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Adaptative mechanism of the equilibrative nucleoside transporter 1 (ENT-1) and blood adenosine levels in elite freedivers

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Abstract

Purpose

Long static or intense dynamic apnoea-like high-altitude exposure is inducing hypoxia. Adenosine is known to participate to the adaptive response to hypoxia leading to the control of heart rate, blood pressure and vasodilation. Extracellular adenosine level is controlled through the equilibrative nucleoside transporter 1 (ENT-1) and the enzyme adenosine deaminase (ADA). The aim of this study was to determine the control of adenosine blood level (ABL) via ENT-1 and ADA during apnoea-induced hypoxia in elite freedivers was similar to high-altitude adaptation.

Methods

Ten freediver champions and ten controls were studied. Biological (e.g. ENT-1, ADA, ABL, PaO2, PaCO2 and pH) and cardiovascular (e.g. heart rate, arterial pressure) parameters were measured at rest and after a submaximal dry static apnoea.

Results

In freedivers, ABL was higher than in control participants in basal condition and increased more in response to apnoea. Also, freedivers showed an ADA increased in response to apnoea. Finally, ENT-1 level and function were reduced for the free divers.

Conclusion

Our results suggest in freedivers the presence of an adaptive mechanism similar to the one observed in human exposed to chronic hypoxia induced by high-altitude environment.

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Abbreviations

ABL:

Adenosine blood level

ADA:

Adenosine deaminase

AIS:

Adenosine level in supernatant

CTL:

Control group

ENT-1:

Equilibrative nucleoside transporter 1

FD:

Freedivers

PaO2 :

Arterial partial pressure in dioxygen

PaCO2 :

Arterial partial pressure in carbon dioxide

SpO2 :

Peripheral saturation in dioxygen

References

  • Andersson J, Schagatay E (1998) Arterial oxygen desaturation during apnea in humans. Undersea Hyperb Med 25:21–25

    CAS  PubMed  Google Scholar 

  • Attias J, Bieles J, Carvil P, Laing C, Lewis F, Jaka O, O’Brien K, Ruchaya P (2017) Altitude exposure and increased heart rate: the role of the parasympathetic nervous system. J Physiol (Lond) 595:4589–4590

    CAS  Google Scholar 

  • Bain AR, Drvis I, Dujic Z, MacLeod DB, Ainslie PN (2018) Physiology of static breath holding in elite apneists. Exp Physiol 103:635–651

    CAS  PubMed  Google Scholar 

  • Baldwin SA, Beal PR, Yao SYM, King AE, Cass CE, Young JD (2004) The equilibrative nucleoside transporter family, SLC29. Pflugers Arch 447:735–743

    CAS  PubMed  Google Scholar 

  • Bärtsch P, Gibbs JSR (2007) Effect of altitude on the heart and the lungs. Circulation 116:2191–2202

    PubMed  Google Scholar 

  • Bonello L, Laine M, Kipson N, Mancini J, Helal O, Fromonot J, Gariboldi V, Condo J, Thuny F, Frere C, Camoin-Jau L, Paganelli F, Dignat-George F, Guieu R (2014) Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J Am Coll Cardiol 63:872–877

    CAS  PubMed  Google Scholar 

  • Boussuges A, Gavarry O, Bessereau J, Coulange M, Bourc’his M, Rossi P (2014) Glossopharyngeal insufflation and breath-hold diving: the more, the worse? Wilderness Environ Med 25:466–471

    PubMed  Google Scholar 

  • Bruzzese L, Fromonot J, By Y, Durand-Gorde J-M, Condo J, Kipson N, Guieu R, Fenouillet E, Ruf J (2014) NF-κB enhances hypoxia-driven T-cell immunosuppression via upregulation of adenosine A(2A) receptors. Cell Signal 26:1060–1067

