Abstract
Purpose
To examine the effects of intermittent hypoxic breathing at rest (IHR) or during exercise (IHT) on blood pressure and nitric oxide metabolites (NOx) and hypoxia-inducible factor-1 alpha levels (HIF-1α) over a 6-week period.
Methods
47 hypertensive patients were randomly allocated to three groups: hypertensive control (CON: n = 17; IHR: n = 15 and IHT: n = 15. The CON received no intervention; whereas, IH groups received eight events of hypoxia (FIO2 0.14), and normoxia (FIO2 0.21), 24-min hypoxia and 24-min normoxia, for 6 weeks. The baseline data were collected 2 days before the intervention; while, the post-test data were collected at days 2 and 28 after the 6-week intervention.
Results
We observed a significant decrease of the SBP in both IH groups: IHR (− 12.0 ± 8.0 mmHg, p = 0.004 and − 9.9 ± 8.8 mmHg, p = 0.028, mean ± 95% CI) and IHT (− 13.0 ± 7.8 mmHg, p = 0.002 and − 10.0 ± 8.4 mmHg, p = 0.016) at days 2 and 28 post-intervention, respectively. Compared to CON, IHR and IHT had increased of NOx (IHR; 8.5 ± 7.6 μmol/L, p = 0.031 and IHT; 20.0 ± 9.1 μmol/L, p < 0.001) and HIF-1α (IHR; 170.0 ± 100.0 pg/mL, p = 0.002 and IHT; 340.5 ± 160.0 pg/mL, p < 0.001). At 2 days post-intervention, NOx and HIF-1α were negatively correlated with SBP in IHT.
Conclusion
IH programs may act as an alternative therapeutic strategy for hypertension patients probably through elevation of NOx and HIF-1α production.
Similar content being viewed by others
Abbreviations
- ATS:
-
American Thoracic Society
- CI:
-
Confidence interval
- EDTA:
-
Ethylenediaminetetraacetic acid
- FIO2 :
-
Fraction inspired of oxygen
- GEE:
-
Generalized estimating equation model
- HIF-1α:
-
Hypoxia-inducible factor-1 alpha levels
- IHR:
-
Intermittent hypoxic breathing at rest
- IHT:
-
Intermittent hypoxic training
- JNC 8:
-
The Eighth Joint National Committee
- MDA:
-
Malondialdehyde
- MWT:
-
Minute walk test
- MWCO:
-
Molecular weight cut-off
- MWD:
-
Minute walk distance
- NOx:
-
Nitric oxide metabolites
- RPD:
-
Rating of perceived of dyspnea
- RPE:
-
Rating of perceived of exertion
- TMB:
-
Tetramethylbenzidine
References
Adams V, Lenk K, Linke A, Lenz D, Erbs S, Sandri M, Tarnok A, Gielen S, Emmrich F, Schuler G, Hambrecht R (2004) Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise-induced ischemia. Arterioscler Thromb Vasc Biol 24(4):684–690. https://doi.org/10.1161/01.ATV.0000124104.23702.a0
ATS (2016) Erratum: ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 193(10):1185. https://doi.org/10.1164/rccm.19310erratum
Basile J, Gradman A, Nesbitt S, Weir M (2011) Treating special populations with hypertension: is a two-drug or fixed-dose combination therapy appropriate initial treatment in hypertension? Med Roundtable Cardiovasc Ed 2(4):225–234
Baum O, Vieregge M, Koch P, Gul S, Hahn S, Huber-Abel FA, Pries AR, Hoppeler H (2013) Phenotype of capillaries in skeletal muscle of nNOS-knockout mice. Am J Physiol Regul Integr Comp Physiol 304(12):1175–1182. https://doi.org/10.1152/ajpregu.00434.2012
Beall CM (2014) Human evolution at high altitude. In: Swenson E, Bärtsch P (eds) High altitude. Springer, Berlin, pp 357–377. https://doi.org/10.1007/978-1-4614-8772-2
Borg G (1998) Borg’s perceived exertion and pain scales. Human kinetics. pp 13-16
