Endocrine Unit, Imperial College of Science, Technology and Medicine Hammersmith Hospital, London W12 ONN, United Kingdom
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ABSTRACT |
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Intravenous
injection of galanin increases plasma growth hormone (GH) and prolactin
(PRL) concentrations. In the rat, the effects of galanin on GH appear
to be mediated via the hypothalamic galanin receptor
GAL-R1, at which galanin-(329) is inactive. In contrast,
the effect of galanin on PRL is mediated via the pituitary-specific
galanin receptor GAL-RW, at which galanin-(3
29) is fully
active. We investigated the effects of an intravenous infusion of human
galanin (hGAL)-(1
30) and -(3
30) on anterior pituitary hormone
levels in healthy females. Subjects were infused with saline,
hGAL-(1
30) (80 pmol · kg
1 · min
1),
and hGAL-(3
30) (600 pmol · kg
1 · min
1)
and with boluses of gonadotropin-releasing hormone,
thyrotropin-releasing hormone, and growth hormone-releasing hormone
(GHRH). Both hGAL-(1
30) and -(3
30) potentiated the rise in
GHRH-stimulated GH levels [area under the curve (AUC), saline,
2,810 ± 500 vs. hGAL-(1
30), 4,660 ± 737, P < 0.01; vs.
hGAL-(3
30), 6,870 ± 1,550 ng · min · ml
1,
P < 0.01]. In contrast to hGAL-(1
30), hGAL-(3
30)
had no effect on basal GH levels (AUC, saline,
110 ± 88 vs. hGAL 1
30, 960 ± 280, P < 0.002; vs.
hGAL-(3
30), 110 ± 54 ng · min · ml
1,
P = not significant). These data suggest that the
effects of galanin on basal and stimulated GH release are mediated via
different receptor subtypes and that the human equivalent of
GAL-RW may exist.
infusion; growth hormone; prolactin; pituitary function test
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INTRODUCTION |
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GALANIN IS A 29-AMINO ACID peptide, originally isolated from porcine small intestine and widely distributed in the central and peripheral nervous system (39). More recently, human galanin (hGAL) has been cloned and found to be a 30-amino acid nonamidated peptide (36). Galanin is both synthesized and stored within the hypothalamus (35) and pituitary gland (24, 36), where it has been colocalized to several peptides (27, 31) and cell types, respectively (21, 22, 24, 38).
In the rat, intracerebroventricular (29, 33, 34), subcutaneous (8), and intravenous injections of porcine galanin (pGAL) increase plasma growth hormone (GH) levels (29, 34). ICV injection of specific galanin antiserum decreases plasma GH levels, suggesting a physiological role for galanin in the control of GH secretion (26, 34). In humans, intravenous pGAL and hGAL increase plasma GH levels (4) and enhance the GH response to exogenous growth hormone-releasing hormone (GHRH) in healthy subjects (12, 17). The mechanism underlying this action is unknown (12, 25, 33).
Galanin administered intracerebroventricularly in rats (29, 34) and intravenously in humans also increases plasma prolactin (PRL) levels (4, 7, 29). An intravenous infusion of galanin in humans has also been shown by some authors (2, 4, 7, 23) to increase thyrotropin-releasing hormone (TRH)-stimulated plasma PRL levels, but this is not a universal finding (16, 30).
Three galanin receptors have been cloned in humans,
hGAL-R1, hGAL-R2 and hGAL-R3 (5, 6,
18, 37). hGAL-R1 has been detected in both the hypothalamus
and anterior pituitary gland (13). hGAL-R2 mRNA has been
detected in the anterior pituitary gland by RT-PCR by one group (13),
but this has not been confirmed by others (5, 6). hGAL-R3
has not been demonstrated in the anterior pituitary gland (37).
