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Recent studies demonstrated that cholecystokinin (CCK) at physiological levels stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway. This study examined whether chemical ablation of afferent vagal fibers influences pancreatic growth and secretion in rats. Bilateral subdiaphragmatic vagal trunks were exposed, and capsaicin solution was applied. Pancreatic wet weight and pancreatic secretion and growth in response to endogenous and exogenous CCK were examined 7 days after capsaicin treatment. Perivagal application of capsaicin increased plasma CCK levels and significantly increased pancreatic wet weight compared with those in the control rats. Oral administration of CCK-1 receptor antagonist loxiglumide prevented the increase in pancreatic wet weight after capsaicin treatment. In addition, continuous intraduodenal infusion of trypsin prevented the increase in plasma CCK levels and pancreatic wet weight after capsaicin treatment. There were no significant differences in the expression levels of CCK-1 receptor mRNA and protein in the pancreas in capsaicin-treated and control rats. Intraduodenal administration of camostat or intravenous infusion of CCK-8 stimulated pancreatic secretion in control rats but not in capsaicin-treated rats. In contrast, repeated oral administrations of camostat or intraperitoneal injections of CCK-8 significantly increased pancreatic wet weight in both capsaicin-treated and control rats. Present results suggest that perivagal application of capsaicin stimulates pancreatic growth via an increase in endogenous CCK and that exogenous and endogenous CCK stimulate pancreatic growth not via vagal afferent fibers but directly in rats.

Introduction Dibutyltin dichloride (DBTC) is widely used as a stabilizer for polyvinylchloride plastics and is of particular toxicologic interest. Aim To examine the effects of DBTC on pancreatic exocrine function in isolated rat pancreatic acini. Methodology Isolated rat pancreatic acini were incubated with various secretagogues in the presence or absence of DBTC. We investigated the effects of DBTC on amylase release, receptor binding, and protein kinase C (PKC) enzyme activity. Results DBTC reduced cholecystokinin octapeptide (CCK-8)–stimulated and carbamylcholine-stimulated amylase release and the binding of [125I]CCK-8 to isolated rat pancreatic acini. Conversely, DBTC potentiated secretin-stimulated amylase release, although it slightly inhibited [125I]secretin binding to its receptors. In addition, DBTC potentiated amylase release stimulated by vasoactive intestinal peptide, 8-bromoadenosine 3´, 5´-monophosphate (8Br-cAMP) or calcium ionophore A23187, whereas it had no influence on amylase release stimulated by 12-O-tetradecanoylphorbol 13-acetate. The protein kinase C (PKC) inhibitor calphostin C abolished the DBTC-induced potentiation of amylase release stimulated by 8Br-cAMP or A23187. Moreover, DBTC caused a significant translocation of PKC enzyme activity from cytosol to membrane fraction. Conclusions These results indicate that DBTC reduces CCK-8- and carbamylcholine-stimulated amylase release by inhibiting their receptor bindings to pancreatic acini, whereas it potentiates cAMP-mediated amylase release by activating PKC in isolated rat pancreatic acini.

Considered to be an etiologic factor of acute pancreatitis, hypersecretion of pancreatic juice and digestive enzymes is often associated with hyperbilirubinemia. We explored the intracellular mechanisms through which bilirubin affects pancreatic exocrine secretory function by examining the effect of bilirubin on isolated rat pancreatic acini. Bilirubin stimulated amylase release in a concentration- and time-dependent manner, significantly increasing amylase release at concentrations >5 mg/100 ml and after 15 min of incubation. Coincubation of bilirubin with vasoactive intestinal polypeptide, 8-bromo-cAMP, or A-23187 had a synergistic effect on amylase release, whereas coincubation with CCK-8, carbamylcholine, or 12- O-tetradecanoylphorbol 13-acetate had an additive effect. Bilirubin did not affect acinar cAMP content or Ca2+efflux. Intracellular Ca2+pool depletion had no influence on bilirubin-evoked amylase release. The protein kinase C (PKC) inhibitors staurosporine and calphostin C partially but significantly inhibited bilirubin-stimulated amylase release, whereas the PKA inhibitor H-89 did not. The tyrosine kinase (TK) inhibitor genistein, phospholipase A2(PLA2) inhibitor indoxam, and PLC inhibitor U-73122 also inhibited amylase release. Bilirubin significantly translocated PKC activity from the cytosol to the membrane fraction and activated TK in cytosol and membrane fractions. These results indicate that bilirubin stimulates amylase release by activating PKC and TK in rat pancreatic acini and that PLC and PLA2partly mediate this process.

