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Cited by 98Neuropeptides and Animal PhysiologyCardiovascular, Neuropeptides, and Oxidative Stress ResearchRegulation of Appetite and Obesity

Melanocortins and cardiovascular regulation

Versteeg, Dirk H.G., Van Bergen, Patricia, Adan, Roger A.H., De Wildt, Dick J.·1998·European Journal of Pharmacology
DOI 10.1016/s0014-2999(98)00615-3
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Abstract

The melanocortins form a family of pro-opiomelanocortin-derived peptides that have the melanocyte-stimulating hormone (MSH) core sequence, His-Phe-Arg-Trp, in common. Melanocortins have been described as having a variety of cardiovascular effects. We review here what is known about the sites and mechanisms of action of the melanocortins with respect to their effects on cardiovascular function, with special attention to the effects of the gamma-melanocyte-stimulating hormones (gamma-MSHs). This is done in the context of present knowledge about agonist selectivity and localisation of the five melanocortin receptor subtypes cloned so far. gamma2-MSH, its des-Gly12 analog (= gamma1-MSH) and Lys-gamma2-MSH are 5-10 times more potent than adrenocorticotropic hormone-(4-10)(ACTH-(4-10)) to induce a pressor and tachycardiac effect following intravenous administration. The Arg-Phe sequence near the C-terminal seems to be important for full in vivo intrinsic activity. Related peptides with a C-terminal extension with (gamma3-MSH) or without the Arg-Phe sequence (alpha-MSH, as well as the potent alpha-MSH analog, [Nle4,D-Phe7]alpha-MSH), are, however, devoid of these effects. In contrast, ACTH-(1-24) has a depressor effect combined with a tachycardiac effect, effects which are not dependent on the presence of the adrenals. Although the melanocortin MC3 receptor is the only melanocortin receptor subtype for which gamma2-MSH is selective, in vivo and in vitro structure-activity data indicate that it is not via this receptor that this peptide and related peptides exert either their pressor and tachycardiac effects or their extra- and intracranial blood flow increasing effect. We review evidence that the pressor and tachycardiac effects of the gamma-MSHs are due to an increase of sympathetic outflow to the vasculature and the heart, secondary to activation of centrally located receptors. These receptors are most likely localised in the anteroventral third ventricle (AV3V) region, a brain region situated outside the blood-brain barrier, and to which circulating peptides have access. These receptors might be melanocortin receptors of a subtype yet to be identified. Alternatively, they might be related to other receptors for which peptides with a C-terminal Arg-Phe sequence have affinity, such as the neuropeptide FF receptor and the recently discovered FMRFamide receptor. Melanocortin MC4 receptors and still unidentified receptors are part of the circuitry in the medulla oblongata which is involved in the depressor and bradycardiac effect of the melanocortins, probably via interference with autonomic outflow. Regarding the effects of the gamma-MSHs on cortical cerebral blood flow, it is not yet clear whether they involve activation of the sympathetic nervous system or activation of melanocortin receptors located on the cerebral vasculature. The depressor effect observed following intravenous administration of ACTH-(1-24) is thought to be due to activation of melanocortin MC2 receptors whose location may be within the peripheral vasculature. Melanocortins have been observed to improve cardiovascular function and survival time in experimental hemorrhagic shock in various species. Though ACTH-(1-24) is the most potent melanocortin in this model, alpha-MSH and [Nle4,D-Phe7]alpha-MSH and ACTH-(4-10) are quite effective as well. As ACTH-(4-10) is a rather weak agonist of all melanocortin receptors, it is difficult to determine via which of the melanocortin receptors the melanocortins bring about this effect. Research into the nature of the receptors involved in the various cardiovascular effects of the melanocortins would greatly benefit from the availability of selective melanocortin receptor antagonists.

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  • Microinjections of α-MSH in the nucleus ambiguus exert excitatory effects on parasympathetic preganglionic neurons via activation of MC4R, resulting in increased vagal input to the heart and bradycardia responses.

    “For instance, microinjections of α-MSH in the nucleus ambiguus (nAMB) exerted excitatory effects on parasympathetic preganglionic neurons via activation of MC4R, resulting in increased vagal input to the heart and bradycardia responses [74–76].”

    From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [75]

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Authors
Versteeg, D. H. G., Van Bergen, P., Adan, R. A. H., & De Wildt, D. J.
Affiliations
Utrecht University (NL)
Corresponding author
Versteeg, Dirk H.G.
ORCID
Adan, Roger A.H.
Venue
European Journal of Pharmacology
Publisher
Elsevier BV
Published
1998-10
Volume
360
Issue
1
Pages
1-14
ISSN
0014-2999 (ISSN-L)
DOI
10.1016/s0014-2999(98)00615-3
OpenAlex
W1965504359
Cited by
98
References
100
Citations by year
2026: 1 · 2022: 4 · 2021: 3 · 2018: 1 · 2017: 2 · 2016: 6 · 2015: 2 · 2014: 1 · 2013: 2 · 2012: 4
FWCI
0.67
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • European Journal of Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Keywords
melanocortin peptides, gamma-MSH, cardiovascular regulation, pressor response, tachycardia, MC3 receptor, sympathetic outflow, anteroventral third ventricle, ACTH1-24, structure-activity relationship, blood flow, proopiomelanocortin
MeSH terms
Animals, Cardiovascular Physiological Phenomena, Humans, Melanocyte-Stimulating Hormones, Pro-Opiomelanocortin, Receptors, Corticotropin, Receptors, Melanocortin

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