José Magalhães^1,2,, António Ascensão^1,2,

¹Research Centre in Physical Activity, Health and Leisure, University of Porto, Portugal

²Department of Sport Biology, Faculty of Sport, University of Porto, Portugal

ABSTRACT

After putting forward some evidence of hypobaric hypoxia as a particular stimulus causing systemic, tissue and cellular challenging strains, the present short review is focused on the current findings relating the reasoning of increased tissue generation of reactive oxygen and nitrogen species (RONS) when humans and animals organisms are exposed to high-altitude environments. In contrast to earlier concepts, hypobaric hypoxia-induced decreased physiological oxygen availability seems to be a prompt condition to cellular loss of redox homeostasis resulting in increased oxidative stress, which does not further augment upon reoxygenation. The apparently paradoxical condition of hypoxia-induced free radical production is regulated by very particular and specific cellular mechanisms, being mitochondria special sources and targets of RONS as well as critical organelles related to cellular death mediated by apoptosis.

Key-words: hypoxia, free radicals, oxidative damage, mitochondria, apoptosis

RESUMO

Hipóxia de altitude. Um estímulo indutor de alterações na homeostasia redox

Após considerar evidências da hipoxia hipobárica enquanto um estímulo particular indutor de alterações deletérias a nível sistémico, tecidual e celular, a presente breve revisão focar-se-á sobre os principais mecanismos associados à produção adicional de espécies reactivas de oxigénio e nitrogénio (ERON) em humanos e animais submetidos a condições ambientais de hipóxia. Em oposição aos conceitos pioneiros, a diminuição da disponibilidade de oxigénio que se verifica em condições de hipoxia hipobárica é uma condição favorável à perda da homeostasia redox celular resultando num incremento do stress oxidativo, o qual não é agravado após períodos de reoxigenação. Esta aparente condição paradoxal de geração adicional de radicais livres é regulada por mecanismos celulares específicos, sendo as mitocôndrias fontes e simultaneamente alvos das ERON, bem como organelos críticos associados à morte celular mediada por apoptose.

Palavras-chave: hipoxia, radicais livres, lesão oxidativa, mitocôndrias, apoptose

Full text only available in PDF format.

Texto completo disponível apenas em PDF.

REFERENCES

1. Abraini JH, Bouquet C, Joulia F, Nicolas M, Kriem B (1998). Cognitive performance during a simulated climb of mount everest: implications for brain function and central adaptive processes under chronic hypoxic stress. Pflugers Arch 436:553-559        [ Links ]

2. Alessio H (2000). Lipid peroxidation in healthy and diseased models: influence of different types of exercise. In: Sen CK, Packer L, Hanninen O (eds) Handbook of oxidants and antioxidants in exercise. Elsevier science B.V., Basel, p 115-127

3. Amicarelli F, Ragnelli AM, Aimola P, Bonfigli A, Colafarina S, Di Ilio C, Miranda M (1999). Age-dependent ultrastructural alterations and biochemical response of rat skeletal muscle after hypoxic or hyperoxic treatments. Biochim Biophys Acta 1453:105-114

4. Appell HJ, Duarte JA, Gloser S, Remiao F, Carvalho F, Bastos ML, Soares JM (1997). Administration of tourniquet. II. Prevention of postischemic oxidative stress can reduce muscle edema. Arch Orthop Trauma Surg 116:101-105

5. Arai M, Imai H, Koumura T, Yoshida M, Emoto K, Umeda M, Chiba N, Nakagawa Y (1999). Mitochondrial phospholipid hydroperoxide glutathione peroxidase plays a major role in preventing oxidative injury to cells. J Biol Chem 274:4924-4933

6. Askew EW (2002). Work at high altitude and oxidative stress: antioxidant nutrients. Toxicology 180:107-119

7. Bailey D, Davies B, Davison G, Young I (2000). Oxidatively stressed out at high-altitude! International Society for Mountain Medicine Newsletter 10:3-13

9. Bailey DM, Davies B, Young IS (2000). Evidence for reactive oxidant generation during acute physical exercise and normobaric hypoxia in man. J Physiol 528P:99P

