乙酰唑胺通过酸中毒诱导脑内的低氧诱导因子预防高原病的实验研究
|
摘要
乙酰唑胺是防治急性高原病(Acute Mountain Sickness,AMS)的首选药物,其机制主要是通过引起机体代谢性酸中毒,增加化学感受器对高原低氧的敏感性。低氧诱导因子-1(hypoxia-inducible factor-1, HIF-1)是机体低氧耐受的核心转录因子,其基因产物在血管形成重塑、葡萄糖和能量代谢、细胞增值等方面发挥重要作用。我们应用Western Blot法、real-time PCR、DNA结合ELISA、报告基因法分别检测了乙酰唑胺给药后(100 mg/kg或50 mg/kg,IP,5 d)大鼠脑组织内和常氧酸性环境处理后(pH6.5,20 h)大鼠原代皮层神经元和PC12细胞内HIF-1蛋白含量及活性的变化。我们发现乙酰唑胺可诱导大鼠脑皮层和海马组织内HIF-1α蛋白及其DNA结合活性的增加,同时其下游基因促红细胞生成素(EPO),血管内皮生长因子(VEGF)、葡萄糖转运蛋白-1(GLUT-1)的mRNA表达增加。常氧酸性环境可使原代皮层神经元和PC12细胞HIF-1α蛋白含量增加,同时HIF-1调控报告基因表达上调。我们推测乙酰唑胺可能通过酸中毒诱导脑内HIF-1使机体产生低氧耐受,预防低氧性损伤,参与乙酰唑胺防治AMS的机制。
Acetazolamide, a potent carbonic anhydrase inhibitor, has had a long history of effectiveness in prevention and treatment of acute mountain sickness (AMS). Traditionally, acetazolamide's efficacy has been attributed to metabolic acidosis, which is allowance of chemoreceptors to respond more fully to hypoxic stimuli at altitude. Hypoxia inducible factor (HIF) controls the transcription of genes involved in angiogenesis, erythropoiesis, glycolysis, and cell survival. HIF-1αlevels are a critical determinant of HIF activity. HIF-1αprotein level and HIF-1 DNA binding activities were increased in cerebral cortices and hippocampus of rats dosed with acetazolamide (100 mg/kg or 50 mg/kg, IP) for 5 days. Moreover, the mRNA levels of erythropoietin (Epo), glucose transporter-1 (Glut-1), vascular endothelial growth factor (Vegf), which are regulated by HIF-1, also increased. The normoxic induction of HIF-1αand HIF-1 mediated genes by acetazolamide might participate the mechanisms in which acetazolamide reduces symptoms of AMS. In further studies, cultured cortical neurons obtained from embryonic day 18 rats and PC12 cells were exposed to AP (pH 6.5) or SD (pH 7.2) media for 20 h under normoxia. The HIF-1αprotein level and activity of HIF-driven chloramphenicol acetyltransferase (CAT) reporters of cortical neurons and PC12 cells treated with acidosis media were significantly enhanced. The normoxic induction of HIF-1 activity by acidosis might play an important role in induction of the critical hypoxic regulatory factor HIF-1 by acetazolamide.
Acetazolamide, a potent carbonic anhydrase inhibitor, has had a long history of effectiveness in prevention and treatment of acute mountain sickness (AMS). Traditionally, acetazolamide's efficacy has been attributed to metabolic acidosis, which is allowance of chemoreceptors to respond more fully to hypoxic stimuli at altitude. Hypoxia inducible factor (HIF) controls the transcription of genes involved in angiogenesis, erythropoiesis, glycolysis, and cell survival. HIF-1αlevels are a critical determinant of HIF activity. HIF-1αprotein level and HIF-1 DNA binding activities were increased in cerebral cortices and hippocampus of rats dosed with acetazolamide (100 mg/kg or 50 mg/kg, IP) for 5 days. Moreover, the mRNA levels of erythropoietin (Epo), glucose transporter-1 (Glut-1), vascular endothelial growth factor (Vegf), which are regulated by HIF-1, also increased. The normoxic induction of HIF-1αand HIF-1 mediated genes by acetazolamide might participate the mechanisms in which acetazolamide reduces symptoms of AMS. In further studies, cultured cortical neurons obtained from embryonic day 18 rats and PC12 cells were exposed to AP (pH 6.5) or SD (pH 7.2) media for 20 h under normoxia. The HIF-1αprotein level and activity of HIF-driven chloramphenicol acetyltransferase (CAT) reporters of cortical neurons and PC12 cells treated with acidosis media were significantly enhanced. The normoxic induction of HIF-1 activity by acidosis might play an important role in induction of the critical hypoxic regulatory factor HIF-1 by acetazolamide.
引文
1. Hackett PH, Rennie D. Acute mountain sickness. Semin Respir Med, 5: 132-140, 1983.
2. Wenger RH Mammalian oxygen sensing, signalling and gene regulation. J. Exp. Biol., 203, 1253–1263, 2000.
3. Loeschcke HH and Gertz KH. Einfluss des O2-Druckes in der Einatmungsluft auf die Atemtatigkeit der Menschen, gepruft unter Konstanthaltung des alveolaren CO2-Druckes. Pflugers Arch Ges Physiol 267: 477, 1958.
