The Effects of High-Altitude Exposure on

Reactive Oxygen and Nitrogen Species 18

Zsolt Radak, Zoltan Acs, Zoltan Bori, Albert W. Taylor, and
Hu Yang

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
High-Altitude Exposure and Generation of RONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
The Effect of High Altitude on Antioxidant Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410
High Altitude and Oxidative Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414

Abstract
High-altitude exposure that results in decreased levels of oxygen pressure, which
could lead to hypoxia, can activate a number of sources that can generate reactive
oxygen and nitrogen species (RONS). Enhanced formation of RONS causes
oxidative damage, which impacts cellular function and could seriously impair
organ function. In addition, high altitude appears to weaken the enzymatic and
nonenzymatic antioxidant systems. Indeed, recent data suggest that the expression
of Mn-SOD in skeletal muscle of mountaineers, who stayed for more than 6 weeks
above 6,000 m, decreased significantly 1 week after leaving that altitude.

Z. Radak (*) Z. Acs Z. Bori

Insitute of Sport Science, Faculty of Physical Education and Sport Science, Semmelweis
University, Budapest, Hungary
e-mail: radak@mail.hupe.hu; cix21@yahoo.com; radak@tf.hu; acs_zoltan@hotmail.com;
bori@tf.hu
A.W. Taylor
School of Kinesiology, Faculty of Health Sciences and Department of Physiology, Faculty of
Medicine and Dentistry, University of Western Ontario, London, ON, Canada
e-mail: ataylor2@uwo.ca
H. Yang
Research Institute, Beijing Sport University, Beijing, China
e-mail: hyyr1@163.com

I. Laher (ed.), Systems Biology of Free Radicals and Antioxidants, 407

DOI 10.1007/978-3-642-30018-9_28, # Springer-Verlag Berlin Heidelberg 2014
408 Z. Radak et al.

Moreover, the expression of Ku70, which plays an important role in DNA repair,
increased after exposure to high altitude, indicating increased DNA damage.
Therefore, it appears that increased nutritional uptake of antioxidant vitamins
reduce altitude-induced oxidative damage. The pattern of high-altitude expo-
sure-associated oxidative damage is similar to ischemia/reperfusion injury. The
adaptive process for this oxidative challenge is relatively long, and physical
exercise or enhanced levels of physical activity at high altitude exacerbate the
extent of the oxidative challenge. Therefore, special attention must be given to any
and all processes which modulate the degree of oxidative stress.

Keywords
Acute mountain sickness Antioxidants High altitude Oxidative damage
Oxidative stress Reactive oxygen and nitrogen species

Introduction

Generation of reactive oxygen and nitrogen species (RONS) is a natural conse-

quence of aerobic metabolism, since a number of RONS-generating systems are
found in the mammalian body. High altitude results in altered metabolism, which
naturally affects RONS production. RONS are physiological modulators of cellular
redox milieu and thereby signaling, controlling factors of a wide range of known
and unknown physiological, pathophysiological processes. Despite the multiline
antioxidant system, the level of RONS generation can exceed the capability of the
defense network, leading to oxidative stress (Askew 2002; Bailey et al. 2009;
Mitteldorf 2010). It is generally assumed that increases in aerobic metabolism,
such as exhaustive exercise or hyperoxia, easily generate increased levels of RONS,
causing alteration of redox homeostasis and oxidative damage to lipids, proteins,
and DNA (Bailey and Davies 2001; Bailey et al. 2001; Mariggio et al. 2010; Radak
et al. 1995, 2001). Physical exercise, which is depicted by mountaineering, could
lead to oxidative challenge and damage to different organs, while exercise and
high-altitude exposure often result in oxidative damage (Radak et al. 1997, 2001;
Wozniak et al. 2001). The increased level of RONS production is due to the
involvement of a number of different RONS-generating systems. Although low
oxygen pressure seems to favor low RONS production, it appears that high-altitude
exposure-associated increases in oxidative damage are a consequence of the altered
activity of the RONS-generating and antioxidant systems. However, high altitude
does not always result in increased levels of ROS in every system (Faoro et al.
2011). Moreover, the fact that increased free radical production (superoxides for
instance) could significantly alter the bioavailability of nitric oxide (NO) compli-
cates redox homeostasis at high altitude (Scherrer et al. 2010b). Indeed, it has been
shown that increased ROS production decreases the bioavailability of NO after
active ascent to 4,500 m (Mariggio et al. 2010), which could be one of the reasons
for high altitude-associated increases in pulmonary artery systolic pressure and
vascular resistance. Moreover, high altitude may alter not only RONS production
18 The Effects of High-Altitude Exposure on Reactive Oxygen and Nitrogen Species 409

