Effect of somatostatin on pancreatic enzyme secretion

The effect of somatostatin (SS) on the pancreatic enzyme secretion was studied in a perfusion system using dispersed pancreatic rat acini in vitro. In addition the effect of SS on pancreatic secretion in vivo was also studied in conscious rats for comparison. In an in vitro study, 6×10^-7M SS-14 caused no significant change in amylase release when added 20 min before stimulation by 10^-5M carbamylcholine (Cch), 10^-6M A23187, 5×10^-7M secretin and 2mM dibutyryl cyclic AMP. The addition of 6×10^-7M SS-28 also caused no significant change in amylase release stimulated by 10^-5M Cch. High performance liquid chromatographic examination indicated that no degradation of either SS-14 or SS-28 occurred after reaction with dispersed acini. In an in vivo study SS-14 caused marked inhibition of basal pancreatic secretion and stimulated pancreatic secretion by bile-pancreatic juice diversion. These results indicate that SS has no direct inhibitory action on rat pancreatic secretion, and that SS may inhibit the pancreatic secretion by indirect mechanisms.     

Selectivity of quercetin inhibition on stimulated amylase release in rat pancreatic acini

Quercetin (Q) has been shown to inhibit Ca2+-dependent processes. The present study evaluates the effect of Q on amylase release stimulated by various agonists in dispersed rat pancreatic acini. Q inhibited amylase release stimulated by an optimal concentration of carbachol. The inhibition was dependent on Q concentration. Preincubation with Q was not necessary. Maximal inhibition (up to 60% of control) was reached at 50 microM of Q and was completely reversible. Full responsiveness of the acini to agonist stimulation was reestablished as early as 5 min upon the removal of Q. At 50 microM, Q inhibited stimulated amylase release by optimal concentrations of tetradecanoylphorbol-13-acetate (TPA) (10(-6) M), A23187 (3 x 10(-6) M), cholecystokinin C-terminal octapeptide (CCK-OP) (10(-9) M) and carbachol (3 x 10(-6) M), but not by vasoactive intestinal polypeptide (VIP) (3 x 10(-7) M). Instead, Q promoted amylase release stimulated by VIP. The inhibition of amylase secretion by Q occurred only at near optimal, optimal, and supraoptimal concentrations of TPA, A23187, CCK-OP, and carbachol. The potentiation effect of Q on VIP-stimulated amylase secretion was, however, seen at all concentrations of VIP used (10(-8) to 10(-6) M). Quercetin also inhibited protein kinase C activity from rat pancreas in a dose-dependent manner. Maximal inhibition (approximately 85%) was seen at 100 microM of Q. These results provide further support that the intermediary steps for stimulated enzyme secretion in pancreatic acini by TPA, A23187, CCK-OP, and carbachol involve calmodulin and/or protein kinase C, whereas VIP does not.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of H7 and staurosporine on cytosolic free calcium and amylase secretion in rat pancreatic acini.

Pretreatment of rat pancreatic acini with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) for 5 or 10 min reduced cytosolic free calcium and amylase secretion stimulated by submaximal concentration (10(-6) M) of carbachol in a dose-dependent manner. 10(-7) M TPA inhibited initial amylase secretion and had no effect on sustained secretion stimulated by 10(-6) M carbachol. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H7), a protein kinase C inhibitor, partially blocked these inhibitory effects of TPA. Cytosolic calcium concentration and initial amylase secretion were recovered with 10-100 microM H7 in TPA-treated acini. H7 was more effective than N-(2-guanidinoethyl)-5-isoquinoline-sulfonamide hydrochloride in increasing cytosolic free calcium in TPA-treated acini. TPA completely blocked an increase in cytosolic free calcium by 10 mM NaF. These findings indicated that TPA caused the inhibitory effects by means of activating protein kinase C, and suggested that protein kinase C might regulate enzyme secretion by inhibiting calcium mobilization, probably through a postreceptor-mediated mechanism.     

