Breathing at high altitude

Abstract

Acclimatization to long-term hypoxia takes place at high altitude and allows gradual improvement of the ability to tolerate the hypoxic environment. An important component of this process is the hypoxic ventilatory acclimatization (HVA) that develops over several days. HVA reveals profound cellular and neurochemical re-organization occurring both in the peripheral chemoreceptors and in the central nervous system (in brainstem respiratory groups). These changes lead to an enhanced activity of peripheral chemoreceptor and re-inforce the central translation of peripheral inputs to efficient respiratory motor activity under the steady low O(2) pressure. We will review the cellular processes underlying these changes with a particular emphasis on changes of neurotransmitter function and ion channel properties in peripheral chemoreceptors, and present evidence that low O(2) level acts directly on brainstem nuclei to induce cellular changes contributing to maintain a high tonic respiratory drive under chronic hypoxia.

Fig. 1

Model of HVA taking into account re-modeling of peripheral chemoreceptors and central integration of CSN inputs. After several days of hypoxic exposure, the carotid bodies are hypertrophied, changes affecting both neurotransmitter release (and postsynaptic receptors) and activity of specific ion channels in chemosensitive cells are completed (see text). In the NTS, the release of glutamate from CSN terminals is sustained at a high level, and target neurons develop a stronger response to glutamate (see text). Norepinephrine turn-over is increased due to increased TH mRNA and protein expression, which exerts an inhibitory tone on breathing. At the same time, the stimulatory effect of dopamine is reinforced (see text). Direct O₂ sensing in brainstem nuclei may contribute to cellular and neurochemical remodeling and contribute to HVA through HIF-1-dependent regulation of gene expression. Relative thickness of the arrows represents the level of activation of the corresponding pathway. Relative excitatory (+) and inhibitory (−) effects of neurotransmitter in the carotid bodies on CSN activity and response to hypoxia are indicated