Melanocortins counteract inflammatory and apoptotic responses to prolonged myocardial ischemia/reperfusion through a vagus nerve-mediated mechanism

Eur J Pharmacol. 2010 Jul 10;637(1-3):124-30. doi: 10.1016/j.ejphar.2010.03.052. Epub 2010 Apr 10.


Recently we reported that an efferent vagal fibre-mediated cholinergic protective pathway, activated by melanocortins acting at brain melanocortin MC(3) 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-alpha (TNF-alpha), 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-alpha 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 [Nle(4), D-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) produced a reduction in TNF-alpha 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-alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Blotting, Western
  • Caspase 3 / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Inflammation / drug therapy*
  • Inflammation / pathology*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Male
  • Melanocortins / pharmacology*
  • Melanocortins / therapeutic use*
  • Myocardial Reperfusion Injury / drug therapy*
  • Myocardial Reperfusion Injury / enzymology
  • Myocardial Reperfusion Injury / metabolism
  • Myocardial Reperfusion Injury / pathology*
  • Rats
  • Rats, Wistar
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism
  • Vagus Nerve / drug effects*
  • Vagus Nerve / physiology


  • Melanocortins
  • Tumor Necrosis Factor-alpha
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Caspase 3