Further evidence that melanocortins prevent myocardial reperfusion injury by activating melanocortin MC3 receptors.
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.
Mioni
Chiara
C
Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, via G. Campi 287, 41100, Modena, Italy. mioni.chiara@unimore.it
Giuliani
Daniela
D
Cainazzo
Maria Michela
MM
Leone
Sheila
S
Iannone
Anna
A
Bazzani
Carla
C
Grieco
Paolo
P
Novellino
Ettore
E
Tomasi
Aldo
A
Bertolini
Alfio
A
Guarini
Salvatore
S
D000818:Animals; D003327:Coronary Disease / Q000150:complications / Q000503:physiopathology; D003366:Cosyntropin / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*; D019835:FMRFamide / Q000737:chemistry / Q000378:metabolism; D005260:Female; D007022:Hypotension / Q000150:complications / Q000188:drug therapy / Q000517:prevention & control; D007275:Injections, Intravenous; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology* / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000401:mortality / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D044104:Receptor, Melanocortin, Type 3 / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction; D017180:Tachycardia, Ventricular / Q000150:complications / Q000517:prevention & control; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000150:complications / Q000517:prevention & control; D000521:alpha-MSH / Q000494:pharmacology* / Q000502:physiology; D019825:gamma-MSH / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology
D044104:Receptor, Melanocortin, Type 3; D019825:gamma-MSH; C103272:SHU 9119; D003366:Cosyntropin; D000521:alpha-MSH; D019835:FMRFamide; D009074:Melanocyte-Stimulating Hormones; D008012:Lidocaine