Long-term intermittent hypoxia increases sympathetic activity and chemosensitivity during acute hypoxia in humans

We determined the effects of 10 daily exposures of intermittent hypoxia (IH; 1 h day⁻¹; oxyhaemoglobin saturation = 80%) on muscle sympathetic nerve activity (MSNA, peroneal nerve) and the hypoxic ventilatory response (HVR) before, during and after an acute 20 min isocapnic hypoxic exposure. We also assessed the potential parallel modulation of the ventilatory and sympathetic systems following IH. Healthy young men ( n = 11; 25 ± 1 years) served as subjects and pre- and post-IH measures of MSNA were obtained on six subjects. The IH intervention caused HVR to significantly increase  (pre-IH = 0.30 ± 0.03; post-IH = 0.61 ± 0.12 l min⁻¹% S _aO2⁻¹)  . During the 20 min hypoxic exposure sympathetic activity was significantly greater than baseline and remained above baseline after withdrawal of the hypoxic stimulus, even though oxyhaemoglobin saturation had normalized and ventilation and blood pressure had returned to baseline levels. When compared to the pre-IH trial, burst frequency increased ( P < 0.01), total MSNA trended towards higher values ( P = 0.06), and there was no effect on burst amplitude ( P = 0.82) during the post-IH trial. Following IH the rise in MSNA burst frequency was strongly related to the change in HVR ( r = 0.79, P < 0.05) suggesting that these sympathetic and ventilatory responses may have common central control.     

Time-dependent changes in glucose and insulin regulation during intermittent hypoxia and continuous hypoxia

Hypoxia manifests in many forms including the short repetitive intermittent hypoxia (IH) of sleep apnoea and the continuous hypoxia (CH) of altitude, both of which may impact metabolic function. Based on our own previous studies and the available literature, we hypothesized that whereas acute exposure to IH and CH would lead to comparable metabolic dysfunction, with longer-term exposure, metabolism would normalize to a greater extent with CH than IH. Studies were conducted in lean C57BL/6J mice exposed to either IH or CH for 1 day or 4 weeks and compared to either intermittent air (IA) or unhandled (UN) controls, respectively. We utilized the frequently sampled intravenous glucose tolerance test and minimal model analyses to determine insulin-dependent (insulin sensitivity; S _I) and insulin-independent (glucose effectiveness; S _g) glucose disposal, as well as the insulin response to glucose (acute insulin response to glucose; AIR_g). Our data show that 1-day exposure impaired the glucose tolerance and caused reductions in S _g and AIR_g in both the IH and CH groups, but only IH caused a significant decrease in S _I (7.5 ± 2.7 vs. 17.0 ± 5.3 μU ml^?1 min^?1; p < 0.05). After 4-week exposure, there was evidence of metabolic adaptation in both hypoxic groups, however, in the CH group, there was a supranormal increase in S _I relative to both UN and IH groups. We conclude that in lean mice, the marked metabolic dysfunction that occurs with acute exposure to hypoxia is reversed to a greater extent with chronic CH exposure than chronic IH exposure.     

Proteomic analysis of mitochondrial proteins in cardiomyocytes from rats subjected to intermittent hypoxia

Intermittent hypoxia (IH) markedly enhances cardiac tolerance against ischemia/reperfusion injury, but its mechanism and molecular basis remain unclear. For exploring the expression of mitochondrial proteins induced by IH, two-dimensional electrophoresis and Thermo Finnigan LTQ mass spectrometer (MS) were applied. After comparing the protein profiles of myocardial mitochondria between IH and normoxic hearts, 14 protein spots were found to be altered more than threefold between the two groups, 11 of which were identified by Finnigan LTQ MS. Among these 11 proteins, 9 were involved in energy metabolism, including 7 that were increased after IH. The latter were identified as aldehyde dehydrogenase, methylmalonate-semialdehyde dehydrogenase, ATP synthase β chain, mitochondrial aconitase, malate dehydrogenase, electron transfer flavoprotein α subunit and sirtuin 5. Two other proteins, ubiquinol-cytochrome C reductase iron-sulfur subunit and aspartate aminotransferase, were decreased after IH. Biochemical tests for energy metabolism in mitochondria supported the proteomic results. IH exposure also increased the expression of a molecular chaperone—heat shock protein 60 and an antioxidant protein, peroxiredoxin 5. These findings will provide clues for understanding the mechanism of IH-induced cardiac protection and may lead to the development of interventional strategies designed to utilize the advantages of IH clinically.     

