Biomechanical effects of hemin and sildenafil treatments on the aortic wall of chronic-hypoxic lambs.

Introduction: Gestation under chronic hypoxia causes pulmonary hypertension, cardiovascular remodeling, and increased aortic stiffness in the offspring. To mitigate the neonatal cardiovascular risk, pharmacological treatments (such as hemin and sildenafil) have been proposed to improve pulmonary vasodilation. However, little is known about the effects of these treatments on the aorta. Therefore, we studied the effect of hemin and sildenafil treatments in the aorta of lambs gestated and raised at highlands, thereby subjected to chronic hypoxia. Methods: Several biomechanical tests were conducted in the descending thoracic aorta (DTA) and the distal abdominal aorta (DAA), assessing 3 groups of study of hypoxic animals: non-treated (Control) and treated either with hemin or sildenafil. Based on them, the stiffness level has been quantified in both zones, along with the physiological strain in the unloaded aortic duct. Furthermore, a morphological study by histology was conducted in the DTA. Results: Biomechanical results indicate that treatments trigger an increment of axial pre-stress and circumferential residual stress levels in DTA and DAA of lambs exposed to high-altitude chronic hypoxia, which reveals a vasodilatation improvement along with an anti-hypertensive response under this characteristic environmental condition. In addition, histological findings do not reveal significant differences in either structure or microstructural content. Discussion: The biomechanics approach emerges as a valuable study perspective, providing insights to explain the physiological mechanisms of vascular function. According to established results, alterations in the function of the aortic wall may not necessarily be explained by morphostructural changes, but rather by the characteristic mechanical state of the microstructural components that are part of the studied tissue. In this sense, the reported biomechanical changes are beneficial in mitigating the adverse effects of hypobaric hypoxia exposure during gestation and early postnatal life.

Preeclampsia and risk of maternal pulmonary hypertension at high altitude in Bolivia.

Women with a history of preeclampsia (PE) have a greater risk of pulmonary arterial hypertension (PAH). In turn, pregnancy at high altitude is a risk factor for PE. However, whether women who develop PE during highland pregnancy are at risk of PAH before and after birth has not been investigated. We tested the hypothesis that during highland pregnancy, women who develop PE are at greater risk of PAH compared to women undergoing healthy highland pregnancies. The study was on 140 women in La Paz, Bolivia (3640m). Women undergoing healthy highland pregnancy were controls (C, n = 70; 29 ± 3.3 years old, mean±SD). Women diagnosed with PE were the experimental group (PE, n = 70, 31 ± 2 years old). Conventional (B- and M-mode, PW Doppler) and modern (pulsed wave tissue Doppler imaging) ultrasound were applied for cardiovascular íííassessment. Spirometry determined maternal lung function. Assessments occurred at 35 ± 4 weeks of pregnancy and 6 ± 0.3 weeks after birth. Relative to highland controls, highland PE women had enlarged right ventricular (RV) and right atrial chamber sizes, greater pulmonary artery dimensions and increased estimated RV contractility, pulmonary artery pressure and pulmonary vascular resistance. Highland PE women had lower values for peripheral oxygen saturation, forced expiratory flow and the bronchial permeability index. Differences remained 6 weeks after birth. Therefore, women who develop PE at high altitude are at greater risk of PAH before and long after birth. Hence, women with a history of PE at high altitude have an increased cardiovascular risk that transcends the systemic circulation to include the pulmonary vascular bed.

Brainstem auditory-evoked responses among children afflicted by severely hypoxic CHD.

