Acute Effects of Systemic Erythropoietin Injections on Carotid Body Chemosensory Activity Following Hypoxic and Hypercapnic Stimulation

  • David C. Andrade
  • Rodrigo Iturriaga
  • Florine Jeton
  • Julio Alcayaga
  • Nicolas Voituron
  • Rodrigo Del RioEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1071)


The carotid body (CB) chemoreceptors sense changes in arterial blood gases. Upon stimulation CB chemoreceptors cells release one or more transmitters to excite sensory nerve fibers of the carotid sinus nerve. While several neurotransmitters have been described to contribute to the CB chemosensory process less is known about modulatory molecules. Recent data suggest that erythropoietin (Epo) is involved in the control of ventilation, and it has been shown that Epo receptor is constitutively expressed in the CB chemoreceptors, suggesting a possible role for Epo in regulation of CB function. Therefore, in the present study we aimed to determine whether exogenous applications of Epo modulate the hypoxic and hypercapnic CB chemosensory responses. Carotid sinus nerve discharge was recorded in-situ from anesthetized adult male and female Sprague Dawley rats (350 g, n = 8) before and after systemic administration of Epo (2000 UI/kg). CB-chemosensitivity to hypoxia and hypercapnia was calculated by exposing the rat to FiO2 5–15% and FiCO2 10% gas mixtures, respectively. During baseline recordings at normoxia, we found no effects of Epo on CB activity both in male and female rats. In addition, Epo had no effect on maximal CB response to hypoxia in both male and female rats. Epo injections enhanced the maximum CB chemosensory response to hypercapnia in female rats (before vs. after Epo, 72.5 ± 7.1 Hz vs. 108.3 ± 6.9 Hz, p < 0.05). In contrast, Epo had no effect on maximum CB chemosensory response to hypercapnia in male rats but significantly increased the response recovery times (time required to return to baseline discharge following hypercapnic stimulus) from 2.1 ± 0.1 s to 8.2 ± 2.3 s (p < 0.05). Taken together, our results suggest that Epo has some modulatory effect on the CB chemosensory response to hypercapnia.


Carotid Body Carotid sinus nerve Erythropoietin Hypoxia Hypercapnia 



This work was supported by an ECOS-SUD program (N.V. action n°C16S03 and Programa de cooperación ECOS-CONICYT C16S03 to R.D.R.) and by Fondecyt grants #1140275 and #1180172 to R.D.R. and #1150040 to R.I. The “Relations Internationales” and the “Invited Professor” programs of the University Paris 13 also supported this study.