4. Swenson ER and Hughes JM. Effects of acute and chronic acetazolamide on resting ventilation and ventilatory responses in men. J Appl Physiol. 74: 230-237, 1993.
5. Maren TH. Carbonic anhydrase: chemistry, physiology and inhibition. Physiol. Rev. 47, 595–781, 1967.
6. Leaf DE, Goldfarb DS. Mechanisms of Action of Acetazolamide in the Prophylaxis and Treatment of Acute Mountain Sickness: A Review. J Appl Physiol. 0: 01572.2005v1, 2006.
7. Semenza G. Signal transduction to hypoxia-inducible factor 1, Biochem. Pharmacol. 64, 993–998, 2002.
8. Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nature Rev. Cancer 2, 673–682, 2002.
9. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294 1337-1340, 2001.
10. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43-54, 2001.
11. Semenza GL. Hypoxia-inducible factor 1 and the molecular physiology ofoxygen homeostasis. J. Lab. Clin. Med. 131, 207-214, 1998.
12. Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev. 14, 1983–1991, 2000.
13. Mekhail K, Gunaratnam L, Bonicalzi ME, Lee S. HIF activation by pH- dependent nucleolar sequestration of VHL. Nat Cell Biol 6:642–647, 2004.
14. Findl O, Hansen RM, Fulton AB. The effects of acetazolamide on the electroretinographic responses in rats. Invest Ophthalmol Vis Sci. 36:1019–1026, 1995.
15. Heller I, Halevy J, Cohen S, Theodor E. Significant metabolic acidosis induced by acetazolamide: not a rare complication. Arch Intern Med. 145:1815–1817, 1985.
16. Ririe KM, Rasmussen RP, Wittwer CT. Product differentiation by analysis of DNA melting curves during the polymerase chain reaction. Anal Biochem. 245: 154–160, 1997.
17. Wittwer CT, Ririe KM, Andrew RV, David DA, Gundry RA, Balis UJ. The LightCycler: microvolume multisample fluorimeter with rapid temperature control Biotechniques. 22:176-181, 1997.
18. Brewer GJ. Serum-free B27/Neurobasal medium supports differentiated growth of neurons from the striatum, substantia. nigra, septum, cerebral cortex, cerebellum, and dentate gyrus. Neurosci. Res. 42, 674–683, 1995.
19. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA. Apr 29;94 (9):4273-8, 1997.
20. Roach RC, Hackett PH. Frontiers of hypoxia research: acute mountain sickness. J Exp Biol, 204: 3161-3170, 2001.
21. Fischer R, Vollmar C, Thiere M. No evidence of cerebral oedema in severe acute mountain sickness. Cephalalgia, 24: 66-71, 2004.
22. Hackett PH, Roach RC. High altitude cerebral edema. High Alt Med Biol,5:136-146, 2004.
23. Bailey DM, Roukens R, Knauth M. Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache. J Cereb Blood Flow Metab, 26: 99-111, 2006.
24. Magalhaes J, Ascensao A, Soares JM. Acute and Chronic Exposition of Mice to Severe Hypoxia: The Role of Acclimatization against Skeletal Muscle Oxidative Stress. Int J Sports Med. 26(2):102-109, 2005.
25. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr. Opin. Cell Biol. 13, 167–171, 2001.
26. JE Albina, JS Reichner. Oxygen and the regulation of gene expression in wounds, Wound Repair Regen. 11, 445– 451, 2003.
27. West JB. The physiologic basis of high-altitude diseases. Ann Intern Med, 141:789-800, 2004.
28. Stoeltzing O, McCarty MF, Wey JS. Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst. 96(12):946-56, 2004.
29. Sadamoto Y, Igase K, Sakanaka M, Sato K, Otsuka H, Sakaki S, Masuda S, Sasaki R. Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem. Biophys. Res. Commun. 253, 26–32, 1998.
30. Semenza GL. Regulation of erythropo iefin production New insights into molecular mechallisms of oxygen homeostasis. Hematol Oncol Clin North Am,8(5):863—884,1994.
31. Scmonza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein sysnthesis binds to the human erythropoietin gene enhance at a site required for transcriptional activation. Mol Cell Bio1. l2:5447-5454, 1992.
32. Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, Petit E. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 19, 643–651, 1999.
33. Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, Sasaki R. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl. Acad. Sci. U. S. A. 95, 4635–4640, 1998.
34. HoPPeler H, Vogt M. Hypoxia training for seal-evel performance training high-living low. Adv Exp Med Biol, 502:61-73,2001.
35. Pichiule P,Agani F,Chavez JC. HIF-l alpha and VEGF expression after transient global cerebral isehemia. Adv Exp Med Biol. 530:61l-617, 2003.
36. Hayashi T, Abe K, Itoyama Y. Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia. J. Cereb. Blood Flow Metab. 18, 887–895, 1998.
37. Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J. Clin. Invest. 111, 1843–1851, 2003.
38. Oesthuyse B,Moon l,Storkebaum E.Delection of the hypoxia response element in the vascular endotheiul growth factor promoter causes motor neuron degeneration.Nat Gcnet, 28(2): 131-138, 2001.
39. Jones NM, Bergeron M. Hypoxic preconditioning induces changes in HIF-1 target genes in neonatal rat brain. J. Cereb. Blood Flow Metab. 21, 1105–1114, 2001.
40. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS & Kaelin WG, Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464-468, 2001.
41. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS & Kaelin WG, Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464-468, 2001.
42. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V and Kaelin WG. Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein.Nature Cell Biol. 2, 423–427, 2000.
43. Tanimoto K, Makino Y, Pereira T and Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel–Lindau tumor suppressor protein. EMBO J., 19, 4298–4309, 2000.
44. Mazure NM, Brahimi-Horn MC, Berta MA. HIF-1:master and commander of thehypoxic world. A pharmacological approach to its regulation by siRNAs. Biochem Pharmacol. 68(6):971-980, 2004.
45. Semenza GL. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda).19:176-182, 2004.
46. Chavez JC, LaManna JC. Activation of hypoxia-inducible factor-1 in the rat cerebral cortex after transient global ischemia: potential role of insulin-like growthbfactor-1. J. Neurosci. 22, 8922–8931, 2002.
47. Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer 2(1):38-47, 2002.
48. Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr. Opin. Genet. Dev. 11, 293– 299, 2001.
49. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences, USA 92, 5510-5514, 1995.
50. Willam C, Warnecke C, Schefold JC, Kugler J, Koehne P, Frei U, Wiesener M, Eckardt KU. Inconsistent effects of acidosis on HIF-alpha protein and its target genes. Pflugers Arch. 451(4):534-43, 2006.
51. Johanson CE, Parandoosh Z, Dyas ML. Maturational differences in acetazolamide-altered pH and HCO3 of choroid plexus, cerebrospinal fluid, and brain. Am J Physiol, 262:R909–R914, 1992.
52. Zhang S, Leske DA, Lanier WL, Berkowitz BA, Holmes JM. Preretinal neovascularization associated with acetazolamide-induced systemic acidosis in the neonatal rat. Invest Ophthalmol Vis Sci, 42:1066-07, 2001.
53. Basnyat B, Gertsch JH, Holck PS, Johnson EW, Luks AM, DonhamBP, Fleischman RJ, Gowder DW, Hawksworth JS, Jensen BT, Kleiman RJ, Loveridge AH, Lundeen EB, Newman SL, Noboa JA, Miegs DP, O'Beirne KA, Philpot KB, Schultz MN, Valente MC, Wiebers MR and Swenson ER. Acetazolamide 125mg BD is not significantly different from 375mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol 7: 17-27, 2006.
54. Ried LD, Carter KA and Ellsworth A. Acetazolamide or dexamethasone for prevention of acute mountain sickness: a meta-analysis. J Wilderness Med 5: 34-48, 1994.
55. Liu Q, Moller U, Flugel D. Induction of plasminogen activator inhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1. Blood. 104(13):3993-4001,2004.
56. Forsythe JA, Jiang BH, Iyer NV. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 16(9):4604-13,1996.
57. Bing OH, Brooks WW, Messer JV. Heart muscle viability following hypoxia: protective effect of acidosis. Science 180:1297–1298, 1973.
58. Penttila A, Trump BF. Extracellular acidosis protects Ehrlich ascites tumor cells and rat renal cortex against anoxic injury. Science 185:277–278, 1974.
59. Currin RT, Gores G.J, Thurman RG, Lemasters JJ. Protection by acidotic pH against anoxic cell killing in perfused rat liver: evidence for a pH paradox. Faseb J. 5, 207–210, 1991.
60. Nielsen OB, de Paoli F, Overgaard K. Protective effects of lactic acid on force production in rat skeletal muscle. J. Physiol. 536, 161–166, 2001.
61. Morimoto Y, Kemmotsu O, Alojado ES. Extracellular acidosis delays cell death against glucose-oxygen deprivation in neuroblastoma x glioma hybrid cells. Crit. Care Med. 25, 841–847, 1997.
62. Tombaugh GC, Sapolsky RM. Mild acidosis protects hippocampalneurons from injury induced by oxygen and glucose deprivation. Brain Res 506: 343 –345, 1990.
63. Giffard RG, Monyer H, Christin CW, Choi DW. Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res. 506, 339–342, 1990.
64. Kaku DA, Giffard RG, Choi DW. Neuroprotective effects of glutamate antagonists and extracellular acidity. Science 260, 1516–1518, 1993.
1. West JB. The physiologic basis of high-altitude diseases [J]. Ann Intern Med, 2004, 141:789-800.
2. Hackett PH, Rennie D. Acute mountain sickness [J]. Semin Respir Med, 1983, 5: 132-140.
3. Swenson ER, Hughes JM. Effects of acute and chronic acetazolamide on resting ventilation and ventilatory responses in men [J]. J Appl Physiol, 1993, 74: 230-237.
