Oxyntomodulin inhibits pancreatic secretion through the nervous system in rats.

Glicentin (GLIC), oxyntomodulin (OXM), and peptide YY (PYY) released in blood by ileocolonic L-cells after meals may inhibit pancreatic secretion. Whereas OXM interacts with glucagon and tGLP-1 receptors, OXM 19-37, a biologically active fragment, does not. The purpose of this study was to measure the effect of OXM, OXM 19-37, GLIC, tGLP-1, and PYY on pancreatic secretion stimulated by 2 deoxyglucose (2DG), electrical stimulation of the vagus nerves (VES), acetylcholine and cholecystokinin octapeptide (CCK8) in anesthetized rats. The effect of OXM was also studied in dispersed pancreatic acini. Plasma oxyntomodulin-like immunoreactivity (OLI) was measured by radioimmunoassay after the exogenous infusion of OXM and after an intraduodenal meal. OXM 19-37, infused at doses mimicking postprandial plasma levels of OLI, decreased pancreatic secretion stimulated by 2DG, VES, or CCK8. Similar effects were found with OXM and GLIC. OXM 19-37 did not change the pancreatic stimulation induced by acetylcholine in vivo, or CCK-induced amylase release in isolated acini. Vagotomy completely suppressed the inhibitory effect of OXM 19-37 on CCK8-stimulated pancreatic secretion. PYY inhibited the effect of 2DG, but not that of CCK8, whereas tGLP-1, even in pharmacologic doses, had no effect on stimulated pancreatic secretion. OXM, OXM 19-37, but not tGLP-1, inhibit pancreatic secretion at physiologic doses, through a vagal neural indirect mechanism, different from that used by PYY, and probably through a GLIC-related peptide-specific receptor.

Comparative study of in vitro and in vivo activities of bombesin pseudopeptide analogs modified on the C-terminal dipeptide fragment.

Analogs of bombesin in which the peptide bond between the two last amino acid residues were replaced by a pseudopeptide bond mimicking the transition state analog were evaluated. These compounds were able to recognize the bombesin receptor on isolated rat pancreatic acini with high potency (Ki from 0.60 +/- 0.27 nM to 4.3 +/- 2.3 nM). Although they were devoid of agonist activity, they were able to antagonize bombesin-induced amylase secretion in this model, with potencies in accordance with their affinities (IC50 from 1.6 +/- 0.3 nM to 10.0 +/- 1.7 nM). When tested in vivo in the anesthetized rat, these bombesin receptor antagonists exhibited high potency in inhibiting bombesin-induced pancreatic secretion (H-DPhe-Gln-Trp-Ala-Val-Gly-His-NH-CH[CH2-CH(CH3)2]-CHOH-(CH 2)3-CH3, JMV845, was among the most potent compounds with ED50 of 7.82 +/- 2.89 nM in inhibiting bombesin-induced protein secretion). The results of this study showed that replacing the peptide bond between the two last amino acid residues in bombesin by mimicking the transition state analog resulted in in vitro and in vivo potent bombesin receptor antagonists.

Differential effects of peptide YY, neuropeptide Y, and sigma ligands on neurally stimulated external pancreatic secretion in the rat.

The endocrine peptide YY (PYY) inhibits pancreatic secretion in animals and in man through indirect pathways. Neuropeptide Y (NPY), whose chemical structure is very close, displays similar effects. Recently, sigma ligands were shown to produce in vivo several neural pharmacologic effects that seemed indistinguishable from those of NPY. This might occur by interaction with the same (or closely related) receptors or by activation of a common final pathway. The purpose of the present work was to test whether PYY, NPY, and sigma agonists also display closely related activities on pancreatic secretion. The sigma ligands (+)-N-allyl normetazocine (d-NANM) and di(ortho-tolyl) guanidine (DTG) were used. Pancreatic secretion was stimulated by the centrally acting agent 2-deoxyglucose (2DG) in anesthetized rats. The rats were also administered either an infusion of peptide (PYY: 25-250 pmol/kg/h, NPY: 75-750 pmol/kg/h), continued for 2 h, or a bolus injection of d-NANM (3 mg/kg) or DTG (1 mg/kg). In antagonist experiments, the dopamine and sigma antagonist haloperidol (1 mg/kg, i.v.), the adrenoceptor antagonists idazoxan (0.3 mg/kg, s.c.), prazosin (0.5 mg/kg, s.c.), propranolol (1 mg/kg, s.c.) and the opiate receptor antagonist naloxone (1 mg/kg, s.c.) were injected, 5 min before the peptide infusion had begun. Neither PYY nor NPY changed basal pancreatic secretion. PYY and NPY produced a dose-related inhibition of 2DG-stimulated pancreatic secretion. The observed inhibition after 250 pmol/kg/h of PYY was volume, 78% (p < 0.01); bicarbonate, 84% (p < 0.01); protein, 78% (p < 0.01); whereas the physiologically relevant dose of 25 pmol/kg/h induced approximately 30% inhibition of these variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of pancreatic secretion by capsaicin-sensitive sensory neurons in the rat.

