title: Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats.
abstract: OBJECTIVE
  A vagus nerve-mediated, brain cholinergic protective mechanism activated by melanocortin peptides is operative in conditions of circulatory shock; moreover, there is anatomical evidence of dual vagal-cardiac efferent pathways in rats, which could play different roles in controlling heart function. Therefore, we investigated the role and functional mechanism of such vagal efferent pathway(s) in an experimental model of ischemic heart disease.
  
  
  METHODS
  Randomized experimental study.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  Adult Wistar rats of either sex.
  
  
  METHODS
  After bilateral cervical vagotomy (with or without pretreatment with atropine), efferent vagal fibers were electrically stimulated in rats subjected to coronary artery occlusion (5 mins) followed by reperfusion (5 mins). Other rats (intact, vagotomized, or pretreated with atropine) were treated with nanomolar doses of melanocortin peptides.
  
  
  RESULTS
  Electrical stimulation of efferent vagal fibers (5 V, 2 m secs, 1-9 Hz, for the whole period of ischemia/reperfusion) strongly reduced the high incidence of severe arrhythmias and lethality, reduced the increase in free radical blood levels and left-ventricle histologic alterations, and augmented the extracellular signal-regulated kinase activation. Treatment with the melanocortin peptides adrenocorticotropin and gamma2-melanocyte-stimulating hormone (162 nmol/kg intravenously or 16.2 nmol/kg intracerebroventricularly, during coronary occlusion) produced the same protective effects of electrical stimulation and with the same muscarinic acetylcholine receptor-dependent mechanism, seemingly through brain activation (mediated by melanocortin MC3 receptors, as previously described) of such efferent vagal pathway.
  
  
  CONCLUSIONS
  The present results give evidence for the identification of a protective, melanocortin-activated, efferent vagal cholinergic pathway, operative in conditions of myocardial ischemia/reperfusion. These data suggest that melanocortins and pertinent compounds able to activate such a pathway could provide the potential for development of a new class of drugs for a novel approach to management of ischemic heart disease.
authors.affiliation: Department of Biomedical Sciences, Sections of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Mioni
authors.forename: Carla
authors.initials: C
authors.lastname: Bazzani
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
authors.forename: Sheila
authors.initials: S
authors.lastname: Leone
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrari
authors.forename: Letteria
authors.initials: L
authors.lastname: Minutoli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bitto
authors.forename: Herbert
authors.initials: H
authors.lastname: Marini
authors.forename: Davide
authors.initials: D
authors.lastname: Zaffe
authors.forename: Annibale R
authors.initials: AR
authors.lastname: Botticelli
authors.forename: Anna
authors.initials: A
authors.lastname: Iannone
authors.forename: Aldo
authors.initials: A
authors.lastname: Tomasi
authors.forename: Albertino
authors.initials: A
authors.lastname: Bigiani
authors.forename: Alfio
authors.initials: A
authors.lastname: Bertolini
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
mesh_terms: D000818:Animals; D003366:Cosyntropin / Q000627:therapeutic use*; D004558:Electric Stimulation; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005609:Free Radicals / Q000097:blood; D008297:Male; D017202:Myocardial Ischemia / Q000209:etiology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D014628:Vagotomy; D014630:Vagus Nerve / Q000502:physiology*
chemical_list: D005609:Free Radicals; D003366:Cosyntropin