Weeks Of Intermittent Hypoxia Research Articles

Enhanced glucose utilization of skeletal muscle after 4 weeks of intermittent hypoxia in a mouse model of type 2 diabetes.

Intermittent hypoxia intervention (IHI) has been shown to reduces blood glucose and improves insulin resistance in type 2 diabetes (T2D) and has been suggested as a complementary or alternative intervention to exercise for individuals with limited mobility. Previous research on IHI has assessed cellular glucose uptake rather than utilization. The purpose of this study was to determine the effect of a 4-week IHI, with or without an aerobic exercise, on skeletal muscle glucose utilization as indicated by the changes in pyruvate, lactate, NAD+, and NADH, using a mouse model of diet-induced T2D. In addition, the effects of one exposure to hypoxia (acute) and of a 4-week IHI (chronic) were compared to explore their relationship. C57BL/6J mice were randomly assigned to normal control and high-fat-diet groups, and the mice that developed diet-induced diabetes were assigned to diabetes control, and intervention groups with 1 hour (acute) or 4 weeks (1 hour/day, 6 days/week) exposure to a hypoxic envrionment (0.15 FiO2), exercise (treadmill run) in normoxia, and exercise in hypoxia, respectively, with N = 7 in each group. The effects of the interventions on concentrations of fasting blood glucose, muscle glucose, GLUT4, lactate, pyruvate, nicotinamide adenine dinucleotide (NAD+), and NADH were measured, and statistically compared between the groups. Compared with diabetes control group, the mice treated in the hypoxic environment for 4 weeks showed a significantly higher pyruvate levels and lower lactate/pyruvate ratios in the quadriceps muscle, and the mice exposed to hypoxia without or with aerobic exercise for either for 4 weeks or just 1 hour showed higher NAD+ levels and lower NADH/NAD+ ratios. Exposure to moderate hypoxia for either one bout or 4 weeks significantly increased the body's mitochondrial NAD cyclethe in diabetic mice even in the absence of aerobic exercise. The hypoxia and exercise interventions exhibited synergistic effects on glycolysis. These findings provide mechanistic insights into the effects of IHI in respect of the management of hyperglycemia.

Phosphodiesterase 4B activation exacerbates pulmonary hypertension induced by intermittent hypoxia by regulating mitochondrial injury and cAMP/PKA/p-CREB/PGC-1α signaling

Proliferation of smooth muscle cells, oxidative stress, and pulmonary vasoconstriction resulting from intermittent hypoxia (IH) facilitate pulmonary hypertension (PH) in patients with obstructive sleep apnea. The role of Phosphodiesterase 4 B (PDE4B) in PH has not yet been established. Herein, we investigated whether PDE4B inhibition ameliorates experimental PH by modulating cAMP signaling. We performed an integrative analysis of PDE4B expression in Gene Expression Omnibus datasets, experimental IH-induced rat PH samples, and IH-induced pulmonary arterial smooth muscle cells (PASMCs). PDE4B expression was modulated using siRNA in vitro and a specific adeno-associated virus serotype 1 in vivo. In the databases of mouse models of IH-induced and sustained hypoxia-induced PH and in a rat model of six weeks of IH, the expression of PDE4B was up-regulated. Inhibition of PDE4B attenuated IH-induced pulmonary vascular remodeling and right ventricular hypertrophy. Our results also showed that PDE4B deficiency inhibited IH-induced proliferation of PASMCs with less mitochondrial reactive oxygen species and mitochondrial damage. Meanwhile, IH induced an increase in ATF4, which positively regulated the expression of PDE4B through transcription, and inhibition of ATF4 exerted effects similar to those of PDE4B inhibition. Mechanistically, downregulating the expression of PDE4B resulted in the activation of the cAMP/PKA/p-CREB/PGC-1α pathway in PASMCs after IH. Taken together, our present study provides evidence that inhibition of PDE4B attenuates IH-induced PH by regulating cAMP signaling.

Temporal changes in coronary artery function and flow velocity reserve in mice exposed to chronic intermittent hypoxia.

Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) that is implicated in an increased risk of cardiovascular disease (i.e., coronary heart disease, CHD) and associated with increased overall and cardiac-specific mortality. Accordingly, we tested the hypothesis that experimental IH progressively impairs coronary vascular function and in vivo coronary flow reserve. Male C57BL/6J mice (8-week-old) were exposed to IH (FiO2 21% 90 s-6% 90 s) or room air (RA; 21%) 12 h/day during the light cycle for 2, 6, 16, and 28 weeks. Coronary artery flow velocity reserve (CFVR) was measured at each time point using a Doppler system. After euthanasia, coronary arteries were micro-dissected and mounted on wire myograph to assess reactivity to acetylcholine (ACh) and sodium nitroprusside (SNP). Endothelium-dependent coronary relaxation to ACh was preserved after 2 weeks of IH (80.6 ± 7.8%) compared to RA (87.8 ± 7.8%, p = 0.23), but was significantly impaired after 6 weeks of IH (58.7 ± 16.2%, p = 0.02). Compared to ACh responses at 6 weeks, endothelial dysfunction was more pronounced in mice exposed to 16 weeks (48.2 ± 5.3%) but did not worsen following 28 weeks of IH (44.8 ± 11.6%). A 2-week normoxic recovery after a 6-week IH exposure reversed the ACh abnormalities. CFVR was significantly reduced after 6 (p = 0.0006) and 28 weeks (p < 0.0001) of IH when compared to controls. Chronic IH emulating the hypoxia-re-oxygenation cycles of moderate-to-severe OSA promotes coronary artery endothelial dysfunction and CFVR reductions in mice, which progressively worsen until reaching asymptote between 16 and 28 weeks. Normoxic recovery after 6 weeks exposure reverses the vascular abnormalities.

Vascular and renal telomere shortening in mice exposed to chronic intermittent hypoxia.

Obstructive sleep apnea (OSA) is a chronic condition characterized by chronic intermittent hypoxia (IH) and is associated with cardiovascular (CVD) and chronic kidney diseases (CKD). Patients with OSA have increased biomarkers of aging such as telomere shortening. We used PCR to report shortened telomere lengths in aortic and renal tissues from mice exposed to 8 weeks of IH. Our data indicate that IH, a hallmark of OSA, accelerates vascular and renal aging that may contribute to OSA-induced CVD and CKD.

Augmented O-GlcNAcylation attenuates intermittent hypoxia-induced cardiac remodeling through the suppression of NFAT and NF-κB activities in mice.

Type 2 diabetes mellitus(T2DM) has been reported to be associated with cardiac remodeling. Although O-GlcNAcylation is known to be elevated in diabetic and ischemic hearts, the effects of O-GlcNAcylation on cardiac remodeling induced by intermittent hypoxia (IH), such as sleep apnea syndrome (SAS), remain unknown. To evaluate the effects, we induced IH in wild-type (WT) and transgenic O-GlcNAc transferase (Ogt-Tg) mice. Two weeks of IH increased O-GlcNAcylation in the heart tissues of both strains of mice, whereas O-GlcNAcylation in Ogt-Tg mice was significantly higher than that in WT mice under both normoxic and IH conditions. WT mice exhibited cardiac remodeling after IH, whereas cardiac remodeling was significantly attenuated in Ogt-Tg mice. Oxidative stress and apoptosis increased after IH in both strains of mice, whereas the rate of increase in these processes in Ogt-Tg mice was significantly lower than that in WT mice. To examine the mechanism of cardiac remodeling attenuation in Ogt-Tg mice after IH, the effects of O-GlcNAcylation on the activities of the master regulators nuclear factor of activated T cells (NFAT) and NF-κB were determined. The O-GlcNAcylation of GSK-3β, a negative regulator of NFAT, was significantly increased in Ogt-Tg mice, whereas the phosphorylation of GSK-3β was reciprocally reduced. The same result was observed for NF-κB p65. An in vitro reporter assay showed that the augmentation of O-GlcNAcylation by an O-GlcNAcase inhibitor suppressed NFAT and NF-κB promoter activity. These data suggest that augmented O-GlcNAcylation mitigates IH-induced cardiac remodeling by suppressing NFAT and NF-κB activities through the O-GlcNAcylation of GSK-3β and NF-κB p65.