Fig. 18.1 This schematic figure summarizes the generation of free radical species and the effects
of antioxidant enzymes

but also the enzymatic and nonenzymatic systems which are affected by exposure to
high altitude (Chao et al. 1999; Imai et al. 1995) (Fig. 18.1). In addition, the activity
of housekeeping enzymes that are involved in the repair of oxidative damage could
also be impaired by high altitude.

High-Altitude Exposure and Generation of RONS

It is well documented that excessive oxygen supply results in increased mitochon-

drial ROS production, and it has been suggested that 12 % of the oxygen which
enters the mitochondria is released as ROS. On the other hand, it appears that
hypoxia can lead to reduced stress, which also results in increased ROS production
by the mitochondrial electron transport system (Mohanraj et al. 1998). It is believed
that ROS are generated at complex I and complex III of the electron transport chain.
During hypoxia, less O2 is available to be reduced to H2O at cytochrome oxidase,
causing accumulation of reducing equivalents within the mitochondrial respiratory
sequence. This phenomenon is known as reductive stress, which leads to ROS
formation by the auto-oxidation of one or more mitochondrial complexes such as the
ubiquinone-ubiquinol redox couple. Khan and OBrien (1995) demonstrated increases
in the cellular NADH/NAD+ ratio during hypoxia-associated reductive stress.
410 Z. Radak et al.

The NADH/NAD+ ratio represents the redox metabolism, and it also influences
NAD-dependent proteins, such as sirtuins, poly-ADP-ribose polymerase, and
lactate dehydrogenase. These proteins control important metabolic processes such
as apoptosis and lactate metabolism. Recently, it has been investigated whether
high-altitude exposure alters the expressions of sirtuins, and it was observed that
SIRT1 and SIRT6 tend to decrease at high altitude (Acs et al., unpublished
observation).
At very low oxygen availability, which occurs with ischemia or exposure to very
low oxygen pressure, such as altitude over 6,000 m, cells tend to generate ATP via
the interaction of two ADP, which are catalyzed by adenylate kinase. This process
also generates AMP, which cannot be recycled and is broken down to form
hypoxanthine. In the presence of calcium-related proteases, xanthine dehydroge-
nase can be converted to xanthine oxidase, which uses molecular oxygen instead of
NAD+ as an electron acceptor, with the consequent production of xanthine plus
superoxide anion or H2O2 (Radak et al. 1995). The xanthine dehydrogenase/oxidase
system is a potent ROS generator during hypoxia/reperfusion conditions. Intermit-
tent exposure to high altitude has similar characteristics as ischemia/reperfusion
(Radak et al. 1994). On the other hand, the changing pattern of ROS and nitric oxide
(NO) is different during ischemia/reperfusion and exposure to high altitude
(Schneider et al. 2001). During ischemia/reperfusion, the initial response is accom-
panied by a reversible increase in the generation of ROS and is blocked by
antioxidants and by interventions that increase the tissue levels of NO. In contrast
to ischemia/reperfusion, ROS levels increase during hypoxia and return to pre-
hypoxic values once normoxia is reached. Acclimatization involves the
upregulation of inducible nitric oxide synthase (iNOS), suggesting that hypoxia
leads to an alteration of the ROS/NO balance, which is eventually restored during
the acclimatization process (Gonzalez and Wood 2001). This phenomenon may
have relevance to the microcirculatory alterations associated with hypoxic expo-
sure, including acute mountain sickness and high-altitude pulmonary and cerebral
edema (Scherrer et al. 2010a, b). The findings of Serrano et al. (2003) indicate that
the involvement of different types of NOS results in a variance in NO production
during high altitude, which can lead to an increased formation of nitrotyrosine in rat
cerebellum after reoxygenation to sea level (Fig. 18.2).
Besides the above-mentioned RONS-generating systems, it is well known that
UV radiation is significantly increased at high altitude, resulting in enhanced
formation of RONS. It seems that high altitude-associated increases in ROS
generation are due to a multitude of sources, including mitochondrial respiratory
chain, xanthine oxidase, and iNOS.