4. Basnyat B, Gertsch JH, Holck PS, et al. Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial [J]. High Alt Med Biol, 2006, 7: 17-27.
5. Roach RC, Hackett PH. Frontiers of hypoxia research: acute mountain sickness [J]. J Exp Biol, 2001, 204: 3161-3170.
6. Fischer R, Vollmar C, Thiere M, et al. No evidence of cerebral oedema in severe acute mountain sickness [J]. Cephalalgia, 2004, 24: 66-71.
7. Hackett PH, Roach RC. High altitude cerebral edema [J]. High Alt Med Biol, 2004, 5:136-146.
8. Bailey DM, Roukens R, Knauth M, et al. Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache [J]. J Cereb Blood Flow Metab, 2006, 26: 99-111.
9. Sutton JR, Houston CS, Mansell AL, et al. Effect of acetazolamide on hypoxemia during sleep at high altitude [J]. N Engl J Med, 1979, 301: 1329-1331.
10. Swenson ER. Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression [J]. Eur Respir J, 1998, 12: 1242-1247.
11. Kiwull-Schone HF, Teppema LJ, Kiwull PJ. Low-dose acetazolamide does affect respiratory muscle function in spontaneously breathing anesthetized rabbits [J]. Am J Respir Crit Care Med, 2001, 163: 478-483.
12. Teppema LJ, Dahan A. Acetazolamide and breathing. Does a clinical dose alter peripheral and central CO2 sensitivity [J]? Am J Respir Crit Care Med, 1999, 160: 1592-1597.
13. Kronenberg RS, Cain SM. Hastening respiratory acclimatization to altitude with benzolamide [J]. Aerosp Med, 1968, 39: 296-300.
14. Tojima H, Kunitomo F, Okita S, et al. Difference in the effects of acetazolamide and ammonium chloride acidosis on ventilatory responses to CO2 and hypoxia in humans [J]. Jpn J Physiol, 1986, 36: 511-521.
15. Vovk A, Duffin J, Kowalchuk JM, et al. Changes in chemoreflex characteristics following acute carbonic anhydrase inhibition in humans at rest [J]. Exp Physiol, 2000, 85: 847-856.
16. Maren TH. Carbonic anhydrase: chemistry, physiology, and inhibition [J]. Physiol Rev, 1967, 47: 595-781.
17. Teppema LJ, Rochette F, Demedts M. Ventilatory response to carbonic anhydrase inhibition in cats: effects of acetazolamide in intact vs peripherally chemodenervated animals [J]. Respir Physiol, 1988, 74: 373-382.
18. Travis DM. Molecular CO2 is inert on carotid chemoreceptor: demonstration by inhibition of carbonic anhydrase [J]. J Pharmacol Exp Ther, 1971, 178: 529-540.
19. Teppema LJ, Bijl H, Gourabi BM, et al. The carbonic anhydrase inhibitors methazolamide and acetazolamide have different effects on the hypoxic ventilatory response in the anaesthetized cat [J]. J Physiol, 2006, 574: 565-572.
20. Swenson ER. Carbonic anhydrase inhibitors and hypoxic pulmonary vasoconstriction [J]. Respir Physiol Neurobiol, 2006, 151: 209-216.
21. Swenson ER, Maren TH. A quantitative analysis of CO2 transport at rest and during maximal exercise. Respir Physiol [J], 1978, 35: 129-159.
22. Javaheri S, Weyne J, Demeester G, et al. Effects of acetazolamide on ionic composition of cisternal fluid during acute respiratory acidosis [J]. J Appl Physiol, 1984, 57: 85-91.
23. Bickler PE, Litt L, Severinghaus JW. Effects of acetazolamide on cerebrocortical NADH and blood volume [J]. J Appl Physiol, 1988, 65: 428-433.
24. Grossmann WM, Koeberle B. The dose-response relationship of acetazolamide on the cerebral blood flow in normal subjects [J]. Cerebrovasc Dis, 2000, 10: 65-69.
25. Zielinski J, Koziej M, Mankowski M, et al. The quality of sleep and periodic breathing in healthy subjects at an altitude of 3200m [J]. High Alt Med Biol, 2000, 1: 331- 336.
26. Hackett PH, Roach RC, Harrison GL, et al. Respiratory stimulants and sleep periodic breathing at high altitude. Almitrine versus acetazolamide [J]. Am Rev Respir Dis, 1987, 135: 896-898.
27. Wickramasinghe H, Anholm JD. Sleep and Breathing at High Altitude [J]. Sleep Breath, 1999, 3: 89-102.
28. Jennum P, Jensen R. Sleep and headache [J]. Sleep Med Rev, 2002, 6: 471-479.
29. Weil JV. Sleep at high altitude [J]. High Alt Med Biol, 2004, 5: 180-189.
30. Smith CA, Nakayama H, Dempsey JA. The essential role of carotid body chemoreceptors in sleep apnea [J]. Can J Physiol Pharmacol, 2003, 81: 774-779.
