Effects Of Intermittent Hypoxia Research Articles

Intermittent Hypoxia Accelerates Cardiac Remodeling due to Postprandial Hyperglycemia in Lean Mice

Objectives: Postprandial hyperglycemia (PPG) and intermittent hypoxia relevant to sleep apnea, which often coexists in patients with metabolic syndrome, are risk factors of cardiovascular disease. The aim of this study was to examine the effect of intermittent hypoxia on left ventricular (LV) remodeling due to PPG, and to evaluate the efficacy of acarbose, an α-glucosidase inhibitor, in lean mice.

Down-regulation of bile acid synthesis and a metabolic co-activator under hypoxic conditions – implications in obstructive sleep apnea

Obstructive sleep apnea is characterized by episodes of intermittent hypoxia that occur while the afflicted person sleeps, and is believed to affect and have a negative impact on many people worldwide. Both observational evidence in obstructive sleep apnea patients and direct studies in mice mimicking the disease strongly support an increased risk for atherosclerosis in these groups. Studies to date on atherosclerosis in obstructive sleep apnea have been focused on cholesterol synthesis. However, dysregulation of bile acid synthesis, which is an important means of cholesterol removal, has not been considered in any sleep disorder model to date. While the relationship between hypoxia and bile acid regulation has been explored in a variety of models, no unifying theory currently ties in the pathologic effect of intermittent hypoxia on bile acid regulation in humans or animals. The goal of this article is to propose the role intermittent hypoxia plays in disrupting bile acid synthesis in patients with obstructive sleep apnea, and its metabolic consequences. Reviewed and discussed are the complex interactions of several key molecular players known to be involved in metabolism with emphasis on the principle bile acid synthesis enzyme, cholesterol 7-alpha-hydroxylase, which is proposed to have reduced activity under hypoxic conditions. Furthermore, the metabolic consequences of reduced levels of active peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) under hypoxia, and hypothetically in obstructive sleep apnea, are explored. A better molecular understanding of bile acid synthesis and metabolic dysregulation in this context will hopefully promote the study of new targets in human sleep apneas, and encourage clinical trials using existing therapeutic and dietary interventions in patients afflicted with these conditions.

Adipose Tissue Lymphocytes and Macrophages in Obesity and Insulin Resistance

Obesity, and more specifically accumulation of adipose tissue in the visceral and subcutaneous abdominal locations, is a major risk factor for the development of cardiovascular pathologies including hypertension and atherosclerosis, as well as metabolic disorders such as type 2 diabetes. During recent years, “metaflammation” or metabolically-triggered inflammation1 has emerged as a key process involved in the clustering of those conditions. Although several metabolically active organs such as the liver, muscle, and, recently, the intestine2 certainly play major roles, the white adipose tissue appears as a central and primary player as both a source and site of inflammation. Accumulation of adipose tissue macrophages (ATMs) has been well-described in obese conditions in mice and humans.3–5 Moreover, the ATM proinflammatory phenotype has been linked to the development of insulin resistance in mice,4 although the exact nature of the proinflammatory myeloid cells, ie, macrophages or dentritic cells, remains to be determined.6 Nevertheless, the causal link between inflammation and insulin resistance was further strengthened by the specific knock-out of the inflammation coordinator IkappaB kinase beta of myeloid cells, which gave protection against insulin resistance.7 The study of Kintscher and al in this issue8 extends those original observations to cells of adaptative immunity. The authors suggest that the accumulation of T-lymphocytes, assessed mainly through gene expression analyses and immunohistochemistry, occurs in the perigonadal adipose tissue of mice on …

Intermittent Hypoxia: Cause of or Therapy for Systemic Hypertension?

