MELANOCORTIN ANTAGONISTS DEFINE 2 DISTINCT PATHWAYS OF CARDIOVASCULARCONTROL BY ALPHA-MELANOCYTE-STIMULATING AND GAMMA-MELANOCYTE-STIMULATING HORMONES

Melanocortin peptides and at least two subtypes of melanocortin recept ors (MC3-R and MC4-R) are present in brain regions involved in cardiov ascular regulation. In urethane-anesthetized rats, unilateral microinj ection of alpha-melanocyte-stimulating hormone (MSH) into the medullar y dorsal-vagal complex (DVC) causes dose-dependent (125-250 pmol) hypo tension and bradycardia, whereas gamma-MSH is less effective. The effe cts of alpha-MSH are inhibited by microinjection to the same site of t he novel MC4-R/MC3-R antagonist SHU9119 (2-100 pmol) but not naloxone (270 pmol), whereas the similar effects of intra-DVC injection of beta -endorphin (1 pmol) are inhibited by naloxone and not by SHU9119. Hypo tensive and bradycardic responses to electrical stimulation of the arc uate nucleus also are inhibited by ipsilateral intra-DVC microinjectio n of SHU9119. gamma-MSH and ACTH(4-10), but not alpha-MSH, elicit dose -dependent (0.1-12.5 nmol) presser and tachycardic effects, which are much more pronounced after intracarotid than after intravenous adminis tration. The effects of gamma-MSH (1.25 nmol) are not inhibited by the intracarotid injection of SHU9119 (1.25-12.5 nmol) or the novel MC3-R antagonist SHU9005 (1.25-12.5 nmol). We conclude that the hypotension and bradycardia elicited by the release of alpha-MSH from arcuate neu rons is mediated by neural melanocortin receptors (MC4-R/MC3-R) locate d in the DVC, whereas the similar effects of beta-endorphin, a peptide derived from the same precursor, are mediated by opiate receptors at the same site. In contrast, neither MC3-R nor MC4-R is involved in the centrally mediated presser and tachycardic actions of gamma-MSH, whic h, likely, are mediated by an as yet unidentified receptor.