Severe sustained hypoxia elicits long‐lasting phrenic motor facilitation (pMF) by an adenosinergic mechanism

Abstract

Moderate acute intermittent hypoxia (AIH; 3, 5‐min episodes) elicits serotonin‐dependent phrenic long‐term facilitation (pLTF); this form of pLTF is enhanced by spinal adenosine 2A (A2A) receptor inhibition. Severe AIH also elicits pLTF, but via an adenosine A2A receptor dependent (serotonin independent) mechanism. This shift may reflect greater spinal adenosine release/formation during severe AIH. Moderate sustained hypoxia (SH; 9–20‐min) fails to elicit pMF, demonstrating pMF pattern‐sensitivity. However, since severe SH may increase extracellular adenosine levels, we hypothesized that severe SH would elicit pMF via an A2A receptor dependent mechanism. Severe SH (PaO2=25–35; 25 min) was studied in anesthetized, paralyzed and ventilated rats +/− spinal A2A receptor inhibition (MSX‐3, i.t., C4). Severe SH elicits pMF (53%±12% at 60 min post‐SH) vs. time controls (10%±3%; p<0.05, both n=8). MSX‐3 pre‐treatment attenuated severe SH induced pMF (10%±5%; p<0.05, n=7). Thus, severe SH and AIH both elicit spinal A2A‐dependent pMF, unlike moderate SH and AIH (Devinney et al., ibid), indicating that adenosine‐dependent pMF is not pattern sensitive. Understanding mechanisms of pattern sensitivity in respiratory plasticity may enable us to “harness” plasticity as a treatment for respiratory insufficiency.[Supported by NIH HL080209 and T32 007654 and the Francis Families Foundation]