Abstract

Melanocortin peptides are known to be extremely potent in causing the sustained reversal of different shock conditions, both in experimental animals and humans; the mechanism of action includes an essential brain loop. Three melanocortin receptor subtypes are expressed in brain tissue: MC₃, MC_4, and MC₅receptors. In a volume-controlled model of hemorrhagic shock in anesthetized rats, invariably causing the death of control animals within 30 min after saline injection, the i.v. bolus administration of the adrenocorticotropin fragment 1–24 (agonist at MC₄ and MC₅ receptors) at a dose of 160 μg/kg i.v. (54 nmol/kg) produced an almost complete and sustained restoration of cardiovascular and respiratory functions. An equimolar dose of γ₁-melanocyte stimulating hormone (selective agonist at MC₃ receptors) was completely ineffective. The selective antagonist at MC₄ receptors, HS014, although having no influence on cardiovascular and respiratory functions per se, dose-dependently prevented the antishock activity of adrenocorticotropin fragment 1–24, with the effect being complete either at the i.v. dose of 200 μg/kg or at the i.c.v. dose of 5 μg/rat (17–20 μg/kg). We concluded that the effect of melanocortin peptides in hemorrhagic shock is mediated by the MC₄receptors in the brain.