The Pattern of Ampakine and Hypoxia Exposure Determines Phrenic Motor Facilitation

Abstract

Phrenic motor facilitation (pMF) is a persistent increase in phrenic nerve activity upon the removal of a triggering stimuli. A variety of stimulation paradigms can induce pMF including electrical activation of the carotid sinus nerve, serotonin or adenosine receptor agonists, acute intermittent hypoxia (AIH) and inactivity. Recently, Wollman et al. (2020) demonstrated a new kind of pMF using a combination of a pharmacological agent (ampakine) and a single brief hypoxic episode. A subsequent study confirmed this finding and also showed that pairing ampakine with multiple hypoxic episodes did not increase magnitude of pMF (Thakre et al., 2021). The present study investigated if ampakine‐hypoxia induced pMF is sensitive to the pattern in which ampakine and hypoxia are administered. Phrenic nerve output was recorded from urethane‐anesthetized, mechanically ventilated and vagotomized adult male Sprague‐Dawley rats. Hypoxic exposures were 5 min in duration with moderate severity (arterial O2 partial pressure approximately 45 mmHg). The ampakine used was CX717, given intravenously (i.v.) at 15 mg/kg. We first verified the impact of a single administration of i.v. ampakine followed after 2 min by hypoxia. In agreement with prior work, this paradigm evoked a sustained increase in phrenic burst amplitude (60 min: 73±19% baseline, n=8). In the next experiments, the order of ampakine and hypoxia was reversed such that hypoxia was followed after 2 min by ampakine. This paradigm did not evoke a sustained increase in phrenic burst amplitude (60 min: 11±15% baseline, n=6). In the final series of experiments, ampakine was delivered during an ongoing episode of hypoxia (2 min after onset). This paradigm also did not evoke a sustained increase in phrenic burst amplitude (60 min: 12±14% baseline, n=7). Our results indicate that the mechanisms of pMF evoked by the ampakine‐hypoxia interaction are sensitive to the order in which these stimuli are presented. The presentation of ampakine followed by a single brief hypoxic episode appears to be ideal for producing pMF. These findings could have significant implications in planning hypoxia‐based neurorehabilitation strategies with ampakines as an adjunct therapy.