Metabolic effects of trekrezan during adaptation of rats to intermittent hypoxic hypoxia

The animals were adapted to intermittent hypoxic hypoxia in a flow pressure chamber for 3 days. Each one-day training session consisted of 4 elevations to an altitude of 6000 m for 20 min (15 m/sec, 20-min intervals between assents). Trekrezan (25 mg/kg intraperitoneally) was injected immediately after the end of daily training over 3 days. We showed that trekrezan increased the degree of adaptive metabolic changes in the brain, heart, and liver of rats during adaptation to hypoxic hypoxia. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 1, pp. 53–56, January, 2008     

Effect of intermittent hypoxia on oxygen uptake during submaximal exercise in endurance athletes

The purpose of the present study was to clarify the following: (1) whether steady state oxygen uptake (O₂) during exercise decreases after short-term intermittent hypoxia during a resting state in trained athletes and (2) whether the change in O₂ during submaximal exercise is correlated to the change in endurance performance after intermittent hypoxia. Fifteen trained male endurance runners volunteered to participate in this study. Each subject was assigned to either a hypoxic group (n=8) or a control group (n=7). The hypoxic group spent 3 h per day for 14 consecutive days in normobaric hypoxia [12.3 (0.2)% inspired oxygen]. The maximal and submaximal exercise tests, a 3,000-m time trial, and resting hematology assessments at sea level were conducted before and after intermittent normobaric hypoxia. The athletes in both groups continued their normal training in normoxia throughout the experiment. O₂ during submaximal exercise in the hypoxic group decreased significantly (P<0.05) following intermittent hypoxia. In the hypoxic group, the 3,000-m running time tended to improve (P=0.06) after intermittent hypoxia, but not in the control group. Neither peak O₂ nor resting hematological parameters were changed in either group. There were significant (P<0.05) relationships between the change in the 3,000-m running time and the change in O₂ during submaximal exercise after intermittent hypoxia. The results from the present study suggest that the enhanced running economy resulting from intermittent hypoxia could, in part, contribute to improved endurance performance in trained athletes.     

Design of equipment for intermittent normobaric hypoxia

Conclusion Hypoxifiers are clinical devices producing HGM for delivering INH while providing respiratory comfort for patients. Hypoxifiers vary depending on the system of HGM production, but incorporate practically identical respiratory units for supply of the HGM to the patient.Hypoxifiers may prepare HGM from compressed or condensed gases, or from atmospheric air.Of the first group, the most widespread are ejection-type hypoxifiers utilizing compressed nitrogen to which atmospheric air is added at a 1:1 ratio. Since ejection-type hypoxifiers have uncomplicated design, provide operational comfort, and are reliable in producing HGM of precise and stable composition, they are the best choice where compressed nitrogen is readily available. In all other cases hypoxifiers of the second group, gas-separating membrane devices and autohypoxifiers with semiclosed circulation systems, are preferable. Less market potential of equipment of the second group results from the absence of adequate pumping devices and HGM composition control components.Practical experience of the use of hypoxifiers demonstrates the need for equipment with more precise and stable HGM composition. The most competitive will be designs avoiding consumable materials and accommodating units to monitor the patient's condition.Center for Prophylactic Hypoxia, Ministry of Health of the USSR, Moscow. Translated from Meditsinskaya Tekhnika, No. 1, pp. 3–8, January–February, 1992.     

Energy metabolism of maternal and fetal tissues during adaptation to intermittent experimental normobaric hypoxia

Energy metabolism of maternal and fetal tissues in adaptation to intermittent normobaric hypoxia was studied in experiments on 72 female Wistar rats. During pregnancy the intensity of tissue respiration in myometry was more than twice that in a nonpregnant uterus. The rate of tissue respiration in vital organs (brain) remained at a high level irrespective of exposure to the effect of a gas hypoxic mixture containing 10% oxygen, i.e. the organism of the mother and fetus provides the developing brain with an optimum amount of oxygen even in its possible deficiency. Thus, adaptation of the maternal and fetal organism to GHM-10 is attended by some shifts in energy metabolism which maintain the aerobic oxidation metabolism in the studied tissues for a long duration through more effective consumption of oxygen in its lack.     

Increased α1-adrenoceptor activity of the rat heart during adaptation to intermittent hypoxia

Research Institute of General Pathology and Pathological Physiology, Academy of Medical Sciences of the USSR, Moscow. Research Institute of Experimental Cardiology, All-Union Cardiologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR A. D. Ado.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 111, No. 6, pp. 570–572, June, 1991.     