Distribution, release, and secretory activity of epidermal growth factor in the pancreas.

This study was designed to determine the distribution of immunoreactive epidermal growth factor (EGF) in the gastrointestinal tract and the action of this peptide on pancreatic secretion in vivo and in vitro. Immunoreactive EGF was found in large amounts in the salivary glands and the pancreas and in the pancreatic juice. EGF infused subcutaneously (50 micrograms/kg-h) in conscious rats with intact or removed salivary glands stimulated pancreatic protein secretion after 4 h of peptide infusion; this effect was completely prevented by the pretreatment with DL-difluoromethyl-ornithine (DFMO) (200 mg/kg), an irreversible inhibitor of activity of ornithine decarboxylase (ODC), a key enzyme in polyamine synthesis. EGF added to the incubation medium in concentrations ranging from 10(-10)-10(-6) M increased, in a concentration-dependent manner both unstimulated and stimulated by caeruelin or urecholine, amylase release from dispersed pancreatic acini obtained from rats pretreated in 3 h with EGF in a dose of 50 micrograms/kg-h. Spermine given at concentrations ranging from 10(-12)-10(-6) M to the freshly prepared rat pancreatic acini also increased amylase release in a concentration-related manner. DFMO injected in a single dose (200 mg/kg), before the infusion of EGF to the rats, completely abolished the stimulatory effect of EGF on amylase release, but failed to affect that of spermine. This study shows that 1. EGF is present in large amounts in pancreatic tissue and pancreatic juice. 2. EGF stimulates pancreatic secretion in vivo and amylase release in vitro from isolated rat pancreatic acini. 3. The activation of ODC and polyamine biosynthesis in acinar cells plays an important role in EGF-induced stimulation of pancreatic secretion.     

Phorbol ester potentiates VIP-stimulated amylase release in rat pancreatic acini

Vasoactive intestinal peptide (VIP) or 12-O-tetradecanoylphorbol-13-acetate (TPA) individually stimulated amylase release in dispersed rat pancreatic acini. Pretreatment of acini with TPA (10(-6) M) for 5 min at 37 degrees C potentiated their subsequent response to stimulation by VIP at a dose range of 10(-8)-10(-6) M in that the treated pancreatic acini released more amylase than could be accounted for by the additive effects of VIP or TPA acting individually. This potentiation effect of TPA was still evident when isobutyl methylxanthine was given together with VIP. Further, the maximal' dose-response curve to VIP shifted 2 log units to the left (3 x 10(-9) versus 3 x 10(-7) M). The TPA preincubation was found also to potentiate VIP-stimulated net increases in intracellular cyclic AMP (cAMP) levels. A close correlation existed between the net releases of amylase and the net increases in intracellular cAMP levels (r = 0.97). This suggested that TPA potentiated the response of rat pancreatic acini to VIP by modulating the cAMP system. The TPA as a potent activator of protein kinase C may act as a modulator of the adenylate cylase-cAMP system in rat pancreatic acini.     

Effect of ursodeoxycholate on pancreatic exocrine secretion in vitro and in vivo study]

In the present study, we examined the effect of ursodeoxycholate (UDCA) and it's taurine conjugate (TUDC) on rat pancreatic exocrine secretion using dispersed pancreatic acini (in vitro) and conscious rats (in vivo). In in vitro study 300 microM UDCA significantly increased 10(-12)-10(-9) M CCK-8 stimulated amylase release and change of intracellular Ca2+ concentration, but TUDC did not have these effects. In in vivo study intraduodenal infusion of UDCA but not TUDC stimulated pancreatic exocrine secretion. Intravenous infusion of secretin antibody decreased bicarbonate output, however, this increase was not prevented by CCK antagonist. Thus, it was suggested that UDCA has direct action on pancreatic acini and UDCA infused intraduodenally stimulates pancreatic secretion, possibly via the release of a secretin-like substance. The taurine conjugate has weak bioactivity on pancreatic exocrine secretion in both in vitro and in vivo.     

