Vol. 273, Issue 6, E1127-E1132, December 1997
A new biological contribution of cyclo(His-Pro) to the
peripheral inhibition of pancreatic secretion
Pascal
Fragner1,
Olivier
Presset2,
Nicole
Bernad3,
Jean
Martinez3,
Claude
Roze2, and
Sonia
Aratan-Spire1
1 Institut National de la
Santé et de la Recherche Médicale Unité 30,
Mécanisme d'Action Cellulaire des Hormones, Hôpital
Necker-Enfants-Malades, Tour Lavoisier, 75743 Paris Cedex 15;
2 Institut National de la
Santé et de la Recherche Médicale Unité 410,
Neuroendocrinologie et Biologie Cellulaire Digestives, 75870 Paris
Cedex 18; and 3 Centre
National de la Recherche Scientifique 5075, Université de
Montpellier I et II, Laboratoire des Aminopeptides, Peptides et
Proteines, Faculté de Pharmacie, 34060 Montpellier Cedex, France
 |
ABSTRACT |
The tripeptide
pyro-Glu-His-Pro-NH2
[thyrotropin-releasing hormone (TRH)] was isolated from the
hypothalamus as a thyrotropin-releasing factor. It has a broad spectrum
of central nervous system-mediated actions, including the stimulation
of exocrine pancreatic secretion. TRH is also synthesized in the
endocrine pancreas and found in the systemic circulation. Enzymatic
degradation of TRH in vivo produces other bioactive peptides such as
cyclo(His-Pro). Because of the short half-life of TRH and the stability
of cyclo(His-Pro) in vivo, we postulated that at least part of the
peripheral TRH effects on the exocrine pancreatic secretion may be
attributed to cyclo(His-Pro), which has been shown to have other
biological activities. This study determines in parallel the peripheral
effects of TRH and cyclo(His-Pro) as well as the putative contribution of other TRH-related peptides on exocrine pancreatic secretion in rats.
TRH and its metabolite cyclo(His-Pro) dose dependently inhibited
2-deoxy-D-glucose
(2-DG)-stimulated pancreatic secretion. TRH and all the related
peptides tested had no effect on the basal and
cholecystokinin-stimulated amylase release from pancreatic acinar cells
in vitro. These data indicate that cyclo(His-Pro) mimics the peripheral
inhibitory effect of TRH on 2-DG-stimulated exocrine pancreatic
secretion. This effect is not detected on isolated pancreatic acini.
Our findings provide a new biological contribution for cyclo(His-Pro)
with potential experimental and clinical applications.
thyrotropin-releasing hormone; histidyl-proline diketopiperazine,
thyroliberinase; serum pyroglutamyl aminopeptidase; methyl
thyrotropin-releasing hormone
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INTRODUCTION |
THYROTROPIN-RELEASING HORMONE (TRH:
pyro-Glu-His-Pro-NH2)
was originally isolated from the hypothalamus on the basis of its ability to stimulate thyroid-stimulating hormone (TSH) secretion (5).
It was then detected in the gastrointestinal tract (23), including the
pancreas (20). We have characterized the mRNA of preproTRH (ppTRH) in
isolated rat islets (1) and localized TRH in insulin-containing cells
of the islets of Langerhans (2).
Like other regulatory peptides, TRH arises from posttranslational
cleavage of a large precursor. Rat ppTRH is a 255-amino acid
polypeptide containing five copies of the TRH progenitor sequence
Gln-His-Pro-Gly (TRH-Gly) flanked by pairs of basic amino acid cleavage
sites (18). TRH-Gly is the immediate precursor peptide for TRH. It is
converted to TRH by peptidyl glycine 
-amidating monooxigenase (PAM).
Both TRH-Gly and PAM have been detected in several
tissues that synthesize TRH, including the pancreas (10, 29).
The endocrine pancreas is an important source of circulating TRH (9).
