Severe acute intermittent hypoxia elicits phrenic long-term facilitation by a novel adenosine-dependent mechanism

Abstract

Acute intermittent hypoxia [AIH; 3, 5-min episodes; 35-45 mmHg arterial PO(2) (Pa(O(2)))] elicits serotonin-dependent phrenic long-term facilitation (pLTF), a form of phrenic motor facilitation (pMF) initiated by G(q) protein-coupled metabotropic 5-HT(2) receptors. An alternate pathway to pMF is induced by G(s) protein-coupled metabotropic receptors, including adenosine A(2A) receptors. AIH-induced pLTF is dominated by the serotonin-dependent pathway and is actually restrained via inhibition from the adenosine-dependent pathway. Here, we hypothesized that severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent form of pMF. pLTF induced by severe (25-30 mmHg Pa(O(2))) and moderate (45-55 mmHg Pa(O(2))) AIH were compared in anesthetized rats, with and without intrathecal (C4) spinal A(2A) (MSX-3, 130 ng/kg, 12 μl) or 5-HT receptor antagonist (methysergide, 300 μg/kg, 15 μl) injections. During severe, but not moderate AIH, progressive augmentation of the phrenic response during hypoxic episodes was observed. Severe AIH (78% ± 8% 90 min post-AIH, n = 6) elicited greater pLTF vs. moderate AIH (41% ± 12%, n = 8; P < 0.05). MSX-3 (28% ± 6%; n = 6; P < 0.05) attenuated pLTF following severe AIH, but enhanced pLTF following moderate AIH (86% ± 26%; n = 8; P < 0.05). Methysergide abolished pLTF after moderate AIH (12% ± 5%; n = 6; P = 0.035), but had no effect after severe AIH (66 ± 13%; n = 5; P > 0.05). Thus severe AIH shifts pLTF from a serotonin-dependent to an adenosine-dependent mechanism; the adenosinergic pathway inhibits the serotonergic pathway following moderate AIH. Here we demonstrate a novel adenosine-dependent pathway to pLTF following severe AIH. Shifts in the mechanisms of respiratory plasticity provide the ventilatory control system greater flexibility as challenges that differ in severity are confronted.

Acute intermittent optogenetic stimulation of nucleus tractus solitarius neurons induces sympathetic long-term facilitation

“…Alternatively, direct vagal afferent inputs to NTS astrocytes have been shown to induce glutamate release (26); perhaps glia receive similar afferent innervation from arterial chemoreceptor afferent inputs. Finally, severe AIH can induce phrenic LTF via an adenosine A 2A receptor mechanism in the spinal cord (31).…”

Adenosine 2A Receptor Inhibition Enhances Intermittent Hypoxia-Induced Diaphragm but Not Intercostal Long-Term Facilitation

“…13 In fact, at this early time post-injury, we suggest that A2A receptor inhibition may limit the potential for alternative, adenosine-dependent pathways to respiratory motor plasticity. 7,25 With this idea in mind, it is possible that the plasticity promoting actions of combinatorial actions of intermittent hypoxia and A2A receptor inhibition in normal or chronic SCI rats may actually undermine intermittent hypoxia-induced plasticity in rats with acute SCI. Something as simple as drinking coffee (a well-known A2A receptor antagonist) may have major, but different consequences with time post-spinal injury.…”

“…To our knowledge, this is the first report of bilateral Dia and T2 EIC EMG measurements after acute and chronic spinal injury in unanesthetized rats. Disruption of descending serotonergic inputs to spinal respiratory motor nuclei 13 and inadequate levels of hypoxemia to achieve serotonin-independent, adenosine-induced LTF 7 may explain 1982 NAVARRETE-OPAZO ET AL.…”

“…6 For example, whereas pLTF is serotonin dependent when AIH consists of mild to moderate hypoxic episodes, it converts to an adenosine dependent (serotonin independent) form of pLTF when AIH consists of severe hypoxic episodes. 7 Although moderate AIH-induced pLTF requires spinal serotonin receptor activation, [8][9][10][11] concurrent spinal adenosine 2A (A2A) receptor activation constrains pLTF. 12 Thus, both systemic and spinal A2A receptor antagonist administration enhances pLTF in uninjured, anesthetized rats.…”

Repetitive acute intermittent hypoxia increases expression of proteins associated with plasticity in the phrenic motor nucleus

“…One alternate pathway to pMF involves activation of adenosine type 2A receptors (A2A), new TrkB synthesis and downstream signaling via protein kinase B/Akt in the region of the phrenic motor nucleus (Golder et al, 2008; Nichols et al, 2012). This novel, adenosine-dependent mechanism assumes predominance when the severity of hypoxic episodes increases, replacing the normal, serotonin-dependent mechanism(Nichols et al, 2012). Another novel pathway involves signaling via the hypoxia-induced growth factor, vascular endothelial growth factor (VEGF; Dale-Nagle et al, 2011).…”