Tumour necrosis factor-alpha as a target of melanocortins in haemorrhagic shock, in the anaesthetized rat

The cytokine tumour necrosis factor-a (TNF-a) 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 e ective 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-a in haemorrhage-shocked rats and on the in vitro production of TNF-a by lipopolysaccharide (LPS)-activated macrophages. Plasma levels of TNF-a 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-a 20 min after bleeding termination. On the other hand, ACTH-(1 ± 24) did not influence TNF-a plasma levels in sham-operated, unbled rats. In vitro, ACTH-(1 ± 24) (25 ± 100 nM) dose- dependently reduced the LPS-stimulated production of TNF-a by peritoneal macrophages harvested from untreated, unbled rats. These results indicate that inhibition of TNF-a overproduction may be an important component of the mechanism of action of melanocortins in reversing haemorrhagic shock.