The half-life of TRH is very short in the adult rat plasma, where it is
rapidly degraded by a postproline-cleaving enzyme and a pyroglutamyl
aminopeptidase (3). Both enzyme activities are also present in the
pancreas and liver (28). The former converts TRH into TRH-OH and the
latter into His-Pro-NH2, which undergoes cyclization to yield a stable dipeptide, His-Pro
diketopiperazine or cyclo(His-Pro) (cHP). Endogenous cHP has been found
in the rat brain and pancreas (17). TRH, TRH-Gly, TRH-OH, and cHP have all been found in rat and human serum (10, 32). TRH was reported to
have a short half-life (12), whereas cHP was cleared from the
circulation unmetabolized and was found in the urine (15).
Most of the published studies on the effect of TRH on the exocrine
pancreatic secretion (EPS) have been limited to the amidated tripeptide. But TRH undergoes rapid, limited proteolysis by circulating and tissue TRH-degrading enzymes. The present in vivo experiments therefore include other TRH-related metabolites, particularly cHP.
Because of the very short half-life of TRH and the relative stability
of cHP, we postulated that at least part of the observed peripheral TRH
effects might be attributed to cHP, which has been shown to have
several biological activities (4, 13).
TRH is directly involved in the secretion of endocrine hormones such as
glucagon (8). Studies on the effects of TRH on pancreatic or gastric
secretion have produced a variety of results. Peripheral (iv)
administration of TRH decreases the gastric and pancreatic secretions
in humans (6, 18), but central (icv or ic) administration of TRH
stimulates pancreatic and gastric secretions in rats (21, 34). This
central stimulatory effect of TRH occurs via the vagal efferent fibers
(25). Exogenous TRH can thus stimulate or inhibit pancreatic secretion,
depending on the injection site (central or peripheral), which reflects differences in the pathways mediating these actions.
Finally, the possible contribution of a direct effect of TRH-related
peptides on the pancreatic acini has not been thoroughly investigated.
This local effect, if any, may be masked by the secretion of endogenous
peptide, since TRH and/or cHP are both present in the islets
and are secreted into the islet-acinar portal vascular system and so
may reach the acinar tissue at high concentrations (22). Therefore, the
present study also investigates the putative direct effect of certain
TRH-related peptides on isolated acinar cells.
The present study examines the effect of TRH and TRH-related
biologically active peptides (Table 1) and
particularly that of cHP on EPS in vivo. These experiments were
conducted in rats with acute pancreatic fistulas that underwent vagally
mediated pancreatic stimulation by
2-deoxy-D-glucose (2-DG). It
also examines the putative direct effect of the same peptides on acinar
cells using isolated dispersed pancreatic acini.
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MATERIALS AND METHODS |
Animals
Wistar rats were obtained from Iffa Credo, St. Germain L'Arbresle,
France. Male rats weighing 300-400 g were used for in vivo experiments, and smaller male rats (200-300 g) were used for the experiments on dispersed acini. Animals were treated according to the
standards of ethics for animal experimentation of the French Council of
Animal Care.
Pancreatic Secretion In Vivo
On the day before the experiment, the rats were deprived of food at 5 PM but allowed free access to water. They were anesthetized with ethyl
urethan (1.2 g/kg im), and an acute pancreatic fistula was installed.
Bile was diverted, the pylorus was ligated, and the pure pancreatic
secretion was collected with a continuous dilution method. A saphenous
vein was catheterized for venous infusions. The animals were maintained
under normothermic conditions (38 ± 0.5°C) throughout the
study. In control experiments, 2-DG (75 mg/kg iv) was infused alone for
3 h. This dose of the glucose analog produces a half-maximal vagally
mediated pancreatic secretory response (24).
Test Compounds
TRH and cHP were purchased from Peninsula and Sigma,
pGlu-3-methyl-His-Pro-NH2
(Me-TRH) from American Peptides and Sigma, and TRH-OH and TRH-Gly from
Sigma (see Table 1 for structural formulas of these peptides). Peptides
were prepared in methanol and kept at 
20°C as stock
solutions. For use, aliquots (10 µl) were evaporated to dryness and
dissolved in 0.9% saline containing 0.1% bovine serum albumin (BSA).
Total protein (ultraviolet absorbance at 280 nm), sodium (flame
photometry), bicarbonate, and amylase (measured by an autoanalyzer technique) were determined on samples of dilute pancreatic juice taken
every 20 min. Because the concentration of sodium in the pancreatic
juice remained constant at 145 ± 3 mM in this preparation, monitoring sodium output was equivalent to measuring the volume of
juice secreted. The average of the two first fractions (40 to 0 min) was taken as the basal value.
