Chronic Hypobaric Hypoxia Research Articles

Chronic Intermittent Hypobaric Hypoxia Restores Hippocampus Function and Rescues Cognitive Impairments in Chronic Epileptic Rats via Wnt/β-catenin Signaling.

Epilepsy is a complex neurological disorder with frequent psychiatric, cognitive, and social comorbidities in addition to recurrent seizures. Cognitive impairment, one of the most common comorbidities, has severe adverse effects on quality of life. Chronic intermittent hypobaric hypoxia (CIHH) has demonstrated neuroprotective efficacy in several neurological disease models. In the present study, we examined the effects of CIHH on cognition and hippocampal function in chronic epileptic rats. CIHH treatment rescued deficits in spatial and object memory, hippocampal neurogenesis, and synaptic plasticity in pilocarpine-treated epileptic rats. The Wnt/β-catenin pathway has been implicated in neural stem cell proliferation and synapse development, and Wnt/β-catenin pathway inhibition effectively blocked the neurogenic effects of CIHH. Our findings indicate that CIHH rescues cognitive deficits in epileptic rats via Wnt/β-catenin pathway activation. This study establishes CIHH and Wnt/β-catenin pathway regulators as potential treatments for epilepsy- induced cognitive impairments.

NMDA Receptor-Mediated Excitotoxicity Is Involved in Neuronal Apoptosis and Cognitive Impairment Induced by Chronic Hypobaric Hypoxia Exposure at High Altitude.

Ji, Weizhong, Yaqing Zhang, Ri-li Ge, Yaqi Wan, and Jie Liu. NMDA receptor-mediated excitotoxicity is involved in neuronal apoptosis and cognitive impairment induced by chronic hypobaric hypoxia exposure at high altitude. High Alt Med Biol. 22:45-57, 2021. Aim: Exposure to chronic hypobaric hypoxia at high altitude can lead to cognitive impairment; however, its underlying mechanism is still unclear. Excessive expression of glutamate and its receptors can induce excitotoxicity and cause neuronal necrosis, which is an important causative factor for the occurrence of various diseases in the nervous system. Therefore, excitotoxicity may also occur after exposure to a chronic hypobaric hypoxic environment. This study concentrates on the action mechanism of glutamate and its receptor-mediated excitotoxicity in cognitive impairment, induced by chronic hypobaric hypoxic exposure. Methods: Sprague-Dawley rats were fed at regions with three different altitudes (4,300, 2,260, and 450 m) for 8 weeks, and had their behavioral changes assessed by the Morris water maze test. Morphological, molecular biological, and biochemical tests were used to determine the role of N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity in neuronal injury and cognitive impairment induced by chronic hypobaric hypoxia exposure. Results: We found that exposure to chronic hypobaric hypoxia at high altitudes could cause cognitive impairment, damage the neurons in the hippocampus and cortex, increase apoptosis, and lead to abnormal Caspase-3 protein expression. The expression of NMDA and a-amino-3-hydroxyl-5-methyl-4-isoxazole acid (AMPA) receptors increased significantly, as did the levels of oxidative stress and free radicals as well. However, no change in cognitive function was observed in the chronic hypobaric hypoxia environment at the middle altitude, there were no statistically significant differences in neuronal apoptosis and related protein expression compared with the rats in the flatland environment group. Conclusion: We show that high-altitude chronic hypobaric hypoxic environment could cause obvious cognitive impairments, which is related to the excitotoxicity mediated by glutamate and its receptors, in contrast to the chronic hypobaric hypoxia environment at middle altitude group and flatland environment group.

Nox2 Upregulation and p38α MAPK Activation in Right Ventricular Hypertrophy of Rats Exposed to Long-Term Chronic Intermittent Hypobaric Hypoxia.

One of the consequences of high altitude (hypobaric hypoxia) exposure is the development of right ventricular hypertrophy (RVH). One particular type of exposure is long-term chronic intermittent hypobaric hypoxia (CIH); the molecular alterations in RVH in this particular condition are less known. Studies show an important role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex-induced oxidative stress and protein kinase activation in different models of cardiac hypertrophy. The aim was to determine the oxidative level, NADPH oxidase expression and MAPK activation in rats with RVH induced by CIH. Male Wistar rats were randomly subjected to CIH (2 days hypoxia/2 days normoxia; n = 10) and normoxia (NX; n = 10) for 30 days. Hypoxia was simulated with a hypobaric chamber. Measurements in the RV included the following: hypertrophy, Nox2, Nox4, p22phox, LOX-1 and HIF-1α expression, lipid peroxidation and H2O2 concentration, and p38α and Akt activation. All CIH rats developed RVH and showed an upregulation of LOX-1, Nox2 and p22phox and an increase in lipid peroxidation, HIF-1α stabilization and p38α activation. Rats with long-term CIH-induced RVH clearly showed Nox2, p22phox and LOX-1 upregulation and increased lipid peroxidation, HIF-1α stabilization and p38α activation. Therefore, these molecules may be considered new targets in CIH-induced RVH.

