Respiratory long-term facilitation following intermittent hypoxia requires reactive oxygen species formation

Acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). LTF is a progressive and sustained increase in respiratory motor output as expressed in phrenic and hypoglossal (XII) nerve activity. Since reactive oxygen species (ROS) play important roles in several forms of neuroplasticity, and ROS production is increased by intermittent hypoxia, we tested the hypothesis that ROS are necessary for phrenic and XII LTF following AIH. Urethane-anesthetized, paralyzed, vagotomized and pump-ventilated Sprague-Dawley rats were exposed to AIH (11% O2, 3, 5 min episodes, 5 min intervals), and both phrenic and XII nerve activity were monitored for 60 min post-AIH. Although phrenic and XII LTF were observed in control rats, i.v. manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP), a superoxide anion scavenger, attenuated both phrenic and XII LTF in a dose dependent manner. Localized application of MnTMPyP (5.5 mM; 10 microl) to the intrathecal space of the cervical spinal cord (C4) abolished phrenic, but not XII LTF. Thus, ROS are necessary for AIH-induced respiratory LTF, and the relevant ROS appear to be localized near respiratory motor nuclei since cervical MnTMPyP injections impaired phrenic (and not XII) LTF. Phrenic LTF is a novel form of ROS-dependent neuroplasticity since its ROS-dependence resides in the spinal cord.