Recently we reported that an efferent vagal fibre-mediated cholinergic protective pathway, activated by melanocortins acting at brain melanocortin MC3 receptors, is operative in a condition of short-term myocardial ischemia/reperfusion associated with a high incidence of severe arrhythmias and death. Here we investigated melanocortin effects, and the role of the vagus nerve-mediated cholinergic protective pathway, in a rat model of prolonged myocardial ischemia/reperfusion associated with marked inflammatory and apoptotic reactions, and a large infarct size. Ischemia was produced in rats by ligature of the left anterior descending coronary artery for 30 min. At the end of the 2-h reperfusion, western blot analysis of the inflammatory and apoptotic markers tumor necrosis factor-α (TNF-α), c-jun N-terminal kinases (JNK) and caspase-3, as well as of the anti-apoptotic extracellular signal-regulated kinases (ERK 1/2), was performed in the left ventricle. In saline-treated ischemic rats there was an increase in TNF-α levels and in the activity of JNK and caspase-3 accompanied, despite an appreciable ERK 1/2 activation, by a large infarct size. Intravenous treatment, during coronary artery occlusion, with the melanocortin analog [Nle4, D-Phe7]α-melanocyte-stimulating hormone (NDP-α-MSH) produced a reduction in TNF-α levels and in the activity of JNK and caspase-3, associated with marked activation of the pro-survival kinases ERK 1/2, and consequent attenuation of infarct size. Bilateral cervical vagotomy blunted the protective effects of NDP-α-MSH. These results indicate that melanocortins modulate the inflammatory and apoptotic cascades triggered by prolonged myocardial ischemia/reperfusion, and reduce infarct size, seemingly by activation of the vagus nerve-mediated cholinergic protective pathway.
|Data di pubblicazione:||2010|
|Titolo:||Melanocortins counteract inflammatory and apoptotic responses to prolonged myocardial ischemia/reperfusion through a vagus nerve-mediated mechanism|
|Autore/i:||Ottani A; Giuliani D; Galantucci M; Spaccapelo L; Novellino E; Grieco P; Jochem J; Guarini S.|
|Digital Object Identifier (DOI):||10.1016/j.ejphar.2010.03.052|
|Codice identificativo ISI:||WOS:000278878900017|
|Codice identificativo Scopus:||2-s2.0-77953288401|
|Citazione:||Melanocortins counteract inflammatory and apoptotic responses to prolonged myocardial ischemia/reperfusion through a vagus nerve-mediated mechanism / Ottani A; Giuliani D; Galantucci M; Spaccapelo L; Novellino E; Grieco P; Jochem J; Guarini S.. - In: EUROPEAN JOURNAL OF PHARMACOLOGY. - ISSN 0014-2999. - STAMPA. - 637 (1-3)(2010), pp. 124-130.|
|Tipologia||Articolo su rivista|
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