estres oxidativo en montaña

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©Journal of Sports Science and Medicine (2004) 3, 64-69 http://www.jssm.org Review article HIGH ALTITUDE AND FREE RADICALS Tibor Bakonyi and Zsolt Radak Department of Exercise Physiology, Faculty of Physical Education and Sport Science, Semmelweis University, Budapest, Hungary Received: 15 April 2004 / Accepted: 10 May 2004 / Published (online): 01 June 2004 ABSTRACT High altitude exposure results in decreased oxygen pressure and an increased formation of reactive oxygen and nitrogen species (

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  ©Journal of Sports Science and Medicine (2004) 3, 64-69http://www.jssm.org Review articleHIGH ALTITUDE AND FREE RADICALS Tibor Bakonyi and Zsolt Radak     Department of Exercise Physiology, Faculty of Physical Education and Sport Science, SemmelweisUniversity, Budapest, HungaryReceived: 15 April 2004 / Accepted: 10 May 2004 / Published (online): 01 June 2004 ABSTRACT High altitude exposure results in decreased oxygen pressure and an increased formation of reactiveoxygen and nitrogen species (RONS), which is often associated with increases in oxidative damage tolipids, proteins and DNA. Exposure to high altitude appears to decrease the activity and effectiveness of antioxidant enzymes system. Moreover, during high altitude exposure several RONS generating sourceare activated, including mitochondrial electron transport chain, xanthine oxidase, and nitric oxidesynthase (NO). Physical exercise at high altitude can further enhance the oxidative stress. The availableinformation suggests that RONS are involved and are even a causative factor of acute mountain sickness.Supplementation of antioxidant seems to be a necessary step to prevent or decrease to high altitudeexposure associated oxidative stress. KEY WORDS : High altitude, reactive oxygen and nitrogen species, oxidative stress, oxidative damage,antioxidants, acute mountain sickness. INTRODUCTION Generation of reactive oxygen and nitrogen species(RONS) is a necessary consequence of aerobemetabolism. RONS are natural and physiologicalmodulators of cellular redox milieu and therebysignaling, controlling factors of a wide range of known and unknown physiological, patho- physiological processes. Despite of the multi lineantioxidant system, the level of RONS generationcan exceed the capability of defense network,leading to oxidative stress (Askew, 2002). It isgenerally assumed that increases in aerobicmetabolism or hyperoxia easily generates increasedlevel of RONS and cause oxidative damage to lipids, proteins and DNA. Indeed, physical exercise,especially a single bout of exercise above a certainintensity or duration can result oxidative challengeand damage to different organs (Radak et al., 2001).However, it appears that the increased level of RONS production is not only due to themitochondrial respiration, because anaerobicexercise also could cause oxidative damage (Radak et al., 1998). Moreover protection of endothelium byexogenous superoxide dismutase (SOD) prevented both the oxidative damage to lipids and xanthineoxidase activity, indicating that exercise-associatedRONS production occurs by variety of sources andmechanism.Similarly to anaerobic physical exerciseexposure to high altitude often result in oxidativedamage to macromolecules. Low oxygen pressureseems to be favorable to low RONS production, butit appears that high altitude exposure associated withincreased oxidative damage, which could be theconsequence of the increased activity of RONSgenerating and decreased activity of antioxidantsystems. Moreover, according to our currentunderstanding it cannot be ruled out the RONS areinvolved and maybe even play a causative role in theacute mountain sickness (AMS), high altitude pulmonary edema (HAPE) and high altitude cerebraledema (HACE) (Bailey et al., 2001, Baumgartner etal., 2002, Chao et al., 1999). The present review willdraw upon the available literature on high altitude,exercise and high altitude and oxidative stress.  