Preparation of Dispersed Acini for In Vitro Studies
Acini were prepared, and the amylase released was assayed as described
(19). Briefly, the pancreata from three rats were digested with
collagenase (Serva, 0.12 mg/ml), and the dispersed acini were suspended
in standard incubation medium (80 ml) supplemented with 1% BSA.
Experimental Design and Determination of Amylase Release
Aliquots of acini suspension (0.5 ml, 0.6-1.2 mg protein) were
incubated for 30 min at 37°C with increasing concentrations of test
compounds (TRH, cHP, TRH-OH) with or without butyloxycarbonyl cholecystokinin-7 (Boc-CCK-7), a potent CCK agonist (19).
Amylase activity was determined using the Phadebas reagent. The amylase released into the extracellular medium is given as a percentage of the
amylase released in the presence of
10
9 M Boc-CCK-7.
Statistical Analysis
All data are means ± SE. Data were compared by one-way analysis of
variance, followed (when significant) by Dunnett's test vs. the
control group. P values of <0.05
were considered significant.
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RESULTS |
In Vivo Studies
Effect of TRH, Me-TRH, and cHP on 2-DG-stimulated exocrine
pancreatic secretion.
CONTROL EXPERIMENTS (2-DG ALONE).
Infusion of 2-DG produced gradual increases in the pancreatic secretion
of sodium, bicarbonate, total protein, and amylase, which peaked
60-100 min after injection and then began to decrease. However,
all the parameters remained significantly higher than the basal level
180 min after 2-DG injection (Fig. 1,
left panels). The cumulative data,
representing the integrated pancreatic response over the basal level
during the 180 min after the 2-DG injection, are shown in the
right panels of Fig 1. All the
increases were significantly greater than the secretion by control
rats, which were not given 2-DG (not shown).
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Fig. 1.
Effects of thyrotropin-releasing hormone (TRH) infusion on
2-deoxy-D-glucose
(2-DG)-stimulated pancreatic secretion.
A, protein output;
B, sodium output;
C, bicarbonate output;
D, amylase output.
Left panels show time course of
effect; right panels show cumulated
response to 2-DG during 3 h over basal level.  , 2-DG alone
(control);  , 2-DG + TRH (2.25 nmol · kg1 · h1);
 , 2-DG + TRH (5.5 nmol · kg1 · h1);
 , 2-DG + TRH (55 nmol · kg1 · h1).
Results are means ± SE for 6-7 rats/group.
* P < 0.01 and
** P < 0.005 compared with
control group.
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TRH AND ME-TRH INFUSIONS.
TRH (2.25-55
nmol · kg1 · h1),
infused for 3 h beginning immediately after 2-DG injection, caused a
dose-related decrease in the 2-DG-stimulated pancreatic secretion. The
protein, sodium, bicarbonate, and amylase outputs were determined every
20 min during 180 min (Fig. 1).
TRH (2.25 nmol · kg1 · h1)
about halved the 2-DG-induced secretion: 55% for protein,
44% for sodium, 52% for bicarbonate, and 62%
for amylase (Fig. 1). A modest dose of TRH (5.5 nmol · kg1 · h1)
produced maximal inhibition of sodium, protein, and amylase output.
Protein output was reduced by 93% (P < 0.005), sodium output by 64% (P < 0.01), bicarbonate output by 65%, and amylase output by 83%
(P < 0.005). The higher dose of TRH
(55 nmol · kg1 · h1)
appeared to be supramaximal, since there was no further inhibition of
protein, sodium, or amylase outputs. However, bicarbonate output was
further inhibited (88%, P < 0.005).
Unlike TRH, Me-TRH, perfused at the same doses as TRH, produced no
changes in protein, sodium, or bicarbonate output (Fig. 2).
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Fig. 2.
Absence of effect of increasing doses of
pGlu-3-methyl-His-Pro-NH2
(Me-TRH) infusions on 2-DG-stimulated pancreatic secretion.
A, protein output;
B, sodium output;
C, bicarbonate output.
