IL-1RA and HSP-70 compared with placebo in AMS-susceptible subjects. Dexamethasone also increased HSP-70 and adrenomedullin in AMS-susceptible subjects. Macrophage inflammatory protein-1β was higher in AMS-susceptible than AMS-resistant subjects after 4 h of hypoxia; dexamethasone minimized this difference. Other biomarkers were unrelated to AMS. Resistance to AMS was accompanied by a marked anti-inflammatory and/or anti-permeability response that may have prevented downstream pathophysiological events leading to AMS. Conversely, AMS susceptibility does not appear to be related to an exaggerated inflammatory response.

Combined inhibition of nitric oxide and vasodilating prostaglandins abolishes forearm vasodilatation to systemic hypoxia in healthy humans

We tested the hypothesis that nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute independently to hypoxic vasodilatation, and that combined inhibition would reveal a synergistic role for these two pathways in the regulation of peripheral vascular tone. In 20 healthy adults, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) responses to steady-state (SS) isocapnic hypoxia (O₂ saturation ~85%). All trials were performed during local α- and β-adrenoceptor blockade (via a brachial artery catheter) to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatory mechanisms. The individual and combined effects of NO synthase (NOS) and cyclooxygenase (COX) inhibition were determined by quantifying the vasodilatation from rest to SS hypoxia, as well as by quantifying how each inhibitor reduced vascular tone during hypoxia. Three hypoxia trials were performed in each subject. In group 1 (n = 10), trial 1, 5 min of SS hypoxia increased FVC from baseline (21 ± 3%; P < 0.05). Infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) for 5 min to inhibit NOS during continuous SS hypoxia reduced FVC by -33 ± 3% (P < 0.05). In Trial 2 with continuous NOS inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (20 ± 3%), and infusion of ketorolac for 5 min to inhibit COX during continuous SS hypoxia reduced FVC by -15 ± 3% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). In group 2 (n = 10), the order of NOS and COX inhibition was reversed. In trial 1, five minutes of SS hypoxia increased FVC from baseline (by 24 ± 5%; P < 0.05), and infusion of ketorolac during SS hypoxia had minimal impact on FVC (-4 ± 3%; NS). In Trial 2 with continuous COX inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (27 ± 4%), and infusion of L-NAME during continuous SS hypoxia reduced FVC by -36 ± 7% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). Our collective findings indicate that (1) neither NO nor PGs are obligatory to observe the normal local vasodilatory response from rest to SS hypoxia; (2) NO regulates vascular tone during hypoxia independent of the COX pathway, whereas PGs only regulate vascular tone during hypoxia when NOS is inhibited; and (3) combined inhibition of NO and PGs abolishes local hypoxic vasodilatation (from rest to SS hypoxia) in the forearm circulation of healthy humans during systemic hypoxia.

Influence of Hydration on Physiological and Renal Responses to Hypoxia

Fluid balance is known to alter with hypoxia and exercise, yet the combined effects have not been investigated using a controlled acute hypoxic exposure. Seven healthy participants were hypohydrated 24hrs prior to testing, using exercise and fluid restriction, causing a ~2.5% loss in body mass. Participants then rested in either normoxia with no fluid replacement (NH) or hypoxia (FIO2:0.12) with no fluid (HH), water (HW) or isotonic fluid (HI) replacement over the first 2 hrs of exposure. After 200mins of rest, participants completed an intermittent walking protocol at 50%VO2max. TBW, ICF, ECF, serum s100b, HSP70, ADH and urine hydration markers were taken pre and post exposure. HR, SaO2, core temperature and perceptual scales were monitored throughout. Fluid compartment volumes increased with rehydration and remained at similar values in the isotonic rehydration trial. HSP70 values increased in all trials (HH=1.48, HW=1.00, HI=0.95, NH=0.46pg/L), increases were greater in hypoxia. Serum s100b increased in all hypoxic trials (HH=0.28, HW=0.25, HI=0.09, NH=−0.005μg/L). Hypoxia and hypohydration induced similar physiological strain, which was exacerbated when the two were combined. Hypoxic disruption of the blood brain barrier increased with water intake, suggesting isotonic rehydration is necessary to reduce physiological strain and symptoms of headache and nausea.

The effects of acute and chronic hypoxia on cortisol, glucose and lactate concentrations in different populations of three-spined stickleback

The response of individuals from three different populations of three-spined sticklebacks to acute and chronic periods of hypoxia (4.4 kPa DO, 2.2 mg l⁻¹) was tested using measures of whole-body cortisol, glucose and lactate. Although there was no evidence of a neuroendocrine stress response to acute hypoxia, fish from the population least likely to experience hypoxia in their native habitat had the largest response to low oxygen, with significant evidence of anaerobic glycolysis after 2 h of hypoxia. However, there was no measurable effect of a more prolonged period (7 days) of hypoxia on any of the fish in this study, suggesting that they acclimated to this low level of oxygen over time. Between-population differences in the analytes tested were observed in the control fish of the acute hypoxia trial, which had been in the laboratory for 16 days. These differences were not apparent among the control fish in the chronic exposure groups that had been held in the laboratory for 23 days, suggesting that these site-specific trends in physiological status were acclimatory. Overall, the results of this study suggest that local environmental conditions may shape sticklebacks' general physiological profile as well as influencing their response to hypoxia.

Human muscle net K+ release during exercise is unaffected by elevated anaerobic metabolism, but reduced after prolonged acclimatization to 4,100 m

It was investigated whether skeletal muscle K(+) release is linked to the degree of anaerobic energy production. Six subjects performed an incremental bicycle exercise test in normoxic and hypoxic conditions prior to and after 2 and 8 wk of acclimatization to 4,100 m. The highest workload completed by all subjects in all trials was 260 W. With acute hypoxic exposure prior to acclimatization, venous plasma [K(+)] was lower (P < 0.05) in normoxia (4.9 +/- 0.1 mM) than hypoxia (5.2 +/- 0.2 mM) at 260 W, but similar at exhaustion, which occurred at 400 +/- 9 W and 307 +/- 7 W (P < 0.05), respectively. At the same absolute exercise intensity, leg net K(+) release was unaffected by hypoxic exposure independent of acclimatization. After 8 wk of acclimatization, no difference existed in venous plasma [K(+)] between the normoxic and hypoxic trial, either at submaximal intensities or at exhaustion (360 +/- 14 W vs. 313 +/- 8 W; P < 0.05). At the same absolute exercise intensity, leg net K(+) release was less (P < 0.001) than prior to acclimatization and reached negative values in both hypoxic and normoxic conditions after acclimatization. Moreover, the reduction in plasma volume during exercise relative to rest was less (P < 0.01) in normoxic than hypoxic conditions, irrespective of the degree of acclimatization (at 260 W prior to acclimatization: -4.9 +/- 0.8% in normoxia and -10.0 +/- 0.4% in hypoxia). It is concluded that leg net K(+) release is unrelated to anaerobic energy production and that acclimatization reduces leg net K(+) release during exercise.