Melanocortin Antagonists Define Two Distinct Pathways of Cardiovascular Control by alpha - and gamma -Melanocyte-Stimulating Hormones

• Published in: The Journal of neuroscience Vol. 16; no. 16; pp. 5182 - 5188
• Main Authors: Li, Si-Jia, Varga, Karoly, Archer, Phillip, Hruby, Victor J, Sharma, Shubh D, Kesterson, Robert A, Cone, Roger D, Kunos, George
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 15.08.1996; Society for Neuroscience
• Subjects: Animals; Blood Pressure - drug effects; Cardiovascular System - drug effects; Carotid Arteries; Heart Rate - drug effects; Injections, Intra-Arterial; Injections, Spinal; Male; Medulla Oblongata - drug effects; Medulla Oblongata - physiology; Melanocyte-Stimulating Hormones - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin - antagonists & inhibitors; Receptors, Melanocortin; Vagus Nerve - physiology
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.16-16-05182.1996

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.