    CAS  PubMed  Google Scholar 

  • Bruzzese L, Rostain J-C, Née L, Condo J, Mottola G, Adjriou N, Mercier L, Berge-Lefranc J-L, Fromonot J, Kipson N, Lucciano M, Durand-Gorde J-M, Jammes Y, Guieu R, Ruf J, Fenouillet E (2015) Effect of hyperoxic and hyperbaric conditions on the adenosinergic pathway and CD26 expression in rat. J Appl Physiol 119:140–147

    CAS  PubMed  Google Scholar 

  • Bulmer AC, Coombes JS, Sharman JE, Stewart IB (2008) Effects of maximal static apnea on antioxidant defenses in trained free divers. Med Sci Sports Exerc 40:1307–1313

    CAS  PubMed  Google Scholar 

  • Casanello P, Torres A, Sanhueza F, González M, Farías M, Gallardo V, Pastor-Anglada M, San Martín R, Sobrevia L (2005) Equilibrative nucleoside transporter 1 expression is downregulated by hypoxia in human umbilical vein endothelium. Circ Res 97:16–24

    CAS  PubMed  Google Scholar 

  • Coney AM, Marshall JM (1998) Role of adenosine and its receptors in the vasodilatation induced in the cerebral cortex of the rat by systemic hypoxia. J Physiol (Lond) 509(Pt 2):507–518

    CAS  Google Scholar 

  • Eichhorn L, Erdfelder F, Kessler F, Dolscheid-Pommerich RC, Zur B, Hoffmann U, Ellerkmann RE, Meyer R (2017) Influence of apnea-induced hypoxia on catecholamine release and cardiovascular dynamics. Int J Sports Med 38:85–91

    CAS  PubMed  Google Scholar 

  • Eltzschig HK, Abdulla P, Hoffman E, Hamilton KE, Daniels D, Schönfeld C, Löffler M, Reyes G, Duszenko M, Karhausen J, Robinson A, Westerman KA, Coe IR, Colgan SP (2005) HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J Exp Med 202:1493–1505

    CAS  PubMed  PubMed Central  Google Scholar 

  • Eltzschig HK, Faigle M, Knapp S, Karhausen J, Ibla J, Rosenberger P, Odegard KC, Laussen PC, Thompson LF, Colgan SP (2006) Endothelial catabolism of extracellular adenosine during hypoxia: the role of surface adenosine deaminase and CD26. Blood 108:1602–1610

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fagoni N, Sivieri A, Antonutto G, Moia C, Taboni A, Bringard A, Ferretti G (2015) Cardiovascular responses to dry resting apnoeas in elite divers while breathing pure oxygen. Respir Physiol Neurobiol 219:1–8

    PubMed  Google Scholar 

  • Feoktistov I, Ryzhov S, Zhong H, Goldstein AE, Matafonov A, Zeng D, Biaggioni I (2004) Hypoxia modulates adenosine receptors in human endothelial and smooth muscle cells toward an A2B angiogenic phenotype. Hypertension 44:649–654

    CAS  PubMed  Google Scholar 

  • Ferretti G, Costa M (2003) Diversity in and adaptation to breath-hold diving in humans. Comp Biochem Physiol Part A Mol Integr Physiol 136:205–213

    Google Scholar 

  • Görlach A (2005) Control of adenosine transport by hypoxia. Circ Res 97:1–3

    PubMed  Google Scholar 

  • Iwamoto T, Umemura S, Toya Y, Uchibori T, Kogi K, Takagi N, Ishii M (1994) Identification of adenosine A2 receptor-cAMP system in human aortic endothelial cells. Biochem Biophys Res Commun 199:905–910

    CAS  PubMed  Google Scholar 

  • Joulia F, Steinberg JG, Faucher M, Jamin T, Ulmer C, Kipson N, Jammes Y (2003) Breath-hold training of humans reduces oxidative stress and blood acidosis after static and dynamic apnea. Respir Physiol Neurobiol 137:19–27

    CAS  PubMed  Google Scholar 

  • Joulia F, Coulange M, Lemaitre F, Costalat G, Franceschi F, Gariboldi V, Nee L, Fromonot J, Bruzzese L, Gravier G, Kipson N, Jammes Y, Boussuges A, Brignole M, Deharo JC, Guieu R (2013) Plasma adenosine release is associated with bradycardia and transient loss of consciousness during experimental breath-hold diving. Int J Cardiol 168:e138–e141