MAIN AIM: To electrophysiologically determine the impact of moderate to severe chronic hypoxia (H) resulting from a wide array of CHD (HCHD) conditions on the integrity of brainstem function. MATERIALS AND METHODS: Applying brainstem auditory-evoked response methodology, 30 chronically afflicted HCHD patients, who already had undergone heart surgery, were compared to 28 healthy control children (1-15 yo) matched by age, gender and socioeconomic condition. Blood oxygen saturation was clinically determined and again immediately before brainstem auditory-evoked response testing. RESULTS: Among HCHD children, auditory wave latencies (I, III and V) were significantly longer (medians: I, 2.02 ms; III, 4.12 ms, and; V, 6.30 ms) compared to control (medians: I, 1.67ms; III, 3.72 ms, and; V, 5.65 ms), as well as interpeak intervals (HCHD medians: I-V, 4.25 ms, and; III-V, 2.25ms; control medians: I-V, 3.90 ms and, III-V, 1.80 ms) without significant differences in wave amplitudes between groups. A statistically significant and inverse correlation between average blood oxygen saturation of each group (control, 94%; HCHD, 78%) and their respective wave latencies and interpeak intervals was found. CONCLUSIONS: As determined by brainstem auditory-evoked responses, young HCHD patients manifestly show severely altered neuronal conductivity in the auditory pathway strongly correlated with their hypoxic condition. These observations are strongly supported by different brainstem neurological and image studies showing that alterations, either in microstructure or function, result from the condition of chronic hypoxia in CHD. The non-altered wave amplitudes are indicative of relatively well-preserved neuronal relay nuclei.

Melatonin treatment during chronic hypoxic gestation improves neonatal cerebrovascular function.

BACKGROUND: Fetal chronic hypoxia is associated with blood flow redistribution and oxidative damage in the brain, leading to increased perinatal morbimortality. Melatonin reduces oxidative stress, improves vascular function, and has neuroprotective effects. OBJECTIVES: This study aimed to determine the effects of an oral melatonin treatment to pregnant ewes at high-altitude, on the cerebrovascular function of their neonates. STUDY DESIGN: Ten high-altitude pregnant sheep received either vehicle or melatonin (10 mg/d) during the last third of gestation until delivery. Postnatal daily hemodynamic measurements were recorded from lambs until 12 days old. In addition, lambs were submitted to a graded oxygenation protocol to assess cerebrovascular responses. Subsequently, lambs were euthanized, and middle cerebral arteries (MCA) were collected for vascular function, protein levels, and morphostructural analyses. RESULTS: Antenatal treatment doubled plasma levels of melatonin in pregnant ewes. Melatonin increased carotid flow and decreased carotid vascular resistance in the lambs by the end of the first week. Furthermore, melatonin increased MCA's maximal vasoconstrictor and vasodilator responses, associated with nitric oxide-dependent and independent mechanisms. CONCLUSIONS: An oral treatment with melatonin during pregnancy promotes postnatal cerebral perfusion in chronically hypoxic neonates. Melatonin is a potential treatment for cerebrovascular dysfunction due to perinatal chronic hypoxia.

High Altitude Pregnancies and Vascular Dysfunction: Observations From Latin American Studies.

An estimated human population of 170 million inhabit at high-altitude (HA, above 2,500 m). The potential pathological effects of HA hypobaric hypoxia during gestation have been the focus of several researchers around the world. The studies based on the Himalayan and Central/South American mountains are particularly interesting as these areas account for nearly 70% of the HA world population. At present, studies in human and animal models revealed important alterations in fetal development and growth at HA. Moreover, vascular responses to chronic hypobaria in the pregnant mother and her fetus may induce marked cardiovascular impairments during pregnancy or in the neonatal period. In addition, recent studies have shown potential long-lasting postnatal effects that may increase cardiovascular risk in individuals gestated under chronic hypobaria. Hence, the maternal and fetal adaptive responses to hypoxia, influenced by HA ancestry, are vital for a better developmental and cardiovascular outcome of the offspring. This mini-review exposes and discusses the main determinants of vascular dysfunction due to developmental hypoxia at HA, such as the Andean Mountains, at the maternal and fetal/neonatal levels. Although significant advances have been made from Latin American studies, this area still needs further investigations to reveal the mechanisms involved in vascular dysfunction, to estimate complications of pregnancy and postnatal life adequately, and most importantly, to determine potential treatments to prevent or treat the pathological effects of being developed under chronic hypobaric hypoxia.