Chronic intermittent hypoxia enhances cat chemosensory and ventilatory responses to hypoxia

The carotid body (CB) chemoreceptors may play an important role in the enhanced hypoxic ventilatory response induced by chronic intermittent hypoxia (CIH). We studied the effects of cyclic hypoxic episodes of short duration on cat cardiorespiratory reflexes, heart rate variability, and CB chemosensory activity. Cats were exposed to cyclic hypoxic episodes  ( P _O2∼ 75 Torr)  repeated during 8 h for 2–4 days. Cats were anaesthetized with sodium pentobarbitone (40 mg kg⁻¹ i.p. , followed by 8–12 mg i.v. ), and ventilatory and cardiovascular responses to NaCN (0.1–100 μg kg⁻¹ i.v. ) and several isocapnic levels of oxygen  ( P _O2∼ 20–740 Torr)  were studied. After studying the reflex responses, we recorded the CB chemosensory responses induced by the same stimuli. Results showed that CIH for 4 days selectively enhanced cat CB ventilatory ( V _T and V _I) responses to hypoxia, while responses to NaCN remained largely unchanged. Similarly, basal CB discharges and responses to acute hypoxia  ( P _O2 < 100 Torr)  were larger in CIH than in control cats, without modification of the responses to NaCN. Exposure to CIH did not increase basal arterial pressure, heart rate, or their changes induced by acute hypoxia or hyperoxia. However, the spectral analysis of heart rate variability of CIH cats showed a marked increase of the low-/high-frequency ratio and an increase of the power spectral distribution of low frequencies of heart rate variability. Thus, the enhanced CB reactivity to hypoxia may contribute to the augmented ventilatory response to hypoxia, as well as to modified heart rate variability due to early changes in autonomic activity.     

慢性间断性缺氧对雄仔鼠肝胰岛素样生长因子-1基因组蛋白修饰的作用

目的:研究慢性间断性缺氧(CIH)时新生雄仔鼠肝形态学改变及胰岛素样生长因子-l(IGF-1)基因表达,探讨其表观遗传学分子机制.方法:将怀孕SD大鼠分为正常呼吸组(对照组)和间断缺氧组(缺氧组),建立CIH大鼠模型.分娩后取对照组和缺氧组1 d雄仔鼠肝组织,用电子显微镜观察肝组织的超微结构,免疫蛋白印迹和免疫组织化学...     

Does intermittent hypoxia increase erythropoiesis in professional cyclists during a 3-week race?

In this study we examined the effects of intermittent hypoxia exposure (IHE) in a group of professional cyclists (n = 6; age 26 +/- 1 yr) competing in the 2001 Vuelta a Espa?a. After each daily stage, treated subjects received four 5-min bouts of normobaric IHE (mean O2 concentration of 12.6%, simulating a mean altitude of 4,000 m) interspersed with 5-min bouts of breathing hotel room air (normoxia) until completing a total IHE of 20-min duration. The primary outcome, compared to a control group of similar characteristics not receiving IHE (n = 5; age 25 +/- 1 yr), was the % increase in erythropoietin (Epo) from the beginning to the end of the Vuelta. Statistical analysis showed that Epo increase tended to be higher (p = 0.052) in the IHE group than in controls (37.4 +/- 5.8% vs. -4.4 +/- 19.5%, respectively). However IHE had no effect on reticulocytes or erythrocyte count (p > 0.05).     

Developmental plasticity of respiratory control following intermittent hypoxia

During development, windows of increased vulnerability to noxious stimulus occur. These critical periods of maturation represent times at which the maturing animal is uniquely susceptible to external perturbations that may alter the ultimate configuration of neural networks and their associated function(s), thereby inducing persistent (mal)adaptive changes. In contrast, when comparable perturbations are applied to adult animals the associated adaptive changes do not typically persist. This principle has been demonstrated in models of respiratory plasticity in developing mammals including exposure to sustained hypoxia, hyperoxia, and pharmacological agents. Recently, intermittent hypoxia (IH) during development has also been implicated as a potent inducer of respiratory plasticity. Altered ventilatory patterning induced by IH is distinct from other stimuli and elicits markedly different responses in the developing mammal as compared to the adult. Furthermore, adaptations to acute IH (AIH) exposure may involve mechanisms that differ from those invoked by chronic IH exposure (CIH). Thus, critical examination of IH exposure paradigms is also an important consideration. Greater understanding of IH-induced ventilatory plasticity, particularly in the developing animal, will undoubtedly increase our understanding of IH related diseases such as sleep disordered breathing, and perhaps provide future directions for intervention strategies.     

