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Molecular Pharmacology

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Research ArticleArticle

Chronic Caffeine Intake in Adult Rat Inhibits Carotid Body Sensitization Produced by Chronic Sustained Hypoxia but Maintains Intact Chemoreflex Output

Silvia V. Conde, Maria J. Ribeiro, Ana Obeso, Ricardo Rigual, Emilia C. Monteiro and Constancio Gonzalez
Molecular Pharmacology December 2012, 82 (6) 1056-1065; DOI: https://doi.org/10.1124/mol.112.081216
Silvia V. Conde
Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid, Facultad de Medicina, Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Cientificas, and Ciber de Enfermedades Respiratorias, Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Valladolid, Spain (S.V.C., A.O., R.R., C.G.); and Centro de Estudos de Doenças Crónicas, Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria, Lisbon, Portugal (S.V.C., M.J.R., E.C.M.)
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Maria J. Ribeiro
Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid, Facultad de Medicina, Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Cientificas, and Ciber de Enfermedades Respiratorias, Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Valladolid, Spain (S.V.C., A.O., R.R., C.G.); and Centro de Estudos de Doenças Crónicas, Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria, Lisbon, Portugal (S.V.C., M.J.R., E.C.M.)
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Ana Obeso
Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid, Facultad de Medicina, Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Cientificas, and Ciber de Enfermedades Respiratorias, Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Valladolid, Spain (S.V.C., A.O., R.R., C.G.); and Centro de Estudos de Doenças Crónicas, Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria, Lisbon, Portugal (S.V.C., M.J.R., E.C.M.)
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Ricardo Rigual
Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid, Facultad de Medicina, Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Cientificas, and Ciber de Enfermedades Respiratorias, Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Valladolid, Spain (S.V.C., A.O., R.R., C.G.); and Centro de Estudos de Doenças Crónicas, Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria, Lisbon, Portugal (S.V.C., M.J.R., E.C.M.)
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Emilia C. Monteiro
Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid, Facultad de Medicina, Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Cientificas, and Ciber de Enfermedades Respiratorias, Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Valladolid, Spain (S.V.C., A.O., R.R., C.G.); and Centro de Estudos de Doenças Crónicas, Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria, Lisbon, Portugal (S.V.C., M.J.R., E.C.M.)
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Constancio Gonzalez
Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid, Facultad de Medicina, Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Cientificas, and Ciber de Enfermedades Respiratorias, Centro de Investigación Biomédica en Red, Instituto de Salud Carlos III, Valladolid, Spain (S.V.C., A.O., R.R., C.G.); and Centro de Estudos de Doenças Crónicas, Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo Mártires da Pátria, Lisbon, Portugal (S.V.C., M.J.R., E.C.M.)
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Abstract

Sustained hypoxia produces a carotid body (CB) sensitization, known as acclimatization, which leads to an increase in carotid sinus nerve (CSN) activity and ensuing hyperventilation greater than expected from the prevailing partial pressure of oxygen. Whether sustained hypoxia is physiological (high altitude) or pathological (lung disease), acclimatization has a homeostatic implication because it tends to minimize hypoxia. Caffeine, the most commonly ingested psychoactive drug and a nonselective adenosine receptor antagonist, alters CB function and ventilatory responses when administered acutely. Our aim was to investigate the effect of chronic caffeine intake on CB function and acclimatization using four groups of rats: normoxic, caffeine-treated normoxic, chronically hypoxic (12% O2, 15 days), and caffeine-treated chronically hypoxic rats. Caffeine was administered in drinking water (1 mg/ml). Caffeine ameliorated ventilatory responses to acute hypoxia in normoxic animals without altering the output of the CB (CSN neural activity). Caffeine-treated chronically hypoxic rats exhibited a decrease in the CSN response to acute hypoxia tests but maintained ventilation compared with chronically hypoxic animals. The findings related to CSN neural activity combined with the ventilatory responses indicate that caffeine alters central integration of the CB input to increase the gain of the chemoreflex and that caffeine abolishes CB acclimatization. The putative mechanisms involved in sensitization and its loss were investigated: expression of adenosine receptors in CB (A2B) was down-regulated and that in petrosal ganglion (A2A) was up-regulated in caffeine-treated chronically hypoxic rats; both adenosine and dopamine release from CB chemoreceptor cells was increased in chronic hypoxia and in caffeine-treated chronic hypoxia groups.

Footnotes

  • The work was supported by Junta de Castilla y Leon [GR242]; Ciber de Enfermedades Respiratorias [CB06/06/0050 (FISS-ICiii)]; Dirección General de Investigación Científica y Tecnológica [BFU2007-61848]; Spanish Micinn/Portugal CRUP [2009-0172]; and Portuguese Foundation for Science and Technology [PTDC/SAU-ORG/111417/2009].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.081216.

  • ABBREVIATIONS:

    CB
    carotid body
    CSN
    carotid sinus nerve
    PG
    petrosal ganglion
    DA
    dopamine
    ACh
    acetylcholine
    VE
    minute ventilation
    PO2
    partial pressure of oxygen
    N
    normoxic
    CafN
    caffeine-treated normoxic
    CH
    chronically hypoxic
    CafH
    caffeine-treated chronically hypoxic
    PCA
    perchloric acid
    HPLC
    high-performance liquid chromatography
    ANOVA
    analysis of variance.

  • Received July 13, 2012.
  • Accepted August 28, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 2012
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Research ArticleArticle

Chronic Caffeine Intake in Sustained Hypoxia

Silvia V. Conde, Maria J. Ribeiro, Ana Obeso, Ricardo Rigual, Emilia C. Monteiro and Constancio Gonzalez
Molecular Pharmacology December 1, 2012, 82 (6) 1056-1065; DOI: https://doi.org/10.1124/mol.112.081216

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Research ArticleArticle

Chronic Caffeine Intake in Sustained Hypoxia

Silvia V. Conde, Maria J. Ribeiro, Ana Obeso, Ricardo Rigual, Emilia C. Monteiro and Constancio Gonzalez
Molecular Pharmacology December 1, 2012, 82 (6) 1056-1065; DOI: https://doi.org/10.1124/mol.112.081216
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