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.

Effect of exercise training in rats exposed to chronic hypoxia: Application for Monge's disease.

Physical exercise may improve hematological conditions in high altitude dwellers suffering from Chronic Mountain Sickness (CMS), in reducing hemoglobin concentration. Therefore, the present study aimed to characterize the effects of 1-month exercise training session in a model of rats exposed to chronic hypoxia. Four groups of male rats were studied: normoxic sedentary (NS, n = 8), normoxic training (NT, n = 8), hypoxic sedentary (HS, n = 8), and hypoxic training group (HT, n = 8). Hypoxic groups were exposed to hypobaric hypoxia for one month (PB =433 Torr). Training intensity was progressively increased from a running speed of 10.4 to 17.8 m/min. Chronic hypoxia led to an increase in hematocrit (HCT) associated with a decrease in plasma volume despite an increase in water intake. Training led to a reduction in HCT (p < 0.01), with a non-significant increase in plasma volume and weight gain. Hypoxia and training had inhibitory effects on haptoglobin (NS group: 379 ± 92; HT: 239 ± 34 µg/ml, p < 0.01). Chronic hypoxia and exercise training increased SpO2 measured after acute hypoxic exposure. Training blunted the decrease in V˙ O2 peak, time of exhaustion, and maximum speed associated with chronic exposure to hypoxia. Chronic hypoxia led to a right ventricular hypertrophy, which was not corrected by 1-month exercise training. Altogether, by decreasing hematocrit, reducing body weight, and limiting performance decrease, training in hypoxia may have a beneficial effect on excessive erythropoiesis in chronic hypoxia. Therefore, regular exercise training might be beneficial to avoid worsening of CMS symptoms in high altitude dwellers and to improve their quality of life.

Effect of altitude on mortality of end-stage renal disease patients on hemodialysis in Peru.

BACKGROUND: In Latin America, the prevalence of end-stage kidney disease (ESKD) has risen tremendously during the last decade. Previous studies have suggested that receiving dialysis at high altitude confers mortality benefits; however, this effect has not been demonstrated at >2000 m above sea level (masl) or in developing countries. METHODS: This historical cohort study analyzed medical records from six Peruvian hemodialysis (HD) centers located at altitudes ranging from 44 to 3827 masl. Adult ESKD patients who started maintenance HD between 2000 and 2010 were included. Patients were classified into two strata based on the elevation above sea level of their city of residence: low altitude (<2000 masl) and high altitude (≥2000 masl). Death from any cause was collected from national registries and Cox proportional hazards models were built. RESULTS: A total of 720 patients were enrolled and 163 (22.6%) resided at high altitude. The low-altitude group was significantly younger, more likely to have diabetes or glomerulonephritis as the cause of ESKD and higher hemoglobin. The all-cause mortality rate was 84.3 per 1000 person-years. In the unadjusted Cox model, no mortality difference was found between the high- and low-altitude groups {hazard ratio [HR] 1.20 [95% confidence interval (CI) 0.89-1.62]}. After multivariable adjustment, receiving HD at high altitude was not significantly associated with higher mortality, but those with diabetes as the cause of ESKD had significantly higher mortality [HR 2.50 (95% CI 1.36-4.59)]. CONCLUSIONS: In Peru, patients receiving HD at high altitudes do not have mortality benefits.

Potential Protective Effect from COVID-19 Conferred by Altitude: A Longitudinal Analysis in Peru During Full Lockdown.