Chronic intermittent hypobaric hypoxia improves markers of iron metabolism in a model of dietary-induced obesity

BackgroundObesity, a risk factor for many chronic diseases, is a potential independent risk factor for iron deficiency. Evidence has shown that chronic intermittent hypobaric hypoxia (CIHH) has protective or improved effects on cardiovascular, nervous, metabolic and immune systems. We hypothesized that CIHH may ameliorate the abnormal iron metabolism in obesity. This study was aimed to investigate the effect and the underlying mechanisms of CIHH on iron metabolism in high-fat-high-fructose-induced obese rats.MethodsSix to seven weeks old male Sprague-Dawley rats were fed with different diet for 16 weeks, and according to body weight divided into four groups: control (CON), CIHH (28-day, 6-h daily hypobaric hypoxia treatment simulating an altitude of 5000 m), dietary-induced obesity (DIO; induced by high fat diet and 10% fructose water feeding), and DIO + CIHH groups. The body weight, systolic arterial pressure (SAP), Lee index, fat coefficient, blood lipids, blood routine, iron metabolism parameters, interleukin6 (IL-6) and erythropoietin (Epo) were measured. The morphological changes of the liver, kidney and spleen were examined. Additionally, hepcidin mRNA expression in liver was analyzed.ResultsThe DIO rats displayed obesity, increased SAP, lipids metabolism disorders, damaged morphology of liver, kidney and spleen, disturbed iron metabolism, increased IL-6 level and hepcidin mRNA expression, and decreased Epo compared to CON rats. But all the aforementioned abnormalities in DIO rats were improved in DIO + CIHH rats.ConclusionsCIHH improves iron metabolism disorder in obese rats possibly through the down-regulation of hepcidin by decreasing IL-6 and increasing Epo.

Global REACH 2018: The carotid artery diameter response to the cold pressor test is governed by arterial blood pressure during normoxic but not hypoxic conditions in healthy lowlanders and Andean highlanders.

What is the central question of this study? What is the impact of oxygen on the circulatory responses to an isocapnic cold pressor test (CPT) in lowlanders and Andean highlanders? What is the main finding and its importance? Overall, the circulatory responses to an isocapnic CPT were largely unaltered with acute normobaric hypoxia and chronic hypobaric hypoxia exposure in lowlanders. However, the relationship between mean arterial pressure and common carotid artery diameter was dampened in hypoxic conditions. Furthermore, there were no differences in the circulatory responses to the CPT between lowlanders and Andean highlanders with lifelong exposure to high altitude. The impact of oxygen on the circulatory responses to a cold pressor test (CPT) in lowlanders and Andean highlanders remains unknown. Our hypotheses were as follows: (i) in lowlanders, acute normobaric and hypobaric hypoxia would attenuate the common carotid artery (CCA) diameter response to the CPT compared with normobaric normoxia; (ii) Andean highlanders would exhibit a greater CCA diameter response compared with lowlanders; and (iii) a positive relationship between CCA diameter and blood pressure in response to the CPT would be present in both lowlanders and highlanders. Healthy lowlanders (n=13) and Andean highlanders (n=8) were recruited and conducted an isocapnic CPT, which consisted of a 3min foot immersion into water at 0-1°C. Blood pressure (finger photoplethysmography) and CCA diameter and blood flow (Duplex ultrasound) were recorded continuously. The CPT was conducted in lowlanders at sea level in isocapnic normoxic and hypoxic conditions and after 10 days of acclimatization to 4300m (Cerro de Pasco, Peru) in hypoxic and hyperoxic conditions. Andean highlanders were tested at rest at high altitude. The main findings were as follows: (i) in lowlanders, normobaric but not hypobaric hypoxia elevated CCA reactivity to the CPT; (ii) no differences in response to the CPT were observed between lowlanders and highlanders; and (iii) although hypobaric hypoxaemia reduced the relationship between CCA diameter and blood pressure compared with normobaric normoxia (P=0.132), hypobaric hyperoxia improved this relationship (P=0.012), and no relationship was observed in Andean highlanders (P=0.261). These data demonstrate that the circulatory responses to a CPT were modified by oxygen in lowlanders, but were unaltered with lifelong hypoxic exposure.

