RT Journal Article
SR Electronic
T1 Melanocortin Antagonists Define Two Distinct Pathways of Cardiovascular Control by α- and γ-Melanocyte-Stimulating Hormones
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 5182
OP 5188
DO 10.1523/JNEUROSCI.16-16-05182.1996
VO 16
IS 16
A1 Si-Jia Li
A1 Károly Varga
A1 Phillip Archer
A1 Victor J. Hruby
A1 Shubh D. Sharma
A1 Robert A. Kesterson
A1 Roger D. Cone
A1 George Kunos
YR 1996
UL http://www.jneurosci.org/content/16/16/5182.abstract
AB 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.