During acute episodes of hypoxia, chemoreceptor-mediated sympathetic activity increases heart rate, cardiac output, peripheral resistance and systemic arterial pressure. However, different intermittent hypoxia paradigms produce remarkably divergent effects on systemic arterial pressure in the post-hypoxic steady state. The hypertensive effects of obstructive sleep apnea (OSA) vs. the depressor effects of therapeutic hypoxia exemplify this divergence. OSA, a condition afflicting 15-25% of American men and 5-10% of women, has been implicated in the pathogenesis of systemic hypertension and is a major risk factor for heart disease and stroke. OSA imposes a series of brief, intense episodes of hypoxia and hypercapnia, leading to persistent, maladaptive chemoreflex-mediated activation of the sympathetic nervous system which culminates in hypertension. Conversely, extensive evidence in animals and humans has shown controlled intermittent hypoxia conditioning programs to be safe, efficacious modalities for prevention and treatment of hypertension. This article reviews the pertinent literature in an attempt to reconcile the divergent effects of intermittent hypoxia therapy and obstructive sleep apnea on hypertension. Special emphasis is placed on research conducted in the nations of the former Soviet Union, where intermittent hypoxia conditioning programs are being applied therapeutically to treat hypertension in patients. Also reviewed is evidence regarding mechanisms of the pro- and anti-hypertensive effects of intermittent hypoxia.

Intermittent hypoxia is a key regulator of cancer cell and endothelial cell interplay in tumours

Solid tumours are complex structures in which the interdependent relationship between tumour and endothelial cells modulates tumour development and metastasis dissemination. The tumour microenvironment plays an important role in this cell interplay, and changes in its features have a major impact on tumour growth as well as on anticancer therapy responsiveness. Different studies have shown irregular blood flow in tumours, which is responsible for hypoxia and reoxygenation phases, also called intermittent hypoxia. Intermittent hypoxia induces transient changes, the impact of which has been underestimated for a long time. Recent in vitro and in vivo studies have shown that intermittent hypoxia could positively modulate tumour development, inducing tumour growth, angiogenic processes, chemoresistance, and radioresistance. In this article, we review the effects of intermittent hypoxia on tumour and endothelial cells as well as its impacts on tumour development.

The Effect of Intermittent Hypoxia on Bodyweight, Serum Glucose and Cholesterol in Obesity Mice

This article tests mice's indicators of body nutritional metabolism under tolerable hypoxic conditions, in order to explore the effects of moderate intermittent hypoxia on the bodyweight, blood sugar and blood cholesterol of obese mice and to identify the role of leptin in these effects; this study applies high-fat diet to establish Mice Obesity Models and observes the intervention effects of intermittent hypoxic training in this Model. Small healthy mice are classified in 4 groups at random, that is, Group A (Normal), Group B (Normal Hypoxia) fed with normal foods and undergoing Intermittent Hypoxic Training (IHT), Group C (Fatty-diet) fed with High-Fat and High-Sugar (HFHS) foods without IHT and Group D (Fatty-diet and Hypoxia) fed with HFHS foods with IHT. After 40 days of feeding and hypoxic training, weigh the mice, measure the levels of blood sugar and blood cholesterol with a full automatic biochemical analyzer, measure serum leptin concentration by enzyme-linked immunosorbent assay (ELISA) technique, inspect liver leptin receptor expression and liver fat slice by immunohistochemistry. It is found that compared to control group, after experiment, the average bodyweight, blood sugar, blood cholesterol and serum leptin concentration in Group C is increased significantly and numerous fat cells are distributed in the liver, which indicates that hyperlipemia model has been successfully established; after intermittent hypoxic training, the average bodyweight, blood sugar, blood cholesterol and liver fat cells distribution density and scope in Group B and D are lower than those in Group A and C, while serum leptin concentration is increased significantly; liver leptin receptor expression in Group D is higher than that in Group C. And hypoxia groups have no trauma conclusion. Moderate intermittent hypoxia can reduce bodyweight by increasing leptin concentration and enhancing liver leptin expression and it can also reduce the level of blood sugar and blood cholesterol and meanwhile prevent steatosis in liver cells effectively.

