title: Enhanced recovery of breathing capacity from combined adenosine 2A receptor inhibition and daily acute intermittent hypoxia after chronic cervical spinal injury.
abstract: Daily acute intermittent hypoxia (dAIH) improves breathing capacity after C2 spinal hemisection (C2HS) in rats. Since C2HS disrupts spinal serotonergic innervation below the injury, adenosine-dependent mechanisms underlie dAIH-induced functional recovery 2weeks post-injury. We hypothesized that dAIH-induced functional recovery converts from an adenosine-dependent to a serotonin-dependent, adenosine-constrained mechanism with chronic injury. Eight weeks post-C2HS, rats began dAIH (10, 5-min episodes, 10.5% O2; 5-min intervals; 7days) followed by AIH 3× per week (3×wAIH) for 8 additional weeks with/without systemic A2Areceptor inhibition (KW6002) on each AIH exposure day. Tidal volume (VT) and bilateral diaphragm (Dia) and T2 external intercostal motor activity were assessed in unanesthetized rats breathing air and during maximum chemoreflex stimulation (MCS: 7% CO2, 10.5% O2). Nine weeks post-C2HS, dAIH increased VTversus time controls (p<0.05), an effect enhanced by KW6002 (p<0.05). dAIH increased bilateral Dia activity (p<0.05), and KW6002 enhanced this effect in contralateral (p<0.05) and ipsilateral Dia activity (p<0.001), but not T2inspiratory activity. Functional benefits of combined AIH plus systemic A2Areceptor inhibition were maintained for 4weeks. Thus, in rats with chronic injuries: 1) dAIH improves VTand bilateral diaphragm activity; 2) VTrecovery is enhanced by A2Areceptor inhibition; and 3) functional recovery with A2A receptor inhibition and AIH "reminders" last 4weeks. Combined dAIH and A2Areceptor inhibition may be a simple, safe, and effective strategy to accelerate/enhance functional recovery of breathing capacity in patients with respiratory impairment from chronic spinal injury.
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA; Teletón Children Rehabilitation Institute, Alameda 4620, Santiago, Chile.
authors.forename: A
authors.initials: A
authors.lastname: Navarrete-Opazo
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Dougherty
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, Madison, WI 53706, USA; Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA. Electronic address: gsmitche@phhp.ufl.edu.
authors.forename: G S
authors.initials: GS
authors.lastname: Mitchell
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002574:Cervical Vertebrae; D003964:Diaphragm / Q000187:drug effects; D004195:Disease Models, Animal; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology; D006935:Hypercapnia / Q000503:physiopathology; D000860:Hypoxia; D008297:Male; D008451:Maximal Voluntary Ventilation / Q000187:drug effects / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D043683:Receptors, Adenosine A2 / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D012120:Respiration Disorders / Q000209:etiology* / Q000628:therapy*; D013119:Spinal Cord Injuries / Q000150:complications*; D013997:Time Factors; D014797:Vital Capacity / Q000187:drug effects / Q000502:physiology
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011687:Purines; D043683:Receptors, Adenosine A2; C111599:istradefylline
keywords: Adenosine receptors; Breathing; Cervical; Chronic; Functional recovery; Hemisection; Intermittent hypoxia; Rehabilitation; Spinal cord injury; Spinal plasticity