Tumour necrosis factor‐α as a target of melanocortins in haemorrhagic shock, in the anaesthetized rat

The cytokine tumour necrosis factor‐α (TNF‐α) is involved (mostly through the activation of inducible nitric oxide synthase) in the pathogenesis of circulatory shock. On the other hand, melanocortin peptides are potent and effective in reversing haemorrhagic shock, both in animals (rat, dog) and in...

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Published in:British journal of pharmacology 1998-08, Vol.124 (8), p.1587-1590
Main Authors: Altavilla, Domenica, Cainazzo, Maria‐Michela, Squadrito, Francesco, Guarini, Salvatore, Bertolini, Alfio, Bazzani, Carla
Format: Article
Language:English
Subjects:
Adrenocorticotropin
Anesthesia
Animals
Biological and medical sciences
Blood and lymphatic vessels
Blood Pressure - drug effects
Cardiology. Vascular system
Cosyntropin - pharmacology
Depression, Chemical
Dose-Response Relationship, Drug
Female
haemorrhagic shock
Heart Rate - drug effects
macrophages
Male
Medical sciences
Miscellaneous
rat
Rats
Rats, Wistar
Respiratory Mechanics - drug effects
Shock, Hemorrhagic - metabolism
Shock, Hemorrhagic - physiopathology
Special Report
Tumor Necrosis Factor-alpha - biosynthesis
tumour necrosis factor‐α
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Summary:The cytokine tumour necrosis factor‐α (TNF‐α) is involved (mostly through the activation of inducible nitric oxide synthase) in the pathogenesis of circulatory shock. On the other hand, melanocortin peptides are potent and effective in reversing haemorrhagic shock, both in animals (rat, dog) and in humans. This prompted us to study the influence of the melanocortin peptide ACTH‐(1–24) on the blood levels of TNF‐α in haemorrhage‐shocked rats and on the in vitro production of TNF‐α by lipopolysaccharide (LPS)‐activated macrophages. Plasma levels of TNF‐α were undetectable before starting bleeding and greatly increased 20 min after bleeding termination in saline‐treated rats. In rats treated with ACTH‐(1–24) the almost complete restoration of cardiovascular function was associated with markedly reduced levels of TNF‐α 20 min after bleeding termination. On the other hand, ACTH‐(1–24) did not influence TNF‐α plasma levels in sham‐operated, unbled rats. In vitro, ACTH‐(1–24) (25–100 nM) dose‐dependently reduced the LPS‐stimulated production of TNF‐α by peritoneal macrophages harvested from untreated, unbled rats. These results indicate that inhibition of TNF‐α overproduction may be an important component of the mechanism of action of melanocortins in reversing haemorrhagic shock. British Journal of Pharmacology (1998) 124, 1587–1590; doi:10.1038/sj.bjp.0702038
ISSN:0007-1188
1476-5381
DOI:10.1038/sj.bjp.0702038