Moderate Normobaric Hypoxia Research Articles

Hormonal and metabolic responses to repeated cycling sprints under different hypoxic conditions

ObjectiveSprint exercise and hypoxic stimulus during exercise are potent factors affecting hormonal and metabolic responses. However, the effects of different hypoxic levels on hormonal and metabolic responses during sprint exercise are not known. Here, we examined the effect of different hypoxic conditions on hormonal and metabolic responses during sprint exercise. DesignSeven male subjects participated in three experimental trials: 1) sprint exercise under normoxia (NSE); 2) sprint exercise under moderate normobaric hypoxia (16.4% oxygen) (HSE 16.4); and 3) sprint exercise under severe normobaric hypoxia (13.6% oxygen) (HSE 13.6). The sprint exercise consisted of four 30s all-out cycling bouts with 4-min rest between bouts. Glucose, free fatty acids (FFA), blood lactate, growth hormone (GH), epinephrine (E), norepinephrine (NE), and insulin concentrations in the HSE trials were measured before exposure to hypoxia (pre 1), 15min after exposure to hypoxia (pre 2), and at 0, 15, 30, 60, 120, and 180min after the exercise performed in hypoxia. The blood samples in the NSE trial were obtained in normoxia at the same time points as the HSE trials. ResultsCirculating levels of glucose, FFA, lactate, GH, E, NE, and insulin significantly increased after all three exercise trials (P<0.05). The area under the curve (AUC) for GH was significantly higher in the HSE 13.6 trial than in the NSE and HSE 16.4 trials (P<0.05). A maximal increase in FFA concentration was observed at 180min after exercise and was not different between trials. ConclusionThese findings suggest that severe hypoxia may be an important factor for the enhancement of GH response to all-out sprint exercise.

Different patterns of pulmonary vascular disease induced by type 1 diabetes and moderate hypoxia in rats

Although type 1 and type 2 diabetes are strongly associated with systemic cardiovascular morbidity, the relationship with pulmonary vascular disease had been almost disregarded until recent epidemiological data revealed that diabetes might be a risk factor for pulmonary hypertension. Recent experimental studies suggest that diabetes induces changes in lung function insufficient to elevate pulmonary pressure. The aim of this study was to assess the effects of diabetes on the sensitivity to other risk factors for pulmonary hypertension. We therefore analysed the effects of the combination of diabetes with exposure to moderate hypoxia on classical markers of pulmonary hypertension. Control (saline-treated) and diabetic (70 mg kg(-1) streptozotocin-treated) male Wistar-Kyoto rats were followed for 4 weeks and exposed to normoxia or moderate normobaric hypoxia (14%) for another 2 weeks. Hypoxia, but not diabetes, strongly reduced voltage-gated potassium currents, whereas diabetes, but not hypoxia, induced pulmonary artery endothelial dysfunction. Both factors independently induced pulmonary vascular remodelling and downregulated the lung bone morphogenetic protein receptor type 2. However, diabetes, but not hypoxia, induced pulmonary infiltration of macrophages, which was markedly increased when both factors were combined. Diabetes plus hypoxia induced a modest increase in diastolic and mean pulmonary artery pressure and right ventricular weight, while each of the two factors alone had no significant effect. The pattern of changes in markers of pulmonary hypertension was different for moderate hypoxia and diabetes, with no synergic effect except for macrophage recruitment, and the combination of both factors was required to induce a moderate elevation in pulmonary arterial pressure.

Intramyocellular Lipid Content Following Normobaric Hypoxia Training in Sedentary Men