The Effect of High Altitude on Antioxidant Systems

There are an increased number of investigations on the effects of high altitude on

the antioxidant system, and the findings seem to vary significantly. It is perhaps
meaningful that some native highlander tribes in India often eat the seeds of
 18

Pulmonary artery systolic pressure

Hypoxia UV Vascular resistanc
ADP+ADP= ATP+AMP Reductive NO
stress
Hypoxanthine
Xanthine RONS
NADH/NAD Sirtuins, PARP,
dehydrogenase lactate dehydrogenase
XO
Metabolism Apoptosis
Xanthine O2 Antioxidant
Mn-SOD, GPX Oxidative
system and
Ku70 stress
capacity
ROS
NO
Protein carbonylation
DNA damage
Acclimatisation Lipid peroxidation

iNOS

Cell, organ function

The Effects of High-Altitude Exposure on Reactive Oxygen and Nitrogen Species

Fig. 18.2 The hypothetical summary of high altitude-induced adaptations to redox systems
411
412 Z. Radak et al.

Trichopus zeylanicus, which have been shown to scavenge free radicals and reduce
the level of lipid peroxidation and DNA damage by their antioxidant capacity
(probably due to their polyphenol and sulfhydryl content) (Tharakan et al. 2005).
In Korea, a traditional nutrient that decreases the deleterious effects of high altitude
has been found (Nugroho et al. 2009). A recent study assessed the uric acid content
of lowlanders and highlanders in India, and it was found that lowlanders had higher
levels of uric acid but not enough to protect against high altitude-induced oxidative
stress (Sinha et al. 2009). One of the first studies on the effect of altitude on an
enzymatic antioxidant system came from our laboratory. We reported that 6 months
of intermittent exposure to high altitude (4,000 m) results in decreased activity and
protein content of mitochondrial SOD in skeletal muscle of rats (Radak et al. 1994).
The decreased levels of Mn-SOD protein mean that intermittent exposure to high
altitude affected the transcription of the enzyme as well. These data were confirmed
by Nakanishi et al. (1995), who found that 5,500 m simulated altitude increased the
levels of immunoreactive Mn-SOD in serum and decreased those in the liver and
lung. The activity of glutathione peroxidase (GPX) also decreased in liver,
suggesting that liver might be especially sensitive to high altitude-induced oxida-
tive stress (Nakanishi et al. 1995). Imai et al. (1995) compared the activity of GPX
in serum of native highlanders (4,000 m) and subjects from sea level. They found
that high-altitude residents had lower levels of GPX activity. The activity and
effectiveness of GPX are strongly dependent upon the state of the thiol system.
Glutamyl-cysteinyl-glycine is one of the main thiol/antioxidant sources of the cell,
which is continuously synthesized by glutamyl cycle. High-altitude exposure
decreases the levels of reduced glutathione (GSH) and increases oxidized glutathi-
one concentration (Ilavazhagan et al. 2001; Joanny et al. 2001). Thus, it appears that
the capacity of enzymatic and nonenzymatic antioxidant systems is somewhat
decreased at high altitude. Schmidt et al. (2002) have applied an antioxidant
mixture containing vitamin E, beta-carotene, ascorbic acid, selenium, alpha-lipoic
acid, N-acetyl 1-cysteine, catechin, lutein, and lycopene to reduce oxidative stress
caused by altitude. This mixture has proven to be effective, and the level of
oxidative damage is reduced after ingestion.
Supplementation of vitamin E (40 mg per rat x d( 1)) orally, 5 days prior to and
during a period of hypoxic exposure to 7,576 m, significantly reduced the high
altitude-induced increase in lipid peroxidation in rats (Ilavazhagan et al. 2001). On
the other hand, an antioxidant supplement mixture containing 20,000 IU beta-
carotene, 400 IU vitamin E, 500 mg vitamin C, 100 mg selenium, and 30 mg zinc
(in a daily base) did not prevent oxidative damage to macromolecules (Pfeiffer et al.
1999). Subudhi et al. revealed that antioxidant supplementation attenuated the high
altitude-induced decreases in ventilatory threshold in exercising man (Subudhi
et al. 2006). Additionally, it appears that resistance to high-altitude pulmonary
edema, which is dependent on antioxidant capacity, is genetically controlled. Two
oxidative-stress-related genes CYBA (cytochrome b-245 a polypeptide) and
GSTP1 (glutathione transferase Pi 1) were studied by Mishra and coworkers
(2012) who found that the genotype distribution of -930A/G, H72Y (C/T), and
I105V (A/G) differed significantly in patients with high-altitude pulmonary edema
18 The Effects of High-Altitude Exposure on Reactive Oxygen and Nitrogen Species 413