    PubMed  Google Scholar 

  • Joulia F, Coulange M, Desplantes A, Barberon B, Kipson N, Gerolami V, Jammes Y, Kerbaul F, Née L, Fromonot J, Bruzzese L, Michelet P, Boussuges A, Brignole M, Deharo J-C, Guieu R (2014) Purinergic profile of fainting divers is different from patients with vasovagal syncope. Int J Cardiol 174:741–743

    PubMed  Google Scholar 

  • Keil VC, Eichhorn L, Mutsaerts HJMM, Träber F, Block W, Mädler B, van de Ven K, Siero JCW, MacIntosh BJ, Petr J, Fimmers R, Schild HH, Hattingen E (2018) Cerebrovascular reactivity during prolonged breath-hold in experienced freedivers. AJNR Am J Neuroradiol 39:1839–1847

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liu H et al (2016) Beneficial role of erythrocyte adenosine A2B receptor-mediated AMPK activation in high altitude hypoxia. Circulation 134:405–421

    CAS  PubMed  PubMed Central  Google Scholar 

  • Maille B et al (2019) Adenosine plasma level in patients with paroxysmal or persistent atrial fibrillation and normal heart during ablation procedure and/or cardioversion. Purinergic Signal 15:45

    CAS  PubMed  Google Scholar 

  • Marlinge M, Vairo D, Marolda V, Bruzzese L, Adjriou N, Guiol C, Kipson N, Bonardel A, Gastaldi M, Kerbaul F, Michelet P, Deharo JC, Mottola G, Mace P, Chefrour M, Guieu R (2017) Rapid measurement of adenosine concentration in human blood using fixed potential amperometry: comparison with mass spectrometry and high-performance liquid chromatography. J Anal Bioanal Technol 8:4

    Google Scholar 

  • Moore LG (2017) Measuring high-altitude adaptation. J Appl Physiol 123:1371–1385

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morelli MS, Greco A, Valenza G, Giannoni A, Emdin M, Scilingo EP, Vanello N (2018) Analysis of generic coupling between EEG activity and PETCO2 in free breathing and breath-hold tasks using maximal information coefficient (MIC). Sci Rep 8:4492

    PubMed  PubMed Central  Google Scholar 

  • Morote-Garcia JC, Rosenberger P, Kuhlicke J, Eltzschig HK (2008) HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood 111:5571–5580

    CAS  PubMed  Google Scholar 

  • Paganelli F, Resseguier N, Marlinge M, Laine M, Malergue F, Kipson N, Armangau P, Pezzoli N, Kerbaul F, Bonello L, Mottola G, Fenouillet E, Guieu R, Ruf J (2018) Specific pharmacological profile of A2A adenosine receptor predicts reduced fractional flow reserve in patients with suspected coronary artery disease. J Am Heart Assoc 7:e008290

    PubMed  PubMed Central  Google Scholar 

  • Plagemann PGW (1986) Transport and metabolism of adenosine in human erthrocytes: effect of transport inhibitors and regulation by phosphate. J Cell Physiol 128:491–500

    CAS  PubMed  Google Scholar 

  • Ruf J, Paganelli F, Bonello L, Kipson N, Mottola G, Fromonot J, Condo J, Boussuges A, Bruzzese L, Kerbaul F, Jammes Y, Gariboldi V, Franceschi F, Fenouillet E, Guieu R (2016) Spare adenosine A2a receptors are associated with positive exercise stress test in coronary artery disease. Mol Med 22:530–536

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ruf J, Vairo D, Paganelli F, Guieu R (2019) Extracellular vesicles with ubiquitinated adenosine A2A receptor in plasma of patients with coronary artery disease. J Cell Mol Med 23:6805–6811