Intermittent Hypoxia Exacerbates Decreased GFR and Increased Blood Pressure in Rats with Chronic Kidney Disease

Kidney injury and sleep apnea (SA) are risk factors for hypertension. This study evaluated interactions between simulated sleep apnea and chronic kidney disease. Rats were exposed to intermittent hypoxia (IH) to simulate SA and were given excess adenine in the diet to cause acute renal injury leading to chronic kidney disease (CKD). We hypothesized that exposing CKD rats to IH would accelerate declines in renal function and increase blood pressure. Male Sprague‐Dawley rats were fed a 0.4% adenine diet or a control diet until plasma urea nitrogen was &gt;140 mg/dL in the adenine group. After two weeks of recovery (normal rat chow for all groups), rats were exposed to IH (20 exposures/hr of 5% O2/5% CO2 7 hr/day) or SHAM for 6 weeks. Arterial pressure (AP) was monitored continuously with indwelling telemeters and plasma and urine samples were collected weekly using metabolism cages to calculate glomerular filtration rate (GFR). AP was increased in rats fed the adenine diet compared to rats on the control diet prior to starting IH. IH treatment further increased AP so that after 6 weeks of Sham or IH treatment AP was elevated in both adenine groups and in the IH only group with pressures in Adenine/IH rats &gt; adenine/Sham rats = Control/IH rats &gt; Control/Sham rats. Histological analysis revealed crystalline deposits and damage to the proximal and distal tubules with interstitial fibrosis in the kidneys of all the adenine fed rats. Fibrosis persisted up to 8 weeks post adenine removal and IH did not cause any apparent additional damage. GFR remained impaired in both the adenine groups throughout the six weeks of IH or SHAM exposures with elevated plasma creatinine levels that were not altered by IH treatment. Therefore simulated SA augments increases in blood pressure in rats with pre‐existing CKD without affecting GFR suggesting that treating apnea should help prevent worsening secondary cardiovascular stresses in CKD patients.Support or Funding InformationNHLBI 123301, Dialysis Clinic Inc. Reserve Fund Grant

PP2A inhibitors repress growth of pancreatic cancer cells through autophagy/p21 pathway

Sleep apnea syndrome (SAS) is considered to be associated with heart failure (HF). It is known that autophagy is induced in various heart diseases thereby promotes survival, but its excess may be maladaptive. Intermittent hypoxia (IH) plays pivotal role in the pathogenesis of SAS. We aimed to clarify the relationships among IH, autophagy, and HF. Rats underwent IH at a rate of 20 cycles/h (nadir of 4% O2 to peak of 21% O2 with 0% CO2) or normal air breathing (control) for 8 h/d for 3 weeks. IH increased the cardiac LC3II/LC3I ratio. The IH induced upregulation of LC3II was attenuated by the administration of an inhibitor of autophagosome formation 3-methyladenine (3-MA), but enhanced by an inhibitor of autophagosome–lysosome fusion chloroquine (CQ), showing enhanced autophagic flux in IH hearts. Electron microscopy confirmed an increase in autophagosomes and lysosomes in IH. With 3-MA or CQ, IH induced progressive deterioration of fractional shortening (FS) on echocardiography over 3 weeks, although IH, 3-MA, or CQ alone had no effects. With CQ, IH for 4 weeks increased serum troponin T levels, reflecting necrosis. Western blotting analyses showed dephosphorylation of Akt and mammalian target of rapamycin (mTOR) at Akt (Ser2448, 2481) sites, suggesting the activation of autophagy via Akt inactivation. Conclusions. IH-mediated autophagy maintains contractile function, whereas when autophagy is inhibited, IH induces systolic dysfunction due to myocyte necrosis. General significance. This study highlighted the potential implications of autophagy in cardio-protection in early SAS patients without comorbidity, reproduced in normal rats by 3 ~ 4 weeks of IH.

Alterations in left ventricular function during intermittent hypoxia: Possible involvement of O-GlcNAc protein and MAPK signaling.

