Long-Term Intermittent Hypobaric Hypoxia Research Articles

The role of NMDA glutamate receptors in lung injury caused by chronic long-term intermittent hypobaric hypoxia

Chronic intermittent hypoxia (CIH), a component of sleep apnea-hypopnea syndrome, is suggested to cause damage to lung tissue, and the role of glutamate is not well studied. We used a chronic long-term intermittent hypobaric hypoxia (CLTIHH) model of rats to find out if such procedure causes lung injury and the potential effect of N-methyl-D-aspartate receptors (NMDARs) by using receptor antagonist MK-801 (dizocilpine). Thirty-two rats were placed into four groups; a control and three CLTIHH groups where rats were placed into a low-pressure chamber set to 430 mmHg for 5 h/day, 5 days/week, for 5 weeks. Only one group received MK-801 (0.3 mg/kg, ip) daily. We evaluated tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and nuclear factor (NF)-kB for the inflammatory process, superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPX), total antioxidant status (TAS), and total oxidant status (TOS) for oxidative stress, and caspase-9 levels. Blood plasma, bronchoalveolar fluid (BALF), and lung tissue extracts were evaluated. Both oxidant and inflammatory parameters were significantly increased in all the mediums of the CLTIHH groups except the group that received MK-801. Significant evidence was collected on MK-801 alleviating the effect of CLTIHH. Histological evaluations revealed lung damage and fibrotic changes in the CLTIHH groups. It was first shown that the CLTIHH procedure caused chronic lung injury, and that inflammation and oxidant stress were influential in the formation of lung injury. Secondly, NMDAR antagonist MK-801 effectively inhibited the development of lung injury and fibrosis.

Biomechanical and structural responses of the aorta to intermittent hypobaric hypoxia in a rat model

High altitude hypoxia is a condition experienced by diverse populations worldwide. In addition, several jobs require working shifts where workers are exposed to repetitive cycles of hypobaric hypoxia and normobaric normoxia. Currently, few is known about the biomechanical cardiovascular responses of this condition. In the present study, we investigate the cycle-dependent biomechanical effects of intermittent hypobaric hypoxia (IHH) on the thoracic aorta artery, in terms of both structure and function. To determine the vascular effects of IHH, functional, mechanical and histological approaches were carried out in the thoracic aorta artery, using uniaxial, pre-stretch, ring opening, myography, and histological tests. Three groups of rats were established: control (normobaric normoxia, NN), 4-cycles of intermittent hypoxia (short-term intermittent hypobaric hypoxia, STH), and 10-cycles of intermittent hypoxia (long-term intermittent hypobaric hypoxia, LTH). The pre-stretch and ring opening tests, aimed at quantifying residual strains of the tissues in longitudinal and circumferential directions, showed that the hypoxia condition leads to an increase in the longitudinal stretch and a marked decrease of the circumferential residual strain. The uniaxial mechanical tests were used to determine the elastic properties of the tissues, showing that a general stiffening process occurs during the early stages of the IH (STH group), specially leading to a significative increase in the high strain elastic modulus (E_{2}) and an increasing trend of low strain elastic modulus (E_{1}). In contrast, the LTH group showed a more control-like mechanical behavior. Myography test, used to assess the vasoactive function, revealed that IH induces a high sensitivity to vasoconstrictor agents as a function of hypoxic cycles. In addition, the aorta showed an increased muscle-dependent vasorelaxation on the LTH group. Histological tests, used to quantify the elastic fiber, nuclei, and geometrical properties, showed that the STH group presents a state of vascular fibrosis, with a significant increase in elastin content, and a tendency towards an increase in collagen fibers. In addition, advanced stages of IH (LTH), showed a vascular remodeling effect with a significant increase of internal and external diameters. Considering all the multidimensional vascular effects, we propose the existence of a long-term passive adaptation mechanism and vascular dysfunction as cycle-dependent effects of intermittent exposures to hypobaric hypoxia.

Short-Term versus Long Term intermittent hypobaric hypoxia on cardiac fibrosis and cardioprotective effects of Natural antioxidants supplementation in rats hearts

Controversial effects of intermittent hypobaric hypoxia (IHH) such as cardiac damage or cardiac protection are still mysterious. It is unclear if short-term and long-term IHH challenges exert different changes of the pro-oxidant/antioxidant balance in the heart and throughout the body. It has been shown that natural antioxidants supplementation (Quercetin, Lycium barbarum and Chitosan) is effective in preventing the hypoxic stress. The aim of this study was to evaluate the protective effect of these natural antioxidants' administration in heart in animals exposed to IHH and therefore exposed to oxidative stress. One hundred male Wistar rats were randomized assigned into ten groups was exposed to short-term and long-term IHH (380 mmHg, 12% O2, 8h/day) for different periods of time (2 days or 4 weeks) or kept in normoxia for 4 weeks. Some of the rats were administered natural antioxidants cu 30 minute before each IHH exposure of IHH. After short-term IHH or long-term IHH challenge, myocardial morphology was determined by histological analysis. Myocardial sections were examined histopathologically to determine the cardiomyocyte viability and morphometry. The results show a negative effect of IHH on the cardiomyocyte viability and cardio-protective effects of natural antioxidants' administration. This study suggests that treatment with Quercetin, Lycium barbarum or Chitosan alone substantially restored the myocardial architecture and acted like cardioprotectants.