Redox modification of ryanodine receptor contributes to impaired Ca2+ homeostasis and exacerbates muscle atrophy under high altitude

At extreme altitude, prolonged and severe hypoxia menaces human function and survival, and also associated with profound loss of muscle mass which results into a debilitating critical illness of skeletal muscle atrophy. Hypobaric hypoxia altered redox homeostasis and impaired calcium ion handling in skeletal muscles. Dysregulated Ca2+ homeostasis and activated calpain is the prime stressor in high altitude hypoxia while the reason for subsequent abnormal release of pathological Ca2+ into cytoplasm is largely unexplored. The present study identified the redox remodeling in the Ca2+ release channel, Ryanodine Receptor (RyR1) owing to its hypernitrosylation state in skeletal muscles in chronic hypobaric hypoxia exposed rats. RyR1-hypernitrosylation decreases the binding of FKBP12/calstabin-1 and other complexes from the channel, causing “leakiness” in RyR1 ion-channel. A strong RyR1 stabilizer, S107 enhanced binding affinity of FKBP12 with hypernitrosylated RyR1, reduced Sarco(endo)plasmic reticulum (SR) Ca2+ leak and improved muscle strength and function under chronic hypoxia. Administration of S107 inhibited the skeletal muscle damage, maintained ultrastructure of sarcomere and sarcolemmal integrity. Histological analysis proved the increase in cross-sectional area of myofibers. Further, the number of apoptotic cells was also reduced by S107 treatment. Conclusively, we proposed that the redox remodeling of RyR1 (hypernitrosylated-RyR1) might be responsible for dysregulated Ca2+ homeostasis which consequently impaired muscle strength and function in response to chronic hypoxic stress. Reduced SR Ca2+ leak and enhanced binding affinity of FKBP12 may provide a novel therapeutic avenue in ameliorating skeletal muscle atrophy at high altitude.

Oxidative Stress, Kinase Activity and Inflammatory Implications in Right Ventricular Hypertrophy and Heart Failure under Hypobaric Hypoxia.

High altitude (hypobaric hypoxia) triggers several mechanisms to compensate for the decrease in oxygen bioavailability. One of them is pulmonary artery vasoconstriction and its subsequent pulmonary arterial remodeling. These changes can lead to pulmonary hypertension and the development of right ventricular hypertrophy (RVH), right heart failure (RHF) and, ultimately to death. The aim of this review is to describe the most recent molecular pathways involved in the above conditions under this type of hypobaric hypoxia, including oxidative stress, inflammation, protein kinases activation and fibrosis, and the current therapeutic approaches for these conditions. This review also includes the current knowledge of long-term chronic intermittent hypobaric hypoxia. Furthermore, this review highlights the signaling pathways related to oxidative stress (Nox-derived O2.- and H2O2), protein kinase (ERK5, p38α and PKCα) activation, inflammatory molecules (IL-1β, IL-6, TNF-α and NF-kB) and hypoxia condition (HIF-1α). On the other hand, recent therapeutic approaches have focused on abolishing hypoxia-induced RVH and RHF via attenuation of oxidative stress and inflammatory (IL-1β, MCP-1, SDF-1 and CXCR-4) pathways through phytotherapy and pharmacological trials. Nevertheless, further studies are necessary.

Effects of melatonin on the passive mechanical response of arteries in chronic hypoxic newborn lambs

