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Volume 16, Number 16, Issue of August 15, 1996 pp. 5182-5188
Copyright ©1996 Society for Neuroscience

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

Received April 11, 1996; revised May 24, 1996; accepted May 30, 1996.

Si-Jia Li¹, Károly Varga¹, Phillip Archer¹, Victor J. Hruby², Shubh D. Sharma², Robert A. Kesterson³, Roger D. Cone³, and George Kunos¹

¹ Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298-0613, ² Department of Chemistry, University of Arizona, Tucson, Arizona 85721, and ³ Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97210

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

Key words: melanocortin receptors; blood pressure; heart rate; melanocortin antagonists; dorsal-vagal complex; -MSH; -MSH

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