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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
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
 ABSTRACT
- INTRODUCTION
- MATERIALS AND METHODS
- RESULTS
- DISCUSSION
- FOOTNOTES
- REFERENCES
ABSTRACT 
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
INTRODUCTION
The melanocortins, melanocyte-stimulating hormone
(MSH) and adrenocorticotropic hormone (ACTH) derived from the common
precursor pro-opiomelanocortin (POMC), affect skin pigmentation and
stimulate the adrenal cortex via the MSH receptor (MC1-R) expressed in
melanocytes and the ACTH receptor (MC2-R) expressed in the adrenal
cortex, respectively (Mountjoy et al., 1992 ). In addition to
blood-borne ACTH and MSH produced in the pituitary, melanocortin
peptides also are expressed in the brain, in the hypothalamic arcuate
nucleus (Jacobowitz and O'Donohue, 1978; Bloom et al., 1980; Osamura
et al., 1982; Umegaki et al., 1983), and in the dorsal medullary
nucleus of the solitary tract (``nucleus tractus solitarii,'' NTS;
Kawai et al., 1984; Yamazoe et al., 1984; Joseph et al., 1985).
However, the physiological role of melanocortins in the brain is not
well understood. The well documented behavioral effects of
melanocortins (Wiegant et al., 1979; De Wied and Jolles, 1982) have
long suggested the existence of additional receptor sites in the brain.
Indeed, three additional melanocortin receptors recently have been
cloned, two of which are expressed primarily in the brain: the MC4-R
(Gantz et al., 1993), which is widely distributed in the brain and has
high affinity for -MSH and low affinity for -MSH (Mountjoy et
al., 1994), and the MC3-R, which is limited to the arcuate nucleus and
some of its projection fields and has high affinity for both -MSH
and -MSH (Roselli-Rehfuss et al., 1993). The highest concentration
of MC4-R mRNA is found in the medullary dorsal-vagal complex (DVC), an
area that includes the dorsal motor nucleus of the vagus and the NTS,
which suggests that MC4-R may be involved in central cardiovascular
control (Mountjoy et al., 1994).
The DVC is the site of the first synapse of the baroreceptor reflex,
and it is also the termination point of POMC-containing neurons
descending from the arcuate nucleus (Palkovits and Eskay, 1987; Sim and
Joseph, 1991). Earlier studies have established that activation of
POMC-containing neurons in the arcuate nucleus causes hypotension and
bradycardia via the release of -endorphin and subsequent activation
of opiate receptors in the medullary DVC (Mosqueda-Garcia et al., 1986;
Mastrianni et al., 1989) and that this pathway may be involved in the
action of certain centrally acting antihypertensive agents (Kunos et
al., 1981; Van Giersbergen et al., 1989; Li et al., 1996). The
hypotension and bradycardia elicited by electrical stimulation of the
arcuate nucleus were eliminated by ipsilateral deafferentation of the
DVC but were inhibited only partially by intra-DVC microinjection of
naloxone or a -endorphin antiserum (Mastrianni et al., 1989). These
findings suggest that -endorphin may be responsible for only part of
these effects and that additional nonopiate mechanisms also are
involved. Here we present evidence that -MSH and -endorphin, both
derived from POMC, cause similar hypotensive and bradycardic effects in
the DVC by interacting with distinct melanocortin and opiate receptors,
respectively, and that both types of receptor can be activated neurally
from the arcuate nucleus. We further show that the centrally mediated
pressor and tachycardic effects of -MSH do not seem to involve the
MC3-R or the MC4-R.