10. Bailey DM, Roukens R, Knauth M, Kallenberg K, Christ S, Mohr A, Genius J, Storch-Hagenlocher B, Meisel F, McEneny J, Young IS, Steiner T, Hess K, Bartsch P (2005). Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache. J Cereb Blood Flow Metab 26(1): 99-111

11. Bakonyi T, Radak Z (2004). High altitude and free radicals. J Sports Sci Med 3:64-69

12. Bartsch P (1999). High altitude pulmonary edema. Med Sci Sports Exerc 31:S23-27

13. Bigard AX, Douce P, Merino D, Lienhard F, Guezennec CY (1996). Changes in dietary protein intake fail to prevent decrease in muscle growth induced by severe hypoxia in rats. J Appl Physiol 80:208-215

14. Bonnon M, Noel-Jorand MC, Therme P (2000). Effects of different stay durations on attentional performance during two mountain expeditions. Aviat Space Environ Med 71:678-684

15. Bouquet C, Gardette B, Gortan C, Therme P, Abraini JH (2000). Color discrimination under chronic hypoxic conditions (simulated climb "Everest-Comex 97"). Percept Mot Skills 90:169-179

16. Cadenas E (2004). Mitochondrial free radical production and cell signaling. Mol Aspects Med 25:17-26

17. Caquelard F, Burnet H, Tagliarini F, Cauchy E, Richalet JP, Jammes Y (2000). Effects of prolonged hypobaric hypoxia on human skeletal muscle function and electromyographic events. Clin Sci (Colch) 98:329-337

19. Chandel NS, Budinger GR, Choe SH, Schumacker PT (1997). Cellular respiration during hypoxia. Role of cytochrome oxidase as the oxygen sensor in hepatocytes. J Biol Chem 272:18808-18816

20. Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT (1998). Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A 95:11715-11720

21. Chandel NS, McClintock DS, Feliciano CE, Wood TM, Melendez JA, Rodriguez AM, Schumacker PT (2000). Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 275:25130-25138

22. Chang SW, Stelzner TJ, Weil JV, Voelkel NF (1989). Hypoxia increases plasma glutathione disulfide in rats. Lung 167:269-276

23. Chao WH, Askew EW, Roberts DE, Wood SM, Perkins JB (1999). Oxidative stress in humans during work at moderate altitude. J Nutr 129:2009-2012

24. Childs AC, Phaneuf SL, Dirks AJ, Phillips T, Leeuwenburgh C (2002). Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Res 62:4592-4598

25. Choksi KB, Boylston WH, Rabek JP, Widger WR, Papaconstantinou J (2004). Oxidatively damaged proteins of heart mitochondrial electron transport complexes. Biochim Biophys Acta 1688:95-101

26. Crompton M (1999). The mitochondrial permeability transition pore and its role in cell death. Biochem J 341 ( Pt 2):233-249

27. Crompton M (2004). Mitochondria and aging: a role for the permeability transition? Aging Cell 3:3-6

29. Dawson TL, Gores GJ, Nieminen AL, Herman B, Lemasters JJ (1993). Mitochondria as a source of reactive oxygen species during reductive stress in rat hepatocytes. Am J Physiol 264:C961-967

30. de Glisezinski I, Crampes F, Harant I, Havlik P, Gardette B, Jammes Y, Souberbielle JC, Richalet JP, Riviere D (1999). Decrease of subcutaneous adipose tissue lipolysis after exposure to hypoxia during a simulated ascent of Mt Everest. Pflugers Arch 439:134-140

31. Dekhuijzen PN (2004). Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J 23:629-636

32. Duarte JA, Gloser S, Remiao F, Carvalho F, Bastos ML, Soares JM, Appell HJ (1997). Administration of tourniquet. I. Are edema and oxidative stress related to each other and to the duration of ischemia in reperfused skeletal muscle? Arch Orthop Trauma Surg 116:97-100

33. Duranteau J, Chandel NS, Kulisz A, Shao Z, Schumacker PT (1998). Intracellular signaling by reactive oxygen species during hypoxia in cardiomyocytes. J Biol Chem 273:11619-11624

34. Ferrari R (1995) Metabolic disturbances during myocardial ischemia and reperfusion. Am J Cardiol 76:17B-24B

35. Ferrari R, Guardigli G, Mele D, Percoco GF, Ceconi C, Curello S (2004). Oxidative stress during myocardial ischaemia and heart failure. Curr Pharm Des 10:1699-1711

