Differential effects of high-altitude exposure on markers of oxidative stress, antioxidant capacity, and iron profiles.

High-altitude (HA) exposure may stimulate significant physiological and molecular changes, resulting in HA-related illnesses. HA may impact oxidative stress, antioxidant capacity, and iron homeostasis, yet it is unclear how both repeated exposure and HA acclimatization may modulate such effects. Therefore, we assessed the effects of weeklong repeated daily HA exposure (2,900-5,050 m) in altitude-naïve individuals (n = 21 individuals, 13 females, mean ± SD, 25.3 ± 3.7 yr) to mirror the working schedule of HA workers (n = 19 individuals, all males, 41.1 ± 9.4 yr) at the Atacama Large Millimeter Array (ALMA) Observatory (San Pedro de Atacama, Chile). Markers of oxidative stress, antioxidant capacity, and iron homeostasis were measured in blood plasma. Levels of protein oxidation (P < 0.001) and catalase activity (P = 0.023) increased and serum iron (P < 0.001), serum ferritin (P < 0.001), and transferrin saturation (P < 0.001) levels decreased with HA exposure in both groups. HA workers had lower levels of oxidative stress, and higher levels of antioxidant capacity, iron supply, and hemoglobin concentration as compared with altitude-naïve individuals. On a second week of daily HA exposure, changes in levels of protein oxidation, glutathione peroxidase, and nitric oxide metabolites were lower as compared with the first week in altitude-naïve individuals. These results indicate that repeated exposure to HA may significantly alter oxidative stress and iron homeostasis, and the degree of such changes may be dependent on if HA is visited naïvely or routinely. Further studies are required to fully elucidate differences in HA-induced changes in oxidative stress and iron homeostasis profiles among visitors of HA.

Cinaciguat (BAY-582667) Modifies Cardiopulmonary and Systemic Circulation in Chronically Hypoxic and Pulmonary Hypertensive Neonatal Lambs in the Alto Andino.

Neonatal pulmonary hypertension (NPHT) is produced by sustained pulmonary vasoconstriction and increased vascular remodeling. Soluble guanylyl cyclase (sGC) participates in signaling pathways that induce vascular vasodilation and reduce vascular remodeling. However, when sGC is oxidized and/or loses its heme group, it does not respond to nitric oxide (NO), losing its vasodilating effects. sGC protein expression and function is reduced in hypertensive neonatal lambs. Currently, NPHT is treated with NO inhalation therapy; however, new treatments are needed for improved outcomes. We used Cinaciguat (BAY-582667), which activates oxidized and/or without heme group sGC in pulmonary hypertensive lambs studied at 3,600 m. Our study included 6 Cinaciguat-treated (35 ug kg-1 day-1 x 7 days) and 6 Control neonates. We measured acute and chronic basal cardiovascular variables in pulmonary and systemic circulation, cardiovascular variables during a superimposed episode of acute hypoxia, remodeling of pulmonary arteries and changes in the right ventricle weight, vasoactive functions in small pulmonary arteries, and expression of NO-sGC-cGMP signaling pathway proteins involved in vasodilation. We observed a decrease in pulmonary arterial pressure and vascular resistance during the acute treatment. In contrast, the pulmonary pressure did not change in the chronic study due to increased cardiac output, resulting in lower pulmonary vascular resistance in the last 2 days of chronic study. The latter may have had a role in decreasing right ventricular hypertrophy, although the direct effect of Cinaciguat on the heart should also be considered. During acute hypoxia, the pulmonary vascular resistance remained low compared to the Control lambs. We observed a higher lung artery density, accompanied by reduced smooth muscle and adventitia layers in the pulmonary arteries. Additionally, vasodilator function was increased, and vasoconstrictor function was decreased, with modifications in the expression of proteins linked to pulmonary vasodilation, consistent with low pulmonary vascular resistance. In summary, Cinaciguat, an activator of sGC, induces cardiopulmonary modifications in chronically hypoxic and pulmonary hypertensive newborn lambs. Therefore, Cinaciguat is a potential therapeutic tool for reducing pulmonary vascular remodeling and/or right ventricular hypertrophy in pulmonary arterial hypertension syndrome.

