© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway
aDepartment of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, via G. Campi 287, 41100 Modena, Italy
bDepartment of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Gazzi, 98125 Messina, Italy
cDepartment of Biomedical Sciences, Section of Physiology, University of Modena and Reggio Emilia, 41100 Modena, Italy
dDepartment of Medicines and Medical Specialties, University of Modena and Reggio Emilia, 41100 Modena, Italy
* Corresponding author: Tel.: +39-59-2055371; fax +39-59-2055376. Email address: guarini.salvatore{at}unimore.it
Objective: Several melanocortin peptides have a prompt and sustained resuscitating effect in conditions of hemorrhagic shock. The transcription nuclear factor kB (NF-kB) triggers a potentially lethal systemic inflammatory response, with marked production of tumor necrosis factor-
(TNF-), 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". Methods and results: Anesthetized rats were stepwise bled until mean arterial pressure (MAP) atabilized 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-kB activity and with decreased TNF- mRNA liver content and TNF- plasma levels. Bilateral cervical vagotomy, pretreatment with the melanocortin MC4 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-kB activity and TNF- 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-kB-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.
KEYWORDS Adrenocorticotropin; Acute hemorrhagic shock; Vagus nerve
Time for primary review 37 days
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