36. Franko J, Pomfy M, Novakova B, Benes L (1999). Stobadine protects against ischemia-reperfusion induced morphological alterations of cerebral microcirculation in dogs. Life Sci 65:1963-1967

37. 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 6:320-326

39. Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT (2005). Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing. Cell Metab 1:401-408

40. Guzy RD, Schumacker PT (2006). Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp Physiol 91:807-819

41. Hackett PH (1999). The cerebral etiology of high-altitude cerebral edema and acute mountain sickness. Wilderness Environ Med 10:97-109

42. Hampl V, Cornfield DN, Cowan NJ, Archer SL (1995). Hypoxia potentiates nitric oxide synthesis and transiently increases cytosolic calcium levels in pulmonary artery endothelial cells. Eur Respir J 8:515-522

43. Hengartner MO (2000). The biochemistry of apoptosis. Nature 407:770-776

44. Hirsch T, Marzo I, Kroemer G (1997). Role of the mitochondrial permeability transition pore in apoptosis. Biosci Rep 17:67-76

45. Hochachka PW, Rupert JL (2003). Fine tuning the HIF-1 'global' O2 sensor for hypobaric hypoxia in Andean high-altitude natives. Bioessays 25:515-519

46. Hochachka PW, Rupert JL, Monge C (1999). Adaptation and conservation of physiological systems in the evolution of human hypoxia tolerance. Comp Biochem Physiol A Mol Integr Physiol 124:1-17

47. Hoppeler H, Vogt M (2001). Muscle tissue adaptations to hypoxia. J Exp Biol 204:3133-3139

49. Hoshikawa Y, Ono S, Suzuki S, Tanita T, Chida M, Song C, Noda M, Tabata T, Voelkel NF, Fujimura S (2001). Generation of oxidative stress contributes to the development of pulmonary hypertension induced by hypoxia. J Appl Physiol 90:1299-1306

50. Houston SC (1997). Operation Everest One and Two. Repiration 64:398-406

51. Hultgren H (1997). High Altitude Medicine. Stanford: Hultgren Publications

52. 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 72:899-903

53. James AM, Murphy MP (2002). How mitochondrial damage affects cell function. J Biomed Sci 9:475-487

54. Joanny P, Steinberg J, Robach P, Richalet JP, Gortan C, Gardette B, Jammes Y (2001). Operation Everest III (Comex'97): the effect of simulated sever hypobaric hypoxia on lipid peroxidation and antioxidant defence systems in human blood at rest and after maximal exercise. Resuscitation 49:307-314

55. Jones D (1985). The role of oxygen concentration in oxidative stress: hypoxic and hyperoxic models. In: Sies H (ed) Oxidative Stress. Academic Press Inc, London, p 151-195

56. karakucuk S, Mirza EG (2000). Ophtnalmological Effects of High Altitude. Ophthalmic Res 32:30-40

57. Kehrer JP, Lund LG (1994). Cellular reducing equivalents and oxidative stress. Free Radic Biol Med 17:65-75

59. Kokoszka JE, Coskun P, Esposito LA, Wallace DC (2001). Increased mitochondrial oxidative stress in the Sod2 (+/-) mouse results in the age-related decline of mitochondrial function culminating in increased apoptosis. Proc Natl Acad Sci U S A 98:2278-2283

60. Kokoszka JE, Waymire KG, Levy SE, Sligh JE, Cai J, Jones DP, MacGregor GR, Wallace DC (2004). The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427:461-465

61. Kowaltowski AJ, Vercesi AE (1999). Mitochondrial damage induced by conditions of oxidative stress. Free Radic Biol Med 26:463-471

62. Kowaltowski AJ, Vercesi AE, Fiskum G (2000). Bcl-2 prevents mitochondrial permeability transition and cytochrome c release via maintenance of reduced pyridine nucleotides. Cell Death Differ 7:903-910

63. Kroemer G, Dallaporta B, Resche-Rigon M (1998). The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 60:619-642

64. Kulisz A, Chen N, Chandel NS, Shao Z, Schumacker PT (2002). Mitochondrial ROS initiate phosphorylation of p38 MAP kinase during hypoxia in cardiomyocytes. Am J Physiol Lung Cell Mol Physiol 282:L1324-1329

