Enhancement of the respiratory response to acidosis in newborn rat by a progestin, involvement of diencephalic areas - 04/04/15

The congenital central hypoventilation syndrome (CCHS) is a neuro-respiratory disease characterized by an alteration of the CO₂/H⁺ chemosensitivity due to dysfunction of the CO₂/H⁺ chemosensitive/PHOX2b-positive neurons. Works suggest that mechanisms may compensate this dysfunction: we fortuitously observed in two CCHS women that consumption of a potent synthetic progestin (desogestrel) was correlated to a recovery of the CO₂/H⁺ chemosensitivity (Respir Physiol Neurobiol 2010;171:171–4). In this regard, we recently reported in central nervous system preparations from newborn rat that etonogestrel, the main metabolite of desogestrel, potentiate the response to metabolic acidosis by a way involving supramedullary areas (Neurosci Lett 2014;567:63–7).

Our aim was to characterize the optimal concentration of etonogestrel and to determine the encephalic region were etonogestrel exercises its influence on the respiratory response to metabolic acidosis in newborn rat.

Experiments were conducted on ex vivo central nervous system preparations from newborn rats containing either only the medulla oblongata or medulla oblongata and pontine, mesencephalic or diencephalic regions. The effect of etonogestrel (0.05, 0.5, 1 and 2μM) on respiratory frequency was analyzed under metabolic acidosis and appreciated in comparison to control preparations (not exposed to etonogestrel). In addition the effect of etonogestrel was examined in case of a preincubation with an antagonist of GABA_A receptor, the bicuculline (3μM).

Under metabolic acidosis, except at high (2μM) and very low (0.05μM) concentration, acute exposure to etonogestrel enhanced the acidosis-induced hyperventilation if and only if diencephalic structures are present. Antagonizing of GABA_Aergic signalization abolished the effect of etonogestrel and the respiratory response to metabolic acidosis.

These data suggest that etonogestrel can potentiate the acidosis-induced hyperventilation by interacting with diencephalic structures and GABA_Aergic signalization. This enhancement of increase in respiratory frequency may involve orexinergic neurons expressing an H⁺ sensitive channel. Immunohistological incoming data will confirmed or not their implication and will permit to reveal whole of the involved areas.