Effects of intermittent hypoxia on pulmonary haemodynamics

Effects of intermittent hypoxia on pulmonary haemodynamics

Intermittent hypoxia and sleep restriction: Motor, cognitive and neurochemical alterations in rats

The present study evaluated the effects of intermittent hypoxia (IH) and sleep restriction (SR) upon motor and cognitive function in rats. Also evaluated were catecholamine concentrations and tyrosine hydroxylase (TH) protein expression in different regions of the forebrain. Wistar Hannover rats were submitted to IH for 4 days or 21 days (2min room air to 2min 10% O2 for 10:00–16:00h), followed by SR for 18h (16:00–10:00h). Rats were randomly assigned into four experimental groups: (1) control (2) IH (3) SR and (4) IH–SR. In the inhibitory avoidance task, an additional group of rats was submitted to paradoxical sleep deprivation (PSD) for 96 consecutive hours. Results showed that SR induced an increase in motor activity without modifying catecholaminergic turnover in the frontal cortex and striatum. The increase in exploratory activity in SR rats could be the result of impaired habituation. Neither SR periods induced cognitive deficits in the inhibitory avoidance task after 5 or 21 days. However, 96h of PSD impaired acquisition/retention in rats. Exposure to IH did not affect motor and cognitive function but IH was associated with SR in increased motor activity. After 21 days, IH and IH–SR reduced striatal norepinephrine concentration although neither SR nor IH affected TH protein expression. The results presented here suggest that hypoxia and sleep loss exert distinct deleterious effects upon the central nervous system.

Noninvasive determination of brain tissue oxygenation during sleep in obstructive sleep apnea: a near-infrared spectroscopic approach.

Recurrent apneas and hypoxemia during sleep in obstructive sleep apnea (OSA) are associated with profound changes in cerebral blood flow to the extent that cerebral autoregulation may be insufficient to protect the brain. Since the brain is sensitive to hypoxia, the cerebrovascular morbidity seen in OSA could be due to chronic, cumulative effects of intermittent hypoxia. Near-infrared spectroscopy (NIRS) has the potential to noninvasively monitor brain tissue oxygen saturation (SO2), and changes in concentration of oxyhemoglobin [O2Hb], deoxyhemoglobin [HHb] and total hemoglobin [tHb] with real-time resolution. We hypothesized that brain tissue oxygenation would be worse during sleep in OSA relative to controls and sought to determine the practical use of NIRS in the sleep laboratory. We evaluated changes in brain tissue oxygenation using NIRS during overnight polysomnography. Studies were conducted at University of Illinois, Chicago and Carle Hospital, Urbana, Illinois. Nineteen subjects with OSA and 14 healthy controls underwent continuous NIRS monitoring during polysomnography. We observed significantly lower indexes of brain tissue oxygenation (SO2: 57.1 +/- 4.9 vs. 61.5 +/- 6.1), [O2Hb]: 22.8 +/- 7.7 vs. 31.5 +/- 9.1, and [tHb]: 38.6 +/- 11.2 vs. 48.6 +/- 11.4 micromol/L) in OSA than controls (all P < 0.05). However, multivariate analysis showed that the differences might be due to age disparity between the two groups. NIRS is an effective tool to evaluate brain tissue oxygenation in OSA. It provides valuable data in OSA assessment and has the potential to bridge current knowledge gap in OSA.

Effects of intermittent hypoxia on SaO2, cerebral and muscle oxygenation during maximal exercise in athletes with exercise-induced hypoxemia

In a placebo-controlled study, the effects of intermittent hypoxic exposures (IHE) or a placebo control for 10 days, were examined on the extent of exercise-induced hypoxemia (EIH), cerebral and muscle oxygenation (near-infrared spectroscopy) and VO(2peak). Eight athletes who had previously displayed EIH (fall in saturation of arterial oxygen (SaO(2)) of >4% from rest) during an incremental maximal exercise test, volunteered for the present research. Prior to (baseline), and 2 days following (post) the IHE or placebo, an incremental maximal exercise test was performed whilst SaO(2), heart rate, cerebral and muscle oxygenation and respiratory gas exchange were measured continuously. After IHE, but not placebo, EIH was less pronounced at VO(2peak) (IHE group, SaO(2) at VO(2peak) baseline 91.23 +/- 1.10%, post 94.10 +/- 2.19%; P < 0.01, mean +/- SD). This reduction was reflected in an increased ventilation (NS), a lower end-tidal CO(2) (P < 0.01), and lowered cerebral TOI during heavy exercise (90% VO(2peak): -6.1 +/- 6.0 Delta%, P = 0.04). Conversely, muscle tHb at maximal exercise, was increased (2.4 +/- 1.8 DeltamicroM, P = 0.01, mean +/- 95 CL) following IHE, whilst de-oxygenated Hb at 90% of VO(2peak) was reduced (-0.9 +/- 0.8 DeltamicroM, P = 0.02). These data indicate that exposure to IHE can attenuate the degree of EIH. Despite a potential compromise in cerebral oxygenation, exposure to IHE may induce some positive physiological adaptations at the muscle tissue level. We speculate that the unchanged VO(2peak) following IHE might reflect a balance between these central (cerebral) and peripheral (muscle) adaptations.