Obstructive sleep apnea, characterized by recurrent episodes of hypoxia [intermittent hypoxia (IH)], has been identified as a risk factor for cardiovascular diseases. The O-linked β-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) of proteins has important regulatory implications on the pathophysiology of cardiovascular disorders. In this study, we examined the role of O-GlcNAcylation in cardiac architecture and left ventricular function following IH. Rats were randomly assigned to a normoxia and IH group (2 min 21% O2; 2 min 6–8% O2). Left ventricular function, myocardial morphology and the levels of signaling molecules were then measured. IH induced a significant increase in blood pressure, associated with a gradually abnormal myocardial architecture. The rats exposed to 2 or 3 weeks of IH presented with augmented left ventricular systolic and diastolic function, which declined at week 4. Consistently, the O-GlcNAc protein and O-GlcNAcase (OGA) levels in the left ventricular tissues steadily increased following IH, reaching peak levels at week 3. The O-GlcNAc transferase (OGT), extracellular signal-regulated kinase 1/2 (ERK1/2) and the p38 mitogen-activated protein kinase (p38 MAPK) phosphorylation levels were affected in an opposite manner. The phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) remained unaltered. In parallel, compared with exposure to normoxia, 4 weeks of IH augmented the O-GlcNAc protein, OGT, phosphorylated ERK1/2 and p38 MAPK levels, accompanied by a decrease in OGA levels and an increase in the levels of myocardial nuclear factor-κB (NF-κB), inflammatory cytokines, caspase-3 and cardiomyocyte apoptosis. Taken together, our suggest a possible involvement of O-GlcNAc protein and MAPK signaling in the alterations of left ventricular function and cardiac injury following IH.

Critical Role of Endoplasmic Reticulum Stress in Chronic Intermittent Hypoxia-Induced Deficits in Synaptic Plasticity and Long-Term Memory.

This study examined the role of endoplasmic reticulum (ER) stress in mediating chronic intermittent hypoxia (IH)-induced neurocognitive deficits. We designed experiments to demonstrate that ER stress is initiated in the hippocampus under chronic IH and determined its role in apoptotic cell death, impaired synaptic structure and plasticity, and memory deficits. Two weeks of IH disrupted ER fine structure and upregulated ER stress markers, glucose-regulated protein 78, caspase-12, and C/EBP homologous protein, in the hippocampus, which could be suppressed by ER stress inhibitors, tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid. Meanwhile, ER stress induced apoptosis via decreased Bcl-2, promoted reactive oxygen species production, and increased malondialdehyde formation and protein carbonyl, as well as suppressed mitochondrial function. These effects were largely prevented by ER stress inhibitors. On the other hand, suppression of oxidative stress could reduce ER stress. In addition, the length of the synaptic active zone and number of mature spines were reduced by IH. Long-term recognition memory and spatial memory were also impaired, which was accompanied by reduced long-term potentiation in the Schaffer collateral pathway. These effects were prevented by coadministration of the TUDCA. These results show that ER stress plays a critical role in underlying memory deficits in obstructive sleep apnea (OSA)-associated IH. Attenuators of ER stress may serve as novel adjunct therapeutic agents for ameliorating OSA-induced neurocognitive impairment.

Raphe serotonergic neurons modulate genioglossus corticomotor activity in intermittent hypoxic rats.

BackgroundGenioglossus activity is greater during wakefulness but decreases to a weaker state during sleep in obstructive sleep apnea syndrome (OSAS) patients, compared to healthy subjects. Previous studies suggested that the corticomotor control of the genioglossus was modified in OSAS patients. Intermittent hypoxia (IH), the typical pathophysiological change in OSAS, can induce genioglossus facilitation. The serotonergic neurons of the raphe dorsal (DRN) and magnus nuclei (RMg) are responsive to hypoxia and play important roles in the control of the genioglossus. However, it remains unknown whether DRN and RMg serotonergic neurons are responsible for the facilitated corticomotor activity of the genioglossus during IH. This study explored the influence of IH on the corticomotor activity of the genioglossus by transcranial magnetic stimulation (TMS), and the role of DRN and RMg serotonergic neurons in this effect.MethodsRats were exposed to IH and divided into two groups. In one group, anti-SERT-SAP was microinjected into the DRN and RMg respectively to kill serotonergic neurons. In the other group, artificial cerebrospinal fluid (ACSF) was injected. Comparisons were conducted between the two groups during four weeks of IH and four weeks after IH.ResultsCompared to the corresponding ACSF-injected group, the DRN lesion group and RMg lesion group showed longer TMS latencies and lower amplitudes during IH from the 1st to the 28th day. After 28 days of IH, longer latencies and lower amplitudes were seen only in the DRN lesion group.ConclusionThese results indicate that DRN and RMg serotonergic neurons play different roles in the facilitation of genioglossus corticomotor activity induced by IH.