Left panels show time course of
effect; right panels show cumulated
response to 2-DG during 3 h over basal level. , 2-DG alone
(control); , 2-DG + Me-TRH (2.25 nmol · kg1 · h1);
, 2-DG + Me-TRH (5.5 nmol · kg1 · h1);
, 2-DG + Me-TRH (55 nmol · kg1 · h1).
Results are means ± SE for 6-7 rats/group.
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CHP INFUSIONS.
The infusion of cHP (2.25-55
nmol · kg1 · h1,
for 3 h) produced between 20 and 180 min of infusion a dose-related
decrease in the 2-DG-stimulated pancreatic secretion (Fig
3). The lowest dose of cHP (2.25 nmol · kg1 · h1)
about halved the 2-DG-induced stimulation, decreasing the protein output by 49%, sodium by 47%, and bicarbonate by 43% (Fig. 3). As
for TRH, inhibition was nearly maximal with 5.5 nmol · kg1 · h1
cHP. This dose reduced protein output by 78%
(P < 0.005), sodium output by 68%
(P < 0.005), and bicarbonate output
by 57% (P < 0.005). There was no
further decrease in response to a larger dose of cHP (55 nmol · kg1 · h1).
The maximal inhibitions obtained with 55 nmol · kg1 · h1
of cHP were 87% for protein, 73% for sodium, 76% for bicarbonate (Fig. 3), and 81% for amylase output (Fig.
4).
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Fig. 3.
Effects of increasing doses of cyclo(His-Pro) (cHP) on 2-DG-stimulated
pancreatic secretion. A, protein
output; B, sodium output;
C, bicarbonate output.
Left panels show time course of
effect; right panels show cumulated
response to 2-DG during 3 h over basal level. , 2-DG alone
(control); , 2-DG + cHP (2.25 nmol · kg1 · h1);
, 2-DG + cHP (5.5 nmol · kg1 · h1);
, 2-DG + cHP (55 nmol · kg1 · h1).
Results are means ± SE for 6-7 rats/group.
* P < 0.01 and
** P < 0.005 compared with
control group.
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Fig. 4.
Comparison of 3-h cumulated responses of pancreatic secretion to 2-DG
after iv infusions of equimolar doses (55 nmol · kg1 · h1)
of TRH, cHP, TRH-OH, TRH-Gly, and Me-TRH. Results are means ± SE
for 6-7 rats/group. * P < 0.01 and ** P < 0.005 compared
with controls (2-DG alone).
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The effect of cHP on pancreatic secretion, expressed as percent
decrease of 2-DG effect, was not significantly different from the
effect of equimolar doses of TRH.
Comparison of TRH-OH and TRH-Gly with TRH, Me-TRH, and cHP.
The TRH precursor TRH-Gly and the TRH metabolite TRH-OH had no effect
on 2-DG-stimulated pancreatic secretion. The integrated pancreatic
responses to 55 nmol · kg1 · h1
TRH-OH and TRH-Gly and the effects of TRH, cHP, and Me-TRH, expressed as a percentage of the response to 2-DG in their respective controls, are shown in Fig. 4. Although 55 nmol · kg1 · h1
of TRH and cHP produced significant decreases in protein (90 and
95%), sodium (68 and 82%), bicarbonate
(88 and 90%), and amylase output (83 and
81%), TRH-OH, TRH-Gly, and Me-TRH produced no significant
changes.
In Vitro Studies
Incubation of rat pancreatic acini for 30 min at 37°C with
increasing concentrations of Boc-CCK-7 led to a dose-dependent increase
in amylase secretion, whereas TRH did not stimulate amylase secretion.
Likewise TRH, cHP, and TRH-OH did not alter Boc-CCK-7-induced amylase
release (Table 2).
| |
DISCUSSION |
It has been established that intracerebroventricular and intracisternal
injections of TRH or TRH analogs activate neurons in the dorsal motor
nucleus of the vagus, leading to stimulation of the digestive system,
including the EPS. It has even been proposed that activation of vagal
efferents by 2-DG may depend on endogenous TRH neurons (25). The
tripeptide TRH itself is inhibitory when injected peripherally. This
action contrary to the central effect should thus be considered to
occur via a peripheral mechanism.