The purpose of this work was to study whether stimulation or destruction of sensory afferents can modulate pancreatic secretion. The neurotoxin capsaicin is specific for a subpopulation of small diameter primary afferent neurons. Small doses of capsaicin were administered to anesthetized rats as intraduodenal or intragastric bolus injections to stimulate digestive sensory fibers, and pancreatic secretory response was measured. In addition, several high-dose subcutaneous capsaicin injections were administered 10 days before the experiments began, in order to inactivate sensory fibers. Basal and 2-deoxy-D-glucose (2DG)-stimulated pancreatic secretion was then measured. Intraduodenal capsaicin (96-3,050 micrograms/kg) induced a progressive (peak response 40-60 min after the injection), dose-related and long-lasting (> 180 min) increase in pancreatic output of sodium, bicarbonate, and total protein. The maximal response was obtained with 964 micrograms/kg capsaicin; it amounted to about 15% of the maximal response to exogenous cholecystokinin octapeptide (CCK8). The response was not decreased by atropine, hexamethonium, vagotomy, a mixture of adrenoceptor antagonists (prazosin + idazoxan + propranolol), or by the CCKB receptor antagonist L365,260. In contrast, the CCKA receptor antagonist L364,718 reduced by 30-40% the sodium and bicarbonate response and reduced by 90% the protein response induced by capsaicin, but not the response induced by methacholine or 2DG. However, intraluminal capsaicin did not release CCK in a preparation of isolated perfused duodeno-jejunum. Intragastric capsaicin did not significantly change pancreatic secretion. Capsaicin pretreatment had no effect on basal and 2DG-stimulated secretion, but abolished the response to intraduodenal capsaicin. In conclusion, intraduodenal capsaicin can stimulate external pancreatic secretion in anesthetized rats through capsaicin-sensitive sensory neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of neurotensin stimulation of external pancreatic secretion in the rat.

The gut and brain peptide neurotensin has been claimed to directly or indirectly stimulate external pancreatic secretion. The purpose of this study was to analyze the mechanism of the neurotensin effect on external pancreatic secretion in the rat. The pancreatic dose-response curve to 40-min venous infusions of neurotensin 1-13 (0.1-10 micrograms/kg-h = 0.06-6 nmol/kg-h) was biphasic; the maximal response occurred at 3.16 micrograms/kg-h and reached approximately 30% of the maximal response to cholecystokinin (CCK). The ED50 was 0.27 micrograms/kg-h (= 0.16 nmol/kg-h) for bicarbonate and 0.45 micrograms/kg-h (= 0.27 nmol/kg-h) for protein output. Pancreatic secretion in response to each neurotensin dose increased steadily during the infusion and peaked 20-40 min after the end of infusion. Atropine and hexamethonium suppressed the stimulatory effect of neurotensin on volume, bicarbonate, and total protein output (p < 0.01). The CCKA receptor antagonist L364718 decreased by 80% sodium and bicarbonate response (p < 0.01) and suppressed protein response (p < 0.01) to neurotensin. Methadone reduced the response to neurotensin by 85%, vagotomy by 80%, and capsaicin pretreatment by 70%. The blockade of alpha 1-, alpha 2-, and beta-adrenoreceptors or of CCKB receptors did not change the neurotensin effect. We conclude that the mechanism of neurotensin stimulation is indirect and neurally mediated and involves nicotinic and muscarinic synapses, CCKA receptors, and, in part, capsaicin-sensitive sensory fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of nalbuphine on external pancreatic secretion in rats]. / Action de la nalbuphine sur la sécrétion pancréatique externe chez le rat.