We examined the effect of troglitazone treatment on pancreatic growth in the CCK-A receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rat, an animal model for type 2 diabetes mellitus. A troglitazone-rich diet (0.2%) was given from 12 to 28 wk of age or from 12 or 28 wk of age to 72 wk of age. Fasting serum glucose concentrations in control OLETF rats increased progressively with age, which was almost completely prevented by troglitazone treatment. Insulin levels in serum and pancreatic content in the control rat markedly increased at 28 wk of age but significantly decreased at 72 wk of age compared with those at 12 wk of age, whereas those in troglitazone-treated rats were nearly the same at all ages and were similar to those in control rats at 12 wk of age. Pancreatic wet weight in control rats decreased with age irrespective of whether they were hyperinsulinemic (28 wk old) or hypoinsulinemic (72 wk old). Troglitazone treatment significantly increased pancreatic wet weight and protein, DNA, and enzyme contents compared with those in the control rats. Moreover, troglitazone treatment completely prevented or reversed histological alterations such as fibrosis, fatty replacement, and inflammatory cell infiltration. Our results indicate that troglitazone stimulates pancreatic growth in the congenitally CCK-A receptor-deficient OLETF rat not only by reducing insulin resistance and potentiating insulin action but also by suppressing inflammatory changes in the pancreas.

Troglitazone has been shown to improve insulin sensitivity and thereby exert hypoglycemic effects in various animal models and humans with insulin resistance and diabetes. The recently established animal model of naturally occurring obese diabetes, the Otsuka Long-Evans Tokushima fatty (OLETF) rat, has many similarities with human type 2 diabetes mellitus and is characterized by a high degree of insulin resistance. In the present study, we examined the effect of pharmacologic intervention with troglitazone on metabolic and histopathologic changes in OLETF rats. Two groups of rats received a troglitazone-rich diet (200 mg/100 g normal chow) from age 12 weeks (ie, before the onset of diabetes) or 28 weeks (ie, after the onset of diabetes) to age 70 weeks, while a third group received standard rat chow. The addition of troglitazone to the diet did not alter food intake or body weight gain. Troglitazone had no influence on visceral adipose depots, but it significantly reduced fasting glucose, insulin, cholesterol, triglyceride (TG), and free fatty acid (FFA) levels. Troglitazone reduced the insulin resistance and maintained the postglycemic insulin response at a normal level, and thus inhibited the development of insulin insensitivity and frank diabetes in OLETF rats up to 70 weeks of age. The pancreatic wet weight and insulin content were significantly higher in the treated rat groups versus the control rats. The morphologic changes observed in the control rats, such as fibrosis and structural disarrangement of islets, were minimal in the troglitazone-treated rats. Our study demonstrates that troglitazone, albeit at a dosage 10 to 15 times higher than that in humans, not only prevents but also reverses the metabolic derangement and histopathologic changes in genetically determined obese diabetes.

Exocrine pancreatic secretion stimulated by vasoactive intestinal polypeptide (VIP), which acts through the adenylyl cyclase-cAMP pathway, is potentiated by stimulation with other secretagogues such as CCK and carbachol (CCh). However, the potentiating effect is abolished by the same secretagogues at supramaximal concentrations. In the present study, we examined the mechanisms by which supramaximal concentrations of CCK octapeptide (CCK-8) or CCh reduce the VIP-induced potentiation of amylase secretion from isolated rat pancreatic acini. VIP-stimulated amylase secretion was potentiated by submaximal stimulatory concentrations of CCK-8 and CCh but was reduced by the same reagents at higher concentrations. Supramaximal concentrations of CCK-8 or CCh also reduced forskolin-induced potentiation of amylase release but did not reduce that induced by 8-bromo-cAMP. Moreover, supramaximal concentrations of CCK-8 or CCh inhibited VIP-stimulated intracellular cAMP production as well as adenylyl cyclase activity. 12- O-tetradecanoylphorbol 13-acetate (TPA) also reduced the magnitude of the potentiation of amylase release caused by VIP plus CCK-8 or CCh, although TPA itself decreased neither VIP-stimulated adenylyl cyclase activity nor intracellular cAMP accumulation. These results indicate that supramaximal concentrations of CCK-8 and CCh reduce the potentiating effect of VIP and forskolin on amylase secretion by inhibiting the adenylyl cyclase activity. In addition, protein kinase C is suggested to be partly implicated in this inhibitory mechanism. The mechanisms that lead to such inhibition may be interlinked but distinct from each other.