  1. Berkenbosch A, Olievier CN, DeGoede J, Kruyt EW (1991) Effect on ventilation of papaverine administered to the brain stem of the anaesthetized cat. J Physiol 443:457–468CrossRefGoogle Scholar
  2. Berkenbosch A, Teppema LJ, Olievier CN, Dahan A (1997) Influences of morphine on the ventilatory response to isocapnic hypoxia. Anesthesiology 86:1342–1349CrossRefGoogle Scholar
  3. Del Rio R, Moya EA, Iturriaga R (2010) Carotid body and cardiorespiratory alterations in intermittent hypoxia: the oxidative link. Eur Respir J 36:143–150. CrossRefPubMedGoogle Scholar
  4. Del Rio R, Munoz C, Arias P, Court FA, Moya EA, Iturriaga R (2011) Chronic intermittent hypoxia-induced vascular enlargement and VEGF upregulation in the rat carotid body is not prevented by antioxidant treatment. Am J Physiol Lung Cell Mol Physiol 301:L702–L711. CrossRefPubMedGoogle Scholar
  5. Despas F, Xhaët O, Senard JM, Verwaerde P, Jourdan G, Curnier D, Galinier M, Pathak A (2006) Chemoreflexes from physiology to practice. MT Cardio 2:321–327Google Scholar
  6. Digicaylioglu M, Bichet S, Marti HH, Wenger RH, Rivas LA, Bauer C, Gassmann M (1995) Localization of specific erythropoietin binding sites in defined areas of the mouse brain. Proc Natl Acad Sci U S A 92:3717–3720CrossRefGoogle Scholar
  7. Feldman JL, Mitchell GS, Nattie EE (2003) Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 26:239–266. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Gonzalez C, Almaraz L, Obeso A, Rigual R (1992) Oxygen and acid chemoreception in the carotid body chemoreceptors. Trends Neurosci 15:146–153CrossRefGoogle Scholar
  9. Gonzalez C, Vicario I, Almaraz L, Rigual R (1995) Oxygen sensing in the carotid body. Biol Signals 4:245–256CrossRefGoogle Scholar
  10. Guyenet PG (2014) Regulation of breathing and autonomic outflows by chemoreceptors. Comp Physiol 4:1511–1562. CrossRefGoogle Scholar
  11. Jelkmann W (1992) Erythropoietin: structure, control of production, and function. Physiol Rev 72:449–489CrossRefGoogle Scholar
  12. Jelkmann W (2011) Regulation of erythropoietin production. J Physiol 589:1251–1258. CrossRefPubMedGoogle Scholar
  13. Jeton F, Soliz J, Marchant D, Joseph V, Richalet JP, Pichon A, Voituron N (2017) Increased ventilation in female erythropoietin-deficient mouse line is not progesterone and estrous stage-dependent. Respir Physiol Neurobiol 245:98–104. CrossRefPubMedGoogle Scholar
  14. Lam SY, Tipoe GL, Fung ML (2009) Upregulation of erythropoietin and its receptor expression in the rat carotid body during chronic and intermittent hypoxia. Adv Exp Med Biol 648:207–214. CrossRefPubMedGoogle Scholar
  15. Lopez-Barneo J, Gonzalez-Rodriguez P, Gao L, Fernandez-Aguera MC, Pardal R, Ortega-Saenz P (2016) Oxygen sensing by the carotid body: mechanisms and role in adaptation to hypoxia. Am J Physiol Cell Physiol 310:C629–C642. CrossRefPubMedGoogle Scholar
  16. Pichon A et al (2016) Erythropoietin and the use of a transgenic model of erythropoietin-deficient mice. Hypoxia 4:29–39. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Prabhakar NR, Peers C (2014) Gasotransmitter regulation of ion channels: a key step in O2 sensing by the carotid body. Physiology 29:49–57. CrossRefPubMedPubMedCentralGoogle Scholar
  18. Smith CA, Blain GM, Henderson KS, Dempsey JA (2015) Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2: role of carotid body CO2. J Physiol 593:4225–4243. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Soliz J (2013) Erythropoietin and respiratory control at adulthood and during early postnatal life. Respir Physiol Neurobiol 185:87–93. CrossRefPubMedGoogle Scholar
  20. Soliz J et al (2005) Erythropoietin regulates hypoxic ventilation in mice by interacting with brainstem and carotid bodies. J Physiol 568:559–571. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Soliz J, Soulage C, Hermann DM, Gassmann M (2007) Acute and chronic exposure to hypoxia alters ventilatory pattern but not minute ventilation of mice overexpressing erythropoietin. Am J Physiol Regul Integr Comp Physiol 293:R1702–R1710. CrossRefPubMedGoogle Scholar
  22. Soliz J, Khemiri H, Caravagna C, Seaborn T (2012) Erythropoietin and the sex-dimorphic chemoreflex pathway. Adv Exp Med Biol 758:55–62. CrossRefPubMedGoogle Scholar
  23. Voituron N et al (2014) Catalyzing role of erythropoietin on the nitric oxide central pathway during the ventilatory responses to hypoxia. Physiol Rep 2:e00223. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • David C. Andrade
    • 1
  • Rodrigo Iturriaga
    • 2
  • Florine Jeton
    • 3
  • Julio Alcayaga
    • 4
  • Nicolas Voituron
    • 3
  • Rodrigo Del Rio
    • 1
    • 5
    • 6
    Email author
  1. 1.Laboratory of Cardiorespiratory Control, Department of Physiology, Faculty of Biological SciencesPontificia Universidad Católica de ChileSantiagoChile
  2. 2.Laboratorio de Neurobiología, Facultad de Ciencias BiológicasPontificia Universidad Católica de ChileSantiagoChile
  3. 3.Laboratoire Hypoxie & PoumonUniversite Paris 13ParisFrance
  4. 4.Laboratorio de Fisiología CelularUniversidad de ChileSantiagoChile
  5. 5.Centro de Envejecimiento y Regeneración (CARE)Pontificia Universidad Católica de ChileSantiagoChile
  6. 6.Centro de Excelencia en Biomedicina de Magallanes (CEBIMA)Universidad de MagallanesPunta ArenasChile

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