Pancreatic secretion is controlled by neural and endocrine mechanisms. The administration of 2-desoxyglucose (2DG) to rats stimulates pancreatic secretion through a mainly vagal pathway, and provides an useful pharmacological model to study the agents (especially opiates and adrenergic drugs) which can modulate this neural pathway. In the present study, basal and 2DG-stimulated pancreatic secretion were measured in anesthetized rats. Nalbuphine had no effect on basal secretion; it antagonized 2DG-induced pancreatic stimulation in a dose-related fashion between 0.5 and 15 mg/kg iv. The effect of nalbuphine was suppressed by naloxone, but not by alpha and beta-adrenoceptor blocking agents, indicating an essentially opiate effect. In order to test whether an inhibition of kappa receptors participates in the nalbuphine effect, centrally or peripherally acting kappa agonists were associated with nalbuphine. Neither U50488H, nor ICI204448 changed 2DG stimulation and nalbuphine effect. In conclusion, the effect of nalbuphine on 2DG-stimulated pancreatic secretion was similar to that of methadone and buprenorphine, required larger doses, and seemed to mainly involve mu receptors.

Large and prolonged in vivo response of pancreatic secretion to phenylethylamide and phenylethylester derivatives of Boc-[Nle28-Nle31]CCK(26-33) in the rat.

Supramaximal doses of cholecystokinin (CCK) induce in vitro submaximal biological responses (i.e., smaller by 50% than the response to a maximal dose of CCK), desensitization and residual stimulation, and in vivo secretory inhibition and edematous pancreatitis. It has been reported previously that supramaximal doses of Boc-[Nle28-Nle31]CCK(27-32)/- phenylethylester (JMV 180) do not produce these effects. The aim of this study was to analyze the in vivo response of pancreatic secretion of the rat to a wide dose range of Boc-[Nle28-Nle31]CCK(26-33) (JMV118), an analog of CCK8 with the same activity spectrum as CCK8, to JMV180 and to Boc-[Nle28-Nle31]CCK(27-32)-phenylethylamide (JMV170). The three peptides were administered as intravenous infusions and as bolus intravenous injections. In the case of infusions, the same maximal effect was observed with all three peptides. It was obtained with 22.5 pmol/kg.min of JMV118; JMV180 and JMV170 were about 700 times less potent. In the case of bolus injections, the maximal response to JMV118 was observed with 450 pmol/kg, and the response peaked 10-15 min after the injection. Higher doses of JMV118 induced a secretory peak that was smaller and delayed relative to the moment of injection. JMV180 and JMV170 were about 500 times less potent: the maximal response was observed with 218700 pmol/kg and peaked 10-15 min after the injection. Larger doses of JMV180 and JMV170 produced neither supramaximal inhibition nor a delayed peak response, but induced a sustained stimulation of pancreatic secretion that could last more than 3 h after the injection.(ABSTRACT TRUNCATED AT 250 WORDS)

CRL41405: a drug with a new pharmacological profile on pancreatic exocrine secretion in the rat.

The recently described compound CRL41405 displays central effects suggesting possible antidepressive and awakening properties. In order to further analyze the pharmacology of this compound, its effects were studied on basal and stimulated pancreatic secretion in anaesthetized rats. CRL41405 alone (7-20 mg/kg, sc) had no effect on basal pancreatic secretion. Larger doses (67-200 mg/kg) increased basal secretion through the stimulation of cholinergic muscarinic receptors, the effect being antagonized by atropine. CRL41405 (20 mg/kg) suppressed the 2-deoxyglucose-induced (but not the acetylcholine-induced) stimulation of pancreatic secretion through an alpha-2 adrenoceptor inhibitory mechanism that was blocked by idazoxan (0.3 mg/kg, sc). In addition, a beta adrenoceptor mediated stimulation of sodium and bicarbonate excretion (blocked by propranolol) was evidenced when the alpha-2 inhibition was suppressed by idazoxan. Under alpha-2 adrenoceptor blockade, water and electrolyte stimulation by CRL41405 could be demonstrated on basal, 2-deoxyglucose-induced and acetylcholine-induced pancreatic secretion. This original profile makes CRL41405 a unique drug in pancreatic pharmacology.

Effect of modafinil on pancreatic exocrine secretion in the rat. A comparison with methadone.

