Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats*

Abstract

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.

Retracted: Vagus Nerve Mediates the Protective Effects of Melanocortins against Cerebral and Systemic Damage after Ischemic Stroke

“…We also found that, in the activation of this pathway, central muscarinic acetylcholine receptors are involved (Guarini et al, 2004;Mioni et al, 2005), as confirmed by other researchers (Pavlov et al, 2006). After preliminary observations in dogs and mice by Lipton's and Tatro's groups (Huh et al, 1997;Huang and Tatro, 2002), more recently we showed the first clear evidence that [Nle 4 , D-Phe 7 ]a-melanocytestimulating hormone (NDP-a-MSH) provides a strong neuroprotection in a broad therapeutic treatment window (until 12 to 18 h) against brain damage consequent to global or focal cerebral ischemia in gerbils and rats (Giuliani et al, 2006a(Giuliani et al, , b, 2007b.…”

“…This indicates that the recently identified vagus nervemediated cholinergic antiinflammatory pathway (Borovikova et al, 2000;Guarini et al, 2003;Altavilla et al, 2006;Tracey, 2007) is involved in the neuroprotective effect of melanocortins against ischemic stroke, as it occurs in circulatory shock and myocardial ischemia (Guarini et al, 2004;Mioni et al, 2005).…”

“…Citoplasmatic proteins were isolated as previously described (Mioni et al, 2005;Giuliani et al, 2006b). After denaturation, cytoplasmic proteins (40 mg for each sample) were electrophoretically separated and transferred onto nitrocellulose membranes with use of a transfer buffer, as previously described (Mioni et al, 2005;Giuliani et al, 2006b). The blots were then blocked, washed, and incubated overnight at 41C with a primary antibody for the phosphorylated (p) and unphosphorylated ERK and JNK forms (Cell Signaling, Charlottesville, VA, USA), TNF-a, and caspase-3 (Chemicon International, Temecula, CA, USA).…”

“…We previously showed that the well recognized life-saving effect of melanocortins-endogenous peptides of the ACTH/MSH group-in circulatory shock and myocardial ischemia is because of the activation of the cholinergic antiinflammatory pathway, by stimulation of melanocortin MC 4 and MC 3 receptors, respectively, within the CNS (Guarini et al, 1999(Guarini et al, , 2004Mioni et al, 2003Mioni et al, , 2005Giuliani et al, 2007a). We also found that, in the activation of this pathway, central muscarinic acetylcholine receptors are involved (Guarini et al, 2004;Mioni et al, 2005), as confirmed by other researchers (Pavlov et al, 2006).…”

Alteration of Cholinergic Anti‐Inflammatory Pathway in Rat With Ischemic Cardiomyopathy–Modified Electrophysiological Function of Heart

“…Improving the cardiac autonomic function markedly attenuated ICM‐induced arrhythmogenic properties 22. To find evidence for the identification of a protective, melanocortin‐activated efferent vagal cholinergic pathway, Mioni et al stimulated efferent vagal fibers electrically after bilateral cervical vagotomy, suggesting that an efferent vagal cholinergic pathway served a protective role against myocardial ischemia/reperfusion‐induced ventricular arrhythmia 10. Zuanetti et al reported that the protective effect of vagal stimulation against reperfusion ventricular fibrillation is mediated by the decreased heart rate; however, they also found no difference in occurrence of complex reperfusion arrhythmias between neutrally intact and postvagotomy animals 11.…”