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
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

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

    INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

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 alpha -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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Table 1.   Peptide derivatives used in this study

    MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

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.

    RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

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. open circle , 2-DG alone (control); black-triangle, 2-DG + TRH (2.25 nmol · kg-1 · h-1); black-square, 2-DG + TRH (5.5 nmol · kg-1 · h-1); bullet , 2-DG + TRH (55 nmol · kg-1 · h-1). Results are means ± SE for 6-7 rats/group. * P < 0.01 and ** P < 0.005 compared with control group.

TRH AND ME-TRH INFUSIONS. TRH (2.25-55 nmol · kg-1 · h-1), 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 · kg-1 · h-1) 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 · kg-1 · h-1) 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 · kg-1 · h-1) 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. open circle , 2-DG alone (control); black-triangle, 2-DG + Me-TRH (2.25 nmol · kg-1 · h-1); black-square, 2-DG + Me-TRH (5.5 nmol · kg-1 · h-1); bullet , 2-DG + Me-TRH (55 nmol · kg-1 · h-1). Results are means ± SE for 6-7 rats/group.

CHP INFUSIONS. The infusion of cHP (2.25-55 nmol · kg-1 · h-1, 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 · kg-1 · h-1) 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 · kg-1 · h-1 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 · kg-1 · h-1). The maximal inhibitions obtained with 55 nmol · kg-1 · h-1 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. open circle , 2-DG alone (control); black-triangle, 2-DG + cHP (2.25 nmol · kg-1 · h-1); black-square, 2-DG + cHP (5.5 nmol · kg-1 · h-1); bullet , 2-DG + cHP (55 nmol · kg-1 · h-1). 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 · kg-1 · h-1) 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).

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 · kg-1 · h-1 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 · kg-1 · h-1 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).

                              
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Table 2.   Action of TRH-related compounds on Boc-CCK-7-induced amylase release from rat pancreatic acini

    DISCUSSION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

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.

    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.

    REFERENCES
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

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AJP Endocrinol Metab 273(6):E1127-E1132
0193-1849/97 $5.00 Copyright © 1997 the American Physiological Society




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