Chronic hypoxia is a condition that increases the cardiovascular complications of newborns gestated and born at high altitude (HA), over 2500 m above sea level (masl). A particularly complex pathology is pulmonary arterial hypertension of the neonate (PHN), which is increased at HA due to hypobaric hypoxia. Basic and clinical research have recognized that new treatments are needed, because current ones are, in general, palliative and with low effectiveness. Therefore, recently we have proposed melatonin as a potential adjuvant treatment to improve cardiopulmonary function. However, melatonin effects on the mechanical response of the arteries and their microstructure are not known. This study assesses the effects of a neonatal treatment with daily low doses of melatonin on the passive biomechanical behavior of the aorta artery and main pulmonary artery of PHN lambs born in chronic hypobaric hypoxia (at 3600 masl). With this purpose, ex-vivo measurements were made on axial stretch, tensile and opening ring tests together with a histological analysis to explore the morphometry and microstructure of the arteries. Our results show that the passive mechanical properties of the aorta artery and main pulmonary artery of lambs do not seem to be affected by a treatment based on low melatonin doses. However, we found evidence that melatonin has microstructural effects, particularly, diminishing cell proliferation, which is an indicator of antiremodeling capacity. Therefore, the use of melatonin as an adjuvant against pathologies like PHN would present antiproliferative effect at the microstructural level, keeping the macroscopic properties of the aorta artery and main pulmonary artery.

Cross-Species Insights Into Genomic Adaptations to Hypoxia.

Over millions of years, vertebrate species populated vast environments spanning the globe. Among the most challenging habitats encountered were those with limited availability of oxygen, yet many animal and human populations inhabit and perform life cycle functions and/or daily activities in varying degrees of hypoxia today. Of particular interest are species that inhabit high-altitude niches, which experience chronic hypobaric hypoxia throughout their lives. Physiological and molecular aspects of adaptation to hypoxia have long been the focus of high-altitude populations and, within the past decade, genomic information has become increasingly accessible. These data provide an opportunity to search for common genetic signatures of selection across uniquely informative populations and thereby augment our understanding of the mechanisms underlying adaptations to hypoxia. In this review, we synthesize the available genomic findings across hypoxia-tolerant species to provide a comprehensive view of putatively hypoxia-adaptive genes and pathways. In many cases, adaptive signatures across species converge on the same genetic pathways or on genes themselves [i.e., the hypoxia inducible factor (HIF) pathway). However, specific variants thought to underlie function are distinct between species and populations, and, in most cases, the precise functional role of these genomic differences remains unknown. Efforts to standardize these findings and explore relationships between genotype and phenotype will provide important clues into the evolutionary and mechanistic bases of physiological adaptations to environmental hypoxia.

Interplay between rotational work shift and high altitude-related chronic intermittent hypobaric hypoxia on cardiovascular health and sleep quality in Chilean miners

Mining activities expose workers to diverse working conditions, rotational shifts and high altitude-related hypobaric hypoxia. Separately, each condition has been reported having a negative impact on miners’ health risk; however, the combination of both stressors has been poorly explored. The present study aimed to analyse the effects of exposure to rotational work shift (RWS) alone or in combination with high altitude-related chronic intermittent hypobaric hypoxia (CIHH) on cardiometabolic, physical activity and sleep quality related markers in copper miners from Los Pelambres mine in Chile. One hundred and eleven male miners working in RWS with or without CIHH were included. Anthropometrics measures, sleep quality assessment, physical activity level (PAL) and handgrip strength were evaluated. Exposure to CIHH exacerbated the detrimental effects of RWS as miners exposed to the combination of RWS and CIHH where more obese and had a wider neck circumference, reduced PAL at work and worsened sleep quality. Practitioner summary: The purpose was to assess cardiometabolic health and sleep quality markers associated with the combined effects of rotational shift work and high altitude-related intermittent hypobaric hypoxia in miners. Findings showed a wider neck circumference, lower physical activity level and higher prevalence of poor sleep quality in exposed miners. Abbreviations: ANOVA: analysis of variance; BM: body mass; BMI: body mass index; CI: confidence intervals; CIHH: chronic intermittent hypobaric hypoxia; CV: cardiovascular; CVR: cardiovascular risk; HA: high altitude; HACE: high-altitude cerebral edema; HGS: handgrip strength; IPAQ-SF: International Physical Activity Questionnaire - Short Form; LSD: Fisher's least standardized difference; MANCOVA: multivariate general lineal model; MET: metabolic equivalent; PAL: physical activity level; PSQI: Pittsburg sleep quality index; RWS: rotational work shift; WHR: waist-to-hip ratio

Muscle sympathetic nerve activity in altitude acclimatized lowlanders during leg cycling exercise