Thomson, Timothy M., Fresia Casas, Harold Andre Guerrero, Rómulo Figueroa-Mujíca, Francisco C. Villafuerte, and Claudia Machicado. Potential protective effect from COVID-19 conferred by altitude: A longitudinal analysis in Peru during full lockdown. High Alt Med Biol. 22: 209-224, 2021. Background: The COVID-19 pandemic had a delayed onset in America. Despite the time advantage for the implementation of preventative measures to contain its spread, the pandemic followed growth rates that paralleled those observed before in Europe. Objectives: To analyze the temporal and geographical distribution of the COVID-19 pandemic at district-level in Perú during the full lockdown period in 2020. Methods: Analysis of publicly available data sets, stratified by altitude and geographical localization. Correlation tests of COVID-19 case and death rates to population prevalence of comorbidities. Results: We observe a strong protective effect of altitude from COVID-19 mortality in populations located above 2,500 m. We provide evidence that internal migration through a specific land route is a significant factor progressively overriding the protection from COVID-19 afforded by high altitude. This protection is independent of poverty indexes and is inversely correlated with the prevalence of hypertension and hypercholesterolemia. Discussion: Long-term adaptation to residency at high altitude may be the third general protective factor from COVID-19 severity and death, after young age and female sex. Multisystemic adaptive traits or acclimatization processes in response to chronic hypobaric hypoxia may explain the apparent protective effect of high altitude from COVID-19 death.

[Chronic exposure to altitude. Clinical characteristics and diagnosis]. / Exposición crónica a la altura. Características clínicas y diagnóstico

Chronic exposure to altitude has been associated with hypobaric hypoxia in its inhabitants. Two entities have been associated with it, high altitude pulmonary hypertension and chronic mountain sickness. Its physiological and pulmonary circulation characteristics are described, as well as its clinical profile and diagnosis.

La exposición crónica a la altitud se ha asociado a hipoxia hipobárica en quienes la experimentan. Dos entidades se han asociado a la hipoxia hipobárica: la hipertensión pulmonar de la alta altitud y el mal de montaña crónico. Se describen sus características fisiológicas y de la circulación pulmonar, así como su perfil clínico y el diagnóstico.

Beneficial effects of melatonin on prostanoids pathways in pulmonary hypertensive neonates.

Pulmonary arterial hypertension of the newborn (PAHN) is a syndrome caused by chronic hypoxia, characterized by decreased vasodilator function, a marked vasoconstrictor activity, proliferation of smooth muscle cells (SMC) and thickening of the extracellular matrix in the pulmonary circulation, among other characteristics. Prostaglandins are derived from the arachidonic acid (AA) metabolism and are important regulators of pulmonary vascular tone. Since hypoxia induces oxidative stress and has been related to PAHN, a postnatal treatment with melatonin has been proposed due to its antioxidant properties. Here, we determined the effects of melatonin on pulmonary vascular homeostasis given by prostanoids. Ten PAHN newborn lambs were divided in two groups and treated either with vehicle or melatonin. After 1 week of treatment, we assessed pulmonary vascular prostanoids function and expression by wire myography, RT-PCR, Western Blot and immunohistochemistry. Melatonin improved in vivo and ex vivo pulmonary vasodilation. This was associated with an increased function and expression of vasodilator prostanoids at the expense of vasoconstrictor prostanoids. Our study demonstrates for the first time that melatonin may enhance the vasodilator prostanoid pathway in PAHN.

Study of the Effect of Treatment With Atrial Natriuretic Peptide (ANP) and Cinaciguat in Chronic Hypoxic Neonatal Lambs on Residual Strain and Microstructure of the Arteries.