Recent studies demonstrated that long-term endurance training under normoxia condition increased intramyocellular lipid (IMCL) content in older adults (Pruchnic et al. 2004). However, the adaptation of the IMCL following hypoxia training has not been reported. PURPOSE: To investigate the effects of normobaric hypoxia training on IMCL content in sedentary men. METHODS: Twenty healthy men were divided into two groups; normobaric hypoxia training group (HYPO; n=9, 30 ± 2 yrs, BMI 25.7 ± 1.3 kg/m2) and normoxia training group (NOR; n=11, 32 ± 3 yrs, BMI 25.5 ± 1.0 kg/m2). Each exercise training (60 min) was conducted with a cycle ergometer at 55% of maximal oxygen uptake (VO2max) under different oxygen concentration in the room (15.0% for HYPO, 20.9% for NOR). The subjects performed 12 training sessions over 4 weeks (3 days/wk). Before and after the training period, the IMCL and extramyocellular lipid (EMCL) contents in the vastus lateralis were determined noninvasively by proton magnetic resonance spectroscopy (1H-MRS). RESULTS: Average workload throughout the 12 training sessions was significantly lower in the HYPO group (92 ± 4 W) than in the NOR group (111 ± 7 W, P < 0.05). Despite lower workload, the HYPO group revealed higher heart rate values during the exercises (139 ± 7 W) compared with the NOR group (131 ± 3 W, P = 0.06). After a 4wk of training period, both groups showed significant increases in VO2max (P < 0.05). The IMCL level increased after the training period in both groups (65 ± 33% in the HYPO group, 39 ± 25% in the NOR group), but it did not reach statistical difference. Contrary to the IMCL, the EMCL decreased in both groups, with a significant difference between pre- and post-training only in the NOR group (P < 0.05). CONCLUSIONS: These results indicate that the training adaptations following moderate endurance training were largely different between the IMCL and EMCL. The data also suggest that moderate normobaric hypoxia exposure during the exercise does not have strong impact on the magnitude of IMCL accumulation over the short-term training period.

Liver Hypoxia and Tissue Injury Are Specific to Sickle Cell Mice in An Experimental Model of Sickle Cell Vaso-Occlusion.

Abstract 2569Poster Board II-546Sickle cell vaso-occlusion causes tissue ischemia, injury, and severe pain in patients with sickle cell disease (SCD). Investigations of the pathophysiology of vaso-occlusion have largely focused on the mechanisms for microcirculatory obstruction, rather than the tissue damage. The liver is frequently involved in human SCD complications and elevated serum levels of hepatic transaminases often accompany vaso-occlusive pain. Animal models can help to study mechanisms of how vaso-occlusive microcirculatory abnormalities cause tissue damage. Sickle cell mice originally developed by Pastzy (“Berkeley sickle mice”) expressing exclusively human sickle hemoglobin have severe hemolytic anemia and physiologic fragility, and are well-suited for examining an acute vaso-occlusive challenge. HYPOTHESIS:Moderate hypoxic exposure will cause liver hypoxia and tissue injury only in homozygote sickle mice, as signs of vaso-occlusive injury. METHODS:We examined vaso-occlusion by challenging male sickle mice with moderate normobaric hypoxia (10% oxygen) for up to 2 hours then restoring them to normoxia and assaying plasma alanine aminotransferase (ALT) as a quantitative measure of hepatic injury. Pimonidazole (HypoxyProbe 60mg/kg, NPI, Inc) was injected intraperitoneally before hypoxia, in order to provide irreversible labeling of cells with pO2 less than 10 torr. Controls included sickle mice without hypoxia, and non-sickle mice with the same hypoxic exposure. Mice were euthanized for blood and tissue harvest. Liver, kidney, and lungs were fixed in formalin, and processed for immunohistochemical staining (HP-100 kit, NPI). A veterinary pathologist unaware of the treatment group scored histologic sections under light microscopy for the extent of staining on a scale of 1 to 4, and intensity of staining on a scale of 1 to 3. RESULTS:Sickle cell mice have significantly greater extent of Hypoxyprobe labeling of liver than wild-type mice with the same hypoxia-reoxygenation challenge (2.6 + 0.5 vs 1.3 + 0.5, p=0.027 by t-test). At normoxic baseline, liver HypoxyProbe staining from sickle mice and wild-type controls had the same extent (1 vs 1) and intensity of liver staining. Kidney had a higher baseline of Hypoxyprobe staining in all normoxic mice, and this did not increase with hypoxia in sickle mice. Lungs had very little Hypoxyprobe staining at baseline, and a few bronchial cell stained under hypoxia in sickle mice, but the change was not statistically significant. ALT was mildly elevated in sickle mice at normoxic baseline, and rose 3-fold to a peak by 18 hours after hypoxia, then declined back to baseline by 48 – 72 hours. CONCLUSION:The extent of HypoxyProbe staining shows that sickle mice suffer significantly greater liver tissue hypoxia with hypoxic exposure than controls with the same mild hypoxia. Sickle mice in normoxia have no greater extent of HypoxyProbe staining than control mice. These results are consistent with hypoxia-triggered vaso-occlusion as the cause of ALT elevation in the sickle mice. The two outcome measures after hypoxic challenge of sickle mice, HypoxyProbe staining for tissue hypoxia and plasma ALT for tissue injury, provide a bioassay system for pre-clinical screening of antisickling therapy. Disclosures:No relevant conflicts of interest to declare.