Acute normobaric hypoxia augments muscle sympathetic nerve activity (MSNA) during dynamic cycling exercise; however, the effects of chronic hypobaric hypoxia exposure on this response remain unknown. The purpose of the present study was to determine MSNA reactivity to moderate intensity cycling exercise in lowlanders at sea‐level (344m; Kelowna, BC, Canada) and after 14–21 days of high‐altitude acclimatization (~4300m; Cerro de Pasco, Peru). MSNA (radial microneurography), mean arterial pressure (brachial artery catheter), and heart rate (electrocardiogram) were measured at rest and during cycling exercise (60% of peak workload) in six healthy male participants. Chronic exposure to hypobaric hypoxia increased resting MSNA burst frequency from 14.0 ± 3.2 burst/min at sea‐level, to 38.2 ± 4.5 burst/min (P<0.001). The increase in MSNA during semi recumbent cycling exercise during chronic hypobaric hypoxia exposure was significantly lower compared to sea‐level (Δ MSNA: sea‐level: 106 ± 46% vs. high‐altitude: 43 ± 15% vs; P<0.001). To our knowledge, this is the first investigation to compare MSNA between normobaric normoxia and chronic hypobaric hypoxia during leg cycling exercise. These data indicate that chronic hypobaric hypoxic exposure blunts the relative increase in MSNA during moderate‐intensity dynamic cycling exercise, potentially due to a sympathetic “ceiling” being reached.Support or Funding InformationWilderness Medical Society research in‐training grant (GM)

Cysteine becomes conditionally essential during hypobaric hypoxia and regulates adaptive neuro-physiological responses through CBS/H2S pathway

Brain is well known for its disproportionate oxygen consumption and high energy-budget for optimal functioning. The decrease in oxygen supply to brain, thus, necessitates rapid activation of adaptive pathways – the absence of which manifest into vivid pathological conditions. Amongst these, oxygen sensing in glio-vascular milieu and H2S-dependent compensatory increase in cerebral blood flow (CBF) is a major adaptive response. We had recently demonstrated that the levels of H2S were significantly decreased during chronic hypobaric hypoxia (HH)-induced neuro-pathological effects. The mechanistic basis of this phenomenon, however, remained to be deciphered. We, here, describe experimental evidence for marked limitation of cysteine during HH – both in animal model as well as human volunteers ascending to high altitude. We show that the preservation of brain cysteine level, employing cysteine pro-drug (N-acetyl-L-cysteine, NAC), markedly curtailed effects of HH – not only on endogenous H2S levels but also, impairment of spatial reference memory in our animal model. We, further, present multiple lines of experimental evidence that the limitation of cysteine was causally governed by physiological propensity of brain to utilize cysteine, in cystathionine beta synthase (CBS)-dependent manner, past its endogenous replenishment potential. Notably, decrease in the levels of brain cysteine manifested despite positive effect (up-regulation) of HH on endogenous cysteine maintenance pathways and thus, qualifying cysteine as a conditionally essential nutrient (CEN) during HH. In brief, our data supports an adaptive, physiological role of CBS-mediated cysteine-utilization pathway – activated to increase endogenous levels of H2S – for optimal responses of brain to hypobaric hypoxia.

Alterations of estrous cycle, 3\u03b2 hydroxysteroid dehydrogenase activity and progesterone synthesis in female rats after exposure to hypobaric hypoxia

The underlying mechanism regulating hypoxia induced alteration in female steroid hormones is first time explored in this study. To understand the mechanistic approach, female Sprague- Dawley rats were exposed to acute and chronic hypobaric hypoxia (282 mm-Hg, ~7620 m, 6 hours, 3 and 7 days). Estrous cycle, body weight, plasma progesterone and estradiol levels, morphology, histology and two key steroidogenic enzymes: 3ß hydroxysteroid dehydrogenase (HSD) and 17ß HSD activity of ovary and adrenal gland were studied. A persistent diestrous phase and a significant decrease in body weight were found in chronic hypoxia groups. Histological study suggested degenerative changes in ovarian corpus luteum of 7 days chronic hypobaric hypoxia (7CHH) group and a declined percentage of adrenocortical cells in 3 days chronic hypobaric hypoxia (3CHH) and 7CHH groups. Plasma estradiol level was unaltered, but progesterone level was decreased significantly in all hypoxic groups. Ovarian 3ß HSD activity was decreased significantly with increasing days of hypoxic treatment along with a significantly low adrenal 3ß HSD activity in 7CHH. In conclusion, hypobaric hypoxia causes a state of low circulatory progesterone level in females likely due to the degenerative changes in the female ovarian and adrenal tissues together with low steroidogenic 3ß HSD enzyme activity.