Oxygen use in Atacama large millimeter and submillimeter (ALMA) arrays in Chajnantor valley at 5050 m / Uso de oxígeno en Atacama large millimeter and submillimeter (ALMA) en el valle de Chajnantor a 5050 m

The Chilean workforce has over 200,000 people that are intermittently exposed to altitudes over 4000 m. In 2012, the Ministry of Health provided a technical guide for high altitude workers that included a series of actions to mitigate the effects of hypoxia. Previous studies have shown the positive effect of oxygen enrichment at high altitudes. The Atacama Large Millimeter / submillimeter Arrays (ALMA) radiotelescope operate at 5,050 m (Array Operation Site, AOS) and is the only place in the world where Pressure Swing Adsorption (PSA) and Liquid Oxygen technologies have been installed at a large scale. Here we discuss our experience using oxygen supplementation at ALMA, to prevent the malaise and/or risks associated with exposure at 5,050 m. Antenna operators experienced chronic intermittent hypobaric hypoxia (CIHH, shiftwork 8 days HA*6 days rest SL) over 4 years. Studies to define normal O2 saturation values were performed in OSF and AOS by continuous recording during the shift. The outcomes showed no differences between production procedures (PSA or Liquid oxygen) in regulating oxygen availability at AOS facilities. As a result, big-scale installations have difficulties reaching the appropriate oxygen concentration due to leaks in high mobility areas. In addition, the PSA plant requires adequation and maintenance to operate at a very high altitude.

La fuerza laboral chilena cuenta con más de 200.000 personas que están expuestas intermitentemente a altitudes superiores a los 4000 m. En 2012, el Ministerio de Salud entregó una guía técnica para trabajadores de altura que incluía una serie de acciones para mitigar los efectos de la hipoxia. Estudios anteriores han demostrado el efecto positivo del enriquecimiento de oxígeno en altitudes elevadas. El radiotelescopio Atacama Large Millimeter/submillimeter Arrays (ALMA) opera a 5.050 m (Array Operation Site, AOS) y es el único lugar en el mundo donde se han instalado tecnologías de adsorción por cambio de presión (PSA) y oxígeno líquido a gran escala. Aquí discutimos nuestra experiencia usando suplementos de oxígeno en ALMA, para prevenir el malestar y/o los riesgos asociados con la exposición a 5.050 m. Los operadores de antena experimentaron hipoxia hipobárica intermitente crónica (CIHH, trabajo por turnos 8 días HA*6 días descanso SL) durante 4 años. Se realizaron estudios para definir valores normales de saturación de O2 en OSF y AOS mediante registro continuo durante el turno. Los resultados no mostraron diferencias entre los procedimientos de producción (PSA u oxígeno líquido) en la regulación de la disponibilidad de oxígeno en las instalaciones de AOS. Como resultado, las instalaciones a gran escala tienen dificultades para alcanzar la concentración de oxígeno adecuada debido a fugas en áreas de alta movilidad. Además, la planta de PSA requiere de adecuación y mantenimiento para operar a gran altura.

Comparison Between Pressure Swing Adsorption and Liquid Oxygen Enrichment Techniques in the Atacama Large Millimeter/Submillimeter Array Facility at the Chajnantor Plateau (5,050 m).

The Chilean workforce has over 200,000 people that are intermittently exposed to altitudes over 4,000 m. In 2012, the Ministry of Health provided a technical guide for high-altitude workers that included a series of actions to mitigate the effects of hypoxia. Previous studies have shown the positive effect of oxygen enrichment at high altitudes. The Atacama Large Millimeter/submillimeter Array (ALMA) radiotelescope operates at 5,050 m [Array Operations Site (AOS)] and is the only place in the world where pressure swing adsorption (PSA) and liquid oxygen technologies have been installed at a large scale. These technologies reduce the equivalent altitude by increasing oxygen availability. This study aims to perform a retrospective comparison between the use of both technologies during operation in ALMA at 5,050 m. In each condition, variables such as oxygen (O2), temperature, and humidity were continuously recorded in each AOS rooms, and cardiorespiratory variables were registered. In addition, we compared portable O2 by using continuous or demand flow during outdoor activities at very high altitudes. The outcomes showed no differences between production procedures (PSA or liquid oxygen) in regulating oxygen availability at AOS facilities. As a result, big-scale installations have difficulties reaching the appropriate O2 concentration due to leaks in high mobility areas. In addition, the PSA plant requires adequacy and maintenance to operate at a very high altitude. A continuous flow of 2-3 l/min of portable O2 is recommended at 5,050 m.

Enhanced Vasoconstriction Mediated by α1-Adrenergic Mechanisms in Small Femoral Arteries in Newborn Llama and Sheep Gestated at Low and High Altitudes.