Role of prostaglandin E2 in stimulus-secretion coupling in rat exocrine pancreas.

Secretin (5 x 10(-9)-5 x 10(-7) M) increased enzyme secretion as well as cellular adenosine 3',5'-cyclic monophosphate (cyclic AMP) in a concentration-dependent manner in dispersed rat pancreatic acini. On the other hand, prostaglandin E2 (10 micrograms/ml) induced an accumulation of the cellular cyclic AMP as observed by secretin (5 x 10(-7) M) but did not stimulate enzyme secretion. Furthermore, 10 micrograms/ml prostaglandin E2 had a small inhibitory effect on the amylase release induced by maximal stimulation of secretin (5 x 10(-7) M), although the combination of prostaglandin E2 and secretin caused a bigger increase in the cellular cyclic AMP than that induced by each alone (additive effect). An inhibitory effect of prostaglandin E2 was also observed on the amylase release induced by maximal stimulation of caerulein (10(-10) M). Prostaglandin E2 had no effect on either the resting or the caerulein-stimulated free cytosolic calcium concentration of the acinar cells measured using fura-2. These results suggest that the inhibitory effect is accounted for by the functionally compartmentalized cyclic AMP produced by prostaglandin E2 or by another noncalcium mobilizing mechanism.     

Disruption of cholecystokinin (CCK)-B receptor gene did not modify bile or pancreatic secretion or pancreatic growth: a study in CCK-B receptor gene knockout mice.

Pancreatic exocrine function and bile secretion were examined in cholecystokinin (CCK)-B receptor gene-targeted mice and compared among different genotypes [i.e., CCK-B receptor gene: (+/+), wild-type; (+/-), heterozygous; and (-/-), homozygous deficient]. The histology and protein concentrations in the pancreas also were examined. Amylase release from the dispersed acini was examined in vitro by using the various doses of CCK-8, carbachol, and secretin. In vivo, the bile and pancreatic juice were collected, and the concentrations of amylase and bile acid were measured in anesthetized mice. The responses to CCK (100 pmol/kg) or acetyl-beta-methylcholine (500 nmol/kg) were examined. In vitro studies showed that the maximal effective concentrations of CCK-8 (10(-l0) M), carbachol (10(-5) M), and secretin (5 x 10(-7) M) were comparable for all genotypes. Fluid, amylase, and bile acid outputs in vivo also were comparable for all genotypes. Pancreatic wet weight and protein concentrations were not significantly different, and no abnormal findings were observed on histologic examination in any genotype. These results indicated that the CCK-B receptor has no role in pancreatic growth, exocrine secretion, or bile secretion in adult mice.     

Direct stimulation of enzyme secretion from rat exocrine pancreas by neurotensin and its naturally occurring fragments

Neurotensin stimulates amylase release from dispersed pancreatic acini at concentrations as low as 10(-15) M. The naturally occurring fragments of neurotensin (NT), NT 1-8 and NT 1-11, also stimulate amylase secretion at concentrations that occur in peripheral plasma (10(-11) M). The analogue D-Phe11 neurotensin was as potent as neurotensin itself with respect to stimulation of amylase secretion. Basal plasma neurotensin levels were approximately 10 pmol/L, a concentration that stimulates the exocrine pancreas in vitro. Increases in plasma neurotensin levels induced by infusion of neurotensin caused greater increases in secretion of pancreatic amylase than did similar changes of neurotensin concentration in vitro. These results suggest that in addition to its direct action, other factors are involved in modulation of the effects of neurotensin on pancreatic exocrine function in vivo.     