Effects of intermittent hypoxia in patients with obstructive sleep apnea syndrome

Effects of intermittent hypoxia in patients with obstructive sleep apnea syndrome

Effects of obstructive sleep apnea style intermittent hypoxia on endothelin-1, nitric oxide, and nitric oxide synthase in endothelium: experiment with human umbilical vein endothelial cells

To investigate the effects of intermittent hypoxia (IH) on the expression of endothelin-1 (ET-1), nitric oxide (NO), and nitric oxide synthase (NOS) in endothelium, and to evaluate the role of functional disorder of endothelium in the mechanism of obstructive sleep apnea syndrome (OSAS) induced hypertension. Human umbilical vein endothelial cells (HUVECs) of the line ECV304 were cultured and divided into 4 groups: IH group (exposed to 1.5% O(2) for 15 s and 21% O(2) for 1 min 15 s, 3 min 45 s, 5 min 15 s, or 8 min 15 s respectively alternatively with 60 episodes), intermittent normal oxygen group (exposed to 21% O(2) for 15 s and 225 s alternatively with 60 episodes), continuous hypoxia group (exposed to 1.5% for 15 min), and blank control group. Then the culture fluid was collected. The levels of activity of ET-1 (EIA) NO, and NOS were detected by enzyme immune assay, nitric acid reductase method, and chemical colorimetric analysis respectively. RT-PCR was used to detect the mRNA expression of endothelial NOS (eNOS). Compared with those of the intermittent normal oxygen group and blank control groups the ET-1 levels of the 4 IH sub groups were significantly higher (F = 28.453, P = 0.000), the NO levels ere significantly lower F = 65.252, P = 0.000), the NOS activity levels were significantly lower (F = 5.969, P = 0.008), and eNOS mRNA was significantly down-regulated (F = 16.630, P = 0.000). Compared with continuous hypoxia group with the exposure time equivalent to the accumulated hypoxia time (15 s with 60 episodes) of the IH group, the ET-1 level was significantly higher (t = 2.742, P = 0.024), the NO level was significantly lower (t = 3.347, P = 0.004), the NOS activity level was significantly lower (t = 3.989, P = 0.004), and the eNOS mRNA expression was down-regulated (t = 5.045, P = 0.000). In the different IH group along with the prolongation of the re-oxygenation time from 105 s to 495 s, while maintaining the duration of hypoxic episodes at 15 s, the ET-1 level increased (F = 213.254, P = 0.000), the NO level decreased (F = 15.747, P = 0.000), NOS activity level decreased (F = 2.933, P = 0.048), and eNOS mRNA expression was down-regulated (F = 5.954, P = 0.002). However, there was a tendency for ET-1 to decrease and the NO system indicators when the re-oxygenation time was 8 min 15 s. Hypoxia and re-oxygenation both cause endothelium dysfunction and unbalance of NO/ET-1, which is important to OSAS with hypertension.