In this study, we assessed the effects of Atrial Natriuretic Peptide (ANP) and Cinaciguat, as experimental medicines to treat neonatal lambs exposed to chronic hypoxic conditions. To compare the different treatments, the mechanical responses of aorta, carotid, and femoral arterial walls were analyzed by means of axial pre-stretch and ring-opening tests, through a study with n = 6 animals for each group analyzed. The axial pre-stretch test measures the level of shortening in different zones of the arteries when extracted from lambs, while the ring-opening test is used to quantify the degree of residual circumferential deformation in a given zone of an artery. In addition, histological studies were carried out to measure elastin, collagen, and smooth muscle cell (SMC) nuclei densities, both in control and treated groups. The results show that mechanical response is related with histological results, specifically in the proximal abdominal aorta (PAA) and distal carotid zones (DCA), where the cell nuclei content is related to a decrease of residual deformations. The opening angle and the elastic fibers of the aorta artery were statistically correlated (p < 0.05). Specifically, in PAA zone, there are significant differences of opening angle and cell nuclei density values between control and treated groups (p-values to opening angle: Control-ANP = 2 ⋅ 10-2, Control-Cinaciguat = 1 ⋅ 10-2; p-values to cell nuclei density: Control-ANP = 5 ⋅ 10-4, Control-Cinaciguat = 2 ⋅ 10-2). Respect to distal carotid zone (DCA), significant differences between Control and Cinaciguat groups were observed to opening angle (p-value = 4 ⋅ 10-2), and cell nuclei density (p-value = 1 ⋅ 10-2). Our findings add evidence that medical treatments may have effects on the mechanical responses of arterial walls and should be taken into account when evaluating the complete medical outcome.

Long-term chronic intermittent hypoxia: a particular form of chronic high-altitude pulmonary hypertension.

In some subjects, high-altitude hypobaric hypoxia leads to high-altitude pulmonary hypertension. The threshold for the diagnosis of high-altitude pulmonary hypertension is a mean pulmonary artery pressure of 30 mmHg, even though for general pulmonary hypertension is ≥25 mmHg. High-altitude pulmonary hypertension has been associated with high hematocrit findings (chronic mountain sickness), and although these are two separate entities, they have a synergistic effect that should be considered. In recent years, a new condition associated with high altitude was described in South America named long-term chronic intermittent hypoxia and has appeared in individuals who commute to work at high altitude but live and rest at sea level. In this review, we discuss the initial epidemiological pattern from the early studies done in Chile, the clinical presentation and possible molecular mechanism and a discussion of the potential management of this condition.

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.

Indicadores de carga física de trabajo en exposición intermitente crónica a gran altura / Indicators of physical work load in chronic intermittent exposure at high altitude

Se han establecido regulaciones para la exposición ocupacional a cargas físicas del trabajo, y a hipoxia intermitente crónica (HIC). También se ha indicado incorporar los riesgos asociados a HIC a un sistema de gestión de seguridad y salud en el trabajo. Dado que las cargas físicas de trabajo (CFT) en HIC pueden condicionar riesgos de trabajo pesado y fatiga física, se considera oportuno revisar el efecto de la CFT a gran altitud, entre 3000 y 5500 m de altura, sobre el riesgo de trabajo pesado, por lo cual se procede a recopilar estudios de campo de la capacidad aeróbica, mediciones de los signos que permiten evaluar el % de Carga Cardiovascular (%CCV) ocupado a gran altura. El %CCV se calcula mediante las frecuencias cardíacas (FC) de reposo, la máxima y la de trabajo. El monitoreo continuo de la FC y mediciones directas de la capacidad aeróbica máxima muestran que en HIC se modifican las tres FC de %CCV, también se muestra que cuando la FC de trabajo en altitud está por sobre 110 latidos/minuto hay mayor riesgo de fatiga y trabajo pesado. Adicionalmente se encontró que la capacidad aeróbica, VO2máx, medido a nivel del mar se reduce en trabajadores aclimatados a HIC con una reducción del 7% de la FC máxima. Este efecto, entendido como frenación fisiológica protectora, se puede perder durante una desaclimatación a nivel de mar por más de 10 días. En vista de una mayor probabilidad de trabajo pesado en HIC se proponen intervenciones para prevenir, controlar y mitigar riesgos de fatiga, cansancio y trabajo pesado que afecten la salud, conducta segura y productividad. En conclusión, en faenas a gran altitud, la CFT se puede evaluar mediante medición del %CCV basada en registros de la FC de reposo, máxima y de trabajo, en cada cota donde se ejecuta la actividad laboral, porque la hipoxia hipobárica modifica los tres componentes de esa ecuación.