Studies on TRH metabolites and analogs are particularly important
because the half-life of TRH in vivo is very short. Such studies will
help to define and compare the real function of each metabolite and
thus contribute to our understanding of the regulatory role of
TRH-converting enzyme(s), which control(s) the enzymatic process and
the amount of metabolite formed (3, 26, 28). The present study shows
that increasing doses of TRH and cHP produce a dose-dependent
inhibition of EPS. Both peptides produced significant inhibition
between 20 and 180 min of perfusion. The percent inhibition was not
significantly different for equimolar doses of the peptides. The
pattern of enzymatic degradation of TRH by serum enzymes has been
studied. TRH is rapidly degraded in vitro into TRH-OH and its
constituent amino acids (3). However, TRH and cHP are cleared from the
circulation biphasically in vivo. TRH is reported to have a half-life
of 2.2-4.16 min (12) and cHP of 1.25-33 min (15). cHP appears
to be associated with a carrier and therefore is not metabolized in the
blood but found, unchanged, in the urine (15). In agreement with this,
endogenous cHP is reported to be the major metabolite of TRH in the
human blood (32). These findings strongly suggest that the peripheral
action of TRH may occur, at least in part, via cHP. The remaining
intact TRH may also assume part of the biological activity, depending
on its accessibility and/or affinity for the appropriate
binding sites (presently unknown). This possibility was also tested
using Me-TRH as a superactive TRH analog (34). The rationale of this
approach was based on the assumption that, if the intact TRH is
involved in the inhibitory effect observed after TRH infusion, Me-TRH
should amplify the same effect. This compound is eight times more
potent than TRH itself in stimulating the release of TSH from the
pituitary cells (11). In clinical studies, intravenous administration of Me-TRH produces a five times greater response than the native TRH
(30). Note, however, that the potency of Me-TRH seems to be correlated
to the presence of TRH receptors (33).
It has been reported that central TRH stimulates pancreatic secretion
(21) and that TRH analogs mimic the central TRH effect (25, 35). This
study shows that intravenous cHP mimics intravenous action of TRH.
Because the main source of endogenous cHP is TRH, these results
strongly suggest that TRH is metabolized to cHP to inhibit EPS. The
absence of any effect of Me-TRH on EPS, which is apparently in
agreement with this, may also suggest that the effect of TRH is not
mediated via well-characterized TRH receptors. The appropriate
TRH/cHP binding sites must therefore be identified and described to
interpret correctly this point.
Finally, the effects of TRH, cHP, TRH-OH, and
TRH-Gly on EPS were compared. TRH-OH is the deamidated
metabolite of TRH, and TRH-Gly is the immediate precursor of TRH, which
is reported to have a central stimulatory effect on gastric acid
secretion (31). As shown in Fig. 4, TRH-OH and TRH-Gly had no effect on
EPS.
It has been suggested that acinar pancreatic cells might be directly
regulated by islet TRH-related peptides transported via the portal
venous system from the endocrine to the exocrine pancreas (22). We
examined this possibility using an in vitro system of dispersed
pancreatic acini. Neither TRH nor cHP altered the Boc-CCK-7-stimulated
or basal amylase release from dispersed acini. This differs from a
previous report that TRH had a small, poorly dose-related inhibitory
effect on amylase release (14). The difference may be due to the
experimental designs used. Our observations suggest the lack of TRH/cHP
binding sites on the acini but not on the whole exocrine pancreas,
which contains other cell types. Therefore, the possibilty of a local
effect cannot be totally excluded.
The major biological role of central TRH is to stimulate TSH release,
which in turn increases the secretion of thyroid hormones. The thyroid
hormones are known to increase a serum-degrading activity that is
highly specific for TRH, thyroliberinase, or serum pyroglutamate aminopeptidase (for review see Refs. 3 and 28), which converts TRH to
cHP. Thus the stimulatory effect of TRH on EPS appears to be
antagonized by cHP. However, the way that cHP acts on the efferent side
remains unknown. The data of the present study indicate that this
inhibitory effect is observed on 2-DG-stimulated exocrine secretion but
is not detectable on isolated acini. The precise signaling pathway of
cHP on the efferent site needs to be characterized. However, the
peripheral mechanisms may involve an interplay between inhibitory (such
as serotonin or dopamine) and stimulatory (such as acetylcholine)
influences. We have adopted two working hypotheses. 1) cHP influences the efferent vagal
activity via peripheral presynaptic receptors that inhibit the release
of acetylcholine from efferent fibers.