The Effect of Chronic Long-Term Intermittent Hypobaric Hypoxia on Bone Mineral Density in Rats: Role of Nitric Oxide

Intermittent hypoxia is the most common pattern of hypoxic exposure in humans. The effect of chronic long-term intermittent hypobaric hypoxia (CLTIHH) on bone metabolism is not investigated. We examined the effect of CLTIHH on bone metabolism and the role of nitric oxide (NO) in this process. The rats were divided into three groups in this study. The animals in groups I and II have been exposed to CLTIHH. The animals in group II were also treated with nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester. To obtain CLTIHH, rats were placed in a hypobaric chamber (430 mm Hg; 5 h/day, 5 days/week, 5 weeks). The group III (control) rats breathed room air in the same environment. At the begining of the experiments, bone mineral density (BMD) of the animals were measured, and blood samples were collected from the tail vein. After the 5-week CLTIHH period, the same measurements were repeated. Parathyroid hormone, calcium, phosphate, bone alkaline phosphatase (b-ALP), NO, interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha levels were determined. The cytokines, NO levels, and BMD in CLTIHH-induced rats were higher compared with baseline and control values. The cytokines, b-ALP, and BMD increased while NO levels decreased in the group II compared with baseline values. BMD values of group II were lower than group I but higher than control group. Our results suggested that CLTIHH has positive effects on bone density. Intermittent hypoxia protocols may be developed for treatment and prevention of osteopenia and osteoporosis.

The effects of chronic long-term intermittent hypobaric hypoxia on blood rheology parameters

The effect of chronic long-term intermittent hypobaric hypoxia (CLTIHH) on blood rheology is not completely investigated. We designed this study to determine the effect of CLTIHH on blood rheology parameters. Present study was performed in 16 male Spraque-Dawley rats that divided into CLTIHH and Control groups. To obtain CLTIHH, rats were placed in a hypobaric chamber (430 mmHg; 5 hours/day, 5 days/week, 5 weeks). The control rats stayed in the same environment as the CLTIHH rats but they breathed room air. In the blood samples aspirated from the heart, hematocrit, whole blood viscosity, plasma viscosity, plasma fibrinogen concentration, erythrocyte rigidity index and oxygen delivery index were determined. The whole blood viscosity, plasma viscosity, hematocrit and fibrinogen concentration values in the CLTIHH group were found to be higher than those of the control group. However, no significant difference was found in erythrocyte rigidity index and oxygen delivery index between the groups. Our results suggested that CLTIHH elevated whole blood viscosity by increasing plasma viscosity, fibrinogen concentration and hematocrit value without effecting the erythrocyte deformability. Hence, CLTIHH that may occur in intermittent high altitude exposure and some severe obstructive sleep apnea (OSA) patients may be responsible for hemorheologic changes in those subjects.

Respiratory Alterations Due to Chronic Long-Term Intermittent Hypobaric Hypoxia in Rabbits: Importance of Peripheral Chemoreceptors

None of the studies carried out so far investigated the effect of denervation of peripheral chemoreceptors on basal ventilation and respiratory responses to acute hypoxia in subjects exposed to chronic long-term intermittent hypobaric hypoxia (CLTIHH). We aimed to research (i) the effect of CLTIHH (430 mmHg, 5 h/day, 5 days/week, 5 weeks) on basal ventilation and respiratory responses to hypoxia and (ii) the effects of CLTIHH on central respiratory mechanisms after peripheral chemodenervation. Sixteen adult albino rabbits were divided into two groups: CLTIHH (n = 8) and control (n = 8). The tidal volume (V(T)) and respiratory frequency (f/min) were initially recorded in both groups and respiratory minute volume (V(E)) was calculated. PaO(2), PaCO(2), and pHa values were determined. The initial values of f/min and V(E) in CLTIHH group were significantly higher than that of control group. After exposure to hypoxic gas mixture (8% O(2)-92% N(2)), the elevations in f/min, V(T), and V(E) in CLTIHH group were significantly higher than those of control group. After denervation of peripheral chemoreceptors, the decrease in V(E) in CLTIHH group was found to be significantly less than that of control group. When the animals in control group were allowed to breathe hypoxic gas mixture, f/min, V(T,) and V(E) decreased significantly and hypoxic depression was obtained. In contrast, hypoxic depression did not occur in the CLTIHH group. Our results suggested that CLTIHH increases the basal ventilation and hypoxic respiratory responses and that enhanced ventilatory responses were due not only to the augmentation of peripheral chemoreceptor activity but also to the augmentation of central respiratory activity.

Effects of short- and long-term hypobaric hypoxia on Bcl2 family in rat heart

Background Controversial effects of intermittent hypobaric hypoxia such as cardiac damage or cardiac protection are still mysterious. It is unclear if short-term and long-term intermittent hypobaric hypoxic challenges exert different effects on cytochrome c oxidase and Bcl-2 family in rat heart. Methods Sixty Sprague–Dawley rats were randomized assigned into two groups: first, short-term intermittent hypobaric hypoxia (STIHH)-normobaric normoxia ( n = 10), hypobaric hypoxia (380 mmHg, 12% O 2, 8 hr/day) for 1 day ( n = 10), and for 4 days ( n = 10) and second, long-term intermittent hypobaric hypoxia (LTIHH)-normobaric normoxia ( n = 10), hypobaric hypoxia for 1 week ( n = 10) and 2 weeks ( n = 10). After STIHH or LTIHH challenge, myocardial morphology, cytochrome c oxidase and pro-apoptotic Bcl-2 family in the excised left ventricle were determined by histological analysis, Western blotting, and RT-PCR. Results Increased wall thickness and abnormal myocardial architecture were observed after LTIHH. Cytochrome c oxidase and anti-apoptotic Bcl-2 protein were significantly increased after STIHH, but were decreased after LTIHH. Pro-apoptotic BNIP3 and Bad proteins were significantly decreased after STIHH but increased after LTIHH. Conclusions STIHH appeared to exert protective effects on hearts whereas LTIHH appeared to exert deleterious effects, which imply that deleterious or advantageous effect of cardiac adaptation after intermittent hypobaric hypoxia is tightly time–course dependent.