Document Type : Research Paper I Open Access I Released under CC BY 4.0 license


1 university razi

2 Associate Professor; Department of exercise physiology, Faculty of Physical of Physical Education and Sport Sciences, Razi University Kermanshah, Kermanshah, Iran.

3 Associate Professor, Faculty of Sports Sciences, Department of Exercise Physiology, Razi University, Kermanshah, Iran

4 Associate Professor, Faculty of Medical Sciences, Department of Biochemistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran


Acute mountain sickness (AMS) caused by rapid ascent to altitudes higher than 2500 m has complex pathophysiological conditions. Therefore, the aim of the present study was to investigate hypoxia related factors in individual susceptible to acute mountain sickness. 21 healthy subjects (mean age 31.7±8.5 year) participated in this study. Fasting blood samples were collected from antecubital vein (sea level) 1 hour and 24 hours after rapid ascent to an altitude of 3550 m by a gondola lift. HIF-1 and Orexin-A were measured by ELISA method. AMS status was measured by the Lake Louise Scoring 6 hours after the exposure to a high altitude. Lake Louise Scoring showed that 11 subjects got AMS after the exposure to a high altitude (LLS≥4). The results showed that Orexin-A and HIF-1 at sea level were higher in AMS-susceptible subjects than AMS-resistant subjects. But Orexin-A and HIF-1 responses were almost higher in AMS-susceptible subjects than AMS-resistant subjects. Orexin-A and HIF-1 at sea level had an inverse relationship with AMS. An increase in these proteins in AMS-susceptible subjects was drastically higher than AMS-resistant subjects after exposure to altitude.


1.   Rodway GW, Hoffman LA, Sanders MH. High-altitude-related disorders—Part I: Pathophysiology, differential diagnosis, and treatment. Heart & Lung: The Journal of Acute and Critical Care. 2003;32(6):353-9.
2.   Roach RC, Hackett PH. Frontiers of hypoxia research: acute mountain sickness. Journal of Experimental Biology. 2001;204(18):3161-70.
3.   Liu B, Huang H, Wu G, Xu G, Sun B-D, Zhang E-L, et al. A signature of circulating microRNAs predicts the susceptibility of acute mountain sickness. Frontiers in physiology. 2017;8.
4.   Liao W-T, Liu B, Chen J, Cui J-H, Gao Y-X, Liu F-Y, et al. Metabolite modulation in human plasma in the early phase of acclimatization to hypobaric hypoxia. Scientific reports. 2016;6.
5.   Grissom CK, Zimmerman GA, Whatley RE. Endothelial selectins in acute mountain sickness and high-altitude pulmonary edema. Chest. 1997;112(6):1572-8.
6.   Lanfranchi PA, Colombo R, Cremona G, Baderna P, Spagnolatti L, Mazzuero G, et al. Autonomic cardiovascular regulation in subjects with acute mountain sickness. American Journal of Physiology-Heart and Circulatory Physiology. 2005;58(6):H2364.
7.   Chen H-C, Lin W-L, Wu J-Y, Wang S-H, Chiu T-F, Weng Y-M, et al. Change in oxygen saturation does not predict acute mountain sickness on Jade Mountain. Wilderness & environmental medicine. 2012;23(2):122-7.
8.   Wu J, Gu H, Luo Y. Differences between the “Chinese AMS Score” and the Lake Louise score in the diagnosis of acute mountain sickness. Medicine. 2016;95(21).
9.   Karinen HM, Peltonen JE, Kähönen M, Tikkanen HO. Prediction of acute mountain sickness by monitoring arterial oxygen saturation during ascent. High altitude medicine & biology. 2010;11(4):325-32.
10. Julian CG, Subudhi AW, Hill RC, Wilson MJ, Dimmen AC, Hansen KC, et al. Exploratory proteomic analysis of hypobaric hypoxia and acute mountain sickness in humans. Journal of Applied Physiology. 2014;116(7):937-44.
11. Painschab MS, Malpartida GE, Dávila-Roman VG, Gilman RH, Kolb TM, León-Velarde F, et al. Association between serum concentrations of hypoxia inducible factor responsive proteins and excessive Erythrocytosis in high altitude Peru. High altitude medicine & biology. 2015;16(1):26-33.
12. Ding H, Liu Q, Hua M, Ding M, Du H, Zhang W, et al. Polymorphisms of hypoxia-related genes in subjects susceptible to acute mountain sickness. Respiration. 2011;81(3):236-41.
13. Droma Y, Ota M, Hanaoka M, Katsuyama Y, Basnyat B, Neupane P, et al. Two hypoxia sensor genes and their association with symptoms of acute mountain sickness in Sherpas. Aviation, space, and environmental medicine. 2008;79(11):1056-60.
14. Liu XH, Morris R, Spiller D, White M, Williams G. Orexin a preferentially excites glucose-sensitive neurons in the lateral hypothalamus of the rat in vitro. Diabetes. 2001;50(11):2431-7.
15. Xu T-R, Yang Y, Ward R, Gao L, Liu Y. Orexin receptors: multi-functional therapeutic targets for sleeping disorders, eating disorders, drug addiction, cancers and other physiological disorders. Cellular signalling. 2013;25(12):2413-23.
16. Tsujino N, Sakurai T. Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacological reviews. 2009;61(2):162-76.
17. Yuan L-b, Dong H-l, Zhang H-P, Zhao R-n, Gong G, Chen X-m, et al. Neuroprotective effect of orexin-A is mediated by an increase of hypoxia-inducible factor-1 activity in rat. The Journal of the American Society of Anesthesiologists. 2011;114(2):340-54.
18. Kline DD, Peng Y-J, Manalo DJ, Semenza GL, Prabhakar NR. Defective carotid body function and impaired ventilatory responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1α. Proceedings of the National Academy of Sciences. 2002;99(2):821-6.
19. Semenza GL. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. The Journal of clinical investigation. 2013;123(9):3664.
20. Sokołowska P, Urbańska A, Biegańska K, Wagner W, Ciszewski W, Namiecińska M, et al. Orexins protect neuronal cell cultures against hypoxic stress: an involvement of Akt signaling. Journal of Molecular Neuroscience. 2014;52(1):48-55.
21. Bourgin P, Huitrón-Reséndiz S, Spier AD, Fabre V, Morte B, Criado JR, et al. Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. Journal of Neuroscience.2005. 20(20). PP: 60-77.
22. Liu Z, Jiang L, Zhu F, Fu C, Lu S, Zhou J, et al. Chronic intermittent hypoxia and the expression of orexin and its receptors in the brains of rats. Sleep and Biological Rhythms. 2014;12(1):22-9.
23. Sikder D, Kodadek T. The neurohormone orexin stimulates hypoxia-inducible factor-1 activity. Genes & development. 2007;21(22):2995-3005.
24. Julian CG, Subudhi AW, Wilson MJ, Dimmen AC, Pecha T, Roach RC. Acute mountain sickness, inflammation, and permeability: new insights from a blood biomarker study. Journal of Applied Physiology. 2011;111(2):392-9.