compared with high-altitude pulmonary edema-resistant lowlanders and healthy

native highlanders.
Thus, exposure to high altitude decreases the activity and content of some
antioxidant enzymes. Moreover, the effectiveness of the thiol system is reduced
at high altitude. There are some indications that antioxidant supplementation
reduces or prevents high altitude-induced oxidative damage to macromolecules.
Moreover, it appears that polymorphism of certain antioxidant genes can modulate
the sensitivity to high altitude-induced pulmonary edema.

High Altitude and Oxidative Damage

The reactivity of RONS makes them difficult to measure, and it is very usual that
from the accumulation of the end product of RONS and lipids, proteins, and DNA
interaction, the extent of oxidative stress is judged. The grade of oxidative damage
reflects the balance between the generation of RONS and antioxidant/repair sys-
tems. It has been shown that intermittent exposure (12 h/day) to simulated altitude
of 4,000 m results in increased lipid peroxidation in skeletal muscle (Radak et al.
1994). It is also known that the level of lipid peroxidation, although it increases in
both fiber types, is related to the metabolic capacity of the muscle (Radak et al.
1994). Interestingly, after 4 weeks of continuous exposure to the same altitude,
increased lipid peroxidation was not observed, which indicates that the intermittent
exposure either increases the RONS more significantly, probably by xanthine
oxidase, or the capability of the antioxidant system declined more significantly
than during continuous exposure to altitude. On the other hand, exposure to 4,000 m
increased the level of oxidative protein damage, measured by carbonyl derivatives
in skeletal muscle of rats (Radak et al. 1997). Immunoblot data suggest, based on
the molecular weight of proteins, that actin could readily accumulate carbonyl
bonds as a result of high-altitude exposure. The level of carbonylation has been
shown to decrease in rat brain with exposure to 4,000 m (Radak et al. 1998). Kumar
et al. also reported that short exposure (5 days) to an altitude of 7,576 m caused
increased lipid peroxidation in rat plasma (Kumar et al. 1999). This result was
confirmed using the same experimental protocol, but adding vitamin E supplanted
groups (Ilavazhagan et al. 2001). Three- and 7-day exposures to 6,100 m significantly
increased RONS and lipid peroxidation in different brain regions (Maiti et al. 2006).
Exposure to 8,235 m for 7 h and reoxygenation resulted in increased activity of nNOS,
eNOS, and associated increases in nitrotyrosine content in rat cerebellum (Serrano
et al. 2003). Although, naturally, there is an organ-specific response to exposure to
high altitude, the effects seem to be systemic, which is nicely demonstrated by
Nakanishi and coworkers (1995) who reported that exposure to 5,500 m resulted in
increased levels of malondialdehyde in serum, lung, liver, heart, and kidney.
Human studies have revealed similar results. Reoxygenation after returning from
3,500 m resulted in oxidative damage to the membrane of erythrocytes obtained
from humans (Gonzalez et al. 2005). Moller et al. (2001) exposed 12 healthy
subjects to an altitude of 4,559 m, which caused a significant increase in DNA
414 Z. Radak et al.