Coulet F, Nadaud S, Agrapart M, Soubrier F (2003) Identification of hypoxia-response element in the human endothelial nitric-oxide synthase gene promoter. J Biol Chem 278(47):46230–46240. https://doi.org/10.1074/jbc.M305420200
Cowburn AS, Takeda N, Boutin AT, Kim JW, Sterling JC, Nakasaki M, Southwood M, Goldrath AW, Jamora C, Nizet V, Chilvers ER, Johnson RS (2013) HIF isoforms in the skin differentially regulate systemic arterial pressure. Proc Natl Acad Sci USA 110(43):17570–17575. https://doi.org/10.1073/pnas.1306942110
Draper HH, Squires EJ, Mahmoodi H, Wu J, Agarwal S, Hadley M (1993) A comparative evaluation of thiobarbituric acid methods for the determination of malondialdehyde in biological materials. Free Radic Biol Med 15(4):353–363. https://doi.org/10.1016/0891-5849(93)90035-s
Faulhaber M, Gatterer H, Haider T, Linser T, Netzer N, Burtscher M (2015) Heart rate and blood pressure responses during hypoxic cycles of a 3-week intermittent hypoxia breathing program in patients at risk for or with mild COPD. Int J Chron Obstruct Pulmon Dis 10:339–345. https://doi.org/10.2147/COPD.S75749
Giles TD (2006) Aspects of nitric oxide in health and disease: a focus on hypertension and cardiovascular disease. J Clin Hypertens (Greenwich) 8(12 Suppl 4):2–16. https://doi.org/10.1111/j.1524-6175.2006.06023.x
Hamlin MJ, Hellemans J (2007) Effect of intermittent normobaric hypoxic exposure at rest on haematological, physiological, and performance parameters in multi-sport athletes. J Sports Sci 25(4):431–441. https://doi.org/10.1080/02640410600718129
Higashi Y, Murohara T (2017) Therapeutic angiogenesis. Springer, Berlin
Huang HH, Han CL, Yan HC, Kao WY, Tsai CD, Yen DH, Huang CI, Chen WT (2008) Oxidative stress and erythropoietin response in altitude exposure. Clin Investig Med 31(6):E380–385. https://doi.org/10.25011/cim.v31i6.4925
Hudlicka O, Brown MD (2009) Adaptation of skeletal muscle microvasculature to increased or decreased blood flow: role of shear stress, nitric oxide and vascular endothelial growth factor. J Vasc Res 46(5):504–512. https://doi.org/10.1159/000226127
James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E (2014) 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311(5):507–520. https://doi.org/10.1001/jama.2013.284427
Korkushko OV, Shatilo VB, Ishchuk VA (2010) Effectiveness of intermittent normabaric hypoxic trainings in elderly patients with coronary artery disease. Adv Gerontol 23(3):476–482
Lippl FJ, Neubauer S, Schipfer S, Lichter N, Tufman A, Otto B, Fischer R (2010) Hypobaric hypoxia causes body weight reduction in obese subjects. Obesity (Silver Spring) 18(4):675–681. https://doi.org/10.1038/oby.2009.509
Lizamore CA, Hamlin MJ (2017) The use of simulated altitude techniques for beneficial cardiovascular health outcomes in nonathletic, sedentary, and clinical populations: a literature review. High Alt Med Biol 18(4):305–321. https://doi.org/10.1089/ham.2017.0050
Luks A, Hackett P (2014) High altitude and common medical conditions. In: Swenson E, Bartsch P (eds) High altitude. Springer, New York, pp 449–477. https://doi.org/10.1007/978-1-4614-8772-2_23
Lyamina NP, Lyamina SV, Senchiknin VN, Mallet RT, Downey HF, Manukhina EB (2011) Normobaric hypoxia conditioning reduces blood pressure and normalizes nitric oxide synthesis in patients with arterial hypertension. J Hypertens 29(11):2265–2272. https://doi.org/10.1097/HJH.0b013e32834b5846