MATERIALS AND METHODS
Adult male Sprague-Dawley rats (300-350 gm) were anesthetized
with urethane, 0.7 gm/kg intravenously plus 0.3 gm/kg
intraperitoneally. Urethane administered according to this protocol was
found to produce stable and long-lasting anesthesia without causing
hypotension or interfering with cardiovascular reflexes (Maggi and
Meli, 1986). Drugs were injected via cannulae in the saphenous vein and
the carotid artery, as indicated. Phasic and mean arterial blood
pressure and heart rate were monitored via a cannula in the femoral
artery connected to a pressure transducer and physiograph (Astro-Med,
West Warwick, RI). Heart rate was derived by a tachograph preamplifier
driven by the pressure wave. For intra-DVC microinjections, the head of
the animal was fixed in a stereotaxic frame, the dorsal surface of the
medulla was exposed by limited craniotomy, and a glass microcannula was
inserted into the NTS by using the coordinates 0.0 mm
(anterior/posterior), +0.5 mm (medial/lateral), and  0.4 mm
(dorsal/ventral) with the obex as reference (Mastrianni et al., 1989).
Proper positioning of the microcannula was verified by dye injection
and postmortem microscopy and by the hypotensive and bradycardic
effects of a test dose of 1 nmol of glutamate. Unilateral insertion of
a bipolar, concentric, stainless steel microelectrode into the arcuate
nucleus and electrical stimulation were done as described (Mastrianni
et al., 1989).
Drugs were dissolved in saline [-MSH, -MSH, and ACTH(4-10)] or
0.5% methanol in saline (SHU9119) and microinjected in a volume of 50 nl. Microinjection of vehicle had no effect on blood pressure or heart
rate. 2-MSH, acetylated -MSH, and
ACTH(4-10) were obtained from Bachem California (Torrence, CA);
-endorphin was obtained from Sigma (St. Louis, MO). SHU9119
(Ac-Nle4-c[Asp5,D-Nal(2)7,Lys10]-MSH-(4-10)-NH2)
and SHU9005
(Ac-[Nle4,D-Phe(pI)7,Lys10]-MSH-(1-13)-NH2)
were synthesized by one of us (S.D.S.). Other drugs were from usual
commercial sources.
Time-dependent changes in blood pressure and heart rate in response to
an agonist in the absence or presence of an antagonist were compared by
two-way ANOVA followed by Tukey's post hoc test. For comparing the
peak response to stimulation in the absence or presence of an
antagonist in the same animal, the paired t test was used.
Differences with a p < 0.05 were considered
statistically significant.
RESULTS
Depressor and bradycardic effects of -MSH in the DVC
In urethane-anesthetized rats, unilateral intra-DVC injections of
-MSH (125-250 pmol/50 nl) caused dose-dependent decreases in mean
arterial pressure and heart rate (Table
1), which peaked within 5-10 min (Fig.
1). The effects were long-lasting, with a return to
baseline values in 60-80 min for the highest dose tested. Intra-DVC
microinjections of -MSH in the same doses caused no significant
change in blood pressure and a reduction in heart rate smaller than
that seen after -MSH (Table 1). In separate animals, the effect of
250 pmol of -MSH microinjected into the DVC was tested 10 min after
the similar microinjection of 270 pmol of l-naloxone into
the same site (Fig. 1B). This dose of l-naloxone
was found, in an earlier study, to cause near-maximal inhibition of the
effects of -endorphin microinjected into the DVC of anesthetized
rats (Mosqueda-Garcia and Kunos, 1987). l-Naloxone did not
modify the effects of -MSH, indicating the lack of opiate receptor
involvement.
Fig. 1.
-MSH-induced hypotension and bradycardia are
inhibited by SHU9119 but not by naloxone. -MSH (250 pmol/50 nl) was
microinjected unilaterally into the DVC of urethane-anesthetized
control rats (filled circles) or rats that
had received 10 pmol of SHU9119 (A) or 270 pmol of
l-naloxone (B) microinjected into the same site
10 min before -MSH (filled squares).
Vertical bars, SE. There were 5-7 animals in each of
the four different treatment groups. *, Significant difference
(p < 0.05) from corresponding control
value.
