Nitric oxide in adaptation to altitude

This review summarizes published information on the levels of nitric oxide gas (NO) in the lungs and NO-derived liquid-phase molecules in the acclimatization of visitors newly arrived at altitudes of 2500 m or more and adaptation of populations whose ancestors arrived thousands of years ago. Studies of acutely exposed visitors to high altitude focus on the first 24-48 h with just a few extending to days or weeks. Among healthy visitors, NO levels in the lung, plasma, and/or red blood cells fell within 2h, but then returned toward baseline or slightly higher by 48 h and increased above baseline by 5 days. Among visitors ill with high-altitude pulmonary edema at the time of the study or in the past, NO levels were lower than those of their healthy counterparts. As for highland populations, Tibetans had NO levels in the lung, plasma, and red blood cells that were at least double and in some cases orders of magnitude greater than other populations regardless of altitude. Red blood cell-associated nitrogen oxides were more than 200 times higher. Other highland populations had generally higher levels although not to the degree shown by Tibetans. Overall, responses of those acclimatized and those presumed to be adapted are in the same direction, although the Tibetans have much larger responses. Missing are long-term data on lowlanders at altitude showing how similar they become to the Tibetan phenotype. Also missing are data on Tibetans at low altitude to see the extent to which their phenotype is a response to the immediate environment or expressed constitutively. The mechanisms causing the visitors' and the Tibetans' high levels of NO and NO-derived molecules at altitude remain unknown. Limited data suggest processes including hypoxic upregulation of NO synthase gene expression, hemoglobin-NO reactions, and genetic variation. Gains in understanding will require integrating appropriate methods and measurement techniques with indicators of adaptive function under hypoxic stress.     

Changes in neutral peptide hydrolase levels in the blood and catecholamine levels in the tissues during adaptation to high altitude hypoxia

Activity of neutral peptide-hydrolases in blood plasma and content of catecholamines in the tissues of rats under conditions of their stay in mountains at different height have been studied in dynamics. Unidirectional phase changes in activity of proteolytic enzymes of blood plasma and content of catecholamines in adrenal glands are revealed. A conclusion is made on participation of neutral blood peptide-hydrolases in organism adapted to Alpine hypoxia. Relations between neutral blood peptide-hydrolases and catecholamines in the organism and possibility of their direct mutual effect are under discussion.     

Thoracic adaptation to high altitude

Growth in the thoracic region and its adaptation to higher altitude was investigated in boys between 5 to 18 years of Rajput origin at two altitudes, i. e. Rampur Bushahr (800 m above sea level) and Kinnaur (3,000 m above sea level). Both places are located in Himachal Pradesh. The sample includes 405 individuals From Bushahr and 676 individuals from Kinnaur. The results of this study reveal that as the higher altitudes are attained the vital capacity also increases relatively more, and these differences become more pronounced after adolescence, indicating longer time of apnoea. The population living at higher altitudes is also characterised by a significant greater chest length.     

Developmental adaptation to high altitude hypoxia

Experimental studies on animals and humans exposed to hypoxic stress have been reviewed. These data suggest that the influence of hypoxic stress, and the organism's response to it, are greater during growth than during adulthood. The organism's responses include alterations in the quantity and size of the alveolar units of the lungs, enlargement of the right ventricle of the heart, slower somatic growth as measured by birth weight and body size, increased aerobic capacity during maximal work, and greater control of ventilation. It is postulated that the organism is more sensitive to the influence of environmental factors during growth and development than during adulthood. Consequently, adaptive traits acquired during the developmental period have profound, long-term consequences, which are reflected in the physiological and morphological characteristics of the adult organism. It is concluded that the differences between the highland and lowland natives in their physiological performance and morphology are mostly due to adaptations acquired during the developmental period.Attention is called to the fact that the principle of developmental sensitivity and plasticity does not imply equally adaptive responses in all biological parameters. In other words, what we consider a deficiency in a given variable may actually reflect the indirect influence of the adaptive success of another variable.Presented at the Seventh International Biometeorological Congress, 17–23 August 1975, College Park Maryland, USA.     