31. Sundstrom ES. Studies on adaptation of man to high altitudes. V. Effect of high altitudes on salt metabolism [J]. Univ Calif Publ Physiol, 2006, 5: 121-132.
32. Honig A. Peripheral arterial chemoreceptors and reflex control ofsodium and water homeostasis [J]. Am J Physiol, 1989, 257: R1282-R1302.
33. Bartsch P, Jilg B, Hohenhaus E. Urine volume in acute mountain sickness is not related to hypoxic ventilatory response [J]. Europ Respir J, 1995, 8: 62S.
34. Loeppky JA, Icenogle MV, Maes D, et al. Early fluid retention and severe acute mountain sickness [J]. J Appl Physiol, 2005, 98: 591-597.
35. Oh MS, Carroll HJ. Mechanism of chloride deficit in the maintenance of metabolic alkalosis [J]. Nephron, 2002, 91: 379-382.
36. Singh I, Khanna PK, Srivastava MC, et al. Acute mountain sickness [J]. N Engl J Med, 1969, 280: 175-184.
37. Currie TT. Spironolactone and acute mountain sickness [J]. Med J Aust, 1977, 1: 419-420.
38. Swenson ER. High Altitude diuresis: fact or fancy. In Hypoxia, women at altitude [J]. In: Hypoxia, women at altitude, edited by Houston CS and Coates G. Burlington VT: Queen City Printers, 2006, p. 272-283.
39. Heinemann H, Goldring R. Bicarbonate and the regulation of ventilation [J]. Am J Med, 1974, 57: 370.
40. Turek Z, Kreuzer F, Scotto P, et al. The effect of blood O2 affinity on the efficiency of O2 transport in blood at hypoxic hypoxia [J]. Adv Exp Med Biol, 1984, 180:357-368.
2. Wenger RH Mammalian oxygen sensing, signalling and gene regulation. J. Exp. Biol., 203, 1253–1263, 2000.
3. Loeschcke HH and Gertz KH. Einfluss des O2-Druckes in der Einatmungsluft auf die Atemtatigkeit der Menschen, gepruft unter Konstanthaltung des alveolaren CO2-Druckes. Pflugers Arch Ges Physiol 267: 477, 1958.
4. Swenson ER and Hughes JM. Effects of acute and chronic acetazolamide on resting ventilation and ventilatory responses in men. J Appl Physiol. 74: 230-237, 1993.
5. Maren TH. Carbonic anhydrase: chemistry, physiology and inhibition. Physiol. Rev. 47, 595–781, 1967.
6. Leaf DE, Goldfarb DS. Mechanisms of Action of Acetazolamide in the Prophylaxis and Treatment of Acute Mountain Sickness: A Review. J Appl Physiol. 0: 01572.2005v1, 2006.
7. Semenza G. Signal transduction to hypoxia-inducible factor 1, Biochem. Pharmacol. 64, 993–998, 2002.
8. Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nature Rev. Cancer 2, 673–682, 2002.
9. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294 1337-1340, 2001.
10. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107, 43-54, 2001.
11. Semenza GL. Hypoxia-inducible factor 1 and the molecular physiology ofoxygen homeostasis. J. Lab. Clin. Med. 131, 207-214, 1998.
12. Semenza GL. HIF-1 and human disease: one highly involved factor. Genes Dev. 14, 1983–1991, 2000.
13. Mekhail K, Gunaratnam L, Bonicalzi ME, Lee S. HIF activation by pH- dependent nucleolar sequestration of VHL. Nat Cell Biol 6:642–647, 2004.
14. Findl O, Hansen RM, Fulton AB. The effects of acetazolamide on the electroretinographic responses in rats. Invest Ophthalmol Vis Sci. 36:1019–1026, 1995.
15. Heller I, Halevy J, Cohen S, Theodor E. Significant metabolic acidosis induced by acetazolamide: not a rare complication. Arch Intern Med. 145:1815–1817, 1985.
16. Ririe KM, Rasmussen RP, Wittwer CT. Product differentiation by analysis of DNA melting curves during the polymerase chain reaction. Anal Biochem. 245: 154–160, 1997.
17. Wittwer CT, Ririe KM, Andrew RV, David DA, Gundry RA, Balis UJ. The LightCycler: microvolume multisample fluorimeter with rapid temperature control Biotechniques. 22:176-181, 1997.
18. Brewer GJ. Serum-free B27/Neurobasal medium supports differentiated growth of neurons from the striatum, substantia. nigra, septum, cerebral cortex, cerebellum, and dentate gyrus. Neurosci. Res. 42, 674–683, 1995.
19. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci USA. Apr 29;94 (9):4273-8, 1997.
20. Roach RC, Hackett PH. Frontiers of hypoxia research: acute mountain sickness. J Exp Biol, 204: 3161-3170, 2001.
21. Fischer R, Vollmar C, Thiere M. No evidence of cerebral oedema in severe acute mountain sickness. Cephalalgia, 24: 66-71, 2004.
