Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats.
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.
Mioni
Chiara
C
Department of Biomedical Sciences, Sections of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy.
Bazzani
Carla
C
Giuliani
Daniela
D
Altavilla
Domenica
D
Leone
Sheila
S
Ferrari
Anna
A
Minutoli
Letteria
L
Bitto
Alessandra
A
Marini
Herbert
H
Zaffe
Davide
D
Botticelli
Annibale R
AR
Iannone
Anna
A
Tomasi
Aldo
A
Bigiani
Albertino
A
Bertolini
Alfio
A
Squadrito
Francesco
F
Guarini
Salvatore
S
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*
D005609:Free Radicals; D003366:Cosyntropin