High altitude and free radicals65   Figure 1. Possible mechanisms of HA induced inflammation. High altitude and oxidative damage In one of our study, we have used intermittentexposure (12 hr in every day) to an altitude of 4000m to study the muscle fiber type dependentchanges in the activity and content of antioxidantenzymes and the level of lipid peroxidation (Radak et al., 1994). Our data revealed that the intermittentexposure to high altitude resulted in significantincrease in lipid peroxidation in both, slow and fasttype of muscle fibers of rats. Interestingly, when weapplied 4 wk of continuous exposure to the samealtitude, we did not measure increase lipid peroxidation, but the level of protein oxidation,measured by carbonyl derivatives was increased(Radak et al., 1997). Kumar et al. (1989) have foundthe short exposure (5 days) to an altitude of 7576 mcaused increased lipid peroxidation level in plasmaof rats. This result was confirmed by the sameexperimental protocol adding vitamin E supplantedgroups (Ilavazhagan et al., 2001). Moreover, Nakanishi and co-workers (1995) reported thatexposure to 5500m result in increased level of malondialdehyde in serum, lung, liver, heart andkidney.Human studies revealed similar results. Moller et al., (2001) exposed twelve healthy subjects to analtitude of 4559 m, which caused a significantincrease in DNA strand breaks, measured fromurine. The damage was more prominent at theendonuclease-III sites. When humans were exposedsimultaneously to high altitude (2700m) and coldexposure the level of urinary lipid peroxidation,DNA damage increased significantly (Schmidt et al.,2002). At the study of Operation Everest III the levelof lipid peroxidation increased by 23% at 6000m,and by 79% at the altitude of 8848m indicating thatthe level of oxidative stress is parallel with theincrease in altitude (Joanny et al., 2001). Thus, bothhuman and animal studies are relativelyconsequently reporting that high altitude associatedhypoxia is causing oxidative damage to lipids, proteins and DNA. This damage can be due to theincreased level of ROS production and/or decreasedlevel of antioxidant capacity. The effect of high altitude on antioxidant systems Aerobic cells developed enzymatic and non-enzymatic antioxidant system to regulate the effectsof RONS. The enzymatic system containsmitochondrial (Mn-SOD), cytosolic (Cu,Zn-SOD,and extra-cellular SOD to convert reactivesuperoxide to less powerful hydrogen peroxide.Glutathione peroxidase (GPX) and catalasedecompose hydrogen peroxide to water. Other enzymes, like thioredoxin and glutaredoxin systemsare not discussed, since data are not available inrelation to high altitude. The nonenzymatic system isvery complex and many non-enzymatic antioxidantsexist in cells. High altitude related studies measuredthe content glutathione, vitamin E, and vitamin Camong the nonenzymatic antioxidant, therefore theseagents are discussed in the present review.There are only a few studies which examinedthe level of antioxidant enzyme capacity at highaltitude. We have reported that 6 month of intermittent exposure to high altitude (4000m)resulted in decreased activity and protein content of mitochondrial SOD in skeletal muscle of rats (Radak   Bakonyi and Radak 66 et al., 1994). This was confirmed by Nakanishi et al(1995), who have found that 5500m simulatedaltitude increased the level immunoreactive Mn-SOD in the serum and decreased it in liver and lungof the animals. The activity of glutathione peroxidase (GPX) also decreased in liver suggestingthat liver might especially sensitive to high altitudeinduced oxidative stress (Nakanishi et al., 1995). Inour other study we could not detect significant effectof 4 wk exposure to 4000m on the activities of antioxidant enzymes (Radak et al. 1997). Imai et al.(1995) compared the activity of GPX in serum of native highlanders (4000m) and subjects from sealevel. They have found that people from highaltitude had lower level of GPX activity. Theactivity and effectiveness of GPX is stronglydependent upon state of thiol system. Glutamyl-cysteinyl-glycine, is one of the main thiol/antioxidant source of the cell, which continuouslysynthesized by glutamyl cycle. High altitudeexposure decreases the level of reduced glutathione(GSH) and increase oxidized glutathioneconcentration (Ilvazhagan et al., 2001, Joanny et al.,2001).Thus, it appears that the capacity of enzymaticand non-enzymatic antioxidant systems is somewhatdecreasing at high altitude. There are trials to prevent the high altitude associated oxidativedamage by supplementation of antioxidants.Schmidt et al., (2002) have applied an antioxidantmixture containing vitamin E, beta-carotene,ascorbic acid, selenium, alpha-lipoic