Regulations have been established for the occupational exposition to physical loads from work, and chronic intermittent hypoxia (HIC). Also, it has been indicated to include the associated HIC risks to a security and health management system at work. Since physical workload (CFT) in HIC can condition risks of hard work and physical fatigue, it is considered appropriate to review the CFT effect at high altitude, between 3000 and 5500m of altitude, over the risks of hard work, which is why is proceeding to compile field studies about the aerobic capacity, measures of signs that allows assessing the % of Cardiovascular load (%CCV) used at great altitudes. The % CCV is estimated by cardiac frequencies (FC) at rest, maximum, and from work. The FC continuous monitoring and direct measures of the maximum aerobic capacity displays that the three FC of %CCV are modified in HIC is also displayed that when the work FC in altitude is over 110 heartbeats/minute there is major fatigue and hard work risk. Moreover, it was determined that aerobic capacity, VO2 max, measured at sea level is reduced in acclimated workers to HIC with a 7% reduction of maximum FC. This effect, known as physiological protective restrain, can be lost during a deacclimation at sea level for more than 10 days. At the sight of a greater probability of hard work in HIC, interventions are proposed to prevent, control, and reduce fatigue risks, tiredness, and hard work that affects health, safe-conduct, and productivity. In conclusion, in chores at high altitudes, CFT can be assessed by measuring the %CCV based on date from the FC in rest, maximum and from work, in each height where work activities are performed, because the hypobaric hypoxia modifies the three components of that equation.

Melatonin long-lasting beneficial effects on pulmonary vascular reactivity and redox balance in chronic hypoxic ovine neonates.

Pulmonary arterial hypertension of the neonate (PAHN) is a pathophysiological condition characterized by maladaptive pulmonary vascular remodeling and abnormal contractile reactivity. This is a multifactorial syndrome with chronic hypoxia and oxidative stress as main etiological drivers, and with limited effectiveness in therapeutic approaches. Melatonin is a neurohormone with antioxidant and vasodilator properties at the pulmonary level. Therefore, this study aims to test whether a postnatal treatment with melatonin during the neonatal period improves in a long-lasting manner the clinical condition of PAHN. Ten newborn lambs gestated and born at 3600 m were used in this study, five received vehicle and five received melatonin in daily doses of 1 mg kg-1 for the first 3 weeks of life. After 1 week of treatment completion, lung tissue and small pulmonary arteries (SPA) were collected for wire myography, molecular biology, and morphostructural analyses. Melatonin decreased pulmonary arterial pressure the first 4 days of treatment. At 1 month old, melatonin decreased the contractile response to the vasoconstrictors K+ , TX2 , and ET-1. Further, melatonin increased the endothelium-dependent and muscle-dependent vasodilation of SPA. Finally, the treatment decreased pulmonary oxidative stress by inducing antioxidant enzymes and diminishing pro-oxidant sources. In conclusion, melatonin improved vascular reactivity and oxidative stress at the pulmonary level in PAHN lambs gestated and born in chronic hypoxia.

Space travel in a high altitude environment: Biology by-passing the pressure laws of physics and BioSpaceForming

After the accident on Apolo1, with 100% oxygen in the cabin, all spaceships now travel with a sea level pressure and 20.9% oxygen. Extravehicular activity requires lowering the pressures. It is complex and time consuming. Permanently reducing the cabin pressure would be a great advantage. A paper by NASA in 2013, proposed for the spaceflight environment: 8 psia / 32% O2 (reducing the sea level pressure (14.7 psi / 20.9% O2), but increasing the fraction of oxygen in order to replicate the sea level PaO2). However, we question this proposal, as it is based on the fear of hypoxia. Our proposal back in 2007 suggested that space travel should take place in a hypobaric environment of 9.5 psi / 20.9% O2 (like in the city of La Paz-Bolivia (3,600m) [11,811ft]). The logic behind it is that at all altitudes on planet Earth, life thrives in a 20.9% Oxygen, 79% Nitrogen. PaCO2 also needs to be considered. In a physiological manner, over 200 million inhabitants of high altitude above 2,000m [6,561ft], have perfectly normal lives. The astronauts could benefit of a Extra-Vehicular Activity (EVA) suit pressure of only 149 mmHg [2.8psi] (lighter, much more comfortable and efficient spacesuits) and space travel anemia could be reduced. The preparation prior-to-space travel could be carried out by adapting and living in a high altitude environment. We consider chronic hypoxia a fundamental step in BioSpaceForming (Adaptation to life in space). As all living beings start to move out of Earth into space, they will have to change their biology and adapt to new conditions.