动物对高原低氧的适应性研究进展

本文从血液学、肺动脉、心肺发育及其它方面简要介绍了动物对高原低氧适应的生理、生化及形态学特征,同时也对其中低氧诱导因子的作用及其遗传性方面的研究进行了概述。关于高原低氧适应的遗传机制仍需进一步的深入研究。     

Metabolism of Immunoglobulin-G in the Horse

The metabolism of immunoglobulin classes has been closely examined in several animal species. Although the horse has received much attention in experimental and applied immunology there seems to be little information available on immunoglobulin kinetics in this species. The present report describes the metabolism of equine IgG in 4 healthy, normoimmunoglobulinaemic horses, in 1 horse with hyperimmunoglobulinaemia and in 1 horse with relatively low immunoglobulin levels.     

Genetic adaptation to high altitude in the Ethiopian highlands

Background

Genomic analysis of high-altitude populations residing in the Andes and Tibet has revealed several candidate loci for involvement in high-altitude adaptation, a subset of which have also been shown to be associated with hemoglobin levels, including EPAS1, EGLN1, and PPARA, which play a role in the HIF-1 pathway. Here, we have extended this work to high- and low-altitude populations living in Ethiopia, for which we have measured hemoglobin levels. We genotyped the Illumina 1M SNP array and employed several genome-wide scans for selection and targeted association with hemoglobin levels to identify genes that play a role in adaptation to high altitude.

Results

We have identified a set of candidate genes for positive selection in our high-altitude population sample, demonstrated significantly different hemoglobin levels between high- and low-altitude Ethiopians and have identified a subset of candidate genes for selection, several of which also show suggestive associations with hemoglobin levels.

Conclusions

We highlight several candidate genes for involvement in high-altitude adaptation in Ethiopia, including CBARA1, VAV3, ARNT2 and THRB. Although most of these genes have not been identified in previous studies of high-altitude Tibetan or Andean population samples, two of these genes (THRB and ARNT2) play a role in the HIF-1 pathway, a pathway implicated in previous work reported in Tibetan and Andean studies. These combined results suggest that adaptation to high altitude arose independently due to convergent evolution in high-altitude Amhara populations in Ethiopia.     

High altitude adaptation in Daghestani populations from the Caucasus

We have surveyed 15 high-altitude adaptation candidate genes for signals of positive selection in North Caucasian highlanders using targeted re-sequencing. A total of 49 unrelated Daghestani from three ethnic groups (Avars, Kubachians, and Laks) living in ancient villages located at around 2,000 m above sea level were chosen as the study population. Caucasian (Adygei living at sea level, N = 20) and CEU (CEPH Utah residents with ancestry from northern and western Europe; N = 20) were used as controls. Candidate genes were compared with 20 putatively neutral control regions resequenced in the same individuals. The regions of interest were amplified by long-PCR, pooled according to individual, indexed by adding an eight-nucleotide tag, and sequenced using the Illumina GAII platform. 1,066 SNPs were called using false discovery and false negative thresholds of ~6%. The neutral regions provided an empirical null distribution to compare with the candidate genes for signals of selection. Two genes stood out. In Laks, a non-synonymous variant within HIF1A already known to be associated with improvement in oxygen metabolism was rediscovered, and in Kubachians a cluster of 13 SNPs located in a conserved intronic region within EGLN1 showing high population differentiation was found. These variants illustrate both the common pathways of adaptation to high altitude in different populations and features specific to the Daghestani populations, showing how even a mildly hypoxic environment can lead to genetic adaptation.     

Functional development of the altitude convulsion mechanism in mice and rabbits

Fifty one young mice from 6 litters and 17 young rabbits from 3 litters at different ages were used for determining their functional maturation of the altitude convulsion mechanism. It was found that none of the 1 to 9-day-old mice exhibited convulsion when they were subjected to severe hypoxia. The frequency of altitude convulsions at ages of 10, 11, 12 and 13 days was 9%, 53%, 71% and 100% respectively. On the other hand, altitude convulsion was observed in 2 of 6 19-day-old (33%), 5 of 8 21-day-old (63%), 5 of 6 23-day-old (83%) and all of 24-day-old rabbits (100%). The average functional maturation period of the altitude convulsion mechanism in young mice and rabbits was shown to be 12 and 22 days of age respectively. It is clear that such a mechanism matures at different rates in different species.     

Enzyme activities in red and white muscles of guinea-pigs and rabbits indigenous to high altitude.