Although hGAL-R1 and hGAL-R2 are only 39%
homologous, they have similar pharmacological profiles; at both, the
NH2-terminal part of the peptide is essential for receptor
binding and biological activity. Thus hGAL-(130) and the fragment
1-15 are active, and the fragment pGAL-(3
29) is inactive at
these receptors. This is in contrast to a pituitary-specific rat
galanin receptor, originally designated "GAL-R2",
which has been characterized in rat anterior pituitary membranes (44). At this receptor, the COOH-terminal part of the peptide is crucial for
receptor binding and biological activity. Hence pGAL-(1
29) and
-(3
29) have similar activity, but 1-15 is ineffective. The recent cloning of another rat galanin receptor in the rat hypothalamus, which has also been called "GAL-R2", has led to some
confusion regarding the nomenclature of the galanin receptors. This
latter receptor, like the rat GAL-R1, does not bind
pGAL-(3
29) (14, 20). For the purposes of this report, we will refer
to the first-described GAL-R2, the pituitary-specific rat
galanin receptor at which the fragment 3-29 is active (and the
only receptor at which this fragment is known to be active) reported by
Wynick et al. (44) as GAL-RW.
The modulatory effects of galanin on PRL and gonadotropin secretion in
vitro in rat tissue have been shown to be mediated via
GAL-RW (40, 42, 44). This contrasts with the effect of
galanin on GH secretion, which appears to be mediated, at least in
part, via the hypothalamic GAL-R1 in the rat (15). Before this study, there was no suggestion of the presence of
GAL-RW in humans. There are no receptor studies in
humans to confirm the presence of the GAL-RW, because of
the unavailability of fresh undamaged human pituitary tissue. Because
hGAL-(130) and pGAL-(1
29) (2, 4, 7, 12) have been shown to have
similar effects on plasma pituitary hormone levels, removal of the
first two NH2-terminal amino acids of hGAL might be
predicted to create a peptide equivalent to pGAL-(3
29), the specific
agonist of the GAL-RW. Thus our aim was to
investigate for the first time the differential effects of hGAL-(1
30)
and its fragment hGAL-(3
30) on basal and stimulated plasma pituitary
hormone concentrations.
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MATERIALS AND METHODS |
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Materials
hGAL-(1Subjects
Nine healthy female volunteers 20-32 yr of age (mean = 27 yr) and weighing 52-70 kg (mean = 60 kg) participated in the study. Subjects gave informed written consent, and ethical approval was obtained from the local Research Ethics Committee. Subjects had no allergies and no abnormalities on physical examination. All routine blood tests were normal.All subjects were studied in the early follicular phase of the menstrual cycle on each occasion. The volunteers were taking no other regular medication.
Protocol
The nine volunteers were entered into a double-blind crossover study of Latin Square design, during which each subject was studied on three occasions separated byAfter two basal blood samples, the infusions of saline, hGAL-(130),
or -(3
30) were commenced at minute 0. The infusion was started at 1/100 the final rate, and this was increased at 10-min intervals to 1/20, 1/10, 1/5, and 1/2 until a final rate of
80 pmol · kg
1 · min
1
of hGAL-(1
30) and 600 pmol · kg
1 · min
1
of hGAL-(3
30) was achieved after 50 min. This infusion rate was
continued for an additional 80 min. These doses of hGAL-(1
30) and
-(3
30) were chosen because the binding affinity and biological activity of the COOH-terminally truncated galanin have been shown to be
between 5 and 10 times less than pGAL-(1
29) (44). The doses were also confirmed by the results of pilot studies showing that
the effects on GHRH-stimulated GH levels produced by the fragments had
a similar relative potency. Intravenous boluses of GHRH (100 µg),
GnRH (100 µg), and TRH (200 µg) were given over 2 min at minute
100, 50 min after the start of the final infusion rate, to
stimulate pituitary secretion of GH, luteinizing hormone (LH),
follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH),
and PRL. Blood samples were taken regularly from minutes
20 to +250. At the beginning and end
of each infusion, a sample of the infusate was collected to measure the
actual infusion rate. Subjects were attached to a cardiac monitor, and
arterial blood pressure was measured regularly with a Critikon Dinamap vital signs indicator.
