Evidence that melanocortin 4 receptor mediates hemorrhagic shock reversal caused by melanocortin peptides

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, MC4, and MC5 receptors. 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 mu g/kg i.v. (54 nmol/kg) produced an almost complete and sustained restoration of cardiovascular and respiratory functions. An equimolar dose of gamma(1)-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 mg/kg or at the i.c.v. dose of 5 mg/rat (17-20 mg/kg). We concluded that the effect of melanocortin peptides in hemorrhagic shock is mediated by the MC4 receptors in the brain.