The Role of Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor in Chronic Fetal Oxygen Deprivation.

The aim of the study was to define the role of brain-derived and glial cell line-derived neurotrophic factors (BDNF and GDNF) in realization of compensative and adaptive mechanisms of a neonatal organism to hypoxia.Materials and MethodsThe experiments in vivo have been carried out on pregnant C57BL/6 mice (n=36). Chronic hypobaric hypoxia has been modeled in different pregnancy trimesters. On gestation days E19–20, concentration of BDNF and GDNF in the blood of the pregnant females was determined by enzyme immunoassay. Further, the number of neonatal mice, their weight and body length parameters have been assessed.Parturient mothers (n=88) and their newborn babies followed up at the Clinic of Obstetrics and Gynecology of Pavlov University took part in the clinical investigations. Concentration of BDNF, GDNF, neuron-specific enolase (NSE), and hypoxia-inducible factor (HIF-1β) in the fetal cord blood has been determined by ELISA. The obtained data were retrospectively compared with cardiotocography, dopplerometry, presence of meconium-stained amniotic fluid and the neonate state at birth, assessment according to the Apgar score, and the course of adaptation period.ResultsChronic hypobaric hypoxia in pregnant mice in trimester I and II resulted in the significant decrease of BDNF and GDNF level, decrease in the number of embryos, and in significant changes in weight/height characteristics of the newborn pups.According to the clinical observations, an increased expression of the neurotrophic factors BDNF, GDNF provides protection to a neonate even if hypoxia factors are present and realized. A low content of BDNF and GDNF was observed in the group of infants with a high risk of developing unfavorable hypoxic damaging effects.ConclusionThe protective role of BDNF and GDNF in the regulation of fetal homeostasis in chronic hypoxia has been established experimentally and clinically.

The Effect of Autophagy on Chronic Intermittent Hypobaric Hypoxia Ameliorating Liver Damage in Metabolic Syndrome Rats

AimOur previous study demonstrated that chronic intermittent hypobaric hypoxia (CIHH) can confer hepatic protection by reducing endoplasmic reticulum stress (ERS) in high-fat-high-fructose induced metabolic syndrome (MS) rats. It is known that there is a functional coupling between autophagy and ERS. This study aimed to investigate the effect of CIHH on autophagy function and adenosine mono-phosphate-activated protein kinase-mammalian target of rapamycin (AMPKα-mTOR) signaling pathway in hepatic tissue of MS rats.Main Methods6-week old male Sprague-Dawley rats were randomly divided into: control (CON), CIHH (treated with hypobaric hypoxia simulating 5000-m altitude for 28 days, 6 h daily), MS (induced by 16-week high fat diet and 10% fructose water feeding), and MS + CIHH groups (exposed to CIHH after 16-week MS model). Food and water intakes, body weight, Lee’s index, fat coefficient, systolic arterial pressure, blood biochemicals, and histopathology of liver were measured, the expression of phosphorylated (p)-AMPK, p-mTOR, autophagy-related and ERS-related proteins were assayed in hepatic tissue.Key FindingsThe MS rats displayed obesity, hypertension, polydipsia, glucose and lipids metabolism disorders, increased inflammatory cytokine, hepatic tissue morphological and functional damage, and the up-regulated expressions of ERS-related, autophagy-related proteins and p-mTOR, and the down-regulated expression of p-AMPKα. All aforementioned abnormalities in MS rats were ameliorated in MS + CIHH rats.SignificanceIn conclusion CIHH confers hepatic protection through activating AMPK-mTOR signaling pathway and the autophagy function, thus inhibiting ERS in hepatic tissue.

P6480Asymmetric dimethylarginine (ADMA) predicts altitude-associated hypoxic pulmonary arterial hypertension