Mahajan AS, Babbar R, Kansal N, Agarwal SK, Ray PC (2007) Antihypertensive and antioxidant action of amlodipine and vitamin C in patients of essential hypertension. J Clin Biochem Nutr 40(2):141–147. https://doi.org/10.3164/jcbn.40.141
Manimmanakorn A, Hamlin MJ, Ross JJ, Taylor R, Manimmanakorn N (2013) Effects of low-load resistance training combined with blood flow restriction or hypoxia on muscle function and performance in netball athletes. J Sci Med Sport 16(4):337–342. https://doi.org/10.1016/j.jsams.2012.08.009
Manukhina EB, Downey HF, Mallet RT (2006) Role of nitric oxide in cardiovascular adaptation to intermittent hypoxia. Exp Biol Med (Maywood) 231(4):343–365. https://doi.org/10.1177/153537020623100401
Margretardottir OB, Thorleifsson SJ, Gudmundsson G, Olafsson I, Benediktsdottir B, Janson C, Buist AS, Gislason T (2009) Hypertension, systemic inflammation and body weight in relation to lung function impairment-an epidemiological study. COPD 6(4):250–255. https://doi.org/10.1080/15412550903049157
Millet GP, Debevec T, Brocherie F, Malatesta D, Girard O (2016) Therapeutic use of exercising in hypoxia: promises and limitations. Front Physiol 7:224. https://doi.org/10.3389/fphys.2016.00224
Pialoux V, Mounier R, Rock E, Mazur A, Schmitt L, Richalet JP, Robach P, Coudert J, Fellmann N (2009) Effects of acute hypoxic exposure on prooxidant/antioxidant balance in elite endurance athletes. Int J Sports Med 30(2):87–93. https://doi.org/10.1055/s-0028-1103284
Puddu P, Puddu GM, Cravero E, Muscari A (2004) Different effects of antihypertensive drugs on endothelial dysfunction. Acta Cardiol 59(5):555–564. https://doi.org/10.2143/AC.59.5.2005232
Saeed O, Bhatia V, Formica P, Browne A, Aldrich TK, Shin JJ, Maybaum S (2012) Improved exercise performance and skeletal muscle strength after simulated altitude exposure: a novel approach for patients with chronic heart failure. J Card Fail 18(5):387–391. https://doi.org/10.1016/j.cardfail.2012.02.003
Schnabel E, Nowak D, Brasche S, Wichmann HE, Heinrich J (2011) Association between lung function, hypertension and blood pressure medication. Respir Med 105(5):727–733. https://doi.org/10.1016/j.rmed.2010.12.023
Semenza GL, Agani F, Booth G, Forsythe J, Iyer N, Jiang BH, Leung S, Roe R, Wiener C, Yu A (1997) Structural and functional analysis of hypoxia-inducible factor 1. Kidney Int 51(2):553–555. https://doi.org/10.1038/ki.1997.77
Semenza GL, Roth PH, Fang HM, Wang GL (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269(38):23757–23763
Sen CK, Packer L (1996) Antioxidant and redox regulation of gene transcription. FASEB J 10(7):709–720. https://doi.org/10.1096/fasebj.10.7.8635688
Serebrovska TV, Serebrovska ZO, Egorov E (2016) Fitness and therapeutic potential of intermittent hypoxia training: a matter of dose. Fiziol Zh 62(3):78–91. https://doi.org/10.15407/fz62.03.078
Serebrovskaya TV, Manukhina EB, Smith ML, Downey HF, Mallet RT (2008) Intermittent hypoxia: cause of or therapy for systemic hypertension? Exp Biol Med (Maywood) 233(6):627–650. https://doi.org/10.3181/0710-MR-267
Sevre K, Lefrandt JD, Nordby G, Os I, Mulder M, Gans RO, Rostrup M, Smit AJ (2001) Autonomic function in hypertensive and normotensive subjects: the importance of gender. Hypertension 37(6):1351–1356. https://doi.org/10.1161/01.hyp.37.6.1351
Tin'kov AN, Aksenov VA (2002) Effects of intermittent hypobaric hypoxia on blood lipid concentrations in male coronary heart disease patients. High Alt Med Biol 3(3):277–282. https://doi.org/10.1089/152702902320604250
