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Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway
Open accessAbstract
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". METHODS AND 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.
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“Another approach to stimulating efferent activity in the cholinergic antiinflammatory pathway in this model is by administration of adrenocorticotropic hormone (ACTH 1-24 ), which significantly increased vagus nerve activity in rats.”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [40]
In the citing paper
“Bilateral vagotomy ablated the protective effects of ACTH 1-24 in hemorrhagic shock, providing evidence that ACTH 1-24 activates proximal neural networks that increase efferent activity in the cholinergic antiinflammatory pathway to suppress cytokine-mediated damage (40).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [40]
In the citing paper
“In addition, previous studies also showed that hemorrhagic shock reversal is mediated via CNS POMC-MC4Rs and may involve activation of efferent vagal cholinergic pathways [74].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [74]
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“In addition, previous studies also showed that hemorrhagic shock reversal is mediated via CNS POMC-MC4Rs and may involve activation of efferent vagal cholinergic pathways [74].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [74]
In the citing paper
“For instance, microinjections of α-MSH in the nucleus ambiguus (nAMB) exerted excitatory effects on parasympathetic preganglionic neurons via activation of MC4R, resulting in increased vagal input to the heart and bradycardia responses [74–76].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [74]
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Metadata
- Authors
- GUARINI, S.
- Affiliations
- University of Modena and Reggio Emilia (IT)
- Corresponding author
- GUARINI, S
- ORCID
- GUARINI, S
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2004-08
- Volume
- 63
- Issue
- 2
- Pages
- 357-365
- ISSN
- 0008-6363 (ISSN-L)
- OpenAlex
- W2122677936
- Cited by
- 131
- References
- 42
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 6 · 2017: 7 · 2016: 4 · 2015: 9 · 2014: 7 · 2013: 7 · 2012: 12
- FWCI
- 5.01
- Type
- journal article
- Language
- en
- Update notices
- expression_of_concern (2023-03-01)
- Open access
- bronze
- doi.org
- Locations
- Cardiovascular Research (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Trauma, Hemostasis, Coagulopathy, Resuscitation
- Keywords
- ACTH, ACTH1-24, hemorrhagic shock, cholinergic anti-inflammatory pathway, vagus nerve, NF-κB, TNF-α, systemic inflammatory response, vagotomy, hypovolemia, resuscitation
- MeSH terms
- Acute Disease, Animals, Atropine, Chlorisondamine, Cosyntropin, Female, Liver, Male, Receptors, Nicotinic, RNA, Messenger, Shock, Hemorrhagic, Tumor Necrosis Factor-alpha, Vagus Nerve, NF-kappa B, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, I-kappa B Proteins, Electrophoretic Mobility Shift Assay, Rats
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