strand breaks, measured from urine samples. The damage was more prominent at
the endonuclease III sites. When humans were exposed simultaneously to high
altitude (2,700 m) and exposure to cold temperature, the levels of urinary lipid
peroxidation and DNA damage increased significantly (Schmidt et al. 2002). The
Operation Everest III study revealed that the levels of lipid peroxidation increased
by 23 % at 6,000 m and by 79 % at 8,848 m, indicating that the level of oxidative
stress is directly correlational with the increase in altitude (Joanny et al. 2001).
In a recent study, the acclimatization to 4,500 m was studied, and blood samples
were collected after 3 and 13 months of exposure (Vij et al. 2005). At 3 months,
increased lipid peroxidation and decreased enzymatic and nonenzymatic defense
systems were noted, while at 13 months, the redox balance was normalized. Indeed,
when well-trained cyclists, who were residents of moderate altitude, have been
subjected to intensive interval exercise sessions at altitude (1,860 m), oxidative
stress markers did not change, suggesting the importance of genetic adaptation
(Wilber et al. 2004). When low- and highlanders resistance to oxidative stress
was evaluated, it turned out that lowlanders have shown higher susceptibility to
hypoxic insult than highlanders at rest, but when subjected to exercise, they
demonstrated a better tolerance to hypoxia than highlanders (Sinha et al. 2010).
Thus, both human and animal studies are relatively consistent in reporting that
high altitude-associated hypoxia causes oxidative damage to lipids, proteins, and
DNA. This damage can be due to the increased level of ROS production and/or
decreased level of antioxidant capacity. It also appears that long-term acclimatiza-
tion or genetic adaptation attenuates or eliminates the high altitude-induced
oxidative stress.

Conclusion

Exposure to high altitude disrupts the efficiency of the antioxidant systems and, due
to the increased level of RONS production, can lead to oxidative damage of
macromolecules. Physical exercise can exacerbate the effects of high altitude and
further can increase the related oxidative stress. Antioxidant supplementation has
been shown to have beneficial effects and can attenuate and/or prevent the oxidative
damage associated with high altitude and exercise at altitude.

References
Askew EW (2002) Work at high altitude and oxidative stress: antioxidant nutrients. Toxicology
180:107119
Bailey DM, Davies B (2001) Acute mountain sickness; prophylactic benefits of antioxidant
vitamin supplementation at high altitude. High Alt Med Biol 2:2129
Bailey DM, Davies B, Young IS, Hullin DA, Seddon PS (2001) A potential role for free
radical-mediated skeletal muscle soreness in the pathophysiology of acute mountain sickness.
Aviat Space Environ Med 72:513521
18 The Effects of High-Altitude Exposure on Reactive Oxygen and Nitrogen Species 415