2) TRH and cHP act with different
affinities for the same binding sites. The second hypothesis could
provide a model of negative feedback regulation of EPS.
We postulate that the enzymatic conversion of TRH in vivo gives rise to
cHP, which acts as an inhibitor to counterbalance the stimulating
effect of central TRH and thereby limits EPS stimulation. Much work
remains to be done to elucidate the regulation of cHP formation and
action.
The conclusions of this study are that cHP mimics the peripheral TRH
effect, dose dependently inhibiting 2-DG-stimulated EPS and therefore
attenuating central stimulatory effects on EPS, including that of
central TRH itself. These findings represent the first observation of a
new biological contribution of cHP, the endogenous TRH metabolite, with
potential experimental and clinical applications.
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ACKNOWLEDGEMENTS |
This study was supported in part by a grant from l'Association
pour la Recherche sur les Tumeurs de la Prostate.
| |
FOOTNOTES |
Address for reprint requests: S. Aratan-Spire, INSERM U. 30, Mécanisme d'action cellulaire des hormones, Hôpital
Necker-Enfants-Malades, Tour Lavoisier, 149 Rue de Sèvres, 75743 Paris Cedex 15, France.
Received 14 July 1997; accepted in final form 4 September 1997.
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REFERENCES |
1.
Aratan-Spire, S.,
R. Scharfmann,
R. M. Lechan,
and
A. H. Tashjian, Jr.
ProTRH Gene expression by fetal pancreatic islets in culture.
Biochem. Biophys. Res. Commun.
168:
952-958,
1990[Medline].
2.
Aratan-Spire, S.,
B. Wolf,
B. Portha,
D. Bailbé,
and
P. Czernichow.
Streptozotocin treatment at birth induces a parallel depletion of thyrotropin-releasing hormone and insulin in the rat pancreas during development.
Endocrinology
114:
2369-2373,
1984[Abstract].
3.
Bauer, K.,
and
P. Kovak.
Characterization of a thyroliberin-degrading serum enzyme catalyzing the hydrolysis of thyroliberin at the pyroglutamyl-histidine bond.
Eur. J. Biochem.
99:
239-246,
1979[Medline].
4.
Bauer, K.,
K. J. Graf,
A. Faivre-Bauman,
S. Beier,
A. Tixier-Vidal,
and
H. Kleinkauf.
Inhibition of prolactin secretion by histidyl-proline diketopiperazine.
Nature
274:
174-175,
1978[Medline].
5.
Boler, J.,
F. Enzman,
K. Folkers,
C. Y. Bowers,
and
A. V. Schally.
The identity of chemical and hormonal properties of the thyrotropin-releasing hormone and pyroglutamyl-histidyl-proline amide.
Biochem. Biophys. Res. Commun.
37:
705-710,
1969[Medline].
6.
Dolva, L. O.,
K. F. Hansen,
A. Berstad,
and
H. Frey.
Thyrotropin-releasing hormone inhibits the pentagastrin stimulated gastric secretion in man; a dose response study.
Clin. Endocrinol. (Oxf.)
10:
281-286,
1979[Medline].
7.
Ebiou, J.-C.,
M. Bulant,
P. Nicolas,
and
S. Aratan-Spire.
Pattern of thyrotropin-releasing hormone secretion from the adult and neonatal rat pancreas: comparison with insulin secretion.
Endocrinology
130:
1371-1380,
1992[Abstract].
8.
Ebiou, J.-C.,
D. Grouselle,
and
S. Aratan-Spire.
Antithyrotropin-releasing hormone serum inhibits secretion of glucagon from isolated perfused rat pancreas: an experimental model for positive feedback regulation of glucagon secretion.
Endocrinology
131:
765-771,
1992[Abstract].
9.
Engler, D.,
M. E. Scanlon,
and
I. M. D. Jackson.
Thyrotropin-releasing hormone in systemic circulation of the neonatal rat is derived from the pancreas and other extraneural tissues.