Abstract Prolonged exposure to altitude-associated chronic hypoxia (CH) may cause high altitude pulmonary hypertension (HAPH). Chronic intermittent hypobaric hypoxia (CIH) occurs in individuals who commute between sea level and high altitude. CIH is associated with repetitive acute hypoxic acclimatization and conveys the long-term risk of HAPH. As nitric oxide (NO) is an important regulator of systemic and pulmonary vascular tone and asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis that increases in hypoxia, we aimed to investigate whether ADMA predicts the incidence of HAPH among Chilean frontiers personnel exposed to six months of CIH. We performed a prospective study of 123 healthy male subjects who were subjected to CIH (5 days at appr. 3,550 m, followed by 2 days at sea level) for six months. ADMA, SDMA, L-arginine, arterial oxygen saturation, systemic arterial blood pressure, and haematocrit were measured at baseline and at months 1, 4, and 6 at high altitude. Acclimatization to high altitude was determined using the Lake Louise Score and the presence of acute mountain sickness (AMS). Echocardiography was performed after six months of CIH in a subgroup of 43 individuals with either good (n=23) or poor (n=20) aclimatization to altitude, respectively. Logistic regression was used to assess the association of biomarkers with HAPH. 100 study participants aged 18.3±1.3 years with complete data sets were included in the final analysis. Arterial oxygen saturation decreased upon the first ascent to altitude and plateaued at about 90% during the further course of the study. Haematocrit increased to about 47% after one month and remained stable thereafter. ADMA continuously increased and SDMA decreased during the study course, whilst L-arginine levels showed no distinct pattern. The incidence of AMS and the Lake Louise Score were high after the first ascent (53 and 3.1±2.4, respectively) and at one month of CIH (47 and 3.0±2.6, respectively), but decreased to 20 and 1.4±2.0 at month 6, respectively (both p<0.001 for trend). In echocardiography, 18 participants (42%) showed a mean pulmonary arterial pressure (mPAP) greater than 25 mm Hg (mean ± SD, 30.4±3.9 mm Hg), out of which 9 (21%) were classified as HAPH (mPAP ≥30 mm Hg; mean ± SD, 33.9±2.2 mm Hg). Baseline ADMA, but not SDMA, was significantly associated with mPAP at month 6 in univariate logistic regression analysis (R = 0.413; p=0.007). In ROC analysis, a cut-off for baseline ADMA of 0.665 μmol/l was determined as the optimal cut-off level to predict HAPH (mPAP >30 mm Hg) with a sensitivity of 100% and a specificity of 63.6%. ADMA concentration increases during long-term CIH. It is an independent predictive biomarker for the incidence of HAPH. SDMA concentration decreases during CIH and shows no association with HAPH. Our data support a role of impaired NO-mediated pulmonary vasodilation in the pathogenesis of high altitude pulmonary hypertension. Acknowledgement/Funding CONICYT/FONDEF/FONIS Sa 09I20007; FIC Tarapaca BIP 30477541-0; BMBF grant 01DN17046 (DECIPHER); Georg & Jürgen Rickertsen Foundation, Hamburg

Effect of chronic intermittent hypobaric hypoxia on heart rate variability in conscious rats

To examine the effect of chronic intermittent hypobaric hypoxia (CIHH) on heart rate variability (HRV), male adult Sprague Dawley rats were exposed to hypoxia (oxygen 11.1%) in a hypobaric chamber for 42days, 6hours each day, simulating an altitude of 5000m. The body weight and blood pressure of rats were recorded once a week, electrocardiograms were analyzed continuously using biotelemetry, before, during and after CIHH treatment each day, and HRV was evaluated using spectrum analysis. No significant difference of body weight and blood pressure was found between CIHH and control rats. After 4weeks of CIHH treatment, total power (TP) and very low-frequency component (VLF) were lower in CIHH rats than in control rats under hypobaric hypoxia condition. During CIHH treatment, low frequency (LF) was higher in 1 week and lower in 5-6weeks in CIHH rats than control rats under hypobaric hypoxia, but not normoxic conditions. The high-frequency component (HF) was not changed during CIHH treatment, so LF/HF increased initially, and then recovered under the hypobaric hypoxia condition following 3weeks of CIHH treatment. In addition, the HR was increased in CIHH rats after 4weeks of CIHH treatment compared with control rats. Furthermore, HRV was altered significantly in control rats, but not in CIHH rats exposed to acute normobaric hypoxia. These data suggest that CIHH treatment modulates cardiac autonomic activity adaptively and inhibits the acute normobaric hypoxia-induced changes in HRV.

Aerobic Capacity, Lactate Concentration, and Work Assessment During Maximum Exercise at Sea Level and High Altitude in Miners Exposed to Chronic Intermittent Hypobaric Hypoxia (3,800 m).