Modafinil is a recently developed drug which increases wakefulness in several animal species and in man, an effect involving, at least in part, central adrenoceptors. In the present experiments, the effect of modafinil was studied on a model of neurally stimulated secretion, pancreatic secretion induced by 2-deoxyglucose (2DG) in the rat, and compared with that of the mu-opiate methadone. Modafinil induced a dose-related inhibition of 2DG-stimulated pancreatic secretion, reaching more than 80% after 250 mg/kg i.p. The modafinil effect was suppressed by idazoxan or by large doses of prazosin but not by naloxone. In addition modafinil (250 mg/kg i.p.) did not change the pancreatic response to electrical vagal stimulation. Methadone also potently suppressed 2DG-stimulated pancreatic secretion, but in contrast to modafinil, the methadone effect was blocked by naloxone, but not by the adrenoceptor antagonists idazoxan, prazosin and propranolol. It is concluded that modafinil decreases centrally 2DG-stimulated pancreatic secretion through a pathway involving alpha 1- and alpha 2-adrenoceptors, without an interaction with opiate receptors.

Synthetic CCK8 analogs with antagonist activity on pancreatic receptors: in vivo study in the rat, compared to non-peptidic antagonists.

The cholecystokinin octapeptide (CCK8)-derived synthetic peptides Boc-Tyr(SO3H)-Nle-Gly-DTrp-Nle-Asp-O-CH2-CH2-C6H5 (JMV179) and Boc-Tyr(SO3H)-Nle-Gly-DTrp-Nle-Asp-NH-CH2-CH2-C6H5 (JMV167) are antagonists of peripheral cholecystokinin (CCK) receptors in vitro. In the present study, antagonist activity of these peptides was studied on rat pancreatic secretion in vivo, and compared to those of other peptidic molecules and to the non-peptidic antagonists L364718, D-, L-, DL-lorglumide, and proglumide. The decreasing order of antagonist potencies on amylase release in vitro was L364718 greater than JMV179 greater than lorglumide greater than JMV167 greater than proglumide; JMV179 was 25 times less potent than L364718 and 300 times more potent than JMV167. The decreasing order of antagonist potencies on protein output in pancreatic juice in vivo was L364718 greater than JMV167 greater than JMV179 greater than lorglumide greater than proglumide; JMV167 was two times more potent than JMV179 and only 8 times less potent than L364718. Increased potency of JMV167, relative to JMV179 under in vivo conditions, is probably due to the slower rate of catabolism of the phenylethylamide group, relative to the phenylethylester group, since the metabolite issued from hydrolysis of the ester bond was totally inactive. This study shows that it is possible to obtain peptidic CCK antagonists, which are active and potent in vivo, and provides a quantitative measurement of potency changes occurring in vivo for several peptidic and non-peptidic antagonists.

[Action of neurotensin on duodenal alkaline secretion in rats. Comparison with pancreatic and gastric secretion]. / Action de la neurotensine sur la sécrétion bicarbonatée duodénale chez le rat. Comparaison avec les sécrétions pancréatique et gastrique.

Neurotensin is released from endocrine N cells of the ileum after meals, and might take part in the regulation of bicarbonate secretion by the pancreas and duodenum. The aim of this study was to define the effect of neurotensin on duodenal bicarbonate secretion, in comparison with its effect on gastric and pancreatic secretions. Neurotensin produced a dose-related increase of duodenal bicarbonate secretion with an ED50 of 60 pmol/kg.h. The maximal effect (about 2 times the basal level) was observed with 600 pmol/kg.h. Equimolar doses (600 pmol/kg.h) of xenopsin, neuromedin N, neurotensin 8-13 produced the same effect as neurotensin 1-13. Neurotensin fragments 1-11 and 9-13 (600 pmol/kg.h) had no significant effect on duodenal bicarbonate secretion. Indomethacin, atropine, naloxone, or the CCK antagonist L364,718 had no effect on neurotensin-stimulated bicarbonate secretion. Hexamethonium and vagotomy reduced the neurotensin effect by about 50 percent (P less than 0.05). Neurotensin produced a dose-related increase of pancreatic bicarbonate secretion with an ED50 of 150 pmol/kg.h, a decrease of gastric acid secretion with an ED50 of 2,400 pmol/kg.h, and a decrease of gastric pepsin secretion with an ED50 of 2,760 pmol/kg.h. This study shows that neurotensin stimulates duodenal bicarbonate secretion in doses which may be physiological. This biological activity depends on the presence of the C-terminal 8-13 fragment. The mechanism is complex, and depends, for approximately half, on vagal fibers (sensitive or motor), nicotinic synapses, and a non cholinergic effector. The other half of the effect, still unexplained, could be a direct effect on mucosal cells. Pancreatic and duodenal bicarbonate secretions were more sensitive to neurotensin than gastric secretion (acid and pepsin).