Después del accidente del Apolo 1, ocurrido con 100 % de oxígeno en la cabina, todas las naves espaciales viajan con una presión de nivel del mar y 20,9 % de oxígeno. La actividad extravehicular requiere que se reduzcan las presiones. Es un proceso complejo que consume mucho tiempo. Reducir la presión de la cabina de manera permanente sería una gran ventaja. En un artículo de la NASA de 2013 se proponen las siguientes condiciones para el entorno de los vuelos espaciales: 8 psia / 32 % O2 (reduciendo la presión de nivel del mar (14,7 psi / 20,9 % O2), pero incrementando la fracción de oxígeno para replicar la PaO2 de nivel del mar). Sin embargo, nosotros nos cuestionamos esa propuesta, ya que está basada en el miedo a la hipoxia. La propuesta que hicimos en 2007 sugería que los vuelos espaciales se realizaran en un entorno hipobárico de 9,5 psi / 20,9 % O2 (como en la ciudad de La Paz, Bolivia (3 600 m) [11 811 ft]). El fundamento lógico es que en el planeta Tierra la vida se desarrolla a todas las alturas con 20,9 % oxígeno, 79 % nitrógeno, aunque también hay que tener en cuenta la PaCO2. Desde el punto de vista fisiológico, más de 200 millones de habitantes de grandes alturas de más de 2 000 m [6 561 ft] tienen una vida perfectamente normal. Para la Actividad Extra-Vehicular (EVA) a los astronautas les convendría más que el traje tuviera una presión de sólo 149 mmHg [2,8 psi], es decir, un traje más ligero y mucho más cómodo y eficiente, a la vez que se reduciría la ocurrencia de anemia espacial. La preparación previa al vuelo espacial podría basarse en la adaptación a un entorno de gran altitud y la vida en el mismo. Consideramos que la hipoxia crónica es un paso fundamental en la adaptación biológica y la supervivencia en el espacio. Todo organismo vivo que se traslade de la Tierra al espacio debe cambiar su biología y adaptarse a las nuevas condiciones.

Antenatal melatonin modulates an enhanced antioxidant/pro-oxidant ratio in pulmonary hypertensive newborn sheep.

Chronic hypobaric hypoxia during fetal and neonatal life induces neonatal pulmonary hypertension. Hypoxia and oxidative stress are driving this condition, which implies an increase generation of reactive oxygen species (ROS) and/or decreased antioxidant capacity. Melatonin has antioxidant properties that decrease oxidative stress and improves pulmonary vascular function when administered postnatally. However, the effects of an antenatal treatment with melatonin in the neonatal pulmonary function and oxidative status are unknown. Therefore, we hypothesized that an antenatal therapy with melatonin improves the pulmonary arterial pressure and antioxidant status in high altitude pulmonary hypertensive neonates. Twelve ewes were bred at high altitude (3600 m); 6 of them were used as a control group (vehicle 1.4% ethanol) and 6 as a melatonin treated group (10 mg d-1 melatonin in vehicle). Treatments were given once daily during the last third of gestation (100-150 days). Lambs were born and raised with their mothers until 12 days old, and neonatal pulmonary arterial pressure and resistance, plasma antioxidant capacity and the lung oxidative status were determined. Furthermore, we measured the pulmonary expression and activity for the antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidase, and the oxidative stress markers 8-isoprostanes, 4HNE and nitrotyrosine. Finally, we assessed pulmonary pro-oxidant sources by the expression and function of NADPH oxidase, mitochondria and xanthine oxidase. Melatonin decreased the birth weight. However, melatonin enhanced the plasma antioxidant capacity and decreased the pulmonary antioxidant activity, associated with a diminished oxidative stress during postnatal life. Interestingly, melatonin also decreased ROS generation at the main pro-oxidant sources. Our findings suggest that antenatal administration of melatonin programs an enhanced antioxidant/pro-oxidant status, modulating ROS sources in the postnatal lung.