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sacramento JF, Melo BF, Conde SV (2018) Adenosine mediates hypercapnic response in the rat carotid body via A2A and A2B receptors. Adv Exp Med Biol 1071:89–93

    CAS  PubMed  Google Scholar 

  • Sampol J, Dussol B, Fenouillet E, Capo C, Mege JL, Halimi G, Bechis G, Brunet P, Rochat H, Berland Y, Guieu R (2001) High adenosine and deoxyadenosine concentrations in mononuclear cells of hemodialyzed patients. J Am Soc Nephrol 12:1721–1728

    CAS  PubMed  Google Scholar 

  • Shah N, Bye K, Marshall A, Woods DR, O’Hara J, Barlow M, Rimmer J, Boos CJ (2020) The effects of apnea training, using voluntary breath holds, on high altitude acclimation: breathe-high altitude study. High Alt Med Biol 21:152–159

    PubMed  Google Scholar 

  • Song A et al (2017) Erythrocytes retain hypoxic adenosine response for faster acclimatization upon re-ascent. Nat Commun 8:14108

    CAS  PubMed  PubMed Central  Google Scholar 

  • Taboni A, Vinetti G, Bruseghini P, Camelio S, D’Elia M, Moia C, Ferretti G, Fagoni N (2018) Cardiovascular responses to dry apnoeas at exercise in air and in pure oxygen. Respir Physiol Neurobiol 255:17–21

    PubMed  Google Scholar 

  • Taboni A, Fagoni N, Moia C, Vinetti G, Ferretti G (2019) Gas exchange and cardiovascular responses during breath-holding in divers. Respir Physiol Neurobiol 267:27–34

    PubMed  Google Scholar 

  • Vinetti G, Lopomo NF, Taboni A, Fagoni N, Ferretti G (2020) The current use of wearable sensors to enhance safety and performance in breath-hold diving: a systematic review. Diving Hyperb Med 50:54–65

    PubMed  Google Scholar 

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Acknowledgements

The authors gratefully acknowledge the freedivers and the control subjects to participate to this study, Dr Mille ML for her help in English and Dr. Fenouillet E, Dr. Rostain JC, Dr. Panganelli F and Dr. Lumet G for their contribution in subjects’ recruitment.

Author information

Author notes

  1. M. Marlinge, D. Vairo, Régis Guieu and F. Joulia participating equally to the work.

Authors and Affiliations

  1. C2VN, INSERM 1263, INRAE 1260, Faculty of Pharmacy, Aix Marseille University, Bvd J Moulin 13005, Marseille, France

    M. Marlinge, D. Vairo, A. Bertaud, L. Bruzzese, M. C. Chaptal, G. Mottola, A. Boussuges, M. Blot-Chabaud, M. Coulange, R. Guieu & F. Joulia

  2. Laboratory of Biochemistry, Timone Hospital, Marseille, France

    M. Marlinge, D. Vairo, C. Vernet, M. Chefrour, G. Mottola & R. Guieu

  3. ERRSO: Institute of Biomedical Research of the French Army (IRBA), Toulon, France

    A. Boussuges & J. J. Risso

  4. UFR STAPS, Toulon University, Toulon, France

    M. Coulange & F. Joulia

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  1. M. Marlinge
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  2. D. Vairo
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Contributions

FJ, MM, RG and JJR conceived and designed the study. DV, AB, CV, MC, LB, MCC, GM, MB-C and FJ recruited the subjects and/or performed the molecular biology. FJ, MC, AB, and RG critically revised the manuscript.

Corresponding author

Correspondence to R. Guieu.

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The authors declare that they have no conflict of interest.

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Communicated by Guido Ferretti.

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Marlinge, M., Vairo, D., Bertaud, A. et al. Adaptative mechanism of the equilibrative nucleoside transporter 1 (ENT-1) and blood adenosine levels in elite freedivers. Eur J Appl Physiol 121, 279–285 (2021). https://doi.org/10.1007/s00421-020-04523-1

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  • DOI: https://doi.org/10.1007/s00421-020-04523-1

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