The effects of vanadate on exocrine pancreatic function were examined in isolated rat pancreatic acini. Vanadate caused a concentration-dependent stimulation of amylase release above a concentration of 1 mM. Co-incubation of vanadate with vasoactive intestinal polypeptide, 8-bromoadenosine 3′:5′-cyclic monophosphate, and the Ca 2+ ionophore A23187 produced a synergistic pattern of amylase release, whereas co-incubation with cholecystokinin octapeptide (CCK-8), carbamylcholine, and 12-O-tetradecanoylphorbol 13-acetate produced an additive effect. Vanadate alone had no influence on acinar cyclic AMP content, Ca 2+ efflux, or intracellular Ca 2+ concentration. However, preincubation with vanadate prevented the plateau phase of CCK-8-induced Ca 2+ transient increase from returning to baseline. Moreover, depletion of the intracellular Ca 2+ pool by pretreatment of acini with CCK-8 in Ca 2+ -free medium (plus ethyleneglycol bis[β-aminoethylether]-N ,N′-tetraacetic acid) had no effect on subsequent stimulation by vanadate, although it abolished the response to both CCK-8 and carbamylcholine stimulation. The protein kinase C (PKC) inhibitors staurosporine and calphostin C significantly inhibited vanadate-stimulated amylase release, whereas the protein tyrosine kinase inhibitor genistein had no inhibitory effect. Moreover, vanadate caused a significant translocation of PKC from cytosol to membrane fraction in pancreatic acinar cells. This translocation was inhibited significantly by staurosporine and calphostin C but not by genistein. These results suggest that vanadate acts directly on pancreatic acini and stimulates amylase release by activating PKC without an effect on Ca 2+ mobilization, cyclic AMP, or protein tyrosine kinase.

1. The pharmacological characteristics of a newly developed serine derivative (R)-1-[3-(3-carboxypyridine-2-yl) thio-2-(indol-2-yl)carbonylamino]propionyl-4-diphenylmethyl- piperazine (TP-680), a cholecystokinin type A (CCKA) receptor antagonist, were studied and compared with those of MK-329 and loxiglumide. 2. TP-680 showed approximately 2 and 22 times greater selectivity for peripheral CCKA receptors relative to brain CCK (CCKB) receptors than MK-329 and loxiglumide, respectively, when IC50 values for inhibition of [125I]-CCK-8 binding in isolated acini and cerebral cortex were compared. 3. TP-680 was approximately 17 times less potent than MK-329, but was 106 times more potent than loxiglumide in inhibiting 100 pM CCK-8-stimulated amylase release from rat pancreatic acini. The antagonism produced by TP-680 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. 4. TP-680 caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase release as did MK-329 and loxiglumide. However, in contrast to MK-329 and loxiglumide, TP-680 suppressed the maximal responses of CCK-8-induced amylase release in a concentration-dependent fashion, indicating that TP-680 is an unsurmountable antagonist. 5. Repeated washing of acini after a 30 min treatment with TP-680 restored the responsiveness but not the sensitivity, causing a residual inhibition on the action of CCK-8. 6. The addition of loxiglumide prior to or together with application of TP-680 protected CCK receptors from unsurmountable and irreversible antagonism by TP-680. 7. Our results indicate that TP-680 is a potent and the most selective CCKA receptor antagonist for the pancreas reported to date.