Bailey DM, Bartsch P, Knauth M, Baumgartner RW (2009) Emerging concepts in acute mountain
sickness and high-altitude cerebral edema: from the molecular to the morphological. Cell Mol
Life Sci 66:35833594
Chao WH, Askew EW, Roberts DE, Wood SM, Perkins JB (1999) Oxidative stress in humans
during work at moderate altitude. J Nutr 129:20092012
Faoro V, Fink B, Taudorf S, Dehnert C, Berger MM, Swenson ER, Bailey DM, Bartsch P,
Mairbaurl H (2011) Acute in vitro hypoxia and high-altitude (4,559 m) exposure decreases
leukocyte oxygen consumption. Am J Physiol Regul Integr Comp Physiol 300:R32R39
Gonzalez NC, Wood JG (2001) Leukocyte-endothelial interactions in environmental hypoxia.
Adv Exp Med Biol 502:3960
Gonzalez G, Celedon G, Escobar M, Sotomayor C, Ferrer V, Benitez D, Behn C (2005) Red cell
membrane lipid changes at 3,500 m and on return to sea level. High Alt Med Biol 6:320326
Ilavazhagan G, Bansal A, Prasad D, Thomas P, Sharma SK, Kain AK, Kumar D, Selvamurthy
W (2001) Effect of vitamin E supplementation on hypoxia-induced oxidative damage in male
albino rats. Aviat Space Environ Med 72:899903
Imai H, Kashiwazaki H, Suzuki T, Kabuto M, Himeno S, Watanabe C, Moji K, Kim SW,
Rivera JO, Takemoto T (1995) Selenium levels and glutathione peroxidase activities in
blood in an Andean high-altitude population. J Nutr Sci Vitaminol (Tokyo) 41:349361
Joanny P, Steinberg J, Robach P, Richalet JP, Gortan C, Gardette B, Jammes Y (2001) Operation
Everest III (Comex97): the effect of simulated sever hypobaric hypoxia on lipid peroxidation
and antioxidant defence systems in human blood at rest and after maximal exercise.
Resuscitation 49:307314
Khan S, OBrien PJ (1995) Modulating hypoxia-induced hepatocyte injury by affecting
intracellular redox state. Biochim Biophys Acta 1269:153161
Kumar D, Bansal A, Thomas P, Sairam M, Sharma SK, Mongia SS, Singh R, Selvamurthy W
(1999) Biochemical and immunological changes on oral glutamate feeding in male albino rats.
Int J Biometeorol 42:201204
Maiti P, Singh SB, Sharma AK, Muthuraju S, Banerjee PK, Ilavazhagan G (2006) Hypobaric
hypoxia induces oxidative stress in rat brain. Neurochem Int 49:709716
Mariggio MA, Falone S, Morabito C, Guarnieri S, Mirabilio A, Pilla R, Bucciarelli T, Verratti V,
Amicarelli F (2010) Peripheral blood lymphocytes: a model for monitoring physiological
adaptation to high altitude. High Alt Med Biol 11:333342
Mishra A, Ali Z, Vibhuti A, Kumar R, Alam P, Ram R, Thinlas T, Mohammad G, Pasha MA
(2012) CYBA and GSTP1 variants associate with oxidative stress under hypobaric hypoxia as
observed in high-altitude pulmonary oedema. Clin Sci (Lond) 122:299309
Mitteldorf J (2010) Aging is not a process of wear and tear. Rejuvenation Res 13:322326
Mohanraj P, Merola AJ, Wright VP, Clanton TL (1998) Antioxidants protect rat diaphragmatic
muscle function under hypoxic conditions. J Appl Physiol 84:19601966
Moller P, Loft S, Lundby C, Olsen NV (2001) Acute hypoxia and hypoxic exercise induce DNA
strand breaks and oxidative DNA damage in humans. FASEB J 15:11811186
Nakanishi K, Tajima F, Nakamura A, Yagura S, Ookawara T, Yamashita H, Suzuki K,
Taniguchi N, Ohno H (1995) Effects of hypobaric hypoxia on antioxidant enzymes in rats.
J Physiol 489(Pt 3):869876
Nugroho A, Kim KH, Lee KR, Alam MB, Choi JS, Kim WB, Park HJ (2009) Qualitative and
quantitative determination of the caffeoylquinic acids on the Korean mountainous vegetables
used for chwinamul and their peroxynitrite-scavenging effect. Arch Pharm Res 32:13611367
Pfeiffer JM, Askew EW, Roberts DE, Wood SM, Benson JE, Johnson SC, Freedman MS
(1999) Effect of antioxidant supplementation on urine and blood markers of oxidative stress
during extended moderate-altitude training. Wilderness Environ Med 10:6674
Radak Z, Lee K, Choi W, Sunoo S, Kizaki T, Oh-ishi S, Suzuki K, Taniguchi N, Ohno H, Asano K
(1994) Oxidative stress induced by intermittent exposure at a simulated altitude of 4000 m
decreases mitochondrial superoxide dismutase content in soleus muscle of rats. Eur J Appl
Physiol Occup Physiol 69:392395
416 Z. Radak et al.