acid, N-acetyl1-cysteine, catechin, lutein, and lycopene to reduceoxidative stress caused by altitude. This mixture waseffective and the level of oxidative damage wasreduced.Supplementation of vitamin E (40 mg per rat·day -1 ) orally, 5 days prior to and during the period of hypoxic exposure of 7,576m to rats,significantly reduced the high altitude-inducedincrease in lipid peroxidation (Ilvazhagan et al.,2001). On the other hand, the antioxidantsupplement mixture containing, 20,000 IU beta-carotene, 400 IU vitamin E, 500 mg vitamin C, 100micrograms selenium, and 30 mg zinc, (in a daily base) did not prevented the oxidative damage of macromolecules (Pfeiffer et al., 1999).A very short exposure to rats to an altitude of 8000 m resulted in increased melatonin level in the blood (Kaur et al., 2002). Melatonin besides a widerange of effects can act as an antioxidant. After thefirst 4 days following the exposure, themitochondrial number and lipid droplets in the pinealocytes appeared to be reduced compared withthose in control rats suggesting another source besides pinealocytes also produce melatonin.It appears that exposure to high altitudedecrease the activity and content of some antioxidantenzymes. Moreover, the effectiveness of thiolsystem is also reduced by high altitude. There aresome indications that antioxidant supplementationreduces or prevents the high altitude inducedoxidative damage to macromolecules. RONS generating systems at high altitude It is well demonstrated that massive oxygen supplyresults in increased formation in mitochondrial ROS production. However, it also appears that hypoxiacan lead to reductive stress, which also results inincreased ROS production by the mitochondrialelectron transport system (Mohanraj et al., 1998).This is believed that ROS is   generated at complex Iand complex III of the electron transport   chain.During hypoxia, less O 2 is available to be reduced   toH 2 O at cytochrome oxidase, causing accumulationof    reducing equivalents within the mitochondrialrespiratory sequence. This called   as reductive stress,which leads to ROS formation by the auto-oxidationof one or more mitochondrial   complexes such as theubiquinone-ubiquinol redox couple. Khan and OBrien (1995) demonstrated increases in the cellular     NADH/NAD + ratio during hypoxia associatedreductive stress.   The xanthine dehydrogenase/oxidase system isa potent ROS generator during hypoxia/reperfusionconditions. Intermittent exposure to high altitude hassimilar characteristics than ischemia/reperfusion(Radak et al., 1994). On the other hand the changing pattern of ROS and nitric oxide (NO) is differentduring ischemia/reperfussion and exposure to highaltitude. During ischemia/reperfusion the initialresponse is accompanied by a reversible increase inthe generation of ROS and is blocked byantioxidants and by interventions that increase thetissue levels of NO. In contrast to ischemia/reperfusion, ROS levels increase during hypoxia andreturn towards pre-hypoxic values after return tonormoxia. Acclimatization involves up-regulation of inducible NO synthase (iNOS), suggesting thathypoxia leads to an alteration of the ROS/NO balance which is eventually restored during theacclimatization process (Gonzalez and Wood, 2001).This phenomenon may have relevance to themicrocirculatory alterations associated with hypoxicexposure, including acute mountain sickness andhigh altitude pulmonary and cerebral edema. Thefindings of Serrano et al. (2002) indicates that theinvolvement of different type of NOS is different in NO production during high altitude, which can leadto increased formation of nitrotyrosine level in ratcerebellum after reoxygenation to sea level. It is wellknown that the UV radiation is significantly  High altitude and free radicals67 increasing at high altitude, resulting in enhancedformation of RONS.Accordingly to our current understanding itseems that high altitude associated increase in ROSgeneration is due to different sources, includingmitochondrial respiratory chain, xanthine oxidase,and iNOS.  