title: 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.
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, School of Veterinary Medicine, Madison, Wisconsin 53706, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Nichols
authors.forename: Erica A
authors.initials: EA
authors.lastname: Dale
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Mitchell
mesh_terms: D000208:Acute Disease; D000241:Adenosine / Q000378:metabolism*; D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage; D000818:Animals; D001794:Blood Pressure; D002245:Carbon Dioxide / Q000097:blood; D004195:Disease Models, Animal; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D007278:Injections, Spinal; D008168:Lung / Q000294:innervation*; D008297:Male; D009473:Neuronal Plasticity / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D010791:Phrenic Nerve / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000187:drug effects / Q000378:metabolism*; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism; D012119:Respiration; D012701:Serotonin / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000008:administration & dosage; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D044348:Receptors, Serotonin, 5-HT2; D058830:Serotonin 5-HT2 Receptor Antagonists; D002245:Carbon Dioxide; D012701:Serotonin; D000241:Adenosine; D010100:Oxygen