Vol. 291, Issue 3, 1023-1027, December 1999

Evidence That Melanocortin 4 Receptor Mediates Hemorrhagic Shock Reversal Caused by Melanocortin Peptides¹

Salvatore Guarini, Carla Bazzani, Maria Michela Cainazzo, Chiara Mioni, Giuseppe Ferrazza, Anna Valeria Vergoni, Helgi B. Schiöth, Jarl E. S. Wikberg and Alfio Bertolini

Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Italy (S.G., C.B., M.M.C., C.M., G.F., A.V.V., A.B.); Department of Pharmaceutical Pharmacology, University of Uppsala, Sweden; and Melacure Therapeutics AB, Uppsala, Sweden (H.B.S., J.E.S.W.).

Melanocortin peptides are known to be extremely potent in causing the sustained reversal of different shock conditions, both in experimental animals and humans; the mechanism of action includes an essential brain loop. Three melanocortin receptor subtypes are expressed in brain tissue: MC₃, MC_4, and MC₅ receptors. In a volume-controlled model of hemorrhagic shock in anesthetized rats, invariably causing the death of control animals within 30 min after saline injection, the i.v. bolus administration of the adrenocorticotropin fragment 1-24 (agonist at MC₄ and MC₅ receptors) at a dose of 160 µg/kg i.v. (54 nmol/kg) produced an almost complete and sustained restoration of cardiovascular and respiratory functions. An equimolar dose of ₁-melanocyte stimulating hormone (selective agonist at MC₃ receptors) was completely ineffective. The selective antagonist at MC₄ receptors, HS014, although having no influence on cardiovascular and respiratory functions per se, dose-dependently prevented the antishock activity of adrenocorticotropin fragment 1-24, with the effect being complete either at the i.v. dose of 200 µg/kg or at the i.c.v. dose of 5 µg/rat (17-20 µg/kg). We concluded that the effect of melanocortin peptides in hemorrhagic shock is mediated by the MC₄ receptors in the brain.