Interaction of the tyrosine phosphatase inhibitor ortho-vanadate on stimulus--secretion coupling in pancreatic acinar cells

BACKGROUND: The effect of the tyrosine phosphatase inhibitor ortho-vanadate on stimulus-secretion coupling was investigated in isolated rat pancreatic acini. METHODS AND RESULTS: Ortho-vanadate (10(3)M) reduced cholecystokinin (CCK)-8 (10(10) M)-stimulated amylase release by 40% (IC50 = 5 x 10(4) M). In contrast, preincubation with 10(3) M ortho-vanadate increased secretin (5 x 10(9) M) and vasoactive intestinal peptide (VIP) (10(7) M)-induced amylase release by 65% and 80% (IC50= 3 x 10(-4) M), respectively. 8-Bromo-cyclic adenosine-5-monophosphate (cAMP) (10(-4) M) and phorbol ester (10(-5) M)-induced secretion was increased by 60% and 50%, respectively, whereas thapsigargin-induced amylase release was not affected. Ortho-vanadate did not affect CCK-8 binding or VIP-induced cAMP synthesis in isolated acini. In contrast, preincubation with 10(-4) M ortho-vanadate resulted in a significant reduction of CCK-8-induced intracellular calcium release. In streptolysin-O-permeabilized acini, ortho-vanadate reduced calcium-induced amlyase secretion by 50%. CONCLUSIONS: The present data provide indirect evidence of a differential involvement of protein tyrosine dephosphorylation in both cAMP- and IP3/Ca(2+)-mediated pancreatic secretion. The differential effects of ortho-vanadate on cAMP- versus calcium-mediated secretion correspond to the results obtained with receptor-independent intracellularly acting secretagogues. Further experiments must define the tyrosine phosphatases involved in both signal-transduction pathways.     

Prostaglandin E analogue inhibition of pancreatic enzyme secretion

The effect of native prostaglandins and their methylated analogues on pancreatic enzyme secretion remains unclear, with previous studies reporting inconsistent results. To determine whether the E series prostaglandins directly influence pancreatic secretion, we studied the effect of rioprostil, a prostaglandin E1 analogue, and 16,16-dimethyl prostaglandin E2 (DMPGE2), a prostaglandin E2 analogue, on enzyme release from dispersed guinea pig pancreatic acini. Basal amylase release (4.3 +/- 0.6% of total acinar content) was not altered by either analogue (10(-10)-10(-5) M). A 50% inhibition of maximal cholecystokinin stimulation (10(-9) M; 28.8 +/- 1.2%) was seen with rioprostil (10(-7) M; 14.6 +/- 1.3%) and DMPGE2 (10(-6) M; 15.9 +/- 0.7%) (both p less than 0.005). Prostaglandin inhibition of carbachol-stimulated amylase was less pronounced. The most effective inhibitory dosage with maximal carbachol (10(-5) M; 30.2 +/- 1.9%) was 10(-6) M for both rioprostil (19.2 +/- 1.6%) and DMPGE2 (22.4 +/- 1.7%) (both p less than 0.005). Incubation of acini with A23187, phorbol ester, and 1-oleoyl-2-acetyl-glycerol resulted in a dose-dependent increase in amylase release that was not altered by maximal concentrations of either prostaglandin analogue. Our results indicate that rioprostil and DMPGE2 can directly inhibit pancreatic acinar secretion. This effect appears to occur before activation of the inositol phospholipid system.     

Characterization of muscarinic receptor subtypes on rat pancreatic acini: pharmacological identification by secretory responses and binding studies.

In order to identify subtypes of muscarinic receptor on the rat pancreas, the effects of new muscarinic receptor antagonists, [11-[[2-(diethylamino)-methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (AF-DX 116) and 4-diphenylacetoxy-N-methylpiperadine-methiodide (4-DAMP), on amylase secretion stimulated by carbachol and binding of [3H]quinuclidinyl benzilate (QNB) were evaluated using isolated rat pancreatic acini. Atropine, pirenzepine, AF-DX 116 and 4-DAMP inhibited carbachol-stimulated amylase release in a dose-dependent manner. All these antagonists caused a concentration-dependent rightward shift of the dose-response curve for carbachol-stimulated amylase release without altering the maximal response. Schild plots revealed that pA2 values for atropine, pirenzepine, AF-DX 116 and 4-DAMP were 9.15, 6.78, 6.09 and 8.79, respectively. Every slope of Schild plots was not different from unity, suggesting that these antagonists act as competitive inhibitors. These antagonists also inhibited the binding of [3H]QNB in a dose-dependent manner. The inhibition constants were 1.21 x 10(-9) M (atropine), 1.26 x 10(-7) M (pirenzepine), 0.57 x 10(-6) M (AF-DX 116) and 2.75 x 10(-9) M (4-DAMP). Thus, the order of inhibitory potencies was atropine > or = 4-DAMP > pirenzepine > AF-DX 116. These findings suggest that 4-DAMP-sensitive M3 receptor may play an important role in the pancreatic exocrine functions.     