Intermittent hypoxia changes HIF-1α phosphorylation pattern in endothelial cells: Unravelling of a new PKA-dependent regulation of HIF-1α

Vascularized tumors are exposed to intermittent hypoxia, that is, hypoxia followed by periods of reoxygenation. Abnormal structure and dysfunction of tumor blood vessels are responsible for these conditions. These repeated short periods of hypoxia concern tumor cells as well as endothelial cells. However, the effects of intermittent hypoxia are poorly understood. The aim of this study was to investigate the effects of intermittent hypoxia on endothelial cells and particularly on HIF-1α, a central actor in adaptive response to hypoxia. For that, endothelial cells were exposed to four repeated cycles of 1-h hypoxia followed by 30 min of reoxygenation. We showed that repeated cycles of hypoxia/reoxygenation induced a modification in HIF-lα phosphorylation pattern: a progressive increase in HIF-1α phosphorylated form was observed during the hypoxic periods. Activation of p42/p44, Akt and PKA was observed in parallel. PKA was shown to be involved in the phosphorylation of HIF-lα under intermittent hypoxia, while p42/p44 and Akt were not. As HIF-1 activity is often associated with enhanced cell survival, a better knowledge of the effects of intermittent hypoxia on endothelial cells and the highlight of particular mechanisms induced by intermittent hypoxia are essential to understand the behavior of endothelial cells during neo-angiogenesis.

Effects of Intermittent Hypoxia on the Heart

Obstructive sleep apnea (OSA) is associated with cardiovascular diseases such as hypertension through mechanisms involving intermittent hypoxia (IH). However, it is not yet clear whether IH directly affects the heart. In a mouse model of OSA, we found that IH causes time-dependent alterations of the susceptibility of the heart to oxidative stress. Acute IH can exert preconditioning-like cardioprotection, in part, through the transcriptional activation of genes such as bcl-x(L) and gata4. We cloned the mouse gata4 promoter and identified an IH-responsive region. The exposure of mice to prolonged IH results in the increased susceptibility of the heart to ischemia-reperfusion injury by increasing the oxidative stress status. This might resemble conditions of OSA patients. In our mouse model, further exposure to prolonged IH allowed reversal of the enhancement of myocardial damage. Understanding the complex effects of IH on the heart should help ultimately to develop therapeutic strategies against OSA-induced complications.

Effects of intermittent hypoxia on oxidative stress-induced myocardial damage in mice

Obstructive sleep apnea is associated with increased risk for cardiovascular diseases. As obstructive sleep apnea is characterized by episodic cycles of hypoxia and normoxia during sleep, we investigated effects of intermittent hypoxia (IH) on ischemia-reperfusion-induced myocardial injury. C57BL/6 mice were subjected to IH (2 min 6% O(2) and 2 min 21% O(2)) for 8 h/day for 1, 2, or 4 wk; isolated hearts were then subjected to ischemia-reperfusion. IH for 1 or 2 wk significantly enhanced ischemia-reperfusion-induced myocardial injury. However, enhanced cardiac damage was not seen in mice treated with 4 wk of IH, suggesting that the heart has adapted to chronic IH. Ischemia-reperfusion-induced lipid peroxidation and protein carbonylation were enhanced with 2 wk of IH, while, with 4 wk, oxidative stress was normalized to levels in animals without IH. H(2)O(2) scavenging activity in adapted hearts was higher after ischemia-reperfusion, suggesting the increased antioxidant capacity. This might be due to the involvement of thioredoxin, as the expression level of this protein was increased, while levels of other antioxidant enzymes were unchanged. In the heart from mice treated with 2 wk of IH, ischemia-reperfusion was found to decrease thioredoxin. Ischemia-reperfusion injury can also be enhanced when thioredoxin reductase was inhibited in control hearts. These results demonstrate that IH changes the susceptibility of the heart to oxidative stress in part via alteration of thioredoxin.

Effects of intermittent hypoxia on cat petrosal ganglion responses induced by acetylcholine, adenosine 5′-triphosphate and NaCN

Exposure to chronic intermittent hypoxia (CIH) for 4 days enhances the cat carotid body (CB) chemosensory responses to acute hypoxia. However, it is not known if CIH enhances the responses of the petrosal ganglion (PG) neurons that innervate the CB chemoreceptor cells. Accordingly, we studied the effects of the CB putative excitatory transmitter acetylcholine (ACh) and adenosine 5´-triphosphate (ATP), and the effects of citotoxic hypoxia (NaCN) applied to the isolated PG from cats exposed to CIH for 4 days. The dose-dependent curve parameters of the frequency of discharges evoked in the carotid sinus nerve by the application of ACh, ATP and NaCN to the isolated PG in control condition were not significantly modified in the CIH-treated cats. Present results suggest that CIH enhances the chemosensory responses to acute hypoxia acting primarily at the chemoreceptor cells, without major changes in the response of PG neurons evoked by the application of putative CB excitatory transmitters to their somata.