65. Lemasters JJ, Nieminen AL (1997). Mitochondrial oxygen radical formation during reductive and oxidative stress to intact hepatocytes. Biosci Rep 17:281-291

66. Lundby C, Pilegaard H, van Hall G, Sander M, Calbet J, Loft S, Moller P (2003). Oxidative DNA damage and repair in skeletal muscle of humans exposed to high-altitude hypoxia. Toxicology 192:229-236

67. MacNee W (2000). Oxidants/antioxidants and COPD. Chest 117:303S-317S

69. Magalhaes J, Ascensao A, Marques F, Soares JM, Ferreira R, Neuparth MJ, Duarte JA (2005). Effect of a high-altitude expedition to a Himalayan peak (Pumori, 7,161 m) on plasma and erythrocyte antioxidant profile. Eur J Appl Physiol 93:726-732

70. Magalhaes J, Ascensao A, Soares JM, Ferreira R, Neuparth MJ, Marques F, Duarte JA (2005). Acute and severe hypobaric hypoxia increases oxidative stress and impairs mitochondrial function in mouse skeletal muscle. J Appl Physiol 99:1247-1253

71. Magalhaes J, Ascensao A, Soares JM, Ferreira R, Neuparth MJ, Oliveira J, Amado F, Marques F, Duarte JA (2005). Acute and chronic exposition of mice to severe hypoxia: the role of acclimatization against skeletal muscle oxidative stress. Int J Sports Med 26:102-109

72. Magalhaes J, Ascensao A, Soares JM, Neuparth MJ, Ferreira R, Oliveira J, Amado F, Duarte JA (2004). Acute and severe hypobaric hypoxia-induced muscle oxidative stress in mice: the role of glutathione against oxidative damage. Eur J Appl Physiol 91:185-191

73. Magalhaes J, Ascensao A, Viscor G, Soares J, Oliveira J, Marques F, Duarte J (2004). Oxidative stress in humans during and after 4 hours of hypoxia at a simulated altitude of 5500 m. Aviat Space Environ Med 75:16-22

74. Magalhaes J, Ferreira R, Neuparth MJ, Oliveira PJ, Marques F, Ascensao A (2007). Vitamin E prevents hypobaric hypoxia-induced mitochondrial dysfunction in skeletal muscle. Clin Sci (Lond)

75. Martinelli M, Winterhalder R, Cerretelli P, Howald H, Hoppeler H (1990). Muscle lipofuscin content and satellite cell volume is increased after high altitude exposure in humans. Experientia 46:672-676

76. Mohanraj P, Merola AJ, Wright VP, Clanton TL (1998). Antioxidants protect rat diaphragmatic muscle function under hypoxic conditions. J Appl Physiol 84:1960-1966

77. 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 15:1181-1186

79. Moore LG (2000). Comparative human ventilatory adaptation to high altitude. Respir Physiol 121:257-276

80. Nicolas M, Thullier-Lestienne F, Bouquet C, Gardette B, Gortan C, Joulia F, Bonnon M, Richalet JP, Therme P, Abraini JH (1999). An anxiety, personality and altitude symptomatology study during a 31-day period of hypoxia in a hypobaric chamber (experiment 'Everest-Comex 1997'). J Environ Psychol 19:407-414

81. Paradies G, Petrosillo G, Pistolese M, Di Venosa N, Federici A, Ruggiero FM (2004). Decrease in mitochondrial complex I activity in ischemic/reperfused rat heart: involvement of reactive oxygen species and cardiolipin. Circ Res 94:53-59

82. Paradies G, Petrosillo G, Pistolese M, Ruggiero FM (2000). The effect of reactive oxygen species generated from the mitochondrial electron transport chain on the cytochrome c oxidase activity and on the cardiolipin content in bovine heart submitochondrial particles. FEBS Lett 466:323-326

83. Paradies G, Petrosillo G, Pistolese M, Ruggiero FM (2002). Reactive oxygen species affect mitochondrial electron transport complex I activity through oxidative cardiolipin damage. Gene 286:135-141