Control of interdigestive and intraduodenal meal-stimulated pancreatic secretion in rats.

Mechanisms of neural (vagal and cholinergic) and hormonal [cholecystokinin (CCK)] control of pancreatic exocrine secretion were studied in basal interdigestive conditions and after stimulation by an intraduodenal meal in rats equipped with a semichronic pancreatic fistula. Bile was recirculated into the duodenum, and a solution of trypsin and electrolytes was continuously infused. Pancreatic secretion was compared in control experiments, after vagotomy, and after venous infusion of cholinergic and CCK antagonists. Basal pancreatic secretion was decreased by atropine, pirenzepine, and hexamethonium and to a lesser extent by vagotomy (protein output decreased more than fluid and HCO3- outputs). The CCK antagonists L364,718 and lorglumide had no effect on basal interdigestive pancreatic secretion. Small doses of atropine (8 and 25 micrograms.kg-1.h-1) did not modify the cumulated pancreatic response to the meal, whereas larger doses (75 and 225 micrograms.kg-1.h-1) increased it by 40-85%, according to the variables. Pirenzepine and hexamethonium did not modify the pancreatic response. Vagotomy had no effect on fluid and HCO3- responses and tended to increase protein response. L364,718 and lorglumide completely inhibited the protein response and decreased the fluid and HCO3- responses by 75 and 40%, respectively. L364,718 also suppressed the increased pancreatic response induced by atropine. This work confirms the prominent role of neural cholinergic mechanisms in the control of basal interdigestive pancreatic secretion in rats. In contrast, the pancreatic protein response to an intraduodenal meal depends on CCK, whereas fluid and HCO3- responses also depend on other hormonal factors. Our results suggest that a muscarinic (probably M3) mechanism can decrease the postprandial CCK release independently of the pancreatic feedback control by trypsin.

Effects of buflomedil and its two derivatives, CRL40634 and CRL40598, on pancreatic exocrine secretion in the rat.

Buflomedil is a vasoactive drug used in the treatment of peripheral vascular disease, and seems to be an antagonist of both alpha 1- and alpha 2-vascular adrenoceptors. CRL40634 and CRL40598 are metabolites of buflomedil and also possess vasoactive properties. The purpose of this study was to investigate whether buflomedil, CRL40634 and CRL40598 have antagonist activity on the alpha 2-adrenoceptors involved in the inhibition of exocrine pancreatic secretion. In acute pancreatic fistula rats, buflomedil, CRL40634 and CRL40598 did not suppress the inhibitory effect of clonidine against 2-deoxy-glucose-induced pancreatic secretion. However, all three drugs inhibited 2-deoxy-glucose-induced pancreatic secretion, their order of potency being CRL40598 greater than CRL40634 greater than buflomedil.

[Effect of buprenorphine on external pancreatic secretion in rats]. / Action de la buprénorphine sur la sécrétion pancréatique externe chez le rat.

2-deoxyglucose stimulates pancreatic secretion through a mainly vagal neural pathway. Buprenorphine antagonized this stimulation in a dose-related fashion between 0.017 and 0.45 mg/kg. i.v. The effect of buprenorphine was suppressed by naloxone, but not by alpha and beta-adrenoceptor blocking agents. The effect of methadone was similar, at doses about ten times larger.

[Relative importance of cholecystokinin and cholinergic nerve mechanisms in the regulation of pancreatic secretion in rats]. / Participation relative de la cholécystokinine et des mécanismes nerveux cholinergiques à la régulation de la sécrétion pancréatique externe chez le rat.