Effects Of Sildenafil On Vo2max In Trained Women With Moderate Normobaric Hypoxia

Effects Of Sildenafil On Vo2max In Trained Women With Moderate Normobaric Hypoxia

Depletion and Restoration of the Intravascular Nitrite (NO2-) Reserve Modulate Susceptibility to Liver Vaso-Occlusive Infarction in Sickle Cell Transgenic Mice.

Multiple studies link low bioavailability of nitric oxide (NO) and major complications of sickle cell disease, especially pulmonary hypertension and acute vaso-occlusive pain episodes. A gender dimorphism has been suggested in human studies, with lower levels of NO availability observed in males. These studies support efforts to develop NO-based therapeutics and the newly characterized small molecule nitrite represents an ideal candidate. Nitrite is a circulating anion that is reduced to NO during physiological and pathological hypoxia and mediates potent cellular cytoprotection at physiologic concentrations in the setting of ischemia and reperfusion injury. Supporting a role for nitrite in sickle cell pathogenesis, we found that nitrite levels are depleted in transgenic mice expressing exclusively sickle hemoglobin (sickle mice), with whole blood nitrite levels 50% lower compared to control mice, and are further reduced by 19% in male sickle mice compared with females. Thus, the murine model demonstrates a sexual dimorphism in nitrite levels, consistent with data on human NO bioavailability. We then examined hepatic vaso-occlusion by challenging sickle mice with 2 hours of moderate normobaric hypoxia (10% oxygen), restoring them to normoxia, and then 18 hours later drawing blood to assay plasma alanine aminotransferase (ALT) levels as a quantitative measure of tissue injury. Sickle mice showed a 4- fold rise in ALT with this hypoxia-reoxygenation (HR) challenge; wild-type controls or non-sickling colony control mice with the same HR challenge had no change in ALT. Sexual dimorphism was again evident such that female mice were less susceptible to HR challenge than males. Therapeutic nitrite supplementation, administered either as 2.4 nanomole/g intraperitoneal injection during HR or oral supplementation (estimated 4 micromole/g/day) for 7 days before HR challenge, abrogated the ALT rise in sickle mice. Pharmacokinetic data indicated that nitrite supplementation at these injected and oral doses raise the nitrite levels in blood and tissue, without affecting methemoglobin levels. These studies provide additional mechanistic evidence for a gender contribution to sickle cell endothelial dysfunction and vasculopathy, and suggest that reduced NO bioavailabity in SCD results in dysregulated nitrite homeostasis. Depleted nitrite reserves are associated with enhanced injury with hypoxia-induced vaso-occlusion and therapeutic restoration of nitrite levels, both by intraperitoneal delivery and in the diet, reduces this injury.