There is strong evidence that genetic factors contribute to the development of obesity in humans as well as laboratory animals. Another important factor leading to obesity is an increase in energy intake. However, it is difficult to make normal rats obese by controlling daily food intake. There is no report of normal adult male Wistar rats becoming obese and diabetic on a high-fat diet. The aim of the present study was, therefore, to make normal adult Wistar rats obese by infusing high fat and hypercaloric diet through the cannula without disturbing the free movement and to investigate the influence of an increase in the caloric intake on body weight and glucose metabolism. High-fat hypercaloric diet (360 kcal/kg body wt./day; H group) or control diet (180 kcal/kg body wt./day; C group) was continuously infused into the stomach of normal adult male Wistar rats weighing approximately 300 g through gastric cannulas for 27 days. On day 28 after a 24-h fasting, serum concentrations of aspartate aminotransferase, alanine aminotransferase, total cholesterol, triglyceride, phospholipid, and free fatty acids (FFA) were determined, and intragastric glucose loading test (2 g/kg body wt.) was performed. The average weekly body weight gain in the H group was twice as much as that of the C group (40.0 +/- 2.4 vs. 19.4 +/- 1.9 g/week, P0.001). Serum levels of triglyceride, phospholipid, total cholesterol, and FFA were significantly elevated in the H group compared to those in the C group. Liver weight in the H group was significantly higher than that in the C group and showed steatosis. Pancreas weight (-13%) as well as protein (-12%), amylase (-53%) and trypsin content (-26%) were all reduced, whereas pancreatic DNA content was significantly increased in the H group compared to those in the C group. Serum glucose and insulin concentrations before and after glucose loading in the H group were significantly higher than those in the C group. Moreover, the insulin response relative to glucose response in the H group was significantly high compared to that in the C group, indicating the presence of insulin resistance. These results indicate that feeding of high-fat hypercaloric diet makes normal Wistar male adult rat obese associated with hyperlipidemia, hyperinsulinemia, and glucose intolerance.

Pancreatic exocrine function of a new inbred strain Otsuka Long-Evans Tokushima Fatty (OLETF) rat that develops spontaneous persistent hyperglycemia was evaluated in in vitro isolated pancreatic acini and compared with that in the control Long-Evans Tokushima Otsuka (LETO) rat. Serum glucose and insulin concentrations in the OLETF rats were significantly high (glucose: 270 +/- 12 vs. 208 +/- 10 mg/100 ml, P < 0.01; insulin: 12.4 +/- 1.7 vs. 4.9 +/- 0.6 ng/ml, P) < 0.01), whereas pancreatic wet weight was significantly low (803 +/- 20 vs. 1,138 +/- 17 mg, P < 0.01) compared with those in the LETO rat. Pancreatic acini isolated from the OLETF rat were totally insensitive to cholecystokinin (CCK)-8 stimulation at concentrations of up to 100 nM. However, neither the responsiveness nor the sensitivity to carbamylcholine, bombesin, and secretin of the acini from the OLETF rat was altered or even increased, probably due to the larger amylase content in the OLETF rat acini compared with those of the LETO rat acini (31.5 +/- 2.0 vs. 13.0 +/- 1.1 Somogyi units/micrograms DNA, P < 0.01). The responsiveness to fluoride, a direct activator of guanine nucleotide-binding protein, in the OLETF rat acini was similar to that in the LETO rat, suggesting that the transmembrane signaling and effectors and subsequent intracellular signal transduction molecules in the OLETF rat acini are normal. Moreover, 125I-CCK binding to the acini prepared from the OLETF rat was totally absent. These present results indicate that the OLETF rat has a selective defect in the binding of CCK to its receptors on the acinar cell surface.