Several substances modulate the function of pancreatic acinar cells in vitro through specific receptors. All of them may also act in vivo, but the relative importance of their effect under physiological conditions is highly variable. The aim of this study was to assess the respective participation of cholinergic nerves and cholecystokinin (CCK) in the interdigestive pancreatic exocrine secretion and in the pancreatic response to intragastric or intraduodenal nutrients. Unanesthetized rats, equipped with a semichronic (5 days) pancreatic fistula, were used. They received a test-meal in the stomach (42 kJ) or the duodenum (21 kJ), and were infused intravenously with an antagonist of muscarinic (atropine, pirenzepin), nicotinic (hexamethonium), or CCK (L364718, lorglumide, Boc-Tyr(SO3)-Nle-Gly-D-Trp-Nle-Asp-NH-CH2-CH2-C6H5) receptors. Basal interdigestive pancreatic exocrine secretion decreased significantly after atropine, pirenzepine or hexamethonium. Protein output decreased more (peak inhibition 60 to 80 percent according to the drugs, p less than 0.01 to p less than 0.001) than volume or bicarbonate output (peak inhibition 25 to 65 percent according to the drugs, p less than 0.05 to p less than 0.01). CCK antagonists did not change the interdigestive pancreatic secretion. The cumulated response to the intraduodenal meal did not change after hexamethonium or pirenzepin, but increased after atropine (by approximately 50 percent, p less than 0.001 for volume and bicarbonate output, and nearly 100 percent, p less than 0.05 for protein output). The CCK antagonists entirely suppressed the protein response to the intraduodenal meal, decreased the volume response by 70 percent (p less than 0.01), and the bicarbonate response by 50 percent (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

External pancreatic secretion in the rat: supramaximal inhibition induced by the cholecystokinin octapeptide [CCK(26-33)] and analogs altered on the 28-29 bond.

Supramaximal doses of cholecystokinin induce in vitro submaximal biological responses, desensitization and residual stimulation. In vivo, supramaximal inhibition and oedematous pancreatitis have been reported. The aim of this study was to analyze the in vivo response of the pancreatic secretion of the rat to a wide range of doses of CCK8 and analogs prepared by alterations of the Met(28)-Gly(29) bond, a modification that may lead to potent agonists. We used Boc-[Nle28-Nle31]-CCK(26-33) (1) and derivatives of (1) with the 28-29 peptide bond replaced by CH2-NH (2), CO-CH2 (3), CH2-CH2 (4), NH-CO (5). On infusions, the ED50's (pmol/kg.min) for protein output were 4 for CCK8 and (1), 11 for (3), 40 for (2) and (4), and 860 for (5). The relative order of the in vivo potencies was near to the one determined in vitro on isolated rat acini. On bolus injections, the maximal response was observed with 300 pmol/kg of CCK8, and peaked 10-15 min after the injection. With higher doses of CCK8, the secretory peak was smaller, and was delayed relative to the moment of the injection. Supramaximal doses of CCK analogs induced the same pattern of response; however, the peak injection delay was in some cases smaller than after CCK8. Determination of the plasma CCK levels indicated that the time of peak effect after supramaximal doses of CCK8 was delayed relative to the time of effective maximal plasma CCK levels. This suggests a slow dissociation of CCK8 from one of its pancreatic binding sites in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo activities of peptide and pseudo-peptide analogs of the C-terminal octapeptide of cholecystokinin on pancreatic secretion in the rat.

Most studies measuring the agonist and antagonist activities of CCK analogs and derivatives on the exocrine pancreas have been done with in vitro models. However, extrapolation to the in vivo situation may be sometimes hazardous, due to the catabolism of the peptides by circulating and tissue peptidases, and to their eventual interaction with various endogenous factors. The present experiments were organized to measure the efficacy and potency on pancreatic secretion of the rat in vivo of a series of CCK 8 analogs whose binding and activity had been previously measured on guinea-pig and rat isolated acini. The molecules tested were derivatives of Boc-(Nle 28-Nle 31)-CCK 26-33 (1), and comprised 2-phenylethylester derivatives, des-Phe derivatives, and a series of pseudo-peptides with a "reduced" bond CH2-NH replacing the peptide bond in position 28-29 to 32-33. They were perfused in anaesthetized rats, and the outputs of sodium, bicarbonate and total protein were measured. All of the derivatives studied had in vivo the same efficacy as (1) on the output of protein, and were 10 to 500 times less potent. For most compounds, the relative order of potencies measured in vivo was similar to that measured in vitro on amylase secretion by rat acini. However, the derivatives with reduced bonds in positions 28-29 and 29-30 were respectively 3 and 2 times less potent in vivo, relative to (1), while derivatives with reduced bonds in positions 30-31, 31-32 and 32-33 were 1.5 to 2.5 times more potent in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)