Severe acute intermittent hypoxia elicits long‐lasting phrenic motor facilitation by a novel adenosinergic mechanism

Abstract

Moderate acute intermittent hypoxia (AIH; 3, 5-min episodes) elicits serotonin-dependent phrenic long-term facilitation (pLTF). This form of phrenic motor facilitation (pMF) arises from a mechanism we refer to as the “Q pathway” to pMF since it is initiated via Gq protein-coupled metabotropic receptor activation (ie. 5HT2). An alternate pathway to pMF is induced by Gs protein-coupled metabotropic receptors (eg. A2A), which we refer to as the “S pathway.” pLTF following moderate AIH is dominated by the Q pathway, and is restrained via cross-talk inhibition from the S pathway. Here, we hypothesized that severe AIH preferentially activates the S pathway due to greater spinal adenosine release and A2A receptor activation. Thus, severe (PaO2=25–30mmHg) and moderate (PaO2=45–55mmHg) AIH-induced pLTF were studied in anesthetized rats with and without spinal A2A receptor inhibition (MSX-3, C4 i.t.). Severe (n=6) AIH elicits greater pLTF vs. moderate (n=8) AIH (78%±8% vs. 41%±12% 90 min post-AIH, p < 0.05). MSX-3 pre-treatment inhibited pLTF after severe AIH (28%±6%; n=6; p<0.05 vs severe hypoxia alone), but enhanced pLTF after moderate AIH as previously reported (86%±26%; n=8; p<0.05 vs. moderate hypoxia alone). Thus, severe AIH shifts pLTF from the Q towards dominant S pathways to pMF. Conversely, blocking the S pathway during moderate AIH removes crosstalk inhibition, enabling greater Q-dependent pLTF.