Activation of an efferent cholinergic pathway produces strong protection against myocardial ischemia/reperfusion injury in rats*
Abstract
OBJECTIVE: A vagus nerve-mediated, brain cholinergic protective mechanism activated by melanocortin peptides is operative in conditions of circulatory shock; moreover, there is anatomical evidence of dual vagal-cardiac efferent pathways in rats, which could play different roles in controlling heart function. Therefore, we investigated the role and functional mechanism of such vagal efferent pathway(s) in an experimental model of ischemic heart disease. DESIGN: Randomized experimental study. SETTING: Research laboratory. SUBJECTS: Adult Wistar rats of either sex. INTERVENTIONS: After bilateral cervical vagotomy (with or without pretreatment with atropine), efferent vagal fibers were electrically stimulated in rats subjected to coronary artery occlusion (5 mins) followed by reperfusion (5 mins). Other rats (intact, vagotomized, or pretreated with atropine) were treated with nanomolar doses of melanocortin peptides. MEASUREMENTS AND MAIN RESULTS: Electrical stimulation of efferent vagal fibers (5 V, 2 m secs, 1-9 Hz, for the whole period of ischemia/reperfusion) strongly reduced the high incidence of severe arrhythmias and lethality, reduced the increase in free radical blood levels and left-ventricle histologic alterations, and augmented the extracellular signal-regulated kinase activation. Treatment with the melanocortin peptides adrenocorticotropin and gamma2-melanocyte-stimulating hormone (162 nmol/kg intravenously or 16.2 nmol/kg intracerebroventricularly, during coronary occlusion) produced the same protective effects of electrical stimulation and with the same muscarinic acetylcholine receptor-dependent mechanism, seemingly through brain activation (mediated by melanocortin MC3 receptors, as previously described) of such efferent vagal pathway. CONCLUSIONS: The present results give evidence for the identification of a protective, melanocortin-activated, efferent vagal cholinergic pathway, operative in conditions of myocardial ischemia/reperfusion. These data suggest that melanocortins and pertinent compounds able to activate such a pathway could provide the potential for development of a new class of drugs for a novel approach to management of ischemic heart disease.
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Vagus nerve signaling inhibits cytokine activities and improves disease endpoints in experimental models of sepsis, ischemia/reperfusion, hemorrhagic shock, myocardial ischemia, ileus, experimental arthritis, and pancreatitis.
“Subsequent work established that vagus nerve signaling inhibits cytokine activities and improves disease endpoints in experimental models of sepsis, ischemia/reperfusion, hemorrhagic shock, myocardial ischemia, ileus, experimental arthritis, and pancreatitis (17)(18)(19)(20)(21)(22)(23)(24)(25).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [19]
Protection against myocardial damage in the ischemia/reperfusion model is also achieved by ACTH 1-24, which stimulates a signal via the vagus nerve.
“The protection against myocardial damage in this model was also achieved by administration of ACTH 1-24 , which stimulated a signal via the vagus nerve (19).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [19]
Stimulation of the vagus nerve during myocardial ischemia/reperfusion in rats significantly reduces accumulation of free radicals and the incidence of severe arrhythmias and lethality.
“Stimulation of the vagus nerve during myocardial ischemia/reperfusion in rats significantly reduced the accumulation of free radicals and reduced the incidence of severe arrhythmias and lethality (19).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [19]
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- Authors
- Mioni, C., Bazzani, C., Giuliani, D., Altavilla, D., Leone, S., Ferrari, A., Minutoli, L., Bitto, A., Marini, H., Zaffe, D., Botticelli, A. R., Iannone, A., Tomasi, A., Bigiani, A., Bertolini, A., Squadrito, F., & Guarini, S.
- Affiliations
- University of Modena and Reggio Emilia (IT)
- University of Messina (IT)
- ORCID
- Venue
- Critical Care Medicine
- Published
- 2005-11
- Volume
- 33
- Issue
- 11
- Pages
- 2621-2628
- ISSN
- 0090-3493 (ISSN-L)
- OpenAlex
- W2042722007
- Cited by
- 148
- References
- 44
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 5 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 4 · 2018: 1 · 2017: 6 · 2016: 9 · 2015: 13 · 2014: 12 · 2013: 12 · 2012: 16
- FWCI
- 4.01
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2023-03-01)
- Open access
- closed
- Locations
- Critical Care Medicine (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- myocardial ischemia-reperfusion injury, melanocortin peptides, ACTH, vagus nerve stimulation, muscarinic receptors, coronary artery occlusion, cardiac arrhythmias, free radicals, extracellular signal-regulated kinase, ischemic heart disease, neuroprotection
- MeSH terms
- Animals, Cosyntropin, Electric Stimulation, Electron Spin Resonance Spectroscopy, Female, Free Radicals, Male, Vagotomy, Vagus Nerve, Myocardial Reperfusion Injury, Myocardial Ischemia, Rats, Wistar, Rats
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