[View Larger Version of this Image (21K GIF file)]
In yet another group of rats, the effects of 250 pmol of -MSH were
tested after the intra-DVC microinjection of 10 pmol of the compound
SHU9119. In a recent study using cells transfected with various cloned
melanocortin receptors (Hruby et al., 1995), SHU9119 was found to be a
highly potent competitive antagonist of human MC4-R
(pA2, 9.3) with minimal agonist activity, a
somewhat less potent antagonist of human MC3-R
(pA2, 8.3) with partial agonist activity, and a
full agonist at the human MC1-R and the mouse MC5-R. In cells
transfected with the rat MC3-R, SHU9119 had a pA2
of 8.5 and an activity profile similar to that in human MC3-R (R. A. Kesterson and R. D. Cone, unpublished data). Intra-DVC microinjection
of 10 pmol of SHU9119 alone did not influence basal blood pressure and
heart rate (2.6 ± 1.0 mmHg and 3 ± 8 beats/min), but it
markedly reduced the effects of subsequently microinjected -MSH
(Fig. 1A). When in two experiments SHU9119 was used
at a 10 times higher dose (100 pmol), it completely blocked the effects
of 250 pmol of -MSH microinjected into the same site (peak response
to -MSH, 1 and 5 mmHg and 5 and +5 beats/min), whereas in two
other experiments a lower dose of SHU9119 (2 pmol) reduced the maximal
hypotensive response to -MSH by only 25% (12 and 18 mmHg) and
the bradycardia by 10% (30 and 43 beats/min).
In agreement with published observations (Petty and De Jong, 1982;
Mosqueda-Garcia and Kunos, 1987; Li et al., 1996), unilateral
microinjection of 1 pmol of -endorphin into the DVC also caused
long-lasting hypotension and bradycardia (Fig. 2).
Interestingly, the hypotensive response to -endorphin developed
slower than the similar effect of -MSH, reaching its peak only after
30-40 min, and recovery to baseline values took 90-120 min. In
contrast to the effects of -MSH, the responses to -endorphin were
not affected significantly by 10 pmol of SHU9119 (Fig. 2B)
but were blocked completely by 270 pmol of l-naloxone (Fig.
2A).
Fig. 2.
-Endorphin-induced hypotension and bradycardia
are inhibited by naloxone but not by SHU9119. -Endorphin (1 pmol/50
nl) was microinjected unilaterally into the DVC in control rats
(filled circles) or in rats pretreated with
270 pmol of l-naloxone (A) or 10 pmol of SHU9119
(B) microinjected into the same site 10 min before
-endorphin (filled squares). Vertical
bars, SE. Each treatment group contained 5-6 animals. *,
Significant difference (p < 0.05) from the
corresponding control value.
[View Larger Version of this Image (22K GIF file)]
Arcuate neurons projecting to the DVC contain both -endorphin and
-MSH (Palkovits et al., 1987). In earlier experiments, the
hypotensive and bradycardic responses elicited by electrical
stimulation of the arcuate nucleus were partially inhibited by
microinjection of naloxone or a -endorphin antiserum into the
ipsilateral DVC (Mastrianni et al., 1989). We tested the effects of
electrical stimulation of the arcuate nucleus before and after the
bilateral intra-DVC microinjection of 10 pmol of SHU9119. As
illustrated in Figure 3, electrical stimulation of the
arcuate nucleus caused a biphasic, depressor/pressor response and
prolonged bradycardia. SHU9119 caused a small but significant reduction
in the hypotension and a more pronounced inhibition of the bradycardia
elicited by electrical stimulation of the arcuate nucleus. In four
experiments, the stimulation-induced maximal decreases of blood
pressure and heart rate were 19 ± 4 mmHg and 25 ± 7 beats/min before and 13 ± 3 mmHg (p < 0.05)
and 9 ± 3 beats/min (p < 0.01) after the
bilateral intra-DVC microinjection of 10 pmol of SHU9119. The secondary
rise in blood pressure that followed the stimulation was similar to
that reported earlier by our own (Mastrianni et al., 1989) and another
laboratory (Brody et al., 1986) and was not affected significantly by
SHU9119. This latter effect has been attributed to vasopressin released
via activation of an arcuate/paraventricular nucleus/posterior
pituitary pathway (Brody et al., 1986; Mastrianni et al., 1989). The
depressor and bradycardic components and their inhibition by SHU9119
are interpreted to indicate that activation of arcuate neurons
projecting to the ipsilateral DVC releases not only -endorphin
(Mastrianni et al., 1989) but also -MSH and that both peptides
contribute to the observed hypotensive and bradycardic effects by
acting via distinct opiate and melanocortin receptors,
respectively.