The authors previously demonstrated that newborn llama (NBLL) express high levels of α1 adrenergic receptors, which provide a potent vasoconstriction response when compared with newborn sheep (NBSH) gestated at sea level. However, data regarding the impact of chronic gestational hypobaric hypoxia on α-adrenergic vasoconstriction in the neonatal life has not been studied. We evaluated if gestation under chronic hypobaric hypoxia modifies α1-adrenergic vasoconstrictor function in NBLL and NBSH. We compared the vasoconstrictor response induced by potassium and α-adrenergic stimuli in isolated small femoral arteries of NBLL and NBSH gestated at high altitude (HA; 3,600 m) or low altitude (LA; 580 m). The maximal contraction (R MAX) and potency (EC50) to potassium, noradrenaline (NA), and phenylephrine (PHE) were larger in HA-NBLL than LA-NBLL. R MAX to potassium, NA, and PHE were lower in HA-NBSH when compared with LA-NBSH and potency results were similar. Competitive blockade with prazosin showed that RNLL LA/HA have a similar pA2. In contrast, NBSH had increased pA2 values in HA when compared with LA. Finally, small femoral arteries denudated or treated with LNAME in LA and HA lacked NO or endothelium participation in response to PHE stimulation. In contrast, NBSH displayed that denudation or blockade with LNAME support NO or endothelium participation in response to PHE activation. In conclusion, HA chronic hypoxia enhances α1 adrenergic receptor activity in small femoral arteries in NBLL to a higher degree than NBSH, implying a higher vasoconstriction function.

Cardiovascular Risk Is Increased in Miner's Chronic Intermittent Hypobaric Hypoxia Exposure From 0 to 2,500 m?

Over the past 40 years, mining activities in Chile have relocated miners who normally live at sea level to work at high altitudes. This results in a form of chronic intermittent hypobaric hypoxia (CIHH) characterized by alternating periods of work at high altitude and rest periods at sea level. Previous studies performed in our laboratory showed that aerobic capacity is reduced at 3,800 m, even when oxygen content is maintained. Our study aimed to determine the corporal composition, food intake, maximum oxygen uptake, and concentration of high sensitivity C reactive protein (hsCRP) in an acclimatized miner population that work from 0 to 2,500 m with CIHH exposure over 4 years. All miners recruited for our study were operators of heavy trucks with CIHH for over 4 years (shiftwork 7*7 days), and our experimental population was composed of 54 miners at sea level, 61 at 1,600 m, and 38 at 2,500 m. All evaluations were performed on the 3rd or 4th day of diurnal shiftwork. To determine corporal composition, we measured weight and height (to calculate body mass index, BMI), skinfolds (to calculate body fatty, BF), and waist circumference (WC); maximal aerobic capacity was evaluated using a ramp-incremental cycling to exhaustion protocol and a venous blood sample before the exercise test to measure (hsCRP) via an ELISA test. We found higher values of BMI, BF, and WC, in the miners' population but observed no significant difference between populations. We found a decrease in VO2 of 11.6% at 1,600 m and 25.9% at 2,500 m compared to miners at sea level. An increase in (hsCRP) at 1,600 and 2,500 m regards sea level. We observed a high prevalence of overweight and obese subjects, which was related to the ad libitum availability of food and low physical activity (sedentarism). We found that work capacity was maintained despite a decreased VO2 max at moderate altitude. However, overweight and obesity support an increased risk of cardiometabolic disease in miner's which is unrelated to altitude. In contrast, an increased hsCRP level could be associated with increased inflammatory mechanisms at 1,600 and 2,500 m.

The Action of 2-Aminoethyldiphenyl Borinate on the Pulmonary Arterial Hypertension and Remodeling of High-Altitude Hypoxemic Lambs.

Calcium signaling is key for the contraction, differentiation, and proliferation of pulmonary arterial smooth muscle cells. Furthermore, calcium influx through store-operated channels (SOCs) is particularly important in the vasoconstrictor response to hypoxia. Previously, we found a decrease in pulmonary hypertension and remodeling in normoxic newborn lambs partially gestated under chronic hypoxia, when treated with 2-aminoethyldiphenyl borinate (2-APB), a non-specific SOC blocker. However, the effects of 2-APB are unknown in neonates completely gestated, born, and raised under environmental hypoxia. Accordingly, we studied the effects of 2-APB-treatment on the cardiopulmonary variables in lambs under chronic hypobaric hypoxia. Experiments were done in nine newborn lambs gestated, born, and raised in high altitude (3,600 m): five animals were treated with 2-APB [intravenous (i.v.) 10 mg kg-1] for 10 days, while other four animals received vehicle. During the treatment, cardiopulmonary variables were measured daily, and these were also evaluated during an acute episode of superimposed hypoxia, 1 day after the end of the treatment. Furthermore, pulmonary vascular remodeling was assessed by histological analysis 2 days after the end of the treatment. Basal cardiac output and mean systemic arterial pressure (SAP) and resistance from 2-APB- and vehicle-treated lambs did not differ along with the treatment. Mean pulmonary arterial pressure (mPAP) decreased after the first day of 2-APB treatment and remained lower than the vehicle-treated group until the third day, and during the fifth, sixth, and ninth day of treatment. The net mPAP increase in response to acute hypoxia did not change, but the pressure area under the curve (AUC) during hypoxia was slightly lower in 2-APB-treated lambs than in vehicle-treated lambs. Moreover, the 2-APB treatment decreased the pulmonary arterial wall thickness and the α-actin immunoreactivity and increased the luminal area with no changes in the vascular density. Our findings show that 2-APB treatment partially reduced the contractile hypoxic response and reverted the pulmonary vascular remodeling, but this is not enough to normalize the pulmonary hemodynamics in chronically hypoxic newborn lambs.

