title: Evidence that melanocortin 4 receptor mediates hemorrhagic shock reversal caused by melanocortin peptides.
abstract: 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: MC(3), MC(4,) and MC(5) 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 MC(4) and MC(5) receptors) at a dose of 160 microg/kg i.v. (54 nmol/kg) produced an almost complete and sustained restoration of cardiovascular and respiratory functions. An equimolar dose of gamma(1)-melanocyte stimulating hormone (selective agonist at MC(3) receptors) was completely ineffective. The selective antagonist at MC(4) 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 microg/kg or at the i.c.v. dose of 5 microg/rat (17-20 microg/kg). We concluded that the effect of melanocortin peptides in hemorrhagic shock is mediated by the MC(4) receptors in the brain.
authors.affiliation: Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Modeno, Italy. Guarini.Salvatore@unimo.it
authors.forename: S
authors.initials: S
authors.lastname: Guarini
authors.forename: C
authors.initials: C
authors.lastname: Bazzani
authors.forename: M M
authors.initials: MM
authors.lastname: Cainazzo
authors.forename: C
authors.initials: C
authors.lastname: Mioni
authors.forename: G
authors.initials: G
authors.lastname: Ferrazza
authors.forename: A V
authors.initials: AV
authors.lastname: Vergoni
authors.forename: H B
authors.initials: HB
authors.lastname: Schiöth
authors.forename: J E
authors.initials: JE
authors.lastname: Wikberg
authors.forename: A
authors.initials: A
authors.lastname: Bertolini
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001810:Blood Volume / Q000502:physiology; D001923:Brain Chemistry / Q000187:drug effects; D003366:Cosyntropin / Q000494:pharmacology; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000627:therapeutic use*; D010455:Peptides / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000187:drug effects / Q000502:physiology*; D015656:Respiratory Mechanics / Q000187:drug effects; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D010455:Peptides; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D003366:Cosyntropin; D009074:Melanocyte-Stimulating Hormones