Fig. 3.
SHU9119 inhibits the hypotensive and bradycardic
responses to electrical stimulation of the arcuate nucleus. The arcuate
nucleus was stimulated unilaterally in a urethane-anesthetized rat via
a stainless steel microelectrode at 100 µA, 0.8 msec, 80 Hz for 15 sec (horizontal lines) before (A) and 10 min after (B) the bilateral microinjection of 100 pmol of
SHU9119 into the DVC. Phasic blood pressure (top), heart
rate (middle), and mean arterial pressure
(bottom) are shown. This experiment was replicated in three
more animals with similar results (see Results).
[View Larger Version of this Image (37K GIF file)]
Centrally mediated pressor and tachycardic effects of -MSH
In urethane-anesthetized rats, intravenous injection of 1.25 nmol
of -MSH had no effect on blood pressure or heart rate, whereas 12.5 nmol of -MSH caused a modest pressor response (Fig.
4). However, when injected into the carotid artery, a
dose of 1.25 nmol of -MSH elicited a marked pressor effect (44 ± 3 mmHg) and tachycardia (+25 ± 3 beats/min), and doses as low
as 0.125 nmol caused similar but smaller effects (Fig. 4) that lasted
2-3 min. Similar but smaller pressor and tachycardic effects were
observed after the intracarotid injections of ACTH(4-10), a peptide
with very low affinity for MC3-R or MC4-R (Adan et al., 1994), whereas
intracarotid injections of -MSH in doses up to 12.5 nmol caused no
change in blood pressure or heart rate (Fig. 4). The effects of 1.25 nmol of -MSH remained unchanged when retested after the intracarotid
injection of 1.25 nmol of SHU9119 (+46 ± 3 mmHg, +29 ± 7 beats/min; n = 5) or 1.25 nmol of SHU9005 (+37 ± 4 mmHg, +18 ± 4 beats/min; n = 5), the
antagonists alone causing no change in blood pressure or heart rate. A
10 times higher dose of the antagonists similarly failed to inhibit
significantly the effects of -MSH; the pressor and tachycardic
response to 1.25 nmol of -MSH were +55 versus +50 mmHg and +20
versus +25 beats/min before versus after 12.5 nmol of SHU9119
(n = 2). The corresponding values before and after 12.5 nmol of SHU9005 were +43 ± 7 versus +38 ± 8 mmHg and
+35 ± 12 versus +27 ± 13 beats/min, respectively (mean ± SE; n = 3). SHU9005 is a novel, potent antagonist of
the cloned, transfected rat MC3-R (pA2, 8.6) and
a full agonist at the cloned human MC4-R (EC50, 4.7 × 10 10 M; Kesterson and Cone, unpublished
observations). In agreement with published findings (Callahan et al.,
1985), the 1-adrenergic receptor antagonist
prazosin, 0.1 mg/kg intravenously, inhibited the pressor response,
whereas the -blocker propranolol, 1 mg/kg intravenously, inhibited
the tachycardia elicited by -MSH (data not shown).
Fig. 4.
The effects of intracarotid injections of -MSH,
ACTH(4-10), and -MSH and of intravenous injection of -MSH on
mean arterial blood pressure and heart rate in urethane-anesthetized
rats. Mean ± SE from 4-5 experiments is
shown.