The Effect of Chronic Intermittent Hypobaric Hypoxia on Sleep Quality and Melatonin Serum Levels in Chilean Miners.

High-altitude mining is an important economic resource for Chile. These workers are exposed to chronic intermittent hypobaric hypoxia (CIHH), which reduces their sleep quality and increases the risk of accidents and long-term illnesses. Melatonin, a hormone produced by the pineal gland, is a sleep inducer that regulates the circadian cycle and may be altered in populations subjected to CIHH. This work aimed to assess the relationship between altitude, sleep quality, and plasma melatonin concentrations in miners with CIHH exposure. 288 volunteers were recruited from five altitudes (0, 1,600, 2,500, 3,500, and 4,500 m). All volunteers worked for 7 days at altitude, followed by 7 days of rest at sea level. We performed anthropometric assessments, nocturnal oximetry, sleep quality and sleepiness surveys, and serum melatonin levels upon awakening. Although oxygen saturation progressively decreased and heart rate increased at higher altitudes, subjective perception of sleep quality was not significantly different, and sleepiness increased in all groups compared to population at sea level. Similarly, melatonin levels increased at all assessed altitudes compared to the population at sea level. These data confirm that sleep disturbances associated with CIHH increase morning melatonin levels. Therefore, this hormone and could potentially serve as a biomarker of sleep quality.

Activation of arginase II by asymmetric dimethylarginine and homocysteine in hypertensive rats induced by hypoxia: a new model of nitric oxide synthesis regulation in hypertensive processes?

In recent years, the increase in blood pressure at high altitudes has become an interesting topic among high-altitude researchers. In our animal studies using Wistar rats, we observed the existence of two rat populations that exhibit differential physiological responses during hypoxic exposure. These rats were classified as hypoxia-induced hypertensive rats and nonhypertensive rats. A decrease in nitric oxide levels was reported in different hypertension models associated with increased concentrations of asymmetric dimethylarginine (ADMA) and homocysteine, and we recently described an increase in arginase type II expression under hypoxia. ADMA and homocysteine decrease nitric oxide (NO) bioavailability; however, whether ADMA and homocysteine have a regulatory effect on arginase activity and therefore regulate another NO synthesis pathway is unknown. Therefore, the aim of this study was to measure basal ADMA and homocysteine levels in hypoxia-induced hypertensive rats and evaluate their effect on arginase II activity. Our results indicate that hypoxia-induced hypertensive rats presented lower nitric oxide concentrations than nonhypertensive rats, associated with higher concentrations of homocysteine and ADMA. Hypoxia-induced hypertensive rats also presented lower dimethylarginine dimethylaminohydrolase-2 and cystathionine ß-synthase levels, which could explain the high ADMA and homocysteine levels. In addition, we observed that both homocysteine and ADMA had a significant effect on arginase II activation in the hypertensive rats. Therefore, we suggest that ADMA and homocysteine have dual regulatory effects on NO synthesis. The former has an inhibitory effect on eNOS, and the latter has a secondary activating effect on arginase II. We propose that arginase II is activated by AMDA and homocysteine in hypoxia-induced hypertensive rats.