Post-translational modification of rat immunoglobulins synthesized in the Xenopus oocyte translation system

The post-translational modification of rat immunoglobulin synthesised in Xenopus laevis oocytes was studied. The major products of translation of rat spleen poly-(A) containing mRNA were found to be assembled 7S immunoglobulin molecules indicating extensive modification of primary translation products. The possibility that these immunoglobulin molecules might include antibodies of defined specificity was investigated using spleen mRNA from rats hyperimmunized with ferritin and keyhole limpet haemocyanin. The presence of antibodies to immunizing antigen in oocyte translation products was determined by affinity chromatography on Sepharose-antigen columns and the synthesis of Sepharose-antigen binding antibodies was observed, equivalent to 2.5-3% of total immunoglobulins. The oocyte produced antibodies were of the same immunoglobulin class as the circulating antibodies from the immunized rats.     

The effects of intermittent exposure to hypoxia during endurance exercise training on the ventilatory responses to hypoxia and hypercapnia in humans

The present study was performed to investigate the effects of a combination of intermittent exposure to hypoxia during exercise training for short periods on ventilatory responses to hypoxia and hypercapnia (HVR and HCVR respectively) in humans. In a hypobaric chamber at a simulated altitude of 4,500?m (barometric pressure 432?mmHg), seven subjects (training group) performed exercise training for 6 consecutive days (30 min?·?day^?1), while six subjects (control group) were inactive during the same period. The HVR, HCVR and maximal oxygen uptake (V˙O_{2 max}) for each subject were measured at sea level before (pre) and after exposure to intermittent hypoxia. The post exposure test was carried out twice, i.e. on the 1st day and 1 week post exposure. It was found that HVR, as an index of peripheral chemosensitivity to hypoxia, was increased significantly (P?V˙O_{2 max} increased significantly in the training group. These results would suggest that endurance training during intermittent exposure to hypoxia depresses the increment of chemosensitivity to hypoxia, and that intermittent exposure to hypoxia in the presence or absence of exercise training does not induce an increase in the chemosensitivity to hypercapnia in humans.     

In vitro intermittent hypoxia: challenges for creating hypoxia in cell culture

Intermittent hypoxia has been implicated in morbidities associated with sleep apnea, and may be a novel cellular signal for inflammation [J. Appl. Physiol. 90 (2001) 1986]. Standard cell culture has two major limitations for studying the effects of steady-state P(O(2)) and intermittent hypoxia. First, convective mixing in the culture media can be variable, making precise control of cellular P(O(2)) difficult. Second, diffusion of oxygen through the culture media slows changes in cellular P(O(2)) after rapid changes in the gas phase P(O(2)). Our estimates of diffusional transients for standard cell culture suggest significant restrictions in the ability to cycle P(O(2)) at frequencies relevant to intermittent hypoxia. We present a novel system for forced convection cell culture with adherent cells inside capillary tubing. Steady state cellular P(O(2)) is regulated to an accuracy of approximately 1 Torr. The response time for cycling of P(O(2)) is less than 1.6 sec. This system is ideally suited for studies of intermittent hypoxia in adherent cells.     

Metabolic response during intermittent graded sprint running in moderate hypobaric hypoxia in competitive middle-distance runners

The purpose of this study was to determine whether the metabolic response and running performance during intermittent graded sprint running were affected by moderate hypobaric hypoxia (H; 2,500 m above sea level) in competitive middle-distance runners. Nine male runners performed intermittent graded sprint running until exhaustion, to evaluate the metabolic response and running performance in H and normobaric normoxia (N). The test constructed of incremental (25 m min⁻¹) 20 s running bouts (4° inclination) interspaced with 100 s recovery periods. Maximal running speed was not different between conditions [453 (7) m min⁻¹ vs. 458 (4) m min⁻¹ in N vs. H]. at each speed was lower in H than N (ANOVA; P < 0.05). Although, oxygen deficit at each speed was not different between N and H (ANOVA; P = 0.1), total accumulated in all bouts was significantly higher in H than N [165 (10) ml kg⁻¹ in N and 173 (10) ml kg⁻¹ in H]. The ratio of was similar in all bouts, but higher in H than N. These results suggest that intermittent graded sprint running performance is not affected by moderate hypobaria despite a reduction in the energy supplied by aerobic metabolism due to a compensatory increase in the energy supplied by the anaerobic metabolism in competitive middle-distance runners.