Expiratory and sympathetic long‐term facilitation and their interactions after acute intermittent hypoxia ( AIH )

The article by Lemes et al. (2016) in this issue has investigated expiratory and sympathetic long-term facilitation (LTF) after acute intermittent hypoxia, and the interaction between expiratory and sympathetic LTF. Acute intermittent hypoxia (AIH) refers to recurrence of (short) hypoxic bouts followed by reoxygenation. Such situation is commonly observed in obstructive sleep apnoea. AIH results in respiratory long-term facilitation (LTF), which refers to increased respiratory motor activity lasting for more than 60 min after the hypoxic bout, and was first demonstrated in 1980 (Millhorn et al. 1980). However, direct evidence for combining LTF and sleep apnoea is still lacking (Mahamed & Mitchell 2007). If recurrent hypoxic bouts occur after previous occurrence of hypoxia–normoxia cycles, chronic intermittent hypoxia (CIH), the respiratory LTF is potentiated (Devinney et al. 2013). In view of this information, it is of some interest that the presence of the phenomenon has, to my knowledge, not been studied in seals, which experience hypoxia–reoxygenation bouts regularly. In contrast, a single hypoxic bout or sustained hypoxia do not cause LTF (Devinney et al. 2013). The existence of respiratory LTF indicates that the neural control of breathing is plastic – only for the past few decades, the plasticity of the control of breathing has been recognized. The respiratory LTF is manifested especially in the phrenic and hypoglossal nerves (Xing et al. 2013). The phrenic system, which has motor, sensory and sympathetic fibres, is the only nerve that innervates the diaphragm. The hypoglossal nerve, on the other hand, controls the function of tongue muscles. Earlier, it has been shown that the respiratory LTF depends largely on inspirational motor output. It appears that respiratory LTF can be generated via multiple pathways (Devinney et al. 2013), which usually involve serotonin and serotonin receptors, and sometimes adenosine receptors on cell membranes. Within the cells, it appears that both protein kinase C- and protein kinase A-dependent signalling routes can be involved. It further appears that reactive oxygen species facilitate respiratory LTF (MacFarlane & Mitchell 2008). In addition to the motor activity, AIH consistently influences the sympathetic activity. Hypertension is developed as vasoconstriction dependent on sympathetic activity takes place. Although LTF has usually been associated with increased respiratory drive, the changes of sympathetic activity do not require (at least inspiratory) respiratory drive (Xing & Pilowsky 2010). In the present issue, Lemes et al. (2016) investigate whether the increased sympathetic activity resulting from AIH could be associated with increased expiratory motor activity. Earlier, an expiratory component to respiratory LTF has generally not been considered significant, although some results have indicated that it does occur (Dick et al. 2004). Further, the increased expiratory motor and sympathetic activity may be associated (Dick et al. 2004). This study of Lemes et al. (2016) investigates the question with several experimental approaches: conscious and anaesthetized rats, and heart–brainstem preparations were used. In addition, muscimol (GABAA receptor agonist) was microinjected. The results show unequivocally that AIH elicits an expiratory LTF. Significantly, this expiratory LTF associates with the increased sympathetic activity. The findings of this study indicate that ventromedullary expiratory neurones are necessary for the emergence of both expiratory and sympathetic LTF, thus showing that although inspiratory respiratory drive is not required to generate sympathetic LTF, expiratory activity is probably needed. None.