22. Hackett PH, Roach RC. High altitude cerebral edema. High Alt Med Biol,5:136-146, 2004.
23. Bailey DM, Roukens R, Knauth M. Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache. J Cereb Blood Flow Metab, 26: 99-111, 2006.
24. Magalhaes J, Ascensao A, Soares JM. Acute and Chronic Exposition of Mice to Severe Hypoxia: The Role of Acclimatization against Skeletal Muscle Oxidative Stress. Int J Sports Med. 26(2):102-109, 2005.
25. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr. Opin. Cell Biol. 13, 167–171, 2001.
26. JE Albina, JS Reichner. Oxygen and the regulation of gene expression in wounds, Wound Repair Regen. 11, 445– 451, 2003.
27. West JB. The physiologic basis of high-altitude diseases. Ann Intern Med, 141:789-800, 2004.
28. Stoeltzing O, McCarty MF, Wey JS. Role of hypoxia-inducible factor 1alpha in gastric cancer cell growth, angiogenesis, and vessel maturation. J Natl Cancer Inst. 96(12):946-56, 2004.
29. Sadamoto Y, Igase K, Sakanaka M, Sato K, Otsuka H, Sakaki S, Masuda S, Sasaki R. Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem. Biophys. Res. Commun. 253, 26–32, 1998.
30. Semenza GL. Regulation of erythropo iefin production New insights into molecular mechallisms of oxygen homeostasis. Hematol Oncol Clin North Am,8(5):863—884,1994.
31. Scmonza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein sysnthesis binds to the human erythropoietin gene enhance at a site required for transcriptional activation. Mol Cell Bio1. l2:5447-5454, 1992.
32. Bernaudin M, Marti HH, Roussel S, Divoux D, Nouvelot A, MacKenzie ET, Petit E. A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 19, 643–651, 1999.
33. Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, Sasaki R. In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc. Natl. Acad. Sci. U. S. A. 95, 4635–4640, 1998.
34. HoPPeler H, Vogt M. Hypoxia training for seal-evel performance training high-living low. Adv Exp Med Biol, 502:61-73,2001.
35. Pichiule P,Agani F,Chavez JC. HIF-l alpha and VEGF expression after transient global cerebral isehemia. Adv Exp Med Biol. 530:61l-617, 2003.
36. Hayashi T, Abe K, Itoyama Y. Reduction of ischemic damage by application of vascular endothelial growth factor in rat brain after transient ischemia. J. Cereb. Blood Flow Metab. 18, 887–895, 1998.
37. Sun Y, Jin K, Xie L, Childs J, Mao XO, Logvinova A, Greenberg DA. VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J. Clin. Invest. 111, 1843–1851, 2003.
38. Oesthuyse B,Moon l,Storkebaum E.Delection of the hypoxia response element in the vascular endotheiul growth factor promoter causes motor neuron degeneration.Nat Gcnet, 28(2): 131-138, 2001.
39. Jones NM, Bergeron M. Hypoxic preconditioning induces changes in HIF-1 target genes in neonatal rat brain. J. Cereb. Blood Flow Metab. 21, 1105–1114, 2001.
40. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS & Kaelin WG, Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464-468, 2001.
41. Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS & Kaelin WG, Jr. HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292, 464-468, 2001.
42. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V and Kaelin WG. Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein.Nature Cell Biol. 2, 423–427, 2000.
43. Tanimoto K, Makino Y, Pereira T and Poellinger L. Mechanism of regulation of the hypoxia-inducible factor-1α by the von Hippel–Lindau tumor suppressor protein. EMBO J., 19, 4298–4309, 2000.
44. Mazure NM, Brahimi-Horn MC, Berta MA. HIF-1:master and commander of thehypoxic world. A pharmacological approach to its regulation by siRNAs. Biochem Pharmacol. 68(6):971-980, 2004.
45. Semenza GL. Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda).19:176-182, 2004.
46. Chavez JC, LaManna JC. Activation of hypoxia-inducible factor-1 in the rat cerebral cortex after transient global ischemia: potential role of insulin-like growthbfactor-1. J. Neurosci. 22, 8922–8931, 2002.
47. Harris AL. Hypoxia--a key regulatory factor in tumour growth. Nat Rev Cancer 2(1):38-47, 2002.
48. Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr. Opin. Genet. Dev. 11, 293– 299, 2001.
49. Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proceedings of the National Academy of Sciences, USA 92, 5510-5514, 1995.
50. Willam C, Warnecke C, Schefold JC, Kugler J, Koehne P, Frei U, Wiesener M, Eckardt KU. Inconsistent effects of acidosis on HIF-alpha protein and its target genes. Pflugers Arch. 451(4):534-43, 2006.
51. Johanson CE, Parandoosh Z, Dyas ML. Maturational differences in acetazolamide-altered pH and HCO3 of choroid plexus, cerebrospinal fluid, and brain. Am J Physiol, 262:R909–R914, 1992.