High altitude and exercise High altitude training is often used by athletes toincrease the number of red blood cells, which is believed to increase endurance performance.However, the oxidative stress related consequence of high altitude training is poorly known. It is wellaccepted that physical exercise increases the oxygenuptake and flux into the mitochondria and after acertain intensity and/or duration can lead tooxidative stress. It was also demonstrated that notonly aerobic, but anaerobic exercise as well can leadto oxidative damage (reviewed by Radak et al.,2001). It is suggested that during anaerobiccondition XO is one major source of ROSgeneration (Radak et al., 1995). The available datasuggests both high altitude exposure and exercisealone could result in oxidative challenge and shiftthe redox state of cells. Therefore it is not surprisingthat the combined effects of high altitude andexercise could result in oxidative damage. We havedemonstrated that training at altitude of 4000mresulted in increased carbonylation of certainmuscular proteins, most probably including actin,which is major contractile protein (Radak et al.,1997). We have suggested that exercise escalateseffects of altitude on ROS production and weakensthe power of antioxidant system. This hypothesiswas confirmed by human studies as well (Wozniak et al., 2001). Moller et al. (2001) concluded thathypoxia undermines the capacity of antioxidantsystem and reduce the body capacity to withstandoxidative stress produced by exhaustive exercise.Joanny et al. (2001) data further support thissuggestion and points out the importance of antioxidant supplementation for individuals engagedwith exercise at high altitude.Increased physical activity at high altitude isincreases the vulnerability of body to oxidativestress and can lead to oxidative damage. Therefore,antioxidant supplementation seems to be animportant and natural tool to reduce the high altitudeand exercise induced oxidative stress.  Acute mountain sickness (AMS) and RONS Our current understanding about AMS is still far from being complete. The most common   symptomsof AMS are headache, nausea, anorexia, insomnia,fatigue/lassitude,   vomiting and dizziness. Many physiological events associated with the pathophysiology   of AMS have been documented,included relative   hypoventilation, impaired gasexchange   (interstitial pulmonary edema) fluidretention and redistribution , and increasedsympathetic   drive (reviewed Hackett, 1999).   Incontrast, increased intracranial pressure and   cerebraledema are documented in moderate to severe AMS,reflecting   the continuum from AMS to HACE. In thedevelopment of HACE elevated cerebral capillary    pressure occurs altering the function of brain blood barrier (BBB) producing brain edema. It appears thatfree radicals (e.g. oxygen and hydroxyl radicals), bradykinin,   histamine, arachidonic acid and NOcould be involved in the alteration of BBB (Schillingand Wahl, 1999).   Indeed there are some implications thatRONS are involved and even are the causative factor of AMS (Bailey and Davies, 2001). HAPE, a potentially fatal clinical condition, represents aserious complication of AMS. HAPE is an increasein capillary permeability, which could occur as aresult of an inflammatory reaction and/or freeradical-mediated injury to the lung (Figure 1). Uponthe findings of their study, Kleger et al. (1996)suggested that the inflammatory reaction, which wasassociated with HAPE, was rather a consequencethan a causative factor of high-altitude pulmonaryedema (Kleger et al., 1996). But, NO inhalation wasused with a success to soften or curbed thesymptoms of HAPE (Anand et al., 1998) and thisobservation suggests that NO play a causative role.The beneficial effects of NO inhalation was alsonicely demonstrated on rat model, in which themortality rate of control rats was 39.5% and just6.2% in the NO treated group (Omura et al., 2000).Therefore it is hypothesized that susceptibility toHAPE may be related to decreased production of  NO, an endogenous modulator of pulmonaryvascular resistance, and that a decrease in exhaled NO could be detected during hypoxic exposure.Since, an exaggerated hypoxic pulmonaryvasoconstriction is essential for development of HAPE.Despite of our limited knowledge about AMS,the available information suggests that RONS areactive players in the process, however it still notclear whether they are causative or associativeagents. CONCLUSIONS Exposure to high altitude disrupts the efficiency of antioxidant system and due to the increased level of RONS production can lead to oxidative damage tomacromolecules. Physical exercise can exacerbate
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