Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway

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 h...

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Bibliographic Details
Published in:Cardiovascular research 2004-08, Vol.63 (2), p.357-365
Main Authors: GUARINI, Salvatore, CAINAZZO, Maria Michela, BAZZANI, Carla, CAPUTI, Achille P, SQUADRITO, Francesco, BERTOLINI, Alfio, GIULIANI, Daniela, MIONI, Chiara, ALTAVILLA, Domenica, MARINI, Herbert, BIGIANI, Albertino, GHIARONI, Valeria, PASSANITI, Maria, LEONE, Sheila
Format: Article
Language:English
Subjects:
Acute Disease
Animals
Atropine - pharmacology
Biological and medical sciences
Cardiology. Vascular system
Chlorisondamine - therapeutic use
Cosyntropin - therapeutic use
Electrophoretic Mobility Shift Assay
Female
I-kappa B Proteins - metabolism
Liver - metabolism
Male
Medical sciences
NF-kappa B - metabolism
Rats
Rats, Wistar
Receptors, Nicotinic - drug effects
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - metabolism
Shock, Hemorrhagic - drug therapy
Shock, Hemorrhagic - physiopathology
Tumor Necrosis Factor-alpha - analysis
Tumor Necrosis Factor-alpha - genetics
Vagus Nerve - drug effects
Vagus Nerve - physiopathology
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Summary: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". 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. 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.
ISSN:0008-6363
1755-3245
DOI:10.1016/j.cardiores.2004.03.029