A key for hypoxia genetic adaptation in alpaca could be a HIF1A truncated bHLH protein domain / Una clave para la adaptacion genética de la hypoxia en las alpacas podria ser un dominio de proteina bHLH truncado con HIF1A

Animals exposed to hypobaric hypoxia triggers a physiological hypoxia response via Hypoxia Inducible Factor (HIF) proteins that functions as transcriptional complexes. As the South American camelids inhabit at high Andean altitudes we have asked if they have developed genetic adaptations to live at high altitudes. In the present study we investigate genetic structures of the HIF1A proteins carried by members of the superorder Cetartiodactyla. During our investigation we discovered the existence of a genetic event that caused the loss of most of the bHLH domain in the proteins borne by the Alpaca and other members of the Cetartiodactyla superorder; we designate them as bHLH short sequences. Further analysis at the nucleotide level revealed in the 12 short sequences included in the study the presence at the 5´end of the bHLH domains stop codons. Seven out of the 12 short HIF1A proteins, have an identical or almost identical nucleotide sequence at their 5´end with a same TAA stop codon and at the same position. As the mutations affects to both the Artiodactyls and Cetaceans, we postulate that the mutation(s) occurred before their divergence about 55 million years ago. The relevance of these findings for genetic adaptation of Alpacas to hypobaric hypoxia of high altitude conditions is discussed.

Los animales expuestos a hypoxia hipobárica generan una respuesta hipóxica fisiológica debido a unas proteinas de Factor-Hipoxia Inducible (HIF) que funcionan como complejos transcripcionales. Debido a que los camelidos Americanos habitan en las grandes alturas andinas, nos hemos preguntado si han desarrollado una adaptación genética para vivir a grandes alturas. Eneste estudio hemos investigado la estructura genética de las proteinas HIF1A que llevan consigo los miembros de la superorden de los cetartiodáctilos. Durante nuestra investigación, descubrimos la existencia de un evento genético que causó la perdida de la mayoría del dominio bHLH en las proteinas transmitidas por la alpaca y otros miembros de la superorden de los cetartiodáctilos; las hemos designado como secuencias cortas de bHLH. Análisis posteriores a nivel nucleótido revelaron que en la doceava secuencia corta incluida en el studio, hubo presencia de codones de terminación en el extreme 5' del dominio de bHLH. Siete de las doce proteinas cortas HIF1A, tiene una secuencia idéntica o casi idéntica de nucleotidos en su extremo 5', con el mismo codón de terminación TAA y en la misma posición. Debido a que la mutación afecta tanto a Artiodáctilos como Cetáceos, proponemos que la mutación(es) ocurrió antes de su divergencia hace unos 55 millones de años. Analizamos la relevancia de estos descubrimientos sobre la adaptación genética de las alpacas a la hipoxia hipobárica en condiciones de grandes alturas.

Oxygen saturation and heart rate in children at high altitude: a different response of Aymaras and non-Aymaras with chronic exposure at 3500 m / Saturación de oxígeno y ritmo cardiaco de niños en zonas de gran altitud: una respuesta distinta entre Aymaras y no Aymaras con exposición crónica a 3500 m

This work aims to determine if there is a difference between the cardiorespiratory response of children who chronically live at high altitude (Aymaras and non-Aymaras) compared to children that arrive as tourist at a high altitude of 3500 m (Putre, Chile). The subjects were children (Aymaras and non-Aymaras) who were born and live in Putre and children who came to the same location for a tourist visit. We used Oxygen saturation (%) and heart rate (HR, bpm) were evaluated by pulse oxymetry in children from Putre. The results showed similar levels of oxygen saturation were observed among chronic Aymaras and non-Aymara children. A lower oxygen saturation was found in children with acute exposure when compared with chronic children (p<0.0001). The HR of Aymaras and non-Aymara chronic children was lower than that observed in the non-native children (p<0.05). In contrast acute children had a higher HR than chronic children (p<0.001). Negative relationships were observed with correlation values (p<0.01) between oxygen saturation and HR in all groups. We concluded that chronic Aymara children exhibited a higher slope and correlation between oxygen saturation vs HR compared to chronic children who are non-Aymaras, suggesting that chronic natives are more sensitive to hypoxia. And, chronic non-Aymara children have an early blunting response to hypoxia. Further studies are needed to understand the physiological mechanisms in this population group.