The activities of several enzymes functioning in different areas of fuel catabolism were measured under standardized conditions, using crude homogenates of sartorius and ventricular muscle from outbred guinea-pigs and rabbits indigenous to high or low altitude. The activities of sartorius and myocardium were found to reflect the metabolic patterns known to be associated with white and red muscle. Both species had right ventricular hypertrophy at high altitude. The enzyme activities in the high altitude guinea-pig were not significantly different from those in the sea level animals. In the high altitude rabbit, compared with the low altitude rabbit, the activities of glyceraldehyde-3-phosphate deydrogenase and phosphofructokinase were greater in both the sartorius and myocardium. In addition, mitochondrial glycerol-3-phosphate dehydrogenase activity was greater in the sartorius at high altitude, while aspartate aminotransferase and beta-hydroxyacylcoenzyme A dehydrogenase activities were greater in the myocardium at high altitude. Succinate dehydrogenase activity was comparable at the two altitudes for both tissues. There was a greater proportion of skeletal muscle type lactate dehydrogenase in the high altitude rabbit myocardium but no difference was found with the guinea-pig.     

Limb skeletal muscle adaptation in athletes after training at altitude

Morphological and biochemical characteristics of biopsies obtained from gastrocnemius (GAS) and triceps brachii muscle (TRI), as well as maximal O2 uptake (VO2 max) and O2 deficit, were determined in 10 well-trained cross-country skiers before and after a 2-wk stay (2,100 m above sea level) and training (2,700 m above sea level) at altitude. On return to sea level, VO2 max was the same as the prealtitude value, whereas an increase in O2 deficit (29%) and in short-term running performance (17%) was observed (P less than 0.05). GAS showed maintained capillary supply but a 10% decrease in mitochondrial enzyme activities (P less than 0.05), whereas an increase in capillary supply (P less than 0.05) but unchanged mitochondrial enzyme activities were observed in TRI. Buffer capacity was increased by 6% in both GAS and TRI (P less than 0.05). A positive correlation was found between the relative increase in buffer capacity of GAS and short-term running time (P less than 0.05). Thus the present study indicates no effect of 2 wk of altitude training on VO2 max but provides evidence to suggest an improvement in short-term exercise performance, which may be the result of an increase in muscle buffer capacity.     

Control of breathing and adaptation to high altitude in the bar-headed goose

The bar-headed goose flies over the Himalayan mountains on its migratory route between South and Central Asia, reaching altitudes of up to 9,000 m. We compared control of breathing in this species with that of low-altitude waterfowl by exposing birds to step decreases in inspired O(2) under both poikilocapnic and isocapnic conditions. Bar-headed geese breathed substantially more than both greylag geese and pekin ducks during severe environmental (poikilocapnic) hypoxia (5% inspired O(2)). This was entirely due to an enhanced tidal volume response to hypoxia, which would have further improved parabronchial (effective) ventilation. Consequently, O(2) loading into the blood and arterial Po(2) were substantially improved. Because air convection requirements were similar between species at 5% inspired O(2), it was the enhanced tidal volume response (not total ventilation per se) that improved O(2) loading in bar-headed geese. Other observations suggest that bar-headed geese depress metabolism less than low-altitude birds during hypoxia and also may be capable of generating higher inspiratory airflows. There were no differences between species in ventilatory sensitivities to isocapnic hypoxia, the hypoxia-induced changes in blood CO(2) tensions or pH, or hypercapnic ventilatory sensitivities. Overall, our results suggest that evolutionary changes in the respiratory control system of bar-headed geese enhance O(2) loading into the blood and may contribute to this species' exceptional ability to fly high.     

Hypoxia and the CNS: Maturation and adaptation at high altitude

The well known circulatory, including hemopoetic, and respiratory adjustments to high altitude often serve as classic examples of adaptation to specific environmental conditions. Less extensively studied are the contributions of the nervous and endocrine systems to such adaptive mechanisms even though their involvement in humans and animals is indisputed. Observations from our and other laboratories have identified in the rat a number of neurologic and endocrine responses to acute and prolonged exposure to high altitude attributable primarily to its hypoxic component. These responses include general retardation in maturation and function of the central nervous system as manifested by alterations in spontaneous and evoked electrical activity particularly in the limbic structures and involving selectively the synapse and are associated with impairment of brain protein and lipid metabolism, myelinogenesis and neurotransmission. Together with these neurologic disturbances, endocrine dysfunctions lead to alterations in growth, fertility and metabolism. Thus hypoxia, even of moderate severity, would affect profoundly the biochemical and functional maturation and activity of the brain and endocrines, and, reciprocally, prevention and treatment of these neuroendocrine imbalances might strengthen the adaptive competence of the individual.