Effects of acute moderate hypoxia on anaerobic capacity in endurance-trained runners

While there is some controversy whether anaerobic capacity might be improved after altitude training little is known about changes in anaerobic capacity during hypoxic exposure in highly trained athletes. In order to analyze the effects of acute moderate normobaric hypoxia on anaerobic capacity, 18 male competitive triathletes, middle- and long-distance runners VO2max 67.4 +/- 3.8 ml kg min(-1) performed 2 supra-VO2max treadmill runs with the same speed, one in normoxia and one after 4 h exposure to normobaric hypoxia (FiO(2) 0.15), for estimation of their maximal accumulated oxygen deficit (MAOD) and measurement of peak capillary lactate and peak capillary ammonia concentration. MAOD was not significantly different in normoxia and in moderate hypoxia while time to exhaustion and accumulated O(2) uptake were significantly (P < 0.001) reduced in hypoxia compared to normoxia by 28 and 45%, respectively. The reduction in time to exhaustion was significantly correlated to the decrement in accumulated O(2) uptake (R = 0.730, P = 0.001). In hypoxia, there was a tendency for peak capillary lactate concentration to be decreased compared to normoxia (12.9 +/- 2.1 vs. 13.8 +/- 2.2 mmol l(-1), P = 0.082); peak capillary ammonia concentration was significantly decreased in hypoxia (97 +/- 52 vs. 121 +/- 44 micromol l(-1), P = 0.032). In conclusion, anaerobic capacity is not significantly changed during acute exposure to moderate hypoxia in endurance-trained athletes. The performance reduction during all-out exercise of short duration has to be attributed to the decrement in aerobic capacity.

Leukocyte Responses To Short-term Normobaric Hypoxia

PURPOSE Severe hypoxia has been shown to exert immunosuppressive effects which must be considered when exposing athletes to hypoxia to enhance endurance capacity. We studied the effect of moderate normobaric hypoxia (HYP) on parameters of immune function and cellular protection in peripheral human leukocytes such as oxidative burst (burst), phagocytosis (phago), expression of heat shock proteins (HSP HO-1). The contribution of oxidative stress was tested by application of antioxidants (a-tocopherol and a-lipoic acid (AO)). METHODS Twelve non-altitude acclimated male subjects (27.1±7.0 yrs, 79.6±8 kg, 184±5 cm) were exposed to 4 h of HYP (FiO2 12.5%, corresponding to an altitude of 4100 m above SL). Blood samples were drawn before (0 h), during (2 h) at the end (+4h), 1 h (+5h), 4 h (+8h) and 20 h (+24h) after the end of HYP. To exclude diurnal changes same procedure was performed in normoxia. AO or placebo were given randomly in a double-blind crossover design. Phago (opsonized FITC-conjugated E. coli), burst (stimulation with opsonized E. coli) and expression of HSP and HO-1 (flow cytometry and RT-PCR, respectively) were quantified in leukocytes. RESULTS Oxygen saturation averaged 87.1±4.3% during HYP. Percentage of phagocytosing granulocytes was reduced after HYP (+5h). Burst was increased during the reoxygenation phase (+5–24h). Nevertheless, these changes remained within the reference range. Protein and mRNA expression of HSP and HO-1 were not significantly changed by HYP. AO did not influence this expression either. CONCLUSIONS Protective HSPs do not seem to be essential after moderate hypoxia as performed in the present study. Also, the cellular redox state appears to be of minor importance. Although phago and burst are slightly influenced by HYP, immune function is likely not impaired. Nevertheless, immunosuppressive effects of HYP may become relevant in context with additional physical stress.

Long-term hypoxia increases the turnover of dopamine but not norepinephrine in rat sympathetic ganglia

The content and turnover of dopamine, 3,4-dihydroxyphenylacetic acid and norepinephrine have been investigated in the superior cervical, coeliac and mesenteric ganglia of rats exposed to moderate normobaric hypoxia (10% O 2 in N 2) lasting for 2–28 days. The turnover was estimated by the decrease in amine contents after inhibition of catecholamine biosynthesis with α-methyl- p-tyrosine. In all 3 sympathetic ganglia, long-term hypoxia elicited a sustained increase in the content and turnover of dopamine. In contrast, the content and turnover of norepinephrine remained unchanged, except for a moderate increase in the coeliac ganglion after 14 and 28 days of hypoxia. These results suggest that the dopamine and norepinephrine pools in ganglia have a different functional significance and that rat sympathetic ganglia contain a pool of dopamine specifically sensitive to long-term hypoxia.