Interaction of the kallikrein kinin system and vascular endothelial growth factor in left ventricle of mice exposed to intermittent hypoxia (544.1)

Intermittent hypoxia (IH) is an experimental model of obstructive sleep apnea syndrome (OSAS). However, the occurrence of cardiac angiogenesis in IH and its related mechanism until now have not yet been clarified. In other models of tissue hypoxia, like ischemia/reperfusion, an interaction between VEGF and the KKS was demonstrated and related to the cardioprotective effects. Aiming to find out evidences for VEGF‐KKS interactions in male mice myocardium after IH, we have performed a RT‐PCR assay in the left ventricle. A significant mRNA level increase in VEGF and B2 bradykinin receptor and a decrease in angiotensin converting enzyme (ACE) were observed after 2 weeks of IH when compared to normoxia group. In models of ischemia/reperfusion it has been suggested that VEGF interaction with B2 receptor agonist is an important step in angiogenesis induction. Our findings allow us to suppose that the increased myocardial expression of VEGF in IH by stimulating the expression of B2 receptor and reducing the expression of ACE could contribute to increase bradykinin, favouring neoangiogenesis in this tissue.Grant Funding Source: Supported by FAPESP (2012/02123‐0)

The impact of obesity and hypoxia on left ventricular function and glycolytic metabolism.

We have previously reported that 4 weeks of intermittent hypoxia (IH) exposure, mimicking the hypoxic stress of obstructive sleep apnea, produces compensatory increases in left ventricular (LV) contractility in lean C57BL/6J mice. In this study we compared the effects of 4 weeks IH to 4 weeks of sustained hypoxia (SH) on LV function and cardiac glycolysis in lean C57BL/6J mice and obese ob/ob mice at 10–12 weeks of age. The four exposure conditions were IH (nadir O2 [5–6%] at 60 cycles/h during the 12 h light period), SH (24 h inspired O2 [10%]), and control groups of intermittent air (IA) or room air. Cardiac function was assessed under isoflurane anesthesia (1–2%) by echocardiography and pressure–volume loop analysis and myocardial glycolytic rates were determined ex vivo using radiolabeled 3H‐glucose. Lean mice exposed to IH exhibited increases in contractile parameters which were associated with elevated glycolytic rates (3.4 vs. 5.7 μg/μL·g; P < 0.05). Ob/ob mice did not show any improvements in contractility after IH. Moreover, cardiac glycolytic rates and LV systolic and diastolic function did not differ from IA ob/ob controls. Following SH exposure, lean mice exhibited increased contractility and glycolytic rates (3.8 vs. 5.7 μg/μL·g; P < 0.05), however, LV lumen dimensions were reduced. In contrast, ob/ob mice exposed to SH show compromised systolic and diastolic function associated with unchanging glycolytic rates. These findings demonstrate that, in a murine model of obesity, an inability to increase glycolysis is associated with an absence of an adaptive cardiac response to IH and marked systolic and diastolic dysfunction in response to SH.

Deletion of metallothionein exacerbates intermittent hypoxia-induced oxidative and inflammatory injury in aorta.

The present study was to explore the effect of metallothionein (MT) on intermittent hypoxia (IH) induced aortic pathogenic changes. Markers of oxidative damages, inflammation, and vascular remodeling were observed by immunohistochemical staining after 3 days and 1, 3, and 8 weeks after IH exposures. Endogenous MT was induced after 3 days of IH but was significantly decreased after 8 weeks of IH. Compared with the wild-type mice, MT knock-out mice exhibited earlier and more severe pathogenic changes of oxidative damages, inflammatory responses, and cellular apoptosis, as indicated by the significant accumulation of collagen, increased levels of connective tissue growth factor, transforming growth factor β1, tumor necrosis factor-alpha, vascular cell adhesion molecule 1,3-nitrotyrosine, and 4-hydroxy-2-nonenal in the aorta. These findings suggested that chronic IH may lead to aortic damages characterized by oxidative stress and inflammation, and MT may play a pivotal role in the above pathogenesis process.

Effect of intermittent hypoxia on atherosclerosis in apolipoprotein E-deficient mice

Objective Obstructive sleep apnea causes intermittent hypoxia (IH) and is associated with increased cardiovascular mortality. This increased risk may be attributable to more extensive or unstable atherosclerotic plaques in subjects with OSA. We studied the effect of chronic IH in atherosclerosis-prone mice. Methods and results Apolipoprotein E-deficient ( ApoE −/ − ) mice fed a high cholesterol diet were exposed to 4 or 12 weeks of IH and compared to intermittent air-exposed controls. At 4 weeks, IH increased plaque size in the aortic sinus and the descending aorta. At 12 weeks, atherosclerosis progressed in all groups, but more rapidly in the descending aorta of IH-exposed animals. Plaque composition was similar between IH and controls. Between 4 and 12 weeks, there were progressive increases in blood pressure, with relatively stable increases in serum lipids and arterial stiffness. Conclusions IH accelerates atherosclerotic plaque growth in ApoE −/ − mice without affecting plaque composition. The mechanisms may include non-additive increases in serum lipids, and cumulative increases in blood pressure.

