Aims: 

Long-term exposure to hypoxia elicits a gradual increase in ventilation termed "ventilatory acclimatization to hypoxia" (VAH). The purpose of this study was to define the neurochemical remodelling induced by sustained hypoxia in the brainstem areas involved in regulation of VAH and its role in modulating VAH.

Methods: 

We assessed (1) the VAH in intact or chemodenervated rats subjected to 10% O₂ in nitrogen for 2 weeks, (2) the expression of tyrosine hydroxylase and HIF-1a in brainstem and (3) the hypoxic ventilatory response after pharmacological induction of HIF-1.

Results: 

In chemodenervated rats, the hypoxic ventilatory response was strongly blunted. After few weeks, the chemodenervated rats recovered their initial hypoxic ventilatory response but the pattern of response differed strikingly from that observed in intact rats. The HIF-1a expression was restricted to catecholaminergic (tyrosine hydroxylase-immunoreactive) neurones located in brainstem cardiorespiratory areas of hypoxic rats. In normoxic rats the overexpression of HIF-1a protein induced by desferrioxamine, an iron chelator, elicited an overexpression of tyrosine hydroxylase in the dorsomedian brainstem. The overexpression of tyrosine hydroxylase did not modify the basal ventilation but in contrast was associated with a moderate increase in hypoxic ventilatory response.

Conclusion: 

The functional remodelling after chemodenervation revealed a central effect of hypoxia on the activity of cardiorespiratory brainstem regions. The plasticity of brainstem catecholaminergic cells plays a pivotal role in acclimatization to hypoxia. HIF-1 may participate in the control of brainstem catecholaminergic neurones within cardiorespiratory areas involved in integration of chemo-afferent inputs or central O₂-sensing.