Biochemical and pharmacologic characteristics of a newly developed benzodiazepine derivative (S)-N-[1-(2-fluorophenyl)-3,4, 6,7-tetrahydro-4-oxo-pyrrolo-[3,2,1-jk] [1,4]benzodiazepine-3-yl]-1H-indole-2-carboxamide (FK480) as a cholecystokinin (CCK) receptor antagonist were examined in the isolated rat pancreatic acini and compared with those of MK-329 and loxiglumide. FK480, MK-329, and loxiglumide inhibited CCK octapeptide (CCK-8)-stimulated amylase release and binding of [125I]CCK-8 in a concentration-dependent manner, with a half-maximal inhibition (ID50) at 1.30 +/- 0.12 nM, 1.33 +/- 0.21 nM, and 1.27 +/- 0.23 microM, respectively, for amylase release, and 0.40 +/- 0.06 nM, 0.68 +/- 0.08 nM, and 0.38 +/- 0.03 microM, respectively, for [125I]CCK-8 binding. The antagonism was competitive in nature because these three compounds caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase secretion, without altering the maximal increase. The antagonism produced by FK480 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. FK480 not only prevented but also reversed CCK-8-stimulated amylase release. This compound caused a residual inhibition of the action of CCK-8. When acini were preincubated with 100 nM FK480 for 30 min, the subsequent dose-response curve to CCK-8 was shifted 10-fold toward higher concentration. Similar results were obtained with MK-329 but not with loxiglumide. FK480 appeared to be bound to the receptors on acinar cells in a slowly dissociating state.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of a newly developed diphenylpyrazolidinone cholecystokinin (CCK) antagonist LY219,057 were examined in the isolated rat pancreatic acini and compared with those of devazepide (previously designated L364,718 or MK-329). LY219,057 caused a concentration-dependent inhibition of 100 pM CCK octapeptide (CCK-8)-stimulated amylase release, with a half-maximal inhibition (ID50) at 287.5 +/- 28.4 nM and was 200 times less potent than devazepide (ID50 = 1.4 +/- 0.2 nM). The antagonism was competitive in nature because LY219,057 caused a parallel rightward shift of the dose-response curve for CCK-8-stimulated amylase secretion without altering the maximal increase. LY219,057 significantly inhibited amylase release in response to CCK-8 and cerulein but had no effect on amylase release stimulated by other receptor secretagogs or agent bypassing receptors. LY219,057, whether added at the beginning or 20 min after the CCK-8 stimulation, inhibited amylase release. This compound caused a residual inhibition of the action of CCK-8. Acini preincubated with 1.0 microM LY219,057 for 30 min at 37 degrees C were threefold less sensitive to CCK-8 than the acini preincubated without LY219,057. These results indicate that LY219,057 acts as a potent, competitive, and specific CCK receptor antagonist of the action of CCK on the exocrine pancreas.

We investigated the pharmacologic characteristics of a newly developed benzodiazepine derivative (S)-(-)-N-[2,3-dihydro-2-oxo-5-phenyl-1-[(1H-tetrazol-5-yl)methyl] -1H-1,4-benzodiazepine-3-yl]-2-indolecarboxamide (TS-941), a cholecystokinin type A (CCK-A)-receptor antagonist, in the isolated rat pancreatic acini and compared with those of well-known CCK-A-receptor antagonists, devazepide and loxiglumide. TS-941 inhibited CCK-8-stimulated amylase release concentration dependently, as did devazepide and loxiglumide, with a half-maximal inhibition (IC50) at 78.6 +/- 10.3 nM. TS-941 was approximately 23 times less potent than devazepide (IC50, 3.4 +/- 0.3 nM), but was 50 times more potent than loxiglumide (IC50, 3,966 +/- 544 nM) in inhibiting 100 pM CCK-8-stimulated amylase release from rat pancreatic acini. TS-941 had a fivefold lower selectivity than devazepide for pancreatic CCK (CCK-A) over brain CCK (CCK-B) receptors but fourfold greater than loxiglumide when IC50 values for inhibition of [125I]CCK-8 binding in isolated acini and cerebral cortex were compared. The antagonism produced by TS-941 was specific for CCK in that the effects of other receptor secretagogues or agents bypassing receptors were not altered. TS-941 caused a parallel rightward shift of the entire dose-response curve for CCK-8-stimulated amylase release without altering the maximal increase, as did devazepide and loxiglumide. TS-941, whether added at the beginning or 20 min after the CCK-8 stimulation, inhibited amylase release. TS-941 caused a concentration-dependent residual inhibition of the action of CCK-8. The acini, once incubated with a high concentration of TS-941 (10 microM; 127 times IC50) for 30 min, was 10-fold less sensitive to CCK-8 than the acini preincubated without TS-941, whereas the sensitivity and the responsiveness to CCK-8 stimulation of those incubated with a low concentration of TS-941 (1.0 microM) were similar to the control acini. These results indicate that TS-941 is a potent, competitive, and selective CCK-A receptor antagonist for the pancreas.