Influence of Intermittent Hypoxia on Myocardial and Hepatic P‐glycoprotein Expression in a Rodent Model

Patients with obstructive sleep apnea who receive drug therapy for cardiovascular disease may experience resistant hypertension, arrhythmias, or more severe heart failure, and many of the drugs used to treat these conditions are substrates for P-glycoprotein (P-gp) transporters. Therefore, we sought to determine if intermittent hypoxia, which mimics obstructive sleep apnea, would upregulate myocardial and hepatic P-gp expression and Abcb1a and Abcb1b messenger RNA (mRNA) expression (genes that encode for P-gp) in an animal model. Prospective, randomized, blinded, parallel-design animal study. University research laboratory. Thirty adult, male Sprague-Dawley rats. Rats were assigned to either 2 weeks of intermittent hypoxia exposure similar to sleep apnea (12 rats) or no hypoxia exposure (controls, 18 rats). After intermittent hypoxia or normoxia exposure, the rats were anesthetized. Heart and liver were harvested, and small samples were taken from the left ventricle (heart) and the liver for analysis. Expression of P-gp was measured by Western blotting, whereas Abcb1a and Abcb1b mRNA expression was assessed by real-time polymerase chain reaction. Band density of myocardial (but not hepatic) P-gp expression (standardized by beta-actin) was significantly higher in hypoxic rats than in control rats (p=0.03). Quantitative polymerase chain reaction revealed that myocardial and hepatic Abcb1a and myocardial Abcb1b mRNA expression were significantly increased in hypoxic rats compared with controls (p<0.05). Myocardial P-gp expression and myocardial and hepatic Abcb1a mRNA expression were significantly increased after 2 weeks of intermittent hypoxia. Hypoxia-induced increases in P-gp expression may partially explain drug-resistant cardiovascular disease in patients with obstructive sleep apnea.

Effect of intermittent hypoxia on atherosclerosis and cardiovascular function in apolipoprotein E‐deficient mice

Obstructive sleep apnea causes intermittent hypoxia (IH) during sleep and contributes to cardiovascular disease. To determine the effect of IH on atherosclerosis, we exposed ApoE−/− mice fed a high cholesterol diet to 4 or 12 weeks of IH or intermittent air (IA) control and measured atherosclerotic lesions, blood pressure, cholesterol, pulse wave velocity (PWV), oxidative stress, and left ventricular (LV) function. The IH regimen consisted of a 5% O2 nadir once per minute for 12 hours/day during the light phase. At 4 weeks, IH doubled plaque size at the aortic root (197,215±24,832 vs. 89,125±25,638 µm2, p&lt;0.05) without affecting lesions in the descending aorta. IH also increased LDL cholesterol, PWV, and LV dimensions. At 12 weeks, IH did not affect lesions at the aortic root (610,287±27,341 vs. 553,600±51,113 µm2, p=NS) but doubled plaque in the descending aorta (32.0±2.8% vs. 14.4±1.6%, p&lt;0.01%). Cholesterol and PWV remained elevated. In addition, LV ejection fraction decreased while triglycerides and cardiac oxidative stress increased. We conclude that IH accelerates atherosclerosis in ApoE−/− mice, initially at the aortic root and later in the descending aorta. This finding is accompanied by exacerbation of dyslipidemia, impaired arterial vasomotion, and the development of LV dysfunction. Funding sources: NIH R01 HL080105, T32 HL07534, SF‐78568‐N, AHA 0765293U.