84. Park Y, Kanekal S, Kehrer JP (1991). Oxidative changes in hypoxic rat heart tissue. Am J Physiol 260:H1395-1405

85. Pearlstein DP, Ali MH, Mungai PT, Hynes KL, Gewertz BL, Schumacker PT (2002). Role of mitochondrial oxidant generation in endothelial cell responses to hypoxia. Arterioscler Thromb Vasc Biol 22:566-573

86. Petrosillo G, Ruggiero FM, Pistolese M, Paradies G (2001). Reactive oxygen species generated from the mitochondrial electron transport chain induce cytochrome c dissociation from beef-heart submitochondrial particles via cardiolipin peroxidation. Possible role in the apoptosis. FEBS Lett 509:435-438

87. 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 10:66-74

89. Radak Z, Lee K, Choi W, Sunoo S, Kizaki T, Oh-ishi S, Suzuli K, Tanig (1994). Oxidative stress induced by intermittent exposure at a simulated altitude of 4000m decreases mitochondrial superoxide dismutase content in soleus muscle of rats. Eur J.Appl Physiol 69:392-395

90. Richter C (1997). Reactive oxygen and nitrogen species regulate mitochondrial Ca2+ homeostasis and respiration. Biosci Rep 17:53-66

91. Risom L, Lundby C, Thomsen JJ, Mikkelsen L, Loft S, Friis G, Moller P (2007). Acute hypoxia and reoxygenation-induced DNA oxidation in human mononuclear blood cells. Mutat Res 625:125-133

92. Riva C, Chevrier C, Pasqual N, Saks V, Rossi A (2001). Bcl-2/Bax protein expression in heart, slow-twitch and fast-twitch muscles in young rats growing under chronic hypoxia conditions. Mol Cell Biochem 226:9-16

93. Rubin BB, Romaschin A, Walker PM, Gute DC, Korthuis RJ (1996). Mechanisms of postischemic injury in skeletal muscle: intervention strategies. J Appl Physiol 80:369-387

94. Rupert JL, Hochachka PW (2001). Genetic approaches to understanding human adaptation to altitude in the Andes. J Exp Biol 204:3151-3160

95. Samaja M (1997). Blood Gas Transport at High Altitude. Respiration:422-428

96. Santos DL, Moreno AJ, Leino RL, Froberg MK, Wallace KB (2002). Carvedilol protects against doxorubicin-induced mitochondrial cardiomyopathy. Toxicol Appl Pharmacol 185:218-227

97. Sarada SK, Dipti P, Anju B, Pauline T, Kain AK, Sairam M, Sharma SK, Ilavazhagan G, Kumar D, Selvamurthy W (2002). Antioxidant effect of beta-carotene on hypoxia induced oxidative stress in male albino rats. J Ethnopharmacol 79:149-153

99. Schild L, Huppelsberg J, Kahlert S, Keilhoff G, Reiser G (2003). Brain mitochondria are primed by moderate Ca2+ rise upon hypoxia/reoxygenation for functional breakdown and morphological disintegration. J Biol Chem 278:25454-25460

100.  Schild L, Reinheckel T, Reiser M, Horn TF, Wolf G, Augustin W (2003). Nitric oxide produced in rat liver mitochondria causes oxidative stress and impairment of respiration after transient hypoxia. Faseb J 17:2194-2201

101.  Schlag MG, Harris KA, Potter RF (2001). Role of leukocyte accumulation and oxygen radicals in ischemia-reperfusion-induced injury in skeletal muscle. Am J Physiol Heart Circ Physiol 280:H1716-1721

102.  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 13:94-105

103.  Severinghaus JW (2000). Stumbling over a bias. What happens to spinal fluid pH at high altitude? Am J Respir Crit Care Med 161:3-4

104.  Shroff EH, Snyder C, Chandel NS (2007). Bcl-2 family members regulate anoxia-induced cell death. Antioxid Redox Signal 9:1405-1409

105.  Simon-Schnass I (2000). Risk of oxidative stress during exercise at high altitude. In: Sen CK, Packer L, Hannienen O (eds) Handbook of oxidants and antioxidants in exercise. Elsevier, Amsterdam, p 191-210