Galanin inhibits amylase secretion from isolated rat pancreatic acini

The neuropeptide galanin is present in intrapancreatic nerve fibers and is known to affect the secretion of the islet hormones. Its most potent effect is thereby the inhibition of insulin secretion. In the present study, we investigated whether galanin influences amylase secretion from isolated rat pancreatic acini. Acini were isolated by the collagenase digestion technique and incubated for 45 min in a Krebs-Henseleit medium with or without addition of the cholinergic agonist carbachol or the C-terminal octapeptide of cholecystokinin (CCK-8) in the presence or absence of galanin. Carbachol, at its optimal concentration (10(-5) M), stimulated amylase secretion to 11.8 +/- 0.5% of total amylase content compared to 4.3 +/- 0.3% in controls (p less than 0.001). Galanin, (10(-8)-10(-9) M), reduced the carbachol-induced amylase secretion to 10.4 +/- 0.3% (p less than 0.01). Galanin at concentration levels below 10(-10) M had no significant effect. At 10(-8) M, CCK-8 stimulated amylase secretion to 9.7 +/- 0.6% compared with 5.2 +/- 0.3% in controls (p less than 0.01). Galanin (10(-7) M) reduced this stimulation to 8.0 +/- 0.4% (p less than 0.05). Galanin did not affect basal amylase secretion. It is concluded that the intrapancreatic neuropeptide galanin weakly inhibits carbachol- and CCK-8-induced amylase secretion from isolated rat pancreatic acini. Thus, galanin has the capability to directly affect not only endocrine but also exocrine pancreatic secretion although its effect of inhibiting amylase secretion seems weak.     

Inhibitory effect of a new proglumide derivative, loxiglumide, on CCK action in isolated rat pancreatic acini

The effect of a new proglumide derivative, loxiglumide (DL-4-(3,4-dichloro-benzoyl-amino)-5-(N-3-methoxy-propyl-pentylamino+ ++)-5-oxo-pentanic acid; CR 1505), on binding of 125I-CCK-8 and amylase release stimulated by CCK-8 was investigated in isolated rat pancreatic acini. Loxiglumide inhibited CCK-8-stimulated amylase release and binding of 125I-CCK-8 to rat pancreatic acini in a dose-dependent manner. Loxiglumide caused a concentration-dependent rightward shift of the dose-response curve for CCK-8-stimulated amylase release without altering the maximal response. Schild plots showed a slope of 0.82 and pA2 value of 7.05. The inhibitory effect of loxiglumide on amylase release was reversible. Loxiglumide significantly inhibited amylase release in response to CCK-8, caerulein and gastrin-I. However, loxiglumide had no effect on amylase release stimulated by other receptor secretagogues (bombesin, carbamylcholine, secretion and vasoactive intestinal polypeptide) or by agents bypassing receptors (A23187 and TPA). These results indicate that loxiglumide acts as a potent, competitive and specific CCK antagonist on the pancreatic acini.     

The site of action of neurotensin in the rat pancreas.