52. Zhang S, Leske DA, Lanier WL, Berkowitz BA, Holmes JM. Preretinal neovascularization associated with acetazolamide-induced systemic acidosis in the neonatal rat. Invest Ophthalmol Vis Sci, 42:1066-07, 2001.
53. Basnyat B, Gertsch JH, Holck PS, Johnson EW, Luks AM, DonhamBP, Fleischman RJ, Gowder DW, Hawksworth JS, Jensen BT, Kleiman RJ, Loveridge AH, Lundeen EB, Newman SL, Noboa JA, Miegs DP, O'Beirne KA, Philpot KB, Schultz MN, Valente MC, Wiebers MR and Swenson ER. Acetazolamide 125mg BD is not significantly different from 375mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial. High Alt Med Biol 7: 17-27, 2006.
54. Ried LD, Carter KA and Ellsworth A. Acetazolamide or dexamethasone for prevention of acute mountain sickness: a meta-analysis. J Wilderness Med 5: 34-48, 1994.
55. Liu Q, Moller U, Flugel D. Induction of plasminogen activator inhibitor I gene expression by intracellular calcium via hypoxia-inducible factor-1. Blood. 104(13):3993-4001,2004.
56. Forsythe JA, Jiang BH, Iyer NV. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 16(9):4604-13,1996.
57. Bing OH, Brooks WW, Messer JV. Heart muscle viability following hypoxia: protective effect of acidosis. Science 180:1297–1298, 1973.
58. Penttila A, Trump BF. Extracellular acidosis protects Ehrlich ascites tumor cells and rat renal cortex against anoxic injury. Science 185:277–278, 1974.
59. Currin RT, Gores G.J, Thurman RG, Lemasters JJ. Protection by acidotic pH against anoxic cell killing in perfused rat liver: evidence for a pH paradox. Faseb J. 5, 207–210, 1991.
60. Nielsen OB, de Paoli F, Overgaard K. Protective effects of lactic acid on force production in rat skeletal muscle. J. Physiol. 536, 161–166, 2001.
61. Morimoto Y, Kemmotsu O, Alojado ES. Extracellular acidosis delays cell death against glucose-oxygen deprivation in neuroblastoma x glioma hybrid cells. Crit. Care Med. 25, 841–847, 1997.
62. Tombaugh GC, Sapolsky RM. Mild acidosis protects hippocampalneurons from injury induced by oxygen and glucose deprivation. Brain Res 506: 343 –345, 1990.
63. Giffard RG, Monyer H, Christin CW, Choi DW. Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res. 506, 339–342, 1990.
64. Kaku DA, Giffard RG, Choi DW. Neuroprotective effects of glutamate antagonists and extracellular acidity. Science 260, 1516–1518, 1993.
1. West JB. The physiologic basis of high-altitude diseases [J]. Ann Intern Med, 2004, 141:789-800.
2. Hackett PH, Rennie D. Acute mountain sickness [J]. Semin Respir Med, 1983, 5: 132-140.
3. Swenson ER, Hughes JM. Effects of acute and chronic acetazolamide on resting ventilation and ventilatory responses in men [J]. J Appl Physiol, 1993, 74: 230-237.
4. Basnyat B, Gertsch JH, Holck PS, et al. Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial [J]. High Alt Med Biol, 2006, 7: 17-27.
5. Roach RC, Hackett PH. Frontiers of hypoxia research: acute mountain sickness [J]. J Exp Biol, 2001, 204: 3161-3170.
6. Fischer R, Vollmar C, Thiere M, et al. No evidence of cerebral oedema in severe acute mountain sickness [J]. Cephalalgia, 2004, 24: 66-71.
7. Hackett PH, Roach RC. High altitude cerebral edema [J]. High Alt Med Biol, 2004, 5:136-146.
8. Bailey DM, Roukens R, Knauth M, et al. Free radical-mediated damage to barrier function is not associated with altered brain morphology in high-altitude headache [J]. J Cereb Blood Flow Metab, 2006, 26: 99-111.
9. Sutton JR, Houston CS, Mansell AL, et al. Effect of acetazolamide on hypoxemia during sleep at high altitude [J]. N Engl J Med, 1979, 301: 1329-1331.
10. Swenson ER. Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression [J]. Eur Respir J, 1998, 12: 1242-1247.
11. Kiwull-Schone HF, Teppema LJ, Kiwull PJ. Low-dose acetazolamide does affect respiratory muscle function in spontaneously breathing anesthetized rabbits [J]. Am J Respir Crit Care Med, 2001, 163: 478-483.
12. Teppema LJ, Dahan A. Acetazolamide and breathing. Does a clinical dose alter peripheral and central CO2 sensitivity [J]? Am J Respir Crit Care Med, 1999, 160: 1592-1597.
13. Kronenberg RS, Cain SM. Hastening respiratory acclimatization to altitude with benzolamide [J]. Aerosp Med, 1968, 39: 296-300.