Radak Z, Asano K, Inoue M, Kizaki T, Oh-Ishi S, Suzuki K, Taniguchi N, Ohno H (1995)

Superoxide dismutase derivative reduces oxidative damage in skeletal muscle of rats during
exhaustive exercise. J Appl Physiol 79:129135
Radak Z, Asano K, Lee KC, Ohno H, Nakamura A, Nakamoto H, Goto S (1997) High altitude
training increases reactive carbonyl derivatives but not lipid peroxidation in skeletal muscle of
rats. Free Radic Biol Med 22:11091114
Radak Z, Asano K, Fu Y, Nakamura A, Nakamoto H, Ohno H, Goto S (1998) The effect of high
altitude and caloric restriction on reactive carbonyl derivatives and activity of glutamine
synthetase in rat brain. Life Sci 62:13171322
Radak Z, Taylor AW, Ohno H, Goto S (2001) Adaptation to exercise-induced oxidative stress:
from muscle to brain. Exerc Immunol Rev 7:90107
Scherrer U, Allemann Y, Jayet PY, Rexhaj E, Sartori C (2010a) High altitude, a natural research
laboratory for the study of cardiovascular physiology and pathophysiology. Prog Cardiovasc
Dis 52:451455
Scherrer U, Rexhaj E, Jayet PY, Allemann Y, Sartori C (2010b) New insights in the pathogenesis
of high-altitude pulmonary edema. Prog Cardiovasc Dis 52:485492
Schmidt MC, Askew EW, Roberts DE, Prior RL, Ensign WY Jr, Hesslink RE Jr (2002) Oxidative
stress in humans training in a cold, moderate altitude environment and their response to
a phytochemical antioxidant supplement. Wilderness Environ Med 13:94105
Schneider JC, Blazy I, Dechaux M, Rabier D, Mason NP, Richalet JP (2001) Response of nitric
oxide pathway to L-arginine infusion at the altitude of 4,350 m. Eur Respir J 18:286292
Serrano J, Encinas JM, Salas E, Fernandez AP, Castro-Blanco S, Fernandez-Vizarra P,
Bentura ML, Rodrigo J (2003) Hypobaric hypoxia modifies constitutive nitric oxide synthase
activity and protein nitration in the rat cerebellum. Brain Res 976:109119
Sinha S, Singh SN, Ray US (2009) Total antioxidant status at high altitude in lowlanders and
native highlanders: role of uric acid. High Alt Med Biol 10:269274
Sinha S, Dutta A, Singh SN, Ray US (2010) Protein nitration, lipid peroxidation and DNA damage
at high altitude in acclimatized lowlanders and native highlanders: relation with oxygen
consumption. Respir Physiol Neurobiol 171:115121
Subudhi AW, Jacobs KA, Hagobian TA, Fattor JA, Muza SR, Fulco CS, Cymerman A,
Friedlander AL (2006) Changes in ventilatory threshold at high altitude: effect of antioxidants.
Med Sci Sports Exerc 38:14251431
Tharakan B, Dhanasekaran M, Manyam BV (2005) Antioxidant and DNA protecting properties of
anti-fatigue herb Trichopus zeylanicus. Phytother Res 19:669673
Vij AG, Dutta R, Satija NK (2005) Acclimatization to oxidative stress at high altitude. High Alt
Med Biol 6:301310
Wilber RL, Holm PL, Morris DM, Dallam GM, Subudhi AW, Murray DM, Callan SD
(2004) Effect of FIO2 on oxidative stress during interval training at moderate altitude. Med
Sci Sports Exerc 36:18881894
Wozniak A, Drewa G, Chesy G, Rakowski A, Rozwodowska M, Olszewska D (2001) Effect of
altitude training on the peroxidation and antioxidant enzymes in sportsmen. Med Sci Sports
Exerc 33:11091113