The tridecapeptide neurotensin, present in endocrine cells of the ileal mucosa and in nerve bodies of cerebral nuclei, may play a role in the physiology of exocrine pancreatic regulation. This assumption is based on two observations: Neurotensin appears in the blood stream after a fatty meal and neurotensin stimulates exocrine pancreatic secretion. There has, however, been controversy on the site of action of this peptide since some investigators did not observe an effect on the pancreas in vitro and suggested, therefore, an indirect, perhaps neural or even central site of action. In the present investigation, we compared the action of neurotensin on the exocrine pancreas in vivo in the anesthetized rat after intracerebroventricular (i.c.v.) injection and after i.v. infusion and in vitro after incubation of the pancreas in three different preparations: isolated dispersed acini, isolated lobuli, and isolated total pancreas. We found that i.c.v. application of neurotensin stimulated exocrine pancreatic secretion only when doses were applied that led to elevated peripheral plasma neurotensin levels. In vitro, the action of neurotensin was very weak and the optimal dose was integrity dependent; e.g., a concentration of 10(-4) and 10(-5) M neurotensin was necessary to stimulate amylase release from isolated acini, 10(-8) M neurotensin induced amylase release from isolates lobuli, and 10(-9) M neurotensin released amylase from the intact pancreas. Intravenously, neurotensin resulted in a greater amylase release over basal than in any of the in vitro experiments. We conclude that neurotensin acts directly on the pancreatic acini but that the sensitivity of the pancreas is greatly enhanced when the organ is intact and has normal neural and vascular communications.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of pancreastatin on pancreatic endocrine and exocrine secretion

Pancreastatin is a novel peptide that was recently purified from extracts of the porcine pancreas. The present study shows that pancreastatin (10(-9)-10(-8) M) can stimulate release of insulin from both the isolated perfused rat pancreas and from cultured rat islet cells in the presence of a low, non-insulinotropic concentration of glucose (4.2 mM). Pancreastatin (10(-9) M) can also inhibit release of insulin stimulated by a high concentration of glucose (16.7 mM). Pancreastatin, at 10(-8) M, can enhance glucose (8.3 mM) induced release of insulin in the static islet cell incubation. In addition, pancreastatin (10(-9)-10(-8) M) can inhibit, in a dose-dependent fashion, cholecystokinin (CCK)-8 stimulated release of amylase from dispersed guinea pig pancreatic acini. Pancreastatin alone, however, did not affect basal release of amylase. Our study shows that pancreastatin can exert a direct effect on both pancreatic endocrine and exocrine secretion.     

Effects of a new proglumide analogue CR 1392 on pancreatic exocrine secretion in the rat

The effects of proglumide analogue. CR 1392, on pancreatic exocrine secretion were studied in the isolated pancreatic acini and the isolated perfused pancreata of rats. In the isolated acini, CR 1392 caused a parallel rightward shift of the dose-response curve for amylase secretion stimulated by cholecystokinin octapeptide (CCK-8). CR 1392 inhibited maximally stimulated amylase release by CCK-8 (100 pM) in a concentration-dependent manner, with a half maximal inhibition (ID50) at 8.0 +/- 0.6 microM. CR 1409, another proglumide analogue, also caused a concentration-dependent inhibition (ID50: 3.2 +/- 0.4 microM). Although CR 1409 was about 2.5-fold more potent than CR 1392 in inhibiting the stimulated amylase release, 1 mM CR 1409 caused 107.4 +/- 0.9% increase in amylase release, suggesting acinar cell damage. CR 1392 (1 mM) also caused 19.9 +/- 2.3% increase in amylase release, but was less toxic than CR 1409. The antagonism produced by CR 1392 was selective for CCK and had no effect on amylase release stimulated by other receptor secretagogues or by agents bypassing receptors. CR 1392 added 20 min after the CCK-8 stimulation rapidly abolished pancreatic exocrine secretion in both isolated acini and isolated perfused pancreas. Although the inhibitory effect of CR 1392 was fully reversible in the isolated acini, the pancreata perfused with 100 microM CR 1392 for 20 min did not respond to the subsequent stimulation with CCK-8 for more than 20 min. These results indicate that CR 1392 is a potent, competitive, specific and long acting antagonist of CCK in rat pancreas.     