14. Tojima H, Kunitomo F, Okita S, et al. Difference in the effects of acetazolamide and ammonium chloride acidosis on ventilatory responses to CO2 and hypoxia in humans [J]. Jpn J Physiol, 1986, 36: 511-521.
15. Vovk A, Duffin J, Kowalchuk JM, et al. Changes in chemoreflex characteristics following acute carbonic anhydrase inhibition in humans at rest [J]. Exp Physiol, 2000, 85: 847-856.
16. Maren TH. Carbonic anhydrase: chemistry, physiology, and inhibition [J]. Physiol Rev, 1967, 47: 595-781.
17. Teppema LJ, Rochette F, Demedts M. Ventilatory response to carbonic anhydrase inhibition in cats: effects of acetazolamide in intact vs peripherally chemodenervated animals [J]. Respir Physiol, 1988, 74: 373-382.
18. Travis DM. Molecular CO2 is inert on carotid chemoreceptor: demonstration by inhibition of carbonic anhydrase [J]. J Pharmacol Exp Ther, 1971, 178: 529-540.
19. Teppema LJ, Bijl H, Gourabi BM, et al. The carbonic anhydrase inhibitors methazolamide and acetazolamide have different effects on the hypoxic ventilatory response in the anaesthetized cat [J]. J Physiol, 2006, 574: 565-572.
20. Swenson ER. Carbonic anhydrase inhibitors and hypoxic pulmonary vasoconstriction [J]. Respir Physiol Neurobiol, 2006, 151: 209-216.
21. Swenson ER, Maren TH. A quantitative analysis of CO2 transport at rest and during maximal exercise. Respir Physiol [J], 1978, 35: 129-159.
22. Javaheri S, Weyne J, Demeester G, et al. Effects of acetazolamide on ionic composition of cisternal fluid during acute respiratory acidosis [J]. J Appl Physiol, 1984, 57: 85-91.
23. Bickler PE, Litt L, Severinghaus JW. Effects of acetazolamide on cerebrocortical NADH and blood volume [J]. J Appl Physiol, 1988, 65: 428-433.
24. Grossmann WM, Koeberle B. The dose-response relationship of acetazolamide on the cerebral blood flow in normal subjects [J]. Cerebrovasc Dis, 2000, 10: 65-69.
25. Zielinski J, Koziej M, Mankowski M, et al. The quality of sleep and periodic breathing in healthy subjects at an altitude of 3200m [J]. High Alt Med Biol, 2000, 1: 331- 336.
26. Hackett PH, Roach RC, Harrison GL, et al. Respiratory stimulants and sleep periodic breathing at high altitude. Almitrine versus acetazolamide [J]. Am Rev Respir Dis, 1987, 135: 896-898.
27. Wickramasinghe H, Anholm JD. Sleep and Breathing at High Altitude [J]. Sleep Breath, 1999, 3: 89-102.
28. Jennum P, Jensen R. Sleep and headache [J]. Sleep Med Rev, 2002, 6: 471-479.
29. Weil JV. Sleep at high altitude [J]. High Alt Med Biol, 2004, 5: 180-189.
30. Smith CA, Nakayama H, Dempsey JA. The essential role of carotid body chemoreceptors in sleep apnea [J]. Can J Physiol Pharmacol, 2003, 81: 774-779.
31. Sundstrom ES. Studies on adaptation of man to high altitudes. V. Effect of high altitudes on salt metabolism [J]. Univ Calif Publ Physiol, 2006, 5: 121-132.
32. Honig A. Peripheral arterial chemoreceptors and reflex control ofsodium and water homeostasis [J]. Am J Physiol, 1989, 257: R1282-R1302.
33. Bartsch P, Jilg B, Hohenhaus E. Urine volume in acute mountain sickness is not related to hypoxic ventilatory response [J]. Europ Respir J, 1995, 8: 62S.
34. Loeppky JA, Icenogle MV, Maes D, et al. Early fluid retention and severe acute mountain sickness [J]. J Appl Physiol, 2005, 98: 591-597.
35. Oh MS, Carroll HJ. Mechanism of chloride deficit in the maintenance of metabolic alkalosis [J]. Nephron, 2002, 91: 379-382.
36. Singh I, Khanna PK, Srivastava MC, et al. Acute mountain sickness [J]. N Engl J Med, 1969, 280: 175-184.
37. Currie TT. Spironolactone and acute mountain sickness [J]. Med J Aust, 1977, 1: 419-420.
38. Swenson ER. High Altitude diuresis: fact or fancy. In Hypoxia, women at altitude [J]. In: Hypoxia, women at altitude, edited by Houston CS and Coates G. Burlington VT: Queen City Printers, 2006, p. 272-283.
39. Heinemann H, Goldring R. Bicarbonate and the regulation of ventilation [J]. Am J Med, 1974, 57: 370.
40. Turek Z, Kreuzer F, Scotto P, et al. The effect of blood O2 affinity on the efficiency of O2 transport in blood at hypoxic hypoxia [J]. Adv Exp Med Biol, 1984, 180:357-368.