Analytical Methods
Blood was collected into heparinized tubes containing 5,000 kIU (0.2 ml) of aprotinin and was centrifuged immediately, and plasma was separated and stored atHuman galanin assay.
hGAL-(130)- and -(3
30)-like immunoreactivity (hGAL-LI) was
measured using a rabbit antiserum raised to synthetic hGAL
conjugated with glutaraldehyde to BSA at a dilution of 1:16,000. This
antibody cross-reacted 22% and 15% with pGAL and rat galanin,
respectively, but there was no cross-reactivity with other known
peptides. The antibody was COOH-terminally directed and cross-reacted
equally with hGAL-(1
30) and -(3
30). Synthetic hGAL was iodinated by the Iodogen method (3). The iodinated product was separated by reversed
phase HPLC with the use of a C18 column on a 15-45% 90-min acetonitrile-water-0.05% trifluoroacetic acid gradient. It had
a specific activity of 45 Bq/fmol, as determined by self-displacement in the assay. The assay standard was synthetic hGAL-(1
30) (1-100 fmol/tube). The plasma samples were diluted with assay buffer, 1:10 for
hGAL-(1
30) and 1:100 for hGAL-(3
30), and 100 µl of this were
added to the assay. Assays were performed in a total volume of
0.7 ml of phosphate buffer (0.06 M, pH 7.4) containing EDTA (10 mM),
sodium azide (8 mmol/l), and 0.3% (wt/vol) BSA and were incubated for
4 days at 4°C before separation of free and antibody-bound peptide
by dextran-coated charcoal (6 mg/tube). The assay could detect changes
of 2.5 fmol/assay tube, and the inter- and intra-assay coefficients of
variation (10 fmol addition) were 8.2 and 12.8%, respectively.
Pituitary hormone assays. Commercial kits were used for the meaurement of plasma GH [chemiluminescence immunometric assay; hGH Kit, Nicholas Institute, San Juan Capistrano, CA; intra-assay coefficient of variation (CV) <6.0%, interassay CV <10%, detection limit 0.02 ng/ml], PRL [microparticle enyzme immunoassay (MEIA), Abbott Laboratories, Diagnostics Division, Abbott Park, IL; intra-assay CV <4.0%, interassay CV <2.7%, detection limit 0.6 ng/ml], TSH (MEIA, Abbott Laboratories; intra-assay CV <11.0%, interassay CV <8.0%, detection limit 0.06 mIU/ml), LH (MEIA, Abbott Laboratories; intra-assay CV <5.0%, interassay CV <4.0%, detection limit 0.5 mIU/ml) and FSH (MEIA, Abbott Laboratories; intra-assay CV <7.0%, interassay CV <5.0%, detection limit 0.37 mIU/ml). All samples were measured in duplicate.
Statistics. Results are shown as means ± SE. For hormone measurements, the area under the curve (AUC) over baseline for each variable was calculated by means of the trapezoidal rule. AUC for the effects of the galanin fragments and saline on basal hormone levels was calculated from initiation of the infusions (minute 0) to injection of hypothalamic releasing factors (minute 100). AUC for the effects of the galanin fragments and saline on stimulated hormone release was calculated from minute 100, thus negating the effect of the fragments in the basal state. For heart rate and blood pressure, individual time points were compared. All data were analyzed by repeated-measures analysis of variance. In all cases, P < 0.05 was considered to be statistically significant.
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RESULTS |
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All subjects reported the characteristic metallic taste and
hypersalivation during the hGAL-(130) infusion only (4, 7). There
were no side effects during the hGAL-(3
30) infusions. All subjects
reported transient flushing immediately after the pituitary function tests.
Plasma Galanin
Plasma hGAL-LI was below the detection limit of the assay used before infusion. Infusion of hGAL-(1
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Hormonal Responses
hGAL-(1
|
hGAL-(130) increased basal plasma PRL levels [AUC, 0-100
min; hGAL-(1
30), 10.4 ± 3.5 vs. saline,
1.5 ± 0.4 µg · min · ml
1;
F = 8.6, P < 0.005]. hGAL-(3
30) did not
significantly alter basal plasma PRL concentrations [AUC,
0-100 min; hGAL-(3
30),
0.5 ± 1.3 µg · min · ml
1
vs. saline; P = NS]. hGAL 1
30 enhanced the rise in
plasma PRL levels after exogenous TRH by 69% [AUC, 100-250
min; hGAL-(1
30), 240 ± 37 vs. saline, 142 ± 17 µg · min · ml
1;
F = 7.2, P < 0.005]. hGAL-(3
30) did not
significantly alter TRH-stimulated plasma PRL concentrations
[AUC, 100-250 min; hGAL-(3
30), 135 ± 19 µg · min · ml
1
vs. saline; P = NS] (Fig.
