Melanocortin antagonists define two distinct pathways of cardiovascular control by alpha- and gamma-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 urethane-anesthetized rats, unilateral microinjection of alpha-melanocyte-stimulating hormone (MSH) into the medullary dorsal-vagal complex (DVC) causes dose-dependent (125-250 pmol) hypotension and bradycardia, whereas gamma-MSH is less effective. The effects of alpha-MSH are inhibited by microinjection to the same site of the novel MG4-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. Hypotensive and bradycardic responses to electrical stimulation of the arcuate nucleus also are inhibited by ipsilateral intra-DVC microinjection of SHU9119. gamma-MSH and ACTH(4-10), but not alpha-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 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 neurons is mediated by neural melanocortin receptors (MC4-R/MC3-R) located 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 pressor and tachycardic actions of gamma-MSH, which, likely, are mediated by an as yet unidentified receptor.
Li
S J
SJ
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond 23298-0613, USA.
Varga
K
K
Archer
P
P
Hruby
V J
VJ
Sharma
S D
SD
Kesterson
R A
RA
Cone
R D
RD
Kunos
G
G
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D002339:Carotid Arteries; D006339:Heart Rate / Q000187:drug effects; D007269:Injections, Intra-Arterial; D007278:Injections, Spinal; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000502:physiology; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors*; D044101:Receptors, Melanocortin; D014630:Vagus Nerve / Q000502:physiology
D018043:Receptors, Corticotropin; D044101:Receptors, Melanocortin; D009074:Melanocyte-Stimulating Hormones