El objetivo de este trabajo es determinar si existe alguna diferencia entre la respuesta cardiorespiratoria de niños que han vivido crónicamente a gran altitud (Aymaras y no Aymaras) comparados con niños llegados como turistas en grandes alturas de 3500m (Putre, Chile). Los sujetos fueron niños (Aymaras y no Aymaras) que nacieron y vivieron en Putre y niños que llegaron a la zona por una visita turística. Utilizamos saturación de oxígeno (%) y ritmo cardíaco (HR, bpm). Los niños de Putre fueron evaluados utilizando la pulsioximetría. Los resultados mostraron niveles similares de saturación de oxígeno entre los niños crónicos Aymaras y no Ayamaras. En los niños con exposición aguda se encontró una baja saturación de oxígeno al compararse con los niños crónicos (p<0.0001). El HR de los niños crónicos Aymaras y no Aymaras fue menor que el observado en niños no nativos (p<0.05). En cambio, los niños con síntomas agudos tenían una mayor HR que los niños crónicos (p<0.001). Se observaron relaciones negativas con los valores de correlación (p<0.01) entre la saturación de oxígeno y HR en todos los grupos. Concluimos que los niños crónicos Aymaras mostraban una gran pendiente y correlacion entre la saturación de oxígeno contra el HR comparado con los niños crónicos no Aymaras, sugiriendo que los nativos crónicos son más susceptibles a la hipoxia, y que los niños crónicos no Aymaras tiene una respuesta temprana a la hipoxia. Se necesitan estudios posteriores para entender los mecanismos fisiológicos en este grupo de población.

Altitude effect on sleep quality and serum melatonin levels in Chilean mining workers / Efecto de la Altitud en la calidad de sueño y niveles séricos de melatonina en trabajadores mineros en Chile

High altitude (HA) mining operations are a very important business in Chile, but reduced availability of oxygen affects the sleep quality, increasing the risk of accidents. An important regulator of sleep-wake cycle is the hormone Melatonin, produced by pineal gland as a sleep inductor. The aim of this study is to evaluate the effect of high altitude (4,500 m) on the quality of sleep of workers undergoing to Chronic Intermittent Hypobaric Hypoxia (CIHH) using self-reported surveys of sleepiness and sleep quality, measurement of sleep apnea (using nocturnal oximetry) and serum levels of melatonin. The Desaturation index (ID4) results revealed higher HA scores compared to sea level (SL). Regarding melatonin levels, the results show that it is increased in HA versus SL and this increase would be related to oxygen saturation during sleep. These data link sleep quality in HA to its melatonin levels, suggesting that melatonin may be a potential biomarker for sleep quality.

Cognitive Effects of Repeated Acute Exposure to Very High Altitude Among Altitude-Experienced Workers at 5050 m.

Background: We investigated altitude effects on different cognitive domains among perennial shift-workers at the Atacama Large Millimeter/submillimeter Array Observatory (5050 m), Chile. Materials and Methods: Twenty healthy male workers were recruited and assigned to either a moderate-altitude first (MAF group, Test 1: 2900 m and Test 2: 5050 m) or to a high-altitude first (HAF group, Test 1: 5050 m and Test 2: 2900 m). Test 1 was conducted at the beginning and Test 2 at the end of the shift-work week. Processing speed (RTI, reaction time), attention (AST, attention-switching task, and RVP, rapid visual processing), and executive function (OTS, One Touch Stockings of Cambridge) were assessed. Results: Of the three cognitive domains assessed, only processing speed showed altitude-at-test group interaction (RTI median five choice reaction time: F1, 17 = 6.980, [Formula: see text] = 0.291, p = 0.017). With acclimatization, there was a decrease in AST reaction latency mean (t17 = -2.155, dz = 1.086, p = 0.046), an increase in RVP accuracy (t17 = 2.733, dz = 1.398, p = 0.014), and a decrease in OTS mean latency first choice (t17 = -2.375, dz = 1.211, p = 0.03). Decreased variability in cognitive function was observed in AST reaction latency standard deviation (t17 = -2.524, dz = 1.282, p = 0.022) and in RVP response latency standard deviation (t17 = -2.35, dz = 1.177, p = 0.03) with acclimatization. At 5050 m of elevation, SpO2 was positively correlated with executive function in the MAF group (OTS problems solved on first choice: r(5) = 0.839, p = 0.018) and negatively correlated with executive function latency standard deviations in the HAF group (OTS latency to first choice standard deviation: r(10) = -0.618, p = 0.032). Conclusions: Our findings highlight the importance of acclimatization and improvement of blood oxygen level, even among high altitude-experienced workers, to optimize performance of cognitively demanding work and reduce high altitude-associated health risks.

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.

Plasmatic Concentrations of ADMA and Homocystein in Llama (Lama glama) and Regulation of Arginase Type II: An Animal Resistent to the Development of Pulmonary Hypertension Induced by Hypoxia.

