Melanocortin antagonists define two distinct pathways of cardiovascular control by α- and γ-melanocyte-stimulating hormones

Academic Article

Abstract

  • 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 urethane-anesthetized rats, unilateral microinjection of α-melanocyte-stimulating hormone (MSH) into the medullary dorsal-vagal complex (DVC) causes dose-dependent (125-250 pmol) hypotension and bradycardia, whereas γ-MSH is less effective. The effects of α-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 β-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. γ-MSH and ACTH(4-10), but not α-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 γ-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 α-MSH from arcuate neurons is mediated by neural melanocortin receptors (MC4-R/MC3-R) located in the DVC, whereas the similar effects of β-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 γ-MSH, which, likely, are mediated by an as yet unidentified receptor.
  • Digital Object Identifier (doi)

    Author List

  • Li SJ; Varga K; Archer P; Hruby VJ; Sharma SD; Kesterson RA; Cone RD; Kunos G
  • Start Page

  • 5182
  • End Page

  • 5188
  • Volume

  • 16
  • Issue

  • 16