Intermittent hypoxia increases exercise tolerance in patients at risk for or with mild COPD

The effects of repeated short-term hypoxia on exercise tolerance in patients at risk for, or with mild COPD were investigated. Eighteen patients (10 males, 8 females; 33-72 years) were randomly assigned in a double-blind fashion to receive 15 sessions of intermittent hypoxia (FiO(2): 0.15-0.12) or normoxia within 3 weeks. Three weeks of intermittent hypoxia increased total haemoglobin mass (+4% vs. 0%, p<0.05), total exercise time (+9.7% vs. 0%, p<0.05) and the exercise time to the anaerobic threshold (+13% vs. -7.8%, p<0.05) compared to controls. Changes in the total exercise time were positively related to the changes in total haemoglobin mass (r=0.59, p<0.05) and changes in the time to the anaerobic threshold were positively related to the changes in the lung diffusion capacity for carbon monoxide (r=0.48, p<0.05). Intermittent hypoxia treatment may be a valuable addition to therapy designed to improve exercise tolerance in patients at risk for, or with mild COPD.

Changes in ventilatory responses to hypercapnia and hypoxia after intermittent hypoxia in humans

The purpose of this study was to clarify the changes in hypercapnic and hypoxic ventilatory responses (HCVR and HVR) after intermittent hypoxia and following the cessation of hypoxic exposure. Twenty-nine males were assigned to one of four groups, i.e., a hypoxic (EX1-H, n=7) or a control (EX1-C, n=7) group in Experiment 1, and a hypoxic (EX2-H, n=8) or a control (EX2-C, n=7) group in Experiment 2. In each experiment, the hypoxic tent system was utilized for intermittent hypoxia, and the oxygen levels in the tent were maintained at 12.3+/-0.2%. In Experiment 1, the EX1-H group spent 3 h/day in the hypoxic tent for 1 week. HCVR and HVR were determined before and after 1 week of intermittent hypoxia, and again 1 and 2 week after the cessation of hypoxic exposure. In Experiment 2, the subjects in the EX2-H group performed 3 h/day for 2 weeks in intermittent hypoxia. HCVR and HVR tests were carried out before and after intermittent hypoxia, and were repeated again after 2 weeks of the cessation of hypoxic exposure. The slope of the HCVR in the EX1-H group did not show a significant increase after 1 week of intermittent hypoxia, while HCVR in the EX2-H group increased significantly after 2 weeks of intermittent hypoxia. The HCVR intercept was unchanged following 1 or 2 weeks of intermittent hypoxia. There was a significant increase in the slope of the HVR after 1 and 2 weeks of intermittent hypoxia. The increased HCVR and HVR returned to pre-hypoxic levels after 2 weeks of the cessation of hypoxia. These results suggest that 3 h/day for 2 weeks of intermittent hypoxia leads to an increase in central hypercapnic ventilatory chemosensitivity, which is not accompanied by a re-setting of the central chemoreceptors, and that the increased hypercapnic and hypoxic chemosensitivities are restored within 2 weeks after the cessation of hypoxia.

Long-term intermittent hypoxia: reduced excitatory hypoglossal nerve output.

Humans with long-standing sleep apnea show mixed responses to serotonergic therapies for obstructive sleep apnea. We hypothesize that long-term intermittent hypoxia may result in oxidative injury to upper airway motoneurons, thereby diminishing serotonergic motoneuronal excitation. Unilateral serotonin and glutamate agonist and antagonist microinjections into the hypoglossal motor nuclei in adult rats exposed to 3 weeks of intermittent hypoxia showed reduced hypoglossal nerve responsiveness (logEC50) for serotonin and N-methyl-D-aspartate. However, long-term intermittent hypoxia did not appear to alter hypoglossal response to alpha-amino-3-hydroxy-methylisoxazole-4-propionic acid injections. There was no reduction in hypoglossal motoneuron soma number or in serotonergic postsynaptic receptor mRNA copy numbers within single-cells; in contrast, there was an increase in isoprostanes in the dorsal medulla. Systemic 4-hydroxyl-2,2,6,6-tetramethylpiperidin-1-oxyl (tempol) throughout exposure to intermittent hypoxia improved the EC50 for serotonin to a larger extent than glutamate and normalized medullary isoprostanes. Protein kinase C activity within the hypoglossal nucleus was increased after long-term intermittent hypoxia. These results suggest that long-term intermittent hypoxia reduces serotonergic and N-methyl-D-aspartate excitatory output of hypoglossal nerves, and that reduced excitatory responsiveness and lipid peroxidation are largely prevented with superoxide dismutase treatment throughout hypoxia/reoxygenation. Similar alterations in neurochemical responsiveness may occur in select persons with obstructive sleep apnea.