A Review of Neuroimaging in Obstructive Sleep Apnea

The authors reviewed neuroimaging studies of obstructive sleep apnea (OSA) to summarize findings, evaluate their contribution to a current understanding of the neurophysiology of the disorder, and propose directions for future research. Manuscripts were identified using the National Institutes of Health PubMed literature search system. Search terms included obstructive sleep apnea, sleep apnea, imaging, neuroimaging, magnetic resonance imaging, MRI, functional magnetic resonance imaging, fMRI, magnetic resonance spectroscopy, and MRS. Inclusion criteria required that research articles (1) were written in English, (2) examined an adult population, and (3) focused on imaging of the brain. Support for structural abnormalities is mixed, but converging evidence suggests the hippocampus may be atrophic in patients with OSA. Neurochemical evidence is supportive of white-matter impairment in OSA, particularly in the frontal lobes. Functional studies utilizing respiratory challenges report widespread neural differences in motor, sensory, and autonomic brain regions. Functional neuroimaging cognitive challenges have reported either a lack of brain activation in dorsolateral prefrontal cortex or increased neural response in frontal lobe, cingulate, thalamus, cerebellum, and juncture of parietal and temporal lobes, depending on the cognitive task employed. The current literature examining neuroimaging-derived neural correlates in patients with OSA has made many important preliminary contributions. Future studies would be strengthened by consideration of potential moderating participant characteristics, such as sex, age, education, OSA severity, and comorbid conditions. Additional investigation employing neuroimaging techniques is needed to advance our understanding of the neurophysiology of OSA.

152 The effect of intermittent hypoxia on maintenance of upper airway tone

152 The effect of intermittent hypoxia on maintenance of upper airway tone

Effect of Intermittent Hypoxia on Exercise Ventilation at a Simulated Moderate Altitude

Effect of Intermittent Hypoxia on Exercise Ventilation at a Simulated Moderate Altitude

Physical Performance after Adaptation to Different Protocols of Intermittent Hypoxia

PURPOSE: Disparity in reports of the effect of adaptation to acutely intermittent hypoxia on physical performance may be due in part to differences in exposure protocols. Here we report effects of differences in the dose of hypoxia on performance in tests simulating a team sport. METHODS: Fifteen club and junior representative rugby players were randomized to one of four hypoxia dose groups. All players used a personal rebreathing device to achieve 1-hour daily sessions of hypoxia consisting of six intervals of hypoxia interspersed with recovery periods of ambient air. The groups differed in the duration of hypoxia+recovery intervals: 5+5, 6+4, 7+3 and 8+2 min. An initial 15-day loading period of exposures was followed by two 5-day maintenance periods, over a total of 45 d. Pulse oximetry was used to progressively reduce each player's oxygen saturation (Day 1, 89–91%, Day 15 onwards, 76–78%). Before and 2 d after the exposure period, players performed a game-length simulation consisting of 14 circuits, each involving five different sprints and two scrum-like drives. The effect of mean dose of hypoxia (6.5 min; an uncontrolled outcome) and effect of dose difference (1.5 min; effectively a controlled outcome) on sprint speed and drive peak power were expressed as percents, and qualitative inferences were derived by standardizing these effects with pre-exposure standard deviations. RESULTS: The effect of the mean dose was mainly trivial for sprint speeds (−0.6% to 2.3%; 90% confidence limits ±1% to ±2%) but harmful for drive power (−6.2% and −7.2%; ±4.2%). Increasing the dose produced a mixture of trivial, beneficial and harmful differences in sprint speed (−2.6% to 2.4%; ±1.2% to ±2.6%) and an increase in the harmful effect on drive power (by 5.2% and 6.1%; ±4.2%). CONCLUSIONS: There was little consistent effect of intermittent hypoxia on sprint speed, and an apparently harmful effect on drive power would be made worse by increasing the duration of the hypoxic intervals.