106.  Singh SN, Vats P, Kumria MM, Ranganathan S, Shyam R, Arora MP, Jain CL, Sridharan K (2001). Effect of high altitude (7,620 m) exposure on glutathione and related metabolism in rats. Eur J Appl Physiol 84:233-237

107.  Steiner DR, Gonzalez NC, Wood JG (2001). Leukotriene B(4) promotes reactive oxidant generation and leukocyte adherence during acute hypoxia. J Appl Physiol 91:1160-1167

109.  Vanden Hoek TL, Li C, Shao Z, Schumacker PT, Becker LB (1997). Significant levels of oxidants are generated by isolated cardiomyocytes during ischemia prior to reperfusion. J Mol Cell Cardiol 29:2571-2583

110.  Vercesi AE, Kowaltowski AJ, Grijalba MT, Meinicke AR, Castilho RF (1997). The role of reactive oxygen species in mitochondrial permeability transition. Biosci Rep 17:43-52

111.  Walker PM (1991). Ischemia/reperfusion injury in skeletal muscle. Ann Vasc Surg 5:399-402

112.  Wallace KB, Eells JT, Madeira VM, Cortopassi G, Jones DP (1997). Mitochondria-mediated cell injury. Symposium overview. Fundam Appl Toxicol 38:23-37

113.  Ward M, Milledge JS, West JB (2000). High Altitude Medicine and Physiology. New York: Oxford University Press Inc.

114.  Webster KA (2007). Hypoxia: life on the edge. Antioxid Redox Signal 9:1303-1307

115.  Wei YH, Lee HC (2002). Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. Exp Biol Med (Maywood) 227:671-682

116.  West JB (1996). Prediction of barometric pressures at high altitude with the use of model atmospheres. J Appl Physiol 81:1850-1854

117.  West JB (1999). Barometric pressures on Mt. Everest: new data and physiological significance. J Appl Physiol 86:1062-1066

119.  Westerterp KR, Meijer EP, Rubbens M, Robach P, Richalet JP (2000). Operation Everest III: energy and water balance. Pflugers Arch 439:483-488

120.  Wood JG, Johnson JS, Mattioli LF, Gonzalez NC (1999). Systemic hypoxia promotes leukocyte-endothelial adherence via reactive oxidant generation. J Appl Physiol 87:1734-1740

121.  Wood JG, Johnson JS, Mattioli LF, Gonzalez NC (2000). Systemic hypoxia increases leukocyte emigration and vascular permeability in conscious rats. J Appl Physiol 89:1561-1568

122.  Wright VP, Klawitter PF, Iscru DF, Merola AJ, Clanton TL (2005). Superoxide scavengers augment contractile but not energetic responses to hypoxia in rat diaphragm. J Appl Physiol 98:1753-1760

123.  Xu XP, Pollock JS, Tanner MA, Myers PR (1995). Hypoxia activates nitric oxide synthase and stimulates nitric oxide production in porcine coronary resistance arteriolar endothelial cells. Cardiovasc Res 30:841-847

124.  Yen HC, Oberley TD, Gairola CG, Szweda LI, St Clair DK (1999). Manganese superoxide dismutase protects mitochondrial complex I against adriamycin-induced cardiomyopathy in transgenic mice. Arch Biochem Biophys 362:59-66

125.  Zamboni M, Armellini F, Turcato E, Robbi R, Micciolo R, Todesco T, Mandragona R, Angelini G, Bosello O (1996). Effect of altitude on body composition during mountaineering expeditions: interrelationships with changes in dietary habits. Ann Nutr Metab 40:315-324

126.  Zhu WZ, Xie Y, Chen L, Yang HT, Zhou ZN (2006). Intermittent high altitude hypoxia inhibits opening of mitochondrial permeability transition pores against reperfusion injury. J Mol Cell Cardiol 40:96-106

127.  Zuo L, Clanton TL (2005). Reactive oxygen species formation in the transition to hypoxia in skeletal muscle. Am J Physiol Cell Physiol 289:C207-C216

CORRESPONDING AUTHOR

José Magalhães

Research Center in Physical Activity, Health and Leisure

Department of Sport Biology

Faculty of Sport Sciences, University of Porto

R. Dr. Plácido Costa, 91

4200-450 Porto

Portugal

Fax: 00-351-225500689

E-mail: jmaga@fade.up.pt