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O2-sensing after carotid chemodenervation: hypoxic ventilatory responsiveness and upregulation of tyrosine hydroxylase mRNA in brainstem catecholaminergic cells

Authors

  • Jean-Christophe Roux,

    1. UMR 5578, Physiologie des Régulations Energétiques, Cellulaires et Moléculaires, CNRS, Université Claude Bernard, 69373 Lyon cedex 08, France
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  • Jean-Marc Pequignot,

    1. UMR 5578, Physiologie des Régulations Energétiques, Cellulaires et Moléculaires, CNRS, Université Claude Bernard, 69373 Lyon cedex 08, France
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  • Sylvie Dumas,

    1. UMR 9923, Génétique Moléculaire de la Neurotransmission et Processus Neurodégénératifs, CNRS, CERVI, Boulevard de l'Hôpital, 75013 Paris, France
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  • Olivier Pascual,

    1. UMR 5578, Physiologie des Régulations Energétiques, Cellulaires et Moléculaires, CNRS, Université Claude Bernard, 69373 Lyon cedex 08, France
    2. Institut Alfred Fessard, CNRS, 91198 Gif/Yvette, France
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  • Ginette Ghilini,

    1. Institut Alfred Fessard, CNRS, 91198 Gif/Yvette, France
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  • Jacqueline Pequignot,

    1. UMR 5578, Physiologie des Régulations Energétiques, Cellulaires et Moléculaires, CNRS, Université Claude Bernard, 69373 Lyon cedex 08, France
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  • Jacques Mallet,

    1. UMR 9923, Génétique Moléculaire de la Neurotransmission et Processus Neurodégénératifs, CNRS, CERVI, Boulevard de l'Hôpital, 75013 Paris, France
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  • Monique Denavit-Saubié

    1. Institut Alfred Fessard, CNRS, 91198 Gif/Yvette, France
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: Dr Jean-Marc Pequignot, as above.
E-mail: pequigno@rockefeller.univ-lyon1.fr

Abstract

Ventilatory responses to acute and long-term hypoxia are classically triggered by carotid chemoreceptors. The chemosensory inputs are carried within the carotid sinus nerve to the nucleus tractus solitarius and the brainstem respiratory centres. To investigate whether hypoxia acts directly on brainstem neurons or secondarily via carotid body inputs, we tested the ventilatory responses to acute and long-term hypoxia in rats with bilaterally transected carotid sinus nerves and in sham-operated rats. Because brainstem catecholaminergic neurons are part of the chemoreflex pathway, the ventilatory response to hypoxia was studied in association with the expression of tyrosine hydroxylase (TH). TH mRNA levels were assessed in the brainstem by in situ hybridization and hypoxic ventilatory responses were measured in vivo by plethysmography. After long-term hypoxia, TH mRNA levels in the nucleus tractus solitarius and ventrolateral medulla increased similarly in chemodenervated and sham-operated rats. Ventilatory acclimatization to hypoxia developed in chemodenervated rats, but to a lesser extent than in sham-operated rats. Ventilatory response to acute hypoxia, which was initially low in chemodenervated rats, was fully restored within 21 days in long-term hypoxic rats, as well as in normoxic animals which do not overexpress TH. Therefore, activation of brainstem catecholaminergic neurons and ventilatory adjustments to hypoxia occurred independently of carotid chemosensory inputs. O2-sensing mechanisms unmasked by carotid chemodenervation triggered two ventilatory adjustments: (i) a partial acclimatization to long-term hypoxia associated with TH upregulation; (ii) a complete restoration of acute hypoxic responsivity independent of TH upregulation.

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