Pattern sensitivity of ampakine-hypoxia interactions for evoking phrenic motor facilitation in anesthetized rat

Repeated hypoxic episodes can produce a sustained (>60 min) increase in neural drive to the diaphragm. The requirement of repeated hypoxic episodes (vs. a single episode) to produce phrenic motor facilitation (pMF) can be removed by allosteric modulation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors using ampakines. We hypothesized that the ampakine-hypoxia interaction resulting in pMF requires that ampakine dosing precedes the onset of hypoxia. Phrenic nerve recordings were made from urethane-anesthetized, mechanically ventilated, and vagotomized adult male Sprague-Dawley rats during isocapnic conditions. Ampakine CX717 (15 mg/kg iv) was given immediately before (n = 8), during (n = 8), or immediately after (n = 8) a 5-min hypoxic episode (arterial oxygen partial pressure 40-45 mmHg). Ampakine before hypoxia (A_prior) resulted in a sustained increase in inspiratory phrenic burst amplitude (i.e., pMF) reaching +70 ± 21% above baseline (BL) after 60 min. This was considerably greater than corresponding values in the groups receiving ampakine during hypoxia (+28 ± 47% above BL, P = 0.005 vs. A_prior) or after hypoxia (+23 ± 40% above BL, P = 0.005 vs. A_prior). Phrenic inspiratory burst rate, heart rate, and systolic, diastolic, and mean arterial pressure (mmHg) were similar across the three treatment groups (all P > 0.3, treatment effect). We conclude that the presentation order of ampakine and hypoxia impacts the magnitude of pMF, with ampakine pretreatment evoking the strongest response. Ampakine pretreatment may have value in the context of hypoxia-based neurorehabilitation strategies.NEW & NOTEWORTHY Phrenic motor facilitation (pMF) is evoked after repeated episodes of brief hypoxia. pMF can also be induced when an allosteric modulator of AMPA receptors (ampakine) is intravenously delivered immediately before a single brief hypoxic episode. Here we show that ampakine delivery before hypoxia (vs. during or after hypoxia) evokes the largest pMF with minimal impact on arterial blood pressure and heart rate. Ampakine pretreatment may have value in the context of hypoxia-based neurorehabilitation strategies.