Urdampilleta A, Gonzalez-Muniesa P, Portillo MP, Martinez JA (2012) Usefulness of combining intermittent hypoxia and physical exercise in the treatment of obesity. J Physiol Biochem 68(2):289–304. https://doi.org/10.1007/s13105-011-0115-1
Vamvakis A, Gkaliagkousi E, Triantafyllou A, Gavriilaki E, Douma S (2017) Beneficial effects of nonpharmacological interventions in the management of essential hypertension. JRSM Cardiovasc Dis 6:2048004016683891. https://doi.org/10.1177/2048004016683891
Verges S, Chacaroun S, Godin-Ribuot D, Baillieul S (2015) Hypoxic conditioning as a new therapeutic modality. Front Pediatr 3:58. https://doi.org/10.3389/fped.2015.00058
Walker R, Whittlesea C (2012) Clinical pharmacy and therapeutics, 5th edn, Elsevier, Churchill Livingstone, China, pp 537-541
Wang GL, Semenza GL (1996) Molecular basis of hypoxia-induced erythropoietin expression. Curr Opin Hematol 3(2):156–162. https://doi.org/10.1097/00062752-199603020-00009
Yoo WS (1995) Long-term therapy of hypertension. Korean J Intern Med 10(2):79–86. https://doi.org/10.3904/kjim.1995.10.2.79
Yuhai GU, Zhen Z (2015) Significance of the changes occurring in the levels of interleukins, SOD and MDA in rat pulmonary tissue following exposure to different altitudes and exposure times. Exp Ther Med 10(3):915–920. https://doi.org/10.3892/etm.2015.2604
Zhao W, Swanson SA, Ye J, Li X, Shelton JM, Zhang W, Thomas GD (2006) Reactive oxygen species impair sympathetic vasoregulation in skeletal muscle in angiotensin II-dependent hypertension. Hypertension 48(4):637–643. https://doi.org/10.1161/01.HYP.0000240347.51386.ea
Zuo L, Zhou T, Pannell BK, Ziegler AC, Best TM (2015) Biological and physiological role of reactive oxygen species—the good, the bad and the ugly. Acta Physiol (Oxf) 214(3):329–348. https://doi.org/10.1111/apha.12515
Acknowledgements
The authors would like to thank all patients for their valuable time. We would like to thank the Exercise and Sport Sciences Developing and Research Group to support the biochemistry laboratory.
Funding
The study was financially supported by grants from the Khon Kaen University in collaboration with the National Research Council of Thailand (NRCT) and an Invitation Research Grant (Grant number IN61142), Faculty of Medicine, Khon Kaen University. Miss Nattha Muangritdech was partly supported by a Postgraduate Study Support Grant of Faculty of Medicine, Khon Kaen University, Thailand.
Author information
Authors and Affiliations
Contributions
NM (first author) and AM conceived and designed the trial. NM (first author), PP, WS, KS, NM conducted experiments. PP performed the molecular laboratory tests, PW provided support throughout the experiment. NM and AM analyzed data. NM, AM and HM wrote the manuscript. All authors read and edited manuscript. AM and HM approved the final version of manuscript for publication.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Communicated by I. Mark Olfert.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Muangritdech, N., Hamlin, M.J., Sawanyawisuth, K. et al. Hypoxic training improves blood pressure, nitric oxide and hypoxia-inducible factor-1 alpha in hypertensive patients. Eur J Appl Physiol 120, 1815–1826 (2020). https://doi.org/10.1007/s00421-020-04410-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00421-020-04410-9