Ampakine pretreatment enables a single brief hypoxic episode to evoke phrenic motor facilitation

Abstract

Glutamatergic synaptic transmission acting through the amino‐3‐hydro‐5‐methyl‐4‐isoxazolepropionate receptors (AMPARs) is critical for respiratory rhythmogenesis and activation of respiratory motor neurons. Ampakines are a class of synthetic pharmacological agents that act as positive allosteric modulators of AMPARs to enhance glutamatergic currents. Ampakines can be respiratory stimulants, especially during conditions of low respiratory motor output. We previously reported that pretreament with ampakine CX717 enhances long‐term facilitation of inspiratory bursting in the hypoglossal nerve following repeated hypoxic exposures in mice. Here, we used an adult rat model to test the hypothesis that ampakine pretreatment would enable a single bout of hypoxia to produce a sustained facilitation of phrenic nerve inspiratory burst amplitude. Phrenic nerve output was recorded in urethane anesthetized, mechanically ventilated and vagotomized male Sprague‐Dawley rats. Inspiratory burst amplitude and frequency, as well as heart rate and mean arterial pressure were evaluated in three experimental groups: 1) intravenous (IV) ampakine (Cx717, 15 mg/kg) (baseline PaCO2= 46.3±2.5 mmHg, n=8), 2) IV Cx717 followed 2 minutes later by a single, 5 min hypoxia challenge (baseline PaO2= 47.2±1.8 mmHg, n=8), and 3) IV vehicle (10% (2‐Hydroxypropyl)‐bcyclodextrin) + hypoxia (baseline PaO2= 46.7±5.2 mmHg, n=8). IV delivery of Cx717 produced a small, transient increase in phrenic burst amplitude and frequency which returned to baseline values by ~ 20 min. When IV ampakine was followed by hypoxia there was a sustained facilitation of phrenic inspiratory bursting that persisted to 90‐min following hypoxia (132±33 %baseline amplitude). There were no sustained changes in heart rate or blood pressure in any of the experimental groups. The sham+hypoxia treatment did not evoke phrenic facilitation, and to our knowledge, there is no evidence in the literature to suggest that a single brief bout of hypoxia can induce sustained facilitation of phrenic nerve bursting – rather the established “long term facilitation” model requires multiple bouts of hypoxia. We conclude that a low dose of ampakine Cx717 has a small and transient impact on cardiorespiratory function, but when paired with a single bout of hypoxia can induce sustained respiratory plasticity. This approach may have value in the context of hypoxia‐based neurorehabilitation strategies.Support or Funding Information1T32HL134621‐01A1 (LBW), K99 HL143207‐01 (KS), F32NS095620‐01(KS), 1R01HL139708‐01A1 (DDF)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.