Facilitation of the respiratory rhythm in mice by acute exposure to a progestin, the etonogestrel. Involvement of medullary areas - 04/04/15
Résumé |
Background |
Works have underlined the facilitatory influence of progestins on central respiratory drive (CRD). The congenital central hypoventilation syndrome (CCHS) is a neuro-respiratory disease characterized by an alteration of the CO2/H+ chemosensitivity due to dysfunction of CO2/H+ chemosensitive/PHOX2b-positive neurons of the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG). In our laboratory, a recovery of the CO2/H+ chemosensitivity was fortuitously observed in two CCHS women who took a potent synthetic progestin, the desogestrel (Respir Physiol Neurobiol 2010;171:171–4).
Objective |
Our aim was to appreciate the effects of an acute exposure to etonogestrel (ETO), the main active metabolite of the desogestrel, on the CRD and to determine its medullary action mechanisms.
Methods |
We used:
– an analysis of the effect of ETO (0.05–2μM) on the CRD of ex vivo medullary-spinal cord preparations from newborn mice in both normopH and metabolic acidosis;
– pharmacological co-application of ETO and muscimol or NMDA, agonists of GABAA or NMDA receptors known to be a target of some steroids;
– an analysis of the c-fos expression in medullary respiratory structures.
Results |
First, the respiratory frequency was:
– dose-dependently increased in normopH by ETO (≈+23–47%; P<0.01) in comparison to control preparations exposed to DMSO, (solvent of ETO);
– increase by metabolic acidosis similarly under ETO (≈+28–37% at 0.05–1μM, P<0.05 and P<0.001, respectively) and DMSO (≈+40%; P<0.001).
Second, changes in respiratory frequency induced by muscimol or NMDA at their EC50 were more potent under ETO (≈−60–63%, P<0.001 and ≈+53±65%, P<0.001 respectively) than under DMSO (≈−33%, P<0.01 and +29%, P<0.05, respectively). Finally, analysis of c-fos revealed ETO activated cells in respiratory medullary areas i.e. the ventrolateral medulla, nucleus of the solitary tract, RTN/pFRG and medullary raphe nuclei.
Conclusions |
As a whole, data suggest that, by medullary mechanisms, the progestin ETO exerts a facilitatory influence on the CRD by acting at the level of respiratory structures. Involved mechanisms would implicate an interaction with GABAA and NMDA receptors. Besides, at least in newborn mice, ETO do not potentiate the respiratory response to metabolic acidosis by intrinsic medullary mechanisms.
Le texte complet de cet article est disponible en PDF.Keywords : Physiology, Ventilatory control