[View Larger Version of this Image (16K GIF file)]
DISCUSSION
The present findings demonstrate that -MSH can cause
hypotension and bradycardia by interacting with distinct melanocortin
receptors in the medullary NTS. Of the three melanocortin receptors
expressed in the brain, the involvement of MC5-R is unlikely, as the
level of the mRNA for this receptor is extremely low in the rat brain
(Griffon et al., 1994), and SHU9119 is a highly potent full agonist at
the MC5-R (Hruby et al., 1995), yet it produced no change in
cardiovascular parameters when microinjected into the DVC. Of the other
two neural melanocortin receptors, MC4-R has lower affinity for -MSH
than for -MSH (Mountjoy et al., 1994), whereas the two peptides are
equieffective at the MC3-R (Roselli-Rehfuss et al., 1993). Thus, the
greater hypotensive and bradycardic potency of - versus -MSH and
the ability of a very low dose of SHU9119 to inhibit these effects
would favor the involvement of MC4-R over MC3-R. However, because of
the limited selectivity of SHU9119 for these two receptors, we cannot
exclude the additional involvement of MC3-R, which also could account
for the more pronounced bradycardic action of -MSH, as reported in
one recent study (De Wildt et al., 1994). In situ
hybridization studies in the rat brain indicate that the DVC represents
the area with the highest concentrations of MC4-R mRNA (Mountjoy et
al., 1994), whereas MC3-R mRNA is absent from the DVC (Roselli-Rehfuss
et al., 1993). However, this does not exclude the possibility that the
very high levels of melanocortin receptors detected in the DVC by
receptor autoradiography (Tatro and Entwistle, 1993) also include MC3-R
present on terminal projections of neurons located elsewhere in the
brain. Therefore, what one can confidently conclude from these findings
is that the cardiovascular depressor effects of melanotropins are
mediated by MC4-R in the DVC with the possible additional involvement
of MC3-R, and the role of opiate receptors in these effects definitely
can be excluded (Fig. 2B).
The finding that SHU9119 also inhibited the hypotensive and bradycardic
response to electrical stimulation of the arcuate nucleus (Fig. 3)
further suggests that MC4-R/MC3-R in the DVC can be activated neurally
by -MSH found at high concentrations in the NTS region (Jacobowitz
and O'Donohue, 1978; Palkovits et al., 1987). This possibility may
seem at odds with the much greater potency of -endorphin as compared
with -MSH, as seen in Figures 1 and 2. However, there is evidence
for preferential processing of POMC into -MSH in the hypothalamus
with -MSH/-endorphin ratios of 4:1 to 15:1 (Mezey et al., 1985).
Furthermore, these ratios tend to increase further from perikarya to
regions containing axonal projections (Mezey at al., 1985), compatible
with the proposal of additional processing during axonal transport
(Barnea et al., 1981). Thus, the lower potency of -MSH may be
compensated by its greater abundance at the sites of release. Also, the
hypotensive response to -endorphin develops much slower than that of
-MSH (see Figs. 1, 2), which would allow a greater contribution of
-MSH in the early stage of the response. Another intriguing feature
of POMC peptides is that the behavioral activity of -endorphin is
decreased and that of -MSH increased by acetylation (O'Donohue et
al., 1982). Thus, one might speculate that the relative contributions
to the net response of -MSH and -endorphin released from the same
neuron may be regulated by the activity of an opiomelanocortin
acetylase.
The results of the microinjection experiments also indicate that, in
agreement with earlier reports (Petty and De Jong, 1982;
Mosqueda-Garcia and Kunos, 1987), -endorphin microinjected at a low
dose into the DVC causes hypotension and bradycardia. Unlike the
similar effects of -MSH, these effects are mediated by
naloxone-sensitive opiate receptors, which are most likely of the
µ-subtype (Mosqueda-Garcia and Kunos, 1987). Thus, activation of the
neural pathway projecting from the arcuate nucleus to the ipsilateral
DVC can produce cardiovascular depressor effects via release of more
than one product of the same precursor, which interact with distinct
receptors. The survival value of such an arrangement and the
possibility that the relative amounts of -MSH and -endorphin
released may be regulated by differential processing remain to be
tested.
