Long term facilitation of phrenic motor output

Episodic hypoxia or electrical stimulation of carotid chemoafferent neurons elicits a sustained, serotonin-dependent augmentation of respiratory motor output known as long term facilitation (LTF). The primary objectives of th is paper are to provide an updated review of the literature pertaining to L TF, to investigate the influence of selected variables on LTF via meta-anal ysis of a large data set from LTF experiments on anesthetized rats, and to propose an updated mechanism of LTF. LTF has been demonstrated in anestheti zed and awake experimental preparations, and can be evoked in some human su bjects during sleep. The mechanism underlying LTF requires episodic chemoaf ferent stimulation, and is not elicited by similar cumulative durations of sustained hypoxia. Meta-analysis of phrenic nerve responses following episo dic hypoxia in 63 experiments on anesthetized rats (conducted by four inves tigators over a period of several years) indicates that phrenic LTF magnitu de correlates with peak phrenic responses during hypoxia and hypercapnia, b ut not with the level of hypoxia during episodic exposures. Potential mecha nisms underlying these relationships are discussed, and currently available data are synthesized into an updated mechanistic model of LTF. In this mod el, we propose that LTF arises predominantly from episodic activation of se rotonergic receptors on phrenic motoneurons, activating intracellular kinas es and, thus, phosphorylating and potentiating ionic currents associated wi th the glutamate receptors that mediate respiratory drive. (C) 2000 Elsevie r Science B.V. All rights reserved.