Effect of bile salt on amylase release from rat pancreatic acini

The effect of different bile salts on amylase release from isolated rat pancreatic acini has been studied. The bile salt-stimulated discharge of amylase could be divided into three situations, depending on the concentration of bile salt. At low concentrations, between 1 and 100 X 10(-6)M, there was a slight increase in amylase secretion, 5-7% of total, which varied with the type of bile salt but was independent of the concentration of bile salt. The release of amylase stimulated by cholecystokinin, secretin, and carbachol was not affected by bile salts at this low concentration. At slightly higher concentrations, between 250 and 1000 X 10(-6)M, there was a large release of amylase, 10-40% of total, which was dependent on both type and concentration of bile salt. This release occurred specifically for amylase and was not followed by release of either membrane-bound dipeptidylpeptidase IV or intracellularly located lactic dehydrogenase. At higher concentrations, 2000-5000 X 10(-6)M, both amylase and dipeptidylpeptidase IV and lactic dehydrogenase were released, accompanying viability changes of the cells with uptake of trypan blue.     

Inhibition of rat pancreatic exocrine secretion by neuropeptide Y: studies in vivo and in vitro.

Neuropeptide Y (NPY) is a unique 36 amino acid peptide with strong sequence homology to pancreatic polypeptide and peptide YY. In the rat pancreas, NPY-positive fibers have been demonstrated in close association with exocrine structures, suggesting a regulatory role for the peptide. In conscious rats with pancreatic ductal cannulas, amylase output stimulated by cholecystokinin octapeptide (CCK-8: 0.2 microgram kg - 1 h -1) was dose-dependently inhibited by intravenous NPY infusion (20, 40, and 80 micrograms kg-1 h-1). Inhibitory effects were rapid in onset but reversed with cessation of NPY infusion. With continuous NPY infusion (40 microgram kg-1 h-1), prolonged inhibition of amylase output by the vagal stimulant 2-deoxyglucose (100 mg kg-1) was observed (greater than 50% inhibition in each of none consecutive 10-min periods). In contrast, NPY infusion in doses of 20, 40, or 80 micrograms kg-1 h-1 produced no alteration in immunoreactive somatostatin levels. In vitro, NPY incubation (10(-13)-10(-8) M) produced no change in basal amylase release from dispersed, purified acinar cells. In addition, co-incubation of NPY (10(-8)-10(-6) M) with CCK-8 (10(-13)-10(-8) M) produced no inhibition of CCK-stimulated amylase release from dispersed acini. In contrast, NPY (10(-6) M) produced significant inhibition of amylase release from pancreatic lobules that had been stimulated by 75 mM potassium (135 +/- 11% versus 177 +/- 18% of basal level) or by 25 microM veratridine (196 +/- 19% versus 398 +/- 152%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory effects of pirenzepine on cholecystokinin and secretin stimulation on exocrine and endocrine rat pancreas

Effects of pirenzepine, a newly developed anticholinergic drug, on exocrine and endocrine pancreatic functions stimulated by cholecystokinin octapeptide and secretin were studied in both isolated pancreatic acini and the isolated perfused pancreas of rats. In the isolated acini, pirenzepine did not have any significant effect on cholecystokinin-inducec amylase release but caused an inhibition of amylase secretion initiated by secretin and shifted the dose-response curve for amylase secretion to the right. In the isolated perfused pancreas stimulated with 100 pM cholecystokinin octapeptide, addition of 10 M pirenzepine before as well as after 20 min of perfusion significantly inhibited pancreatic juice flow but not enzyme output. In contrast, pirenzepine caused an inhibition of secretin-stimulated enzyme secretion, but not pancreatic juice flow. The stimulatory effect of both cholecystokinin octapeptide and secretin on insulin secretion was also inhibited by pirenzepine. The present data indicate that pirenzepine may have an influence on pancreatic exocrine and endocrine function by inhibiting endogenous cholinergic activity of the pancreas when a large dose is given.