Melanocortins protect against myocardial ischemia/reperfusion injury through the activation of an efferent cholinergic pathway

A vagus nerve-mediated brain cholinergic protective mechanism, is operative in circulatory schock. We investigated, therefore, role and functional mechanism of such vagal efferent pathway (s) in a model of ischemic heart disease. Anesthetized rats were subjected to transient coronary artery occlusion (5 min) followed by reperfusion: occurrence of ventricular tachycardia (VT), ventricular fibrillation (VF), and lethality, were recorded up to the 5th min after reperfusion. Electrical stimulation of efferent vagal fibres (5 V, 2 ms, 1-9 Hz, for the whole period of ischemia/reperfusion) reduced the high incidence of VT , VF and lethality, the increase in free radical blood levels and left ventricle histological alteration. Treatment with same melanocortin peptides (162 nmol/kg i.v. or 16.2 nmol/kgi.c.v.) produced the same protective effects of electrical stimulation, and with the same muscarinic receptor-dependent mechanism, seemingly through brain activation (mediated by melanocortin MC3 receptors) of such efferent vagal pathway. These findings could provide the potential for a novel approach to management of ischemic heart disease.