The melanocortins form a family of pro-opiomelanocortin-derived peptid
es that have the melanocyte-stimulating hormone (MSH) core sequence, H
is-Phe-Arg-Trp, in common. Melanocortins have been described as having
a variety of cardiovascular effects. We review here what is known abo
ut the sites and mechanisms of action of the melanocortins with respec
t to their effects on cardiovascular function, with special attention
to the effects of the gamma-melanocyte-stimulating hormones (gamma-MSH
s). This is done in the context of present knowledge about agonist sel
ectivity and localisation of the five melanocortin receptor subtypes c
loned so far. gamma(2)-MSH, its des-Gly(12) analog (= gamma(1)-MSH) an
d Lys-gamma(2)-MSH are 5-10 times more potent than adrenocorticotropic
hormone-(4-10) (ACTH-(4-10)) to induce a presser and tachycardiac eff
ect following intravenous administration. The Arg-Phe sequence near th
e C-terminal seems to be important for full in vivo intrinsic activity
. Related peptides with a C-terminal extension with (gamma(3)-MSH) or
without the Arg-Phe sequence (alpha-MSH, as well as the potent alpha-M
SH analog, [Nle(4),D-Phe(7)]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 presenc
e of the adrenals. Although the melanocortin MC3 receptor is the only
melanocortin receptor subtype for which gamma(2)-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 thei
r presser and tachycardiac effects or their extra- and intracranial bl
ood flow increasing effect. We review evidence that the presser and ta
chycardiac effects of the gamma-MSHs are due to an increase of sympath
etic outflow to the vasculature and the heart, secondary to activation
of centrally located receptors. These receptors are most likely local
ised in the anteroventral third ventricle (AV3V) region, a brain regio
n situated outside the blood-brain barrier, and to which circulating p
eptides have access. These receptors might be melanocortin receptors o
f a subtype yet to be identified. Alternatively, they might be related
to other receptors for which peptides with a C-terminal Arg-Phe seque
nce have affinity, such as the neuropeptide FF receptor and the recent
ly discovered FMRFamide receptor. Melanocortin MC4 receptors and still
unidentified receptors are part of the circuitry in the medulla oblon
gata which is involved in the depressor and bradycardiac effect of the
melanocortins, probably via interference with autonomic outflow. Rega
rding the effects of the gamma-MSHs on cortical cerebral blood flow, i
t 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 intraven
ous administration of ACTH-(1-24) is thought to be due to activation o
f melanocortin MC2 receptors whose location may be within the peripher
al vasculature. Melanocortins have been observed to improve cardiovasc
ular function and survival time in experimental hemorrhagic shock in v
arious species. Though ACTH-(1-24) is the most potent melanocortin in
this model, alpha-MSH and [Nle(4),D-Phe(7)]alpha-MSH and ACTH-(4 -10)
are quite effective as well. As ACTH-(4-10) is a rather weak agonist o
f all melanocortin receptors, it is difficult to determine via which o
f the melanocortin receptors the melanocortins bring about this effect
. Research into the nature of the receptors involved in the various ca
rdiovascular effects of the melanocortins would greatly benefit from t
he availability of selective melanocortin receptor antagonists. (C) 19
98 Elsevier Science B.V. All rights reserved.