Melanocortin Antagonists Define Two Distinct Pathways of Cardiovascular Control by a- and g-Melanocyte-Stimulating Hormones

Melanocortin peptides and at least two subtypes of melanocortin receptors (MC3-R and MC4-R) are present in brain regions involved in cardiovascular regulation. In urethaneanesthetized rats, unilateral microinjection of a-melanocytestimulating hormone (MSH) into the medullary dorsal–vagal complex (DVC) causes dose-dependent (125–250 pmol) hypotension and bradycardia, whereas g-MSH is less effective. The effects of a-MSH are inhibited by microinjection to the same site of the novel MC4-R/MC3-R antagonist SHU9119 (2–100 pmol) but not naloxone (270 pmol), whereas the similar effects of intra-DVC injection of b-endorphin (1 pmol) are inhibited by naloxone and not by SHU9119. Hypotensive and bradycardic responses to electrical stimulation of the arcuate nucleus also are inhibited by ipsilateral intra-DVC microinjection of SHU9119. g-MSH and ACTH(4–10), but not a-MSH, elicit dose-dependent (0.1–12.5 nmol) pressor and tachycardic effects, which are much more pronounced after intracarotid than after intravenous administration. The effects of g-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 a-MSH from arcuate neurons is mediated by neural melanocortin receptors (MC4-R/MC3-R) located in the DVC, whereas the similar effects of b-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 pressor and tachycardic actions of g-MSH, which, likely, are mediated by an as yet unidentified receptor.