There are animal species that have adapted to life at high altitude and hypobaric hypoxia conditions in the Andean highlands. One such species is the llama (Lama glama), which seem to have developed efficient protective mechanisms to avoid maladaptation resulting from chronic hypoxia, such as a resistance to the development of hypoxia -induced pulmonary hypertension. On the other hand, it is widely known that different models of hypertension can arise as a result of changes in endothelial function. The respect, one of the common causes of deregulation in endothelial vasodilator function have been associated with down-regulation of the NO synthesis and an increase in plasma levels of asymmetric dimethylarginine (ADMA) and homocysteine. Additionally, it is also known that NO production can be regulated by plasma levels of L-arginine as a result of the competition between nitric oxide synthase (NOS) and arginase. The objective of this study, was to determine the baseline concentrations of ADMA and homocysteine in llama, and to evaluate their effect on the arginase pathway and their involvement in the resistance to the development of altitude-induced pulmonary hypertension. METHOD: Lowland and highland newborn sheep and llama were investigated near sea level and at high altitude. Blood determinations of arterial blood gases, ADMA and homocysteíne are made and the effect of these on the arginase activity was evaluated. RESULTS: The basal concentrations of ADMA and homocysteine were determined in llama, and they were found to be significantly lower than those found in other species and in addition, the exposure to hypoxia is unable to increase its concentration. On the other hand, it was observed that the llama exhibited 10 times less arginase II activity as compared to sheep, and the expression was not induced by hypoxia. Finally, ADMA y Hcy, has no effect on the type II arginase pathway. CONCLUSION: Based on our results, we propose that low concentrations of ADMA and homocysteine found in llamas, the low expression of arginase type II, DDAH-2 and CBS, as well as its insensitivity to activation by homocysteine could constitute an adaptation mechanism of these animals to the hypoxia.

The Effect of Oxygen Enrichment on Cardiorespiratory and Neuropsychological Responses in Workers With Chronic Intermittent Exposure to High Altitude (ALMA, 5,050 m).

It is estimated that labor activity at high altitudes in Chile will increase from 60,000 to 120,000 workers by the year 2020. Oxygenation of spaces improves the quality of life for workers at high geographic altitudes (<5,000 m). The aim of this study was to determine the effect of a mobile oxygen module system on cardiorespiratory and neuropsychological performance in a population of workers from Atacama Large Millimeter/submillimeter Array (ALMA, 5,050 m) radiotelescope in the Chajnantor Valley, Chile. We evaluated pulse oximetry, systolic and diastolic arterial pressure (SAP/DAP), and performed neuropsychological tests (Mini-Mental State examination, Rey-Osterrieth Complex Figure test) at environmental oxygen conditions (5,050 m), and subsequently in a mobile oxygenation module that increases the fraction of oxygen in order to mimic the higher oxygen partial pressure of lower altitudes (2,900 m). The use of module oxygenation at an altitude of 5,050 m, simulating an altitude of 2,900 m, increased oxygen saturation from 84 ± 0.8 to 91 ± 0.8% (p < 0.00001), decreased heart rate from 90 ± 8 to 77 ± 12 bpm (p < 0.01) and DAP from 96 ± 3 to 87 ± 5 mmHg (p < 0.01). In addition, mental cognitive state of workers (Mini-Mental State Examination) shown an increased from 19 to 31 points (p < 0.02). Furthermore, the Rey-Osterrieth Complex Figure test (memory) shown a significant increase from 35 to 70 (p < 0.0001). The results demonstrate that the use of an oxygen module system at 5,050 m, simulating an altitude equivalent to 2,900 m, by increasing FiO2 at 28%, significantly improves cardiorespiratory response and enhances neuropsychological performance in workers exposed to an altitude of 5,050 m.

Chronic Intermittent Hypobaric Hypoxia (4600 M) Attenuates Pulmonary Vasodilation Induced by Acetylcholine or Sodium Nitroprusside.

Moraga, Fernando A., Giselle Miranda, Vasthi López, Carmen Vallejos, and Daniel Silva. Chronic intermittent hypobaric hypoxia (4600 M) attenuates pulmonary vasodilation induced by acetylcholine or sodium nitroprusside. High Alt Med Biol. 19:149-155, 2018. BACKGROUND: Previous studies performed in rats exposed to chronic intermittent hypobaric hypoxia (CIHH), at a simulated altitude of 4600 m, showed reduced nitric oxide (NO) production, increased arginase activity, and increased oxidative stress. However, studies on vascular function are scarce. Our aim was to measure plasma nitrate and nitrite (NOx) concentration and study pulmonary vascular function in rats exposed to CIHH in the presence of potassium chloride (KCl), acetylcholine (Ach), and sodium nitroprusside (SNP). METHODS: Thirty male Wistar rats were divided into two groups: A control group (normoxia (N), n = 10) and a CIHH group (2N × 2H × 30 days, n = 20). CIHH exposure was performed in a hypobaric chamber at 428 Torr (4600 m). Noninvasive systolic blood pressure (SBP), heart rate, and body weight (BW) were measured. Blood samples were obtained to measure NOx levels and hematocrit (Hct). CIHH animals that gained BW and presented a Hct <20% and maintained SBP were classified as tolerant, and animals that lost >30% of their BW, increased Hct and SBP >20% were classified as intolerant. Animals were sacrificed and small pulmonary arteries (SPA) were obtained to perform concentration-response curves to KCl, Ach, and SNP. RESULTS AND CONCLUSIONS: Intolerant rats (30%) had decreased NOx levels. SPA had a larger vasocontraction response to KCl and a lower dilation response to SNP in the SPA compared to tolerant and control animals. In addition, SPA had a lower dilatation response to Ach compared with the control. Together, these results show that CIHH alters endothelium-dependent vasodilation.

