title: δ-Opioid receptors: Pivotal role in intermittent hypoxia-augmentation of cardiac parasympathetic control and plasticity.
abstract: Intermittent hypoxia training (IHT) produces robust myocardial protection against ischemia-reperfusion induced infarction and arrhythmias. Blockade of this cardioprotection by antagonism of either β1-adrenergic or δ-opioid receptors (δ-OR) suggests autonomic and/or opioidergic adaptations.
  
  
  
  To test the hypothesis that IHT shifts cardiac autonomic balance toward greater cholinergic and opioidergic influence.
  
  
  
  Mongrel dogs completed 20d IHT, non-hypoxic sham training, or IHT with the δ-OR antagonist naltrindole (200μg/kgsc). The vagolytic effect of the δ-OR agonist met-enkephalin-arg-phe delivered by sinoatrial microdialysis was evaluated following IHT. Sinoatrial, atrial and left ventricular biopsies were analyzed for changes in δ-OR, the neurotrophic monosialoganglioside, GM-1, and cholinergic and adrenergic markers.
  
  
  
  IHT enhanced vagal bradycardia vs. sham dogs (P<0.05), and blunted the δ2-OR mediated vagolytic effect of met-enkephalin-arg-phe. The GM-1 labeled fibers overlapped strongly with cholinergic markers, and IHT increased the intensity of both signals (P<0.05). IHT increased low and high intensity vesicular acetylcholine transporter labeling of sinoatrial nodal fibers (P<0.05) suggesting an increase in parasympathetic arborization. IHT reduced select δ-OR labeled fibers in both the atria and sinoatrial node (P<0.05) consistent with moderation of the vagolytic δ2-OR signaling described above. Furthermore, blockade of δ-OR signaling with naltrindole during IHT increased the protein content of δ-OR (atria and ventricle) and vesicular acetylcholine transporter (atria) vs. sham and untreated IHT groups. IHT also reduced the sympathetic marker, tyrosine hydroxylase in ventricle (P<0.05).
  
  
  
  IHT shifts cardiac autonomic balance in favor of parasympathetic control via adaptations in opioidergic, ganglioside, and adrenergic systems.
authors: Institute of Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors: Juan A
authors: JA
authors: Estrada
authors: Institute of Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors: Mathew A
authors: MA
authors: Barlow
authors: Institute of Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors: Darice
authors: D
authors: Yoshishige
authors: Institute of Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors: Arthur G
authors: AG
authors: Williams
authors: Institute of Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors: H Fred
authors: HF
authors: Downey
authors: Institute of Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX, USA. Electronic address: Robert.Mallet@unthsc.edu.
authors: Robert T
authors: RT
authors: Mallet
authors: Institute of Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, TX, USA.
authors: James L
authors: JL
authors: Caffrey
mesh_terms: D000818:Animals; D004285:Dogs; D004744:Enkephalin, Methionine / Q000494:pharmacology; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000860:Hypoxia / Q000188:drug therapy*; D017551:Microdialysis / Q000379:methods; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D012849:Sinoatrial Node / Q000187:drug effects; D014630:Vagus Nerve / Q000503:physiopathology
chemical_list: D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D004744:Enkephalin, Methionine; D009271:Naltrexone; C055382:naltrindole; D009638:Norepinephrine
keywords: Acetylcholine; Enkephalin; GM-1; Naltrindole; Vagus