3).
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hGAL-(130) and -(3
30) did not alter basal TSH levels [AUC,
0-100 min; saline
6.2 ± 1.1 vs. hGAL-(1
30),
8.0 ± 2.8; vs. hGAL-(3
30),
6.7 ± 1.3 µIU · min · l
1;
both P = NS]. The hGAL fragments did not influence
TRH-stimulated plasma TSH levels [AUC, 100-250 min; saline
980 ± 214 vs. hGAL-(1
30), 1,023 ± 212; vs.
hGAL-(3
30), 949 ± 175 µIU · min · l
1;
both P = NS].
Although the GnRH-stimulated rise in plasma LH levels tended to be
lower with both hGAL-(130) and -(3
30), this did not reach statistical significance [AUC, 100-250 min; saline 2,000 ± 800 vs. hGAL-(1
30), 1,600 ± 370; vs. hGAL-(3
30), 1,300 ± 341 mIU · min · l
1;
both P = NS]. hGAL-(1
30) and -(3
30) did not affect
basal plasma LH concentrations (P = NS). hGAL did not
significantly alter basal or LHRH-stimulated plasma FSH concentrations
[AUC, 0-100 min; saline
21 ± 8 vs. hGAL-(1
30),
40 ± 12; vs. hGAL-(3
30),
45 ± 15 mIU · min · l
1;
both P = NS and AUC, 100-250 min; saline 322 ± 72 vs.
hGAL-(1
30), 397 ± 65; vs. hGAL-(3
30), 301 ± 37 mIU · min · l
1;both
P = NS].
Cardiovascular Responses
Changes in mean heart rate values are shown in Fig. 4A. The preinfusion heart rate was 68 ± 1 with no differences between studies. During the hGAL-(1
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DISCUSSION |
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hGAL-(330) had not previously been infused into humans and was well
tolerated in our volunteers. hGAL-LI was undetectable before the
infusion in our study. This is in contrast to previous studies
demonstrating the presence of galanin in the peripheral circulation
(9-11). Because galanin normally circulates at very low
concentrations, those studies aimed to measure picomole-per-liter concentrations of plasma galanin levels and to detect the low concentrations; therefore, the plasma samples were concentrated by
extraction. In contrast, the aim of our study was to measure the much
higher levels of exogenously administered galanin at nanomole-per-liter
concentrations; therefore, our plasma samples were diluted in assay
buffer and not extracted. Thus the natural circulating plasma hGAL-LI
before the infusions was below the detection limit of the assay used in
our study, which was optimized specifically for the high concentrations
produced by our infusions. Both hGAL-(1
30) and -(3
30) increased
GHRH-stimulated plasma GH levels. The peak level and AUC after GHRH
were enhanced with hGAL-(1
30) compared with saline, even when the
stimulatory effect on basal GH level was taken into account.
hGAL-(1
30) and -(3
30) infusions gave a greater additional
integrated release of GH after GHRH compared with saline. This
enhancement of GH release may indicate potentiation by galanin. Only
hGAL-(1
30) increased basal plasma GH concentrations. The differential
effects of the galanin fragments on basal and GHRH-stimulated GH
concentrations suggest that these two effects may be mediated via
different pathways, perhaps even via different receptors, in humans.