In contrast to the cardiovascular depressor effects elicited in the
DVC, intravenous injection of higher doses of MSH peptides has been
reported to cause pressor and tachycardic effects (Callahan et al.,
1985; 1988; Gruber and Callahan, 1989; Sun et al., 1992; De Wildt et
al., 1993). Indeed, intravenous injection of melanocortins or some of
their analogs was found to improve survival in experimental hemorrhagic
shock (Bertolini et al., 1986). Findings to date also indicate that
these effects are mediated indirectly via activation of sympathetic
outflow to the heart and vasculature (Callahan et al., 1985) and
therefore are likely to be of central origin. In the present
experiments, -MSH was both more potent and efficacious in increasing
blood pressure and heart rate via intracarotid as compared with
intravenous administration, whereas -MSH was ineffective via either
route. This has two important implications. First, the pressor and
tachycardic effects are, most likely, generated at a central site of
action. Because -MSH is a water-soluble peptide, it may act at sites
outside the blood-brain barrier, such as certain circumventricular
organs (Callahan et al., 1988), or it may act on the cerebral
vasculature to cause hypoxic activation of sympathetic outflow (De
Wildt et al., 1993). The second and potentially more important
conclusion is that -MSH acts at an as yet unidentified melanocortin
receptor. Of the five melanocortin receptors identified to date, the
MC3-R has equal high affinity for -MSH and -MSH (Roselli-Rehfuss
et al., 1993), whereas all of the other four receptors have high
affinity for -MSH and much lower affinity for -MSH. Thus, the
observed selectivity of -MSH for producing pressor and tachycardic
effects and the lack of activity of -MSH does not match the
pharmacological profile of any of the five melanocortin receptors.
Furthermore, the heptapeptide ACTH(4-10) is known to have very low or
no activity at either the MC4-R or the MC3-R (Adan et al., 1994;
Mountjoy et al., 1994), whereas ACTH(4-10) is reasonably potent in
eliciting pressor and tachycardic effects on intracarotid
administration (Fig. 4). Finally, pretreatment with either SHU9119 or
SHU9005 was unable to inhibit the pressor and tachycardic effects of
-MSH, even when either was administered at a dose ratio of 10:1.
In vitro studies of cells transfected with MC3-R yielded an
EC50 value of 5 nM for
-MSH to increase cAMP (Adan et al., 1994) and an antagonist
IC50 value of <5 nM for
SHU-9119 (Hruby et al., 1995) and <10 nM for
SHU9005 (Kesterson and Cone, unpublished observations). Thus, the
involvement of MC3-R or MC4-R in the pressor and tachycardic effects of
-MSH can be ruled out.
In summary, the present findings indicate at least two distinct central
pathways of cardiovascular control by melanotropins, one involving the
MC4-R in the medullary dorsal-vagal complex and the other an as yet
unidentified melanocortin binding site that preferentially recognizes
-MSH. Neural activation of MC4-R and possibly MC3-R in the dorsal
medulla suggests a possible physiological role of -MSH in central
cardiovascular regulation. The lack of involvement of these receptors
in the pressor and tachycardic effects of -MSH suggests the
existence of another, as yet unknown, melanocortin receptor in the
brain or cerebral vasculature.
FOOTNOTES
Received April 11, 1996; revised May 24, 1996; accepted May 30, 1996.
This work was supported by National Institutes of Health Grants
HL-49938 to G.K., DK-17420 to V.J.H., and HD-30236 to R.D.C.
Correspondence should be addressed to Dr. George Kunos, Department of
Pharmacology and Toxicology, Virginia Commonwealth University, Box
980613, Richmond, VA 23298.
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