title: Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway.
abstract: OBJECTIVE
  Several melanocortin peptides have a prompt and sustained resuscitating effect in conditions of hemorrhagic shock. The transcription nuclear factor kappaB (NF-kappaB) triggers a potentially lethal systemic inflammatory response, with marked production of tumor necrosis factor-alpha (TNF-alpha), in hemorrhagic shock. Here we investigated whether the hemorrhagic shock reversal produced by the melanocortin ACTH-(1-24) (adrenocorticotropin) depends on the activation of the recently recognized, vagus nerve-mediated, brain "cholinergic anti-inflammatory pathway".
  
  
  RESULTS
  Anesthetized rats were stepwise bled until mean arterial pressure (MAP) stabilized at 20-25 mm Hg. The severe hypovolemia was incompatible with survival, and all saline-treated animals died within 30 min. In rats intravenously (i.v.) treated with ACTH-(1-24), neural efferent activity along vagus nerve (monitored by means of a standard system for extracellular recordings) was markedly increased, and the restoration of cardiovascular and respiratory functions was associated with blunted NF-kappaB activity and with decreased TNF-alpha mRNA liver content and TNF-alpha plasma levels. Bilateral cervical vagotomy, pretreatment with the melanocortin MC(4) receptor antagonist HS014, atropine sulfate or chlorisondamine, but not with atropine methylbromide, prevented the life-saving effect of ACTH-(1-24) and the associated effects on NF-kappaB activity and TNF-alpha levels. HS014 and atropine sulfate prevented, too, the ACTH-(1-24)-induced increase in neural efferent vagal activity, and accelerated the evolution of shock in saline-treated rats.
  
  
  CONCLUSIONS
  The present data show, for the first time, that the melanocortin ACTH-(1-24) suppresses the NF-kappaB-dependent systemic inflammatory response triggered by hemorrhage, and reverses shock condition, by brain activation (in real-time) of the "cholinergic anti-inflammatory pathway", this pathway seeming to be melanocortin-dependent.
authors.affiliation: Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, via G. Campi 287, 41100 Modena, Italy. guarini.salvatore@unimore.it
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guarini
authors.forename: Maria Michela
authors.initials: MM
authors.lastname: Cainazzo
authors.forename: Daniela
authors.initials: D
authors.lastname: Giuliani
authors.forename: Chiara
authors.initials: C
authors.lastname: Mioni
authors.forename: Domenica
authors.initials: D
authors.lastname: Altavilla
authors.forename: Herbert
authors.initials: H
authors.lastname: Marini
authors.forename: Albertino
authors.initials: A
authors.lastname: Bigiani
authors.forename: Valeria
authors.initials: V
authors.lastname: Ghiaroni
authors.forename: Maria
authors.initials: M
authors.lastname: Passaniti
authors.forename: Sheila
authors.initials: S
authors.lastname: Leone
authors.forename: Carla
authors.initials: C
authors.lastname: Bazzani
authors.forename: Achille P
authors.initials: AP
authors.lastname: Caputi
authors.forename: Francesco
authors.initials: F
authors.lastname: Squadrito
authors.forename: Alfio
authors.initials: A
authors.lastname: Bertolini
mesh_terms: D000208:Acute Disease; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002714:Chlorisondamine / Q000627:therapeutic use; D003366:Cosyntropin / Q000627:therapeutic use*; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics; D014630:Vagus Nerve / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D014409:Tumor Necrosis Factor-alpha; D003366:Cosyntropin; D001285:Atropine; D002714:Chlorisondamine