Carotid Body Type-I Cells Under Chronic Sustained Hypoxia: Focus on Metabolism and Membrane Excitability.

Chronic sustained hypoxia (CSH) evokes ventilatory acclimatization characterized by a progressive hyperventilation due to a potentiation of the carotid body (CB) chemosensory response to hypoxia. The transduction of the hypoxic stimulus in the CB begins with the inhibition of K+ currents in the chemosensory (type-I) cells, which in turn leads to membrane depolarization, Ca2+ entry and the subsequent release of one- or more-excitatory neurotransmitters. Several studies have shown that CSH modifies both the level of transmitters and chemoreceptor cell metabolism within the CB. Most of these studies have been focused on the role played by such putative transmitters and modulators of CB chemoreception, but less is known about the effect of CSH on metabolism and membrane excitability of type-I cells. In this mini-review, we will examine the effects of CSH on the ion channels activity and excitability of type-I cell, with a particular focus on the effects of CSH on the TASK-like background K+ channel. We propose that changes on TASK-like channel activity induced by CSH may contribute to explain the potentiation of CB chemosensory activity.

Melatonin Decreases Pulmonary Vascular Remodeling and Oxygen Sensitivity in Pulmonary Hypertensive Newborn Lambs.

Background: Chronic hypoxia and oxidative stress during gestation lead to pulmonary hypertension of the neonate (PHN), a condition characterized by abnormal pulmonary arterial reactivity and remodeling. Melatonin has strong antioxidant properties and improves pulmonary vascular function. Here, we aimed to study the effects of melatonin on the function and structure of pulmonary arteries from PHN lambs. Methods: Twelve lambs (Ovis aries) gestated and born at highlands (3,600 m) were instrumented with systemic and pulmonary catheters. Six of them were assigned to the control group (CN, oral vehicle) and 6 were treated with melatonin (MN, 1 mg.kg-1.d-1) during 10 days. At the end of treatment, we performed a graded oxygenation protocol to assess cardiopulmonary responses to inspired oxygen variations. Further, we obtained lung and pulmonary trunk samples for histology, molecular biology, and immunohistochemistry determinations. Results: Melatonin reduced the in vivo pulmonary pressor response to oxygenation changes. In addition, melatonin decreased cellular density of the media and diminished the proliferation marker KI67 in resistance vessels and pulmonary trunk (p < 0.05). This was associated with a decreased in the remodeling markers α-actin (CN 1.28 ± 0.18 vs. MN 0.77 ± 0.04, p < 0.05) and smoothelin-B (CN 2.13 ± 0.31 vs. MN 0.88 ± 0.27, p < 0.05). Further, melatonin increased vascular density by 134% and vascular luminal surface by 173% (p < 0.05). Finally, melatonin decreased nitrotyrosine, an oxidative stress marker, in small pulmonary vessels (CN 5.12 ± 0.84 vs. MN 1.14 ± 0.34, p < 0.05). Conclusion: Postnatal administration of melatonin blunts the cardiopulmonary response to hypoxia, reduces the pathological vascular remodeling, and increases angiogenesis in pulmonary hypertensive neonatal lambs.These effects improve the pulmonary vascular structure and function in the neonatal period under chronic hypoxia.