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Aging Impairs Phrenic Long‐Term Facilitation in Rats by an Adenosine‐Dependent Mechanism
Author(s) -
Marciante Alexandria B.,
Mitchell Gordon S.
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r2584
Subject(s) - adenosine , intermittent hypoxia , receptor , medicine , respiratory system , adenosine receptor , phrenic nerve , adenosine a2a receptor , adenosine a1 receptor , facilitation , anesthesia , endocrinology , pharmacology , biology , neuroscience , agonist , obstructive sleep apnea
Phrenic long‐term facilitation (pLTF) is a form of respiratory plasticity elicited by acute intermittent hypoxia (AIH). AIH activates competing intracellular signaling cascades, initiated by phrenic motor neuron serotonin 2 and adenosine 2A (A 2A ) receptors, respectively. With moderate AIH (mAIH), the serotonin‐dependent Q pathway to phrenic motor facilitation dominates, with an adenosine constraint. Consequently, spinal A 2A receptor inhibition enhances mAIH‐induced pLTF. In middle‐aged male, and geriatric acyclic female rats, pLTF is attenuated through unknown mechanisms. We hypothesize that basal spinal adenosine levels are elevated in aged rats, thereby undermining mAIH‐induced pLTF. Thus, we predict that spinal A 2A receptor inhibition in aged male rats will restore pLTF to levels equal to young male rats with A 2A receptor inhibition. A selective A 2A receptor antagonist (MSX‐3; 10 uM, 12 uL) or vehicle (0.9% sterile saline) were delivered intrathecally (C4) in anesthetized, vagotomized, paralyzed and ventilated young (3‐6 months) and aged (20‐22 months) male Sprague‐Dawley rats prior to mAIH (3, 5 min hypoxic episodes; arterial Po 2 = 45‐55 mmHg). In young males, mAIH elicits ~ 60% pLTF at 60 min post‐AIH. Spinal A 2A receptor inhibition significantly enhanced mAIH‐induced pLTF in young males (119 + 5%; n = 6) vs vehicle controls (55 + 9%; n = 6; p < 0.001) and time controls (12 + 4%; n = 6; p < 0.001). In aged males, A 2A receptor inhibition enhanced mAIH‐induced pLTF to a greater extent (186 + 19%; n = 7) vs vehicle controls (25 + 11%; n = 7; p < 0.001) and time controls (3 + 5%; n = 4; p < 0.001). Measured basal adenosine levels in ventral C3‐C5 homogenates were significantly elevated in aged vs young males (p = 0.008). Preliminary data suggest aged female rats (16‐18 months) also have enhanced mAIH‐induced pLTF with A 2A receptor inhibition (173 + 24%; n = 3) vs vehicle controls (53 + 7%; n = 3) and time controls (5 + 17%; n = 2) in persistent estrus. These findings advance our understanding of mechanisms whereby age undermines mAIH‐induced phrenic motor plasticity. Understanding age and sex effects on AIH‐induced respiratory motor plasticity is crucial as we harness therapeutic AIH to treat severe neuromuscular disorders that compromise breathing.