Efferent Vagal Fibre Stimulation Blunts Nuclear Factor-κB Activation and Protects Against Hypovolemic Hemorrhagic Shock
Open accessAbstract
Background— We investigated whether electrical stimulation (STIM) of efferent vagus nerves may suppress nuclear factor (NF)-κB activation and the inflammatory cascade in hemorrhagic (Hem) shock. Methods and Results— Rats were subjected to bilateral cervical vagotomy (VGX) or sham surgical procedures. Hem shock was induced by intermittent withdrawing of blood until mean arterial pressure stabilized within the range of 35 to 40 mm Hg. Application of constant voltage pulses to the caudal vagus ends (STIM; 5 V, 2 ms, 1 Hz for 12 minutes, 5 minutes after mean arterial pressure stabilization) increased survival time (VGX+Hem+Sham STIM=38±3 minutes; VGX+Hem+STIM >180 minutes), reverted the marked hypotension (VGX+Hem+Sham STIM=33±3 mm Hg; VGX+Hem+STIM=66±5 mm Hg), inhibited IκBα liver loss, and blunted the augmented NF-κB activity, decreased hepatic tumor necrosis factor (TNF)-α mRNA (VGX+Hem+Sham STIM=1.42±0.5 amount of TNF-α m-RNA; VGX+Hem+STIM=0.51±0.2 amount of TNF-α mRNA), and reduced plasma TNF-α (VGX+Hem+Sham STIM=190±24 pg/mL; VGX+Hem+STIM=87±15 pg/mL). Chlorisondamine, a nicotinic receptor antagonist, abated the effects of vagal stimulation. Conclusions— Our results show a parasympathetic inhibition of NF-κB by which the brain opposes NF-κB activation in the liver and modulates the inflammatory response during acute hypovolemic hemorrhagic shock.
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Vagus nerve control of cytokine damage in hemorrhagic shock is attributable to cholinergic signals transduced intracellularly via nicotinic receptors.
“The protective effects of vagus nerve stimulation in this model were reversed by administration of a nicotine receptor antagonist (chlorisondamine), indicating that vagus nerve control of cytokine damage is attributable to cholinergic signals transduced intracellularly via nicotinic receptors (21).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [21]
Vagus nerve stimulation of rats during lethal hemorrhagic shock confers protection against hypotension, prolonged survival, and decreased TNF production.
“Vagus nerve stimulation of rats during lethal hemorrhagic shock conferred significant protection against the development of hypotension, prolonged survival, and decreased TNF production (21).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [21]
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“For example, direct electrical stimulation of the efferent vagus nerve inhibits the synthesis of TNF- in multiple organs, decreases circulating levels of TNF- , and attenuates serum TNF- levels during endotoxemia and other diseases associated with excessive cytokine release (1,12).”
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“Previous studies have shown that vagus nerve stimulation, which releases acetylcholine, and administration of cholinergic agonists, including nicotine and GTS-21, reduce cytokine production in preclinical models of acute, systemic inflammation, including endotoxemia, hemorrhagic shock, ischemia-reperfusion injury, and…”
BackgroundMuscularis macrophages: Key players in intestinal homeostasis and disease
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“Pretreatment with the irreversible nicotinic acetylcholine receptor antagonist chlorisondamine (16) did not modify survival in SAOshocked rats but prevented the protective effect of vagal stimulation on survival rate and time (74 T 5 min; Table 1).”
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- Authors
- Guarini, S., Altavilla, D., Cainazzo, M.-M., Giuliani, D., Bigiani, A., Marini, H., Squadrito, G., Minutoli, L., Bertolini, A., Marini, R., Adamo, E. B., Venuti, F. S., & Squadrito, F.
- Affiliations
- University of Modena and Reggio Emilia (IT)
- ORCID
- Venue
- Circulation
- Published
- 2003-03-04
- Volume
- 107
- Issue
- 8
- Pages
- 1189-1194
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- OpenAlex
- W2098655301
- Semantic Scholar
- 919d8a5ae0075ccd6d7dd152a6fe9773763923b4
- Cited by
- 315
- References
- 24
- Citations by year
- 2026: 2 · 2025: 10 · 2024: 9 · 2023: 8 · 2022: 14 · 2021: 13 · 2020: 18 · 2019: 12 · 2018: 10 · 2017: 15 · 2016: 10 · 2015: 18 · 2014: 22 · 2013: 16 · 2012: 21
- FWCI
- 6.64
- Type
- journal article
- Language
- en
- Update notices
- expression_of_concern (2022-08-23)
- Open access
- green
- hdl.handle.net
- Licence
- cc-by
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- Funders
- Consiglio Nazionale delle Ricerche
- Università degli Studi di Messina
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Trauma, Hemostasis, Coagulopathy, Resuscitation
- Keywords
- vagus nerve stimulation, NF-κB activation, inflammation, TNF-α, parasympathetic nervous system, vagotomy, nicotinic acetylcholine receptors, liver inflammation
- MeSH terms
- NF-KappaB Inhibitor alpha, Animals, Blood Pressure, Efferent Pathways, Electric Stimulation, Inflammation, Liver, Male, Nerve Fibers, RNA, Messenger, Shock, Hemorrhagic, Tumor Necrosis Factor-alpha, Vagus Nerve, Survival Analysis, NF-kappa B, Rats, Wistar, I-kappa B Proteins, Hypovolemia, Rats
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