The aim of this study was to clarify the effect of ethanol on stimulus-secretion coupling in pancreatic exocrine secretion. We investigated the effects of 600 mM ethanol on cholecystokinin octapeptide (CCK-8)-stimulated amylase release, cytosolic free Ca 2+ concentration ([Ca 2+ ] i ) and Ca 2+ fluxes using in vitro isolated rat pancreatic acini. Ethanol, given alone, stimulated both the initial and the sustained phases of amylase release. On the other hand, ethanol inhibited only the sustained phase of amylase release stimulated by CCK-8. Ethanol also inhibited amylase release in response to fluoride, a direct activator of guanine nucleotide-binding protein, suggesting that ethanol affects intracellular signal transduction molecules. Ethanol had no influences on the initial rise but increased the sustained rise in [Ca 2+ ] i stimulated by CCK-8 and inhibited CCK-8-stimulated Ca 2+ outflux without affecting Ca 2+ influx. 8-Bromoguanosine 3' :5'-cyclic monophosphate, a membrane-permeable analogue of cGMP regulating membrane Ca 2+ -pump activity in various cells, completely reversed the ethanol-induced inhibition of amylase release and Ca 2+ outflux in response to CCK-8 as well as fluoride. Given that Ca 2+ plays a critical role in stimulus-secretion coupling in pancreatic exocrine secretion, our results indicate that 600 mM ethanol inhibits CCK-8-stimulated amylase release by inhibiting Ca 2+ -pump activity on the plasma membrane.

Summary The effects of a newly developed compound having antiulcer action, (Z)-2-(4-methylpiperazin-1-yl)-1-[4-(2-phenyl-ethyl)phenyl]-ethanone oxime hydrochloride monohydrate (MCI-727), on pancreatic exocrine secretion were studied in anesthetized rats and evaluated its preventive and therapeutic effects on acute pancreatitis in two experimental rat models. Intraduodenal administration of MCI-727 [25, 50, or 100 mg/kg body weight (wt)] stimulated a dose-dependent increase in pancreatic juice and bicarbonate output without increasing the protein output or plasma cholecystokinin concentration. MCI-727-stimulated pancreatic exocrine secretion was completely abolished by antisecretin serum but not by the cholecystokinin receptor antagonist loxiglumide (50 mg/kg body wt/h) or cholinergic receptor antagonist atropine (100 μg/kg body wt/h). In rats with acute pancreatitis induced by four subcutaneous injections of 20 μg/kg body wt cerulein at hourly intervals over 3 h, MCI-727 administered orally at a dose of 100 mg/kg body wt 30 min before the first cerulein injection significantly reduced the increases in serum amylase and lipase activity and pancreatic wet weight and induced improvements in the results of histologic examination. Moreover, when given 30 min before and 90 min after the first cerulein injection, MCI-727 had even more dramatic protective effects on all these parameters. In addition, even when administered immediately after the last cerulein injection, MCI-727 effectively ameliorated all these alterations of acute pancreatitis. However, MCI-727 had no apparent beneficial effects on the biochemical and histologic alterations of acute pancreatitis in the severe form induced by retrograde intraductal injection of 1.0 ml/kg body wt of 4% sodium taurocholate. These findings suggest that oral administration of MCI-727 stimulates pancreatic exocrine secretion by endogenous secretin release and that it has therapeutic as well as preventive effects on mild forms of acute pancreatitis in rats.

The effects of tetraprenylacetone (TPN), an acyclic polyisoprenoid with antiulcer actions, on pancreatic exocrine secretion, and its preventive and therapeutic effects on acute pancreatitis in two experimental models were studied in rats. Intraduodenal administration of TPN (0, 100, 200, and 400 mg/kg/h) caused dose-dependent increases in pancreatic juice and bicarbonate output without increasing protein output and plasma cholecystokinin (CCK) concentrations. TPN-stimulated pancreatic exocrine secretion was completely abolished by antisecretin serum but it was not by CCK receptor antagonist loxiglumide (50 mg/kg/h). In acute pancreatitis induced by four subcutaneous injections of 20 micrograms/kg cerulein at hourly intervals over, 3 h, TPN (400 mg/kg) given by an oral route either 1 h before the first cerulein injection or immediately after the last injection significantly reduced the increases in serum amylase and lipase activities and pancreatic wet wt. Pretreatment with TPN caused histologic improvements, whereas posttreatment failed to ameliorate histologic alterations. In severe type of acute pancreatitis induced by retrograde intraductal injection of 1.0 mL/kg of 4% sodium taurocholate, TPN exerted no apparent beneficial effects on biochemical and histologic alterations of acute pancreatitis. It is concluded that TPN given by an oral route stimulates pancreatic exocrine secretion through an increase in endogenous secretin release and causes beneficial effects on the experimental model of mild acute pancreatitis in rats.