J. Clin. Invest.
67:
800-808,
1981.
10.
Fuse, Y.,
D. H. Polk,
R. W. Lam,
and
D. A. Fischer.
Distribution of thyrotropin-releasing hormone (TRH) and precursor peptide (TRH-Gly) in adult rat tissues.
Endocrinology
127:
2501-2505,
1990[Abstract].
11.
Griffiths, E. C.,
J. A. Kelly,
A. Ashcroft,
D. J. Ward,
and
B. Robson.
Comparative metabolism and conformation of TRH and its analogues.
Ann. NY Acad. Sci.
553:
217-231,
1989[Medline].
12.
Jackson, I. M. D.,
P. D. Papapetrou,
and
S. Reichlin.
Metabolic clearance of thyrotropin-releasing hormone in the rat in hypothyroid and hyperthyroid states: comparison with serum degradation in vitro.
Endocrinology
104:
1292-1298,
1979[Medline].
13.
Jikihara, H.,
H. Ikegami,
K. Koike,
K. Wada,
I. Morishige,
H. Kurachi,
K. Hirota,
A. Mirake,
and
O. Tanizawa.
Intraventricular administration of histidyl-proline-diketopiperazine [cyclo (His-Pro)] suppresses prolactin secretion and synthesis: a possible role of cyclo (His-Pro) as dopamine uptake blocker in rat hypothalamus.
Endocrinology
132:
953-958,
1993[Abstract].
14.
Kemmer, T. P.,
L. Duntas,
W. Munz,
and
P. Malfertheiner.
Inhibitory effect of thyrotropin-releasing hormone on enzyme secretion from isolated rat pancreatic acinar cells.
Horm. Metab. Res.
27:
367-371,
1995[Medline].
15.
Koch, Y.,
F. Battaini,
and
A. Peterkofsky.
[3H]cyclo(histidyl-proline) in rat tissues: distribution, clearance and binding.
Biochem. Biophys. Res. Commun.
104:
623-829,
1982.
16.
Komiya, I.,
T. Yamada,
Y. Kanno,
T. Aizawa,
K. Hashizume,
F. Yamagishi,
F. Ijima,
K. Iwatsuki,
and
S. Chiba.
Inhibitory action of thyrotropin-releasing hormone on serum amylase activity and its mechanism.
J. Clin. Endocrinol. Metab.
58:
1059-1063,
1984[Abstract].
17.
Lamberton, R. P.,
R. M. Lechan,
and
I. M. D. Jackson.
Ontogeny of thyrotropin-releasing hormone and histidyl-proline diketopiperazine in the rat central nervous system and pancreas.
Endocrinology
115:
2400-2405,
1984[Abstract].
18.
Lechan, R. M.,
P. Wu,
I. M. D. Jackson,
H. Wolf,
S. Cooperman,
G. Mandel,
and
R. H. Goodman.
Thyrotropin-releasing hormone precursor: characterization in rat brain.
Science
231:
159-161,
1986[Abstract/Free Full Text].
19.
Lignon, M.,
M. Galas,
M. Rodriguez,
J. Laur,
A. Aumelas,
and
J. Martinez.
A synthetic peptide derivative that is a cholecystokinin receptor antagonist.
J. Biol. Chem.
262:
7226-7231,
1987[Abstract/Free Full Text].
20.
Martino, E.,
A. Lernmark,
H. Sco,
D. Steiner,
and
S. Refetoff.
High concentration of thyrotropin-releasing hormone in pancreatic islets.
Proc. Natl. Acad. Sci. USA
75:
4265-4267,
1978[Abstract/Free Full Text].
21.
Messmer, B.,
F. G. Zimmerman,
and
H. J. Lenz.
Regulation of exocrine pancreatic secretion by cerebral TRH and CGRP: role of VIP, muscarinic, and adrenergic pathways.
Am. J. Physiol.
264 (Gastrointest. Liver Physiol. 27):
G237-G242,
1993[Abstract/Free Full Text].
22.
Miller, R. E.
Pancreatic neuroendocrinology: peripheral neural mechanisms in the regulation of the islets of Langerhans.
Endocr. Rev.