Hemoconcentration During Maximum Exercise in Miners with Chronic Intermittent Exposure to Hypobaric Hypoxia (3800 m).

Moraga, Fernando A., Jorge Osorio, Rodrigo Calderón-Jofré, and Andrés Pedreros. Hemoconcentration during maximum exercise in miners with chronic intermittent exposure to hypobaric hypoxia (3800 m). High Alt Med Biol. 19:15-20, 2018. OBJECTIVE: To evaluate the effect of maximum exercise on hemoconcentration in miners with chronic intermittent hypobaric hypoxia (CIHH) at 3800 m. MATERIALS AND METHODS: Sixteen miners with CIHH at high altitude (3800 m) were subjected to maximum exercise levels on a cycle ergometer, increasing exercise load by 50 W every 3 minutes at sea level and high altitude (3800 m). During exercise, arterial oxygen saturation and heart rate were measured. Blood samples were taken at each step to measure hemoglobin concentration and hematocrit. Arterial blood oxygen content was also calculated. RESULTS: At sea level, a decrease in arterial oxygen saturation to 92.1% ± 2.5% was observed at 150 W and the hematocrit, hemoglobin concentration and oxygen content were not altered. At high altitude, arterial oxygen saturation decreased, reaching 88.2% ± 4.9% at 50 W and remained constant during the entire exercise protocol. Hemoglobin concentration and hematocrit increased reaching 16.4 ± 0.9 g/dL and 48.8% ± 1.6%, respectively, at 100 W and were maintained until recovery. Arterial oxygen content was constant during exercise and increased in the recovery period. CONCLUSION: An increase in hemoglobin concentration during exercise compensates for the decline in arterial oxygen saturation, meanwhile arterial oxygen content remains constant.

2-AMINOETHYLDIPHENYLBORINATE MODIFIES THE PULMONARY CIRCULATION IN PULMONARY HYPERTENSIVE NEWBORN LAMBS WITH PARTIAL GESTATION AT HIGH ALTITUDE.

Calcium signaling through store operated channels (SOC) is involved in hypoxic pulmonary hypertension. We determined whether a treatment with 2-aminoethyldiphenylborinate (2-APB), a compound with SOC blocker activity, reduces pulmonary hypertension and vascular remodeling. Twelve newborn lambs exposed to perinatal chronic hypoxia were studied, 6 of them received a 2-APB treatment and the other 6 received vehicle treatment, for 10 days in both cases. Throughout this period, we recorded cardiopulmonary variables and on day 11 we evaluated the response to an acute hypoxic challenge. Additionally, we assessed the vasoconstrictor and vasodilator function in isolated pulmonary arteries as well as their remodeling in lung slices. 2-APB reduced pulmonary arterial pressure at the third and tenth days, cardiac output between the fourth and eighth days, and pulmonary vascular resistance at the tenth day of treatment. The pulmonary vasoconstrictor response to acute hypoxia was reduced by the end of treatment. 2-APB also decreased maximal vasoconstrictor response to the thromboxane mimetic U46619 and endothelin-1 and increased maximal relaxation to 8-Br-cGMP. The maximal relaxation and potency to phosphodiesterase-5 and Rho-kinase inhibition with sildenafil and fasudil respectively, were also increased. Finally, 2-APB reduced the medial and adventitial layers' thickness, the expression of α-actin and the percentage of Ki67+ nuclei of small pulmonary arteries. Taken together, our results indicate that 2-APB reduces pulmonary hypertension, vasoconstrictor responses and pathological remodeling in pulmonary hypertensive lambs. We conclude that SOC targeting may be a useful strategy for the treatment of neonatal pulmonary hypertension, however, further testing of specific blockers is needed.