In rats subjected to
myocardial ischemia/reperfusion,
melanocortin peptides, including gamma(1)-melanocyte-stimulating
hormone (gamma(1)-MSH), are able to exert a protective effect by stimulating brain
melanocortin MC(3) receptors. A non-
melanocortin receptor belonging to a group of receptors for Phe-Met-Arg-Phe-NH(2) (
FMRFamide)-like
peptides may be involved in some of the cardiovascular effects of the gamma-MSHs.
FMRFamide-like
peptides and gamma(1)-/gamma(2)-
MSH share, among other things, the C-terminal Arg-Phe sequence, which seems to be essential for cardiovascular effects in normal animals. So we aimed to further investigate which receptor and which structure are involved in the protective effects of
melanocortins in anesthetized rats subjected to
myocardial ischemia by
ligature of the left anterior descending coronary artery (5 min), followed by reperfusion. In saline-treated rats, reperfusion induced, within a few seconds, a high incidence of
ventricular tachycardia and
ventricular fibrillation, and a high percentage of death within the 5 min of observation period. Reperfusion was associated with a massive increase in
free radical blood levels and with an abrupt and marked fall in systemic arterial pressure. The i.v. treatment (162 nmol/kg) during the ischemic period with the
adrenocorticotropin fragment 1-24 [
ACTH-(1-24): the reference protective
melanocortin which binds all
melanocortin receptors], as well as with both the
melanocortin MC(3) receptor agonists gamma(2)-MSH and [D-Trp(8)]gamma(2)-
MSH, reduced the incidence of
ventricular tachycardia,
ventricular fibrillation and death, the increase in
free radical blood levels and the fall in arterial pressure. On the contrary, gamma(2)-MSH-(6-12) (a fragment unable to bind
melanocortin receptors) was ineffective. Such protective effect was prevented by the
melanocortin MC(3)/MC(4) receptor antagonist
SHU 9119. In normal (i.e., not subjected to
myocardial ischemia/reperfusion) rats, the same i.v. dose (162 nmol/kg) of gamma(2)-MSH, [D-Trp(8)]gamma(2)-
MSH and gamma(2)-MSH-(6-12) provoked a prompt and transient increase in arterial pressure; on the other hand, ACTH-(1-24), which lacks the C-terminal Arg-Phe sequence, decreased arterial pressure, but only at higher doses. Heart rate of normal rats was not affected by any of the assayed
peptides. The present data confirm and extend our previous findings that
melanocortins prevent
myocardial reperfusion injury by activating
melanocortin MC(3) receptors. Moreover, they further support the notion that, in normal rats, cardiovascular effects of gamma-MSHs are mediated by receptors for
FMRFamide-like
peptides, for whose activation, but not for that of
melanocortin MC(3) receptors, the C-terminal Arg-Phe structure being relevant.