2:
471-495,
1981[Medline].
23.
Morley, J. E.,
T. J. Garvin,
A. E. Pekary,
and
J. M. Hershman.
Thyrotropin-releasing hormone in the gastointestinal tract.
Biochem. Biophys. Res. Commun.
79:
314-318,
1977[Medline].
24.
Nagain, C.,
M. Rodriguez,
J. Martinez,
and
C. Rozé.
In vivo activities of peptide and pseudo-peptide analogs of the C-terminal octapeptide of cholecystokinin on pancreatic secretion in the rat.
Peptides
8:
1023-1028,
1987[Medline].
25.
Okumura, T.,
I. L. Taylor,
and
T. N. Pappas.
Microinjection of TRH analogue into the dorsal vagal complex stimulates pancreatic secretion in rats.
Am. J. Physiol.
269 (Gastrointest. Liver Physiol. 32):
G328-G334,
1995[Abstract/Free Full Text].
26.
Prasad, C.,
M. Mori,
W. Pierson,
J. F. Wilber,
and
R. M. Ewards.
Developmental changes in the distribution of rat brain pyroglutamate aminopeptidase, a possible determinant of endogenous cyclo (His-Pro) concentrations.
Neurochem. Res.
8:
389-399,
1983[Medline].
27.
Saperas, E.,
M. Mourelle,
J. Santos,
S. Moncada,
and
J. R. Malagelada.
Central vagal activation by an analogue of TRH stimulates gastric nitric oxide release in rats.
Am. J. Physiol.
268 (Gastrointest. Liver Physiol. 31):
G895-G899,
1995[Abstract/Free Full Text].
28.
Scharfmann, R.,
J. C. Ebiou,
J. L. Morgat,
and
S. Aratan-Spire.
Thyroid status regulates particulate but not soluble TRH-degrading pyroglutamate aminopeptidase activity in the rat liver.
Acta Endocrinol.
123:
84-89,
1990.
29.
Scharfmann, R.,
P. Leduque,
S. Aratan-Spire,
P. Dubois,
A. Basmaciogullari,
and
P. Czernichow.
Persistence of peptidylglycine -amidating monooxygenase activity and elevated thyrotropin-releasing hormone concentrations in fetal rat islets in culture.
Endocrinology
123:
1329-1334,
1988[Abstract].
30.
Sowers, J. R.,
J. M. Hershman,
A. E. Pekary,
M. G. Nair,
and
C. M. Baugh.
Effect of N3im-methyl-thyrotropin releasing hormone on the human pituitary-thyroid axis.
J. Clin. Endocrinol. Metab.
43:
741-748,
1976[Abstract].
31.
Stephens, R. L., Jr.,
A. E. Pekary,
J. J. Di Stephano,
E. Landaw,
and
Y. Taché.
Intracisternal injection of TRH precursor, TRH-Glycine, stimulates gastric acid secretion in rats.
Regul. Pept.
25:
51-60,
1989[Medline].
32.
Takahara, Y.,
F. Battaini,
D. D. Ross,
S. A. Akman,
N. R. Bachur,
K. R. Bailey,
E. Lakatos,
and
A. Peterkofsky.
Detection in the human serum by radioimmunoassay of histidyl-proline diketoperazine, a metabolite of thyrotropin-releasing hormone.
Endocrinology
56:
312-319,
1983.
33.
Taylor, R. L.,
and
D. R. Burt.
Species differences in the brain regional distribution of receptor binding for thyrotropin-releasing hormone.
J. Neurochem.
38:
1649-1656,
1982[Medline].
34.
Vale, W.,
J. Rivier,
and
R. Burgus.
Synthetic TRF (thyrotropin releasing factor) analogues. II. pGlu-N3im Me-His-Pro-NH2: a synthetic analogue with specific activity greater than that of TRF.
Endocrinology
89:
1485-1488,
1971[Medline].
35.
Yanagisawa, K.,
and
Y. Taché.
Intracisternal TRH analogue RX 77368 stimulates gastric histamine release in rats.
Am. J. Physiol.
259 (Gastrointest. Liver Physiol. 22):
G599-G644,
1990[Abstract/Free Full Text].
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Abstract
Introduction