We previously showed that arterial oxygen content during maximum exercise remains constant at high altitude (HA) in miners exposed to chronic intermittent hypobaric hypoxia (CIHH). Nevertheless, information about VO2, lactate concentration [Lac], and work efficiency are absent in this CIHH miner population. Our aim was to determine aerobic capacity, [Lac], and work efficiency at sea level (SL) and HA during maximum exercise in miners acclimatized to CIHH at 3,800 m. Eight volunteer miners acclimatized to CIHH at HA (> 4 years) performed an exercise test at SL and HA. The test was performed on the 4th day at HA or SL and consisted of three phases: Rest (5 min); Exercise test, where the load was increased by 50 W every 3 min until exhaustion; and a Recovery period of 30 min. During the procedure VO2, transcutaneous arterial saturation (SpO2, %), and HR (bpm) were assessed at each step by a pulse oximeter and venous blood samples were taken to measure [Lac] and hemoglobin concentration. No differences in VO2 and [Lac] in SL vs. HA were observed in this CIHH miner population. By contrast, a higher HR and lower SpO2 were observed at SL compared with HA. During maximum exercise, a reduction in VO2 and [Lac] was observed without differences in intensity (W) and HR. A decrease in [Lac] was observed at maximum effort (250 W) and recovery at HA vs. SL. These findings are related to an increased work efficiency assessment such as gross and net efficiency. This study is the first to show that miners exposed to CIHH maintain their work capacity (intensity) with a fall in oxygen consumption and a decrease in plasmatic lactate concentration at maximal effort at HA. These findings indicate that work efficiency at HA is enhanced.

Abstract P145: Notch3 Mutation is Involved in Pulmonary Vascular Dysfunction and Development of Pulmonary Arterial Hypertension

Notch3 is implicated in CADASIL and pulmonary arterial hypertension (PAH), two diseases characterized by vascular dysfunction and remodelling. Mice harbouring the CADASIL-causing Notch3 mutation (TgNotch3 R169C ) exhibit gain-of-function Notch3 signalling. As increased Notch3 signalling has been demonstrated in several PAH models, we investigated the contribution of R169C mutation to pulmonary vascular dysfunction and PAH development. Briefly, vascular reactivity was studied by wire myography using pulmonary intralobar arteries from 24-week male mice overexpressing either a WT or R169C mutant Notch3 gene. Further mice were exposed to 2 weeks of normoxia or chronic hypobaric hypoxia (10% O 2 ) before assessing PAH development by in vivo haemodynamic measurements. Notch3 effector gene Hes5, implicated in PAH development, was significantly increased in R169C but not WT lung (8.7 fold change vs WT) suggesting increased pulmonary Notch3 activation. Hypercontractility of R169C pulmonary arteries to both 5HT (Emax R169C 146 ± 10% vs WT 92 ± 6%) and ET-1 (Emax R169C 211 ± 15% vs WT 154 ± 32%) was observed; an effect attenuated by ROCK inhibitor Fasudil (5HT Emax R169C + Fas. 117% ± 20%, ET-1 R169C + Fas. 154 ± 11%) (p<0.05). In addition, gene expression for Rho-guanine nucleotide exchange factors LARG and PDZ, which can activate RhoA/ROCK signalling, was upregulated in R169C lung (R169C 33.5 fold vs WT, R169C 18.7 fold vs WT respectively), with no changes to ROCK gene or protein expression. Reduced endothelial-dependent (ACh Emax WT 43 ± 3% vs R169C 36 ± 3%) and -independent relaxation (SNP Emax WT 62 ± 4% vs R169C 57 ± 4%) were also observed in R169C vessels (p<0.05). Chronic hypoxia did not affect systemic haemodynamic parameters. RV systolic pressure increased in hypoxic animals vs normoxic; this was exacerbated in R169C hypoxic animals (WT hypoxic 27.46 ± 0.97 vs WT normoxic 22.76 ± 2.17mmHg, R169C hypoxic 32.18 ± 1.13 mmHg vs R169C normoxic 23.60 ± 1.44) (p<0.05). R169C hypoxic animals also exhibited RV hypertrophy (RV/LV+S) (hypoxic 0.26 ± 0.033 vs normoxic 0.16 ± 0.012). These data demonstrate Notch3 R169C mutation may contribute to pulmonary vascular hypercontractility and PAH susceptibility, and highlight ROCK as a potential mechanism.

Effect of chronic hypobaric hypoxia on the expression of Neuropeptide Y in an animal model of Parkinson's disease

Effect of chronic hypobaric hypoxia on the expression of Neuropeptide Y in an animal model of Parkinson's disease