In rats, GHRH immunoneutralization abolishes the stimulatory effect of
galanin on GH release (28), suggesting that the effect is mediated, at
least in part, by an increase in GHRH release. Galanin has also been
shown to increase GHRH release from rat hypothalamic median eminence
fragments in vitro (1). There is no evidence for a direct
effect of galanin on the pituitary in the rat (33). In humans, however,
we have demonstrated that galanin not only increases basal plasma GH
levels but also enhances the GH response to exogenous GHRH, suggesting
a dual mechanism of action. The effect of galanin on basal GH release
may be mediated at the level of the median eminence via the
hypothalamic hGAL-R1, causing an increase in release of
GHRH or a decrease of release of somatotropin release-inhibiting
hormone (12, 25). The observation that hGAL-(330) had no effect on
basal GH levels could support this, because the COOH-terminal portion
of the peptide has not been shown to bind to the hypothalamic galanin
receptors in the rat. In contrast, because hGAL-(3
30) increased
GHRH-stimulated GH levels but had no effect on basal GH
concentrations, the effect of galanin on GHRH-stimulated GH
secretion may be mediated via a direct effect on the somatotrophs,
perhaps by sensitizing the cell to GHRH. One could speculate that this
effect is mediated by a human equivalent of GAL-RW. Thus
this apparent dichotomy of effects of the hGAL-(3
30) in the absence
or presence of GHRH could be explained by two different galanin
receptor subtypes mediating galanin stimulation of basal and stimulated
GH release.
We have also demonstrated in this study that, in healthy women,
hGAL-(130) increased basal plasma PRL concentrations and enhanced the
lactotroph responsiveness to exogenous TRH, although hGAL-(3
30) was completely without effect. The peak level and AUC
after TRH were enhanced with hGAL-(1
30) compared with saline, even
when the stimulatory effect on basal PRL levels was taken into account.
Because hGAL-(1
30) infusion gave a greater additional integrated
release of PRL after TRH compared with saline, this enhancement again
may indicate potentiation by galanin. There is evidence in the
rat that the stimulatory effect of galanin on PRL release is mediated
via a direct action on the anterior pituitary gland. Pituitary galanin
is synthesized in the lactotroph and appears to mediate the lactotroph
proliferation induced by estrogen and to stimulate PRL secretion via
the pituitary-specific GAL-RW (38, 42, 43, 44). The lack of
a demonstrable effect of hGAL-(3
30) on plasma PRL levels in our study
may be thought surprising in light of the animal data and suggests that
the putative pituitary-specific human equivalent of GAL-RW
may not mediate this effect in humans. Therefore, one could speculate
that the stimulatory effects of hGAL-(1
30) on basal PRL secretion may be due to changes in hypothalamic inhibitory or releasing factors at
the level of the median eminence. Galanin has been shown to inhibit
dopamine release from the median eminence, a site at which galanin and
dopamine have been found to coexist in nerve terminals (32).
hGAL-(130) has previously been shown to cause a dose-dependent
increase in heart rate, with the abolition of sinus arrhythmia (7).
hGAL-(3
30) infused at seven times the dose had no effect on heart
rate in this study. The mechanism and site of action for the
galanin-induced increase in heart rate remain undetermined in humans,
but there is evidence it is by vagal inhibition (19, 41, 45). The
tachycardia induced by hGAL-(1
30) and not -(3
30) implies not only
that the putative human GAL-RW is not mediating this effect
in humans but that the hormonal effects of hGAL-(3
30) are specific
and not mediated through nonspecific stress pathways.
In summary, we have given intravenous infusions of hGAL-(330) in
humans for the first time. Our results suggest that the stimulatory
effect of galanin on basal plasma GH, basal PRL, and TRH-stimulated PRL
levels may be mediated via one of the cloned galanin receptors.
However, the effect of galanin on GHRH-stimulated plasma GH levels
could be mediated via a novel pathway, perhaps the GAL-RW.
Therefore, these results provide the first suggestion that a
GAL-RW-like receptor that binds the COOH-terminal portion of the peptide may be present in humans, and physiologically, this
potentially allows separate mediation of basal and stimulated GH
release by galanin.
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ACKNOWLEDGEMENTS |
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We thank Steve Virdee and Patricia Hill for help with the human pituitary hormone assays.
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FOOTNOTES |
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We thank the Wellcome Trust for funding Dr. J. F. Todd (Wellcome Research Training Fellow) and the British Diabetic Association for funding Dr. C. M. B. Edwards (R. D. Lawrence Research Fellow).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: S. R. Bloom, ICSM Endocrine Unit, Hammersmith Hospital, Du Cane Road, London W12 ONN, United Kingdom (E-mail: s.bloom{at}ic.ac.uk).
Received 17 August 1999; accepted in final form 13 January 2000.
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