Exocrine Enzymes Research Articles

自発的運動習慣が膵酵素活性及び膵腺房細胞に及ぼす影響

The authors have found that compulsory training using treadmill running increases pancreatic weight, protein content, and enzyme activity in hypertrophied acinar cells in rats. The purpose of the present study was to investigate the effect of voluntary running exerise on the exocrine pancreas in rats. Female F344 rats were divided into control, compulsory training, and voluntary training groups. The compulsory trained rats were exercised for 60 min on a treadmill (final speed, 35 m/min), 5 days a week, for 8 weeks. The voluntary trained rats were exercised on a voluntary basis on a wheel ergometer with a load of 30% of their body weight every day. Mean running distance for the voluntary training group was 5.2±1.0 km/day. Final body weight for the compulsory and voluntary training groups was significantly lower than for the control group. Soleus muscle weight and citrate synthase activity of the plantaris muscle for the compulsory and voluntary training groups were significantly higher than for the control group. Pancreatic wet weight, protein content, and amylase and lipase activities for the compulsory and voluntary training groups were significantly higher than for the control group. Pancreatic wet weight, protein content, and amylase and lipase activities for the compulsory and voluntary training groups were significantly higher than for the control group. Total DNA content of whole pancreas in the voluntary training group was significantly higher than for the control and compulsory training groups. Electron micrographs revealed that acinar cells obviously hypertrophied and zymogen granules increased in the compulsory and voluntary training groups rats compared with the compulsory group. These results suggest that voluntary training increases pancreatic weight and protein content in hypertrophied and/or hyperplasic acinar cells, which in turn increases synthesis and the storage of exocrine pancreatic enzymes.

Postoperative pancreatic exocrine function influences body weight maintenance after pylorus-preserving pancreatoduodenectomy

Background: Most patients who undergo pylorus-preserving pancreatoduodenectomy (PPPD) are able to gain their weight postoperatively. However, sometimes patients experience a lack of weight gain even at long term after PPPD. The aim of this study was to examine factors influencing a body weight change after PPPD. Methods: In 34 Japanese patients with PPPD, 28 clinical parameters were assessed as possible factors affecting body weight maintenance at long term (1 year) after the operation by univariate and multivariate analyses. Results: Univariate analysis showed that long operation time ( P = 0.02), extended retroperitoneal lymph node dissection ( P = 0.0005), intraoperative radiotherapy ( P = 0.02), adjuvant postoperative chemotherapy ( P = 0.02), histopathological diagnosis of pancreatic cancer ( P = 0.02), postoperative ulceration ( P = 0.007), and insufficient postoperative pancreatic exocrine function ( P = 0.002) were significantly related with the lack of weight gain at long term after PPPD. Multivariate analysis regarding the seven profound factors revealed that the insufficient postoperative pancreatic exocrine function significantly affected the lack of weight gain after PPPD. The use of ordinary amount of pancreatic exocrine enzymes did not influence the weight gain after PPPD ( P = 0.23). Conclusions: In patients refractory to an ordinary amount of medicine, a large dosage of enzymes may be necessary to gain weight after PPPD.

Estradiol Has a Direct Impact on the Exocrine Pancreas as Demonstrated by Enzyme and Vigilin Expression

Background: Estrogen receptors have been found in the exocrine pancreas; however, the exact role of estrogen in pancreatic enzyme synthesis and secretion remains to be elucidated. Vigilin, a multi-KH domain protein, is part of a tRNA-containing ribonucleoprotein complex and may be a suitable marker for stimulation of the translational machinery. In the present study, we investigated the influence of estradiol and compared it to CCK on the expression of vigilin, trypsin and amylase in rat pancreatic acini. Methods: Acini were isolated and incubated with CCK or estradiol. The change in amylase and trypsin levels in the medium and in cell extracts were determined using a photometric method. The change in vigilin mRNA and protein expression were determined by RT-PCR and Western blotting, respectively. Results: Treatment of isolated exocrine pancreatic cells with estradiol caused stimulation of amylase and trypsin production and inhibition of secretion, while treatment with CCK showed only a minor effect on enzyme production and resulted mainly in a stimulation of secretion. Further we found an increase in vigilin mRNA and protein expression in acini stimulated with both CCK-8 and estradiol. Conclusion: Our data suggest that estradiol may play a role in inducing exocrine enzyme production but not secretion, and that vigilin, as a marker for translational activity, is stimulated in parallel to the pancreatic enzymes: amylase and trypsin.

Effect of glycolysis on pancreatic microcirculation and cellular functions in anesthetized rats.

It has been reported that aerobic glycolysis in the pancreas contributes less than 10% to oxidative phosphorylation based on in vitro experiments using pancreatic tissue segments. However, its contribution to aerobic glycolysis in vivo remains uncertain. We investigated the effect of inhibiting glycolysis on O2 metabolism in microvessels, exocrine enzyme secretion, and the blood glucose level in the pancreas of anesthetized rats in vivo. Inhibition of glycolysis, by superfusing the pancreas of anesthetized rats with 2-deoxyglucose (10 mM) or sodium fluoride (2 mM), significantly decreased O2 release from erythrocytes flowing in the microvessels by 30-40%. Inhibiting glycolysis did not affect the exocrine secretion of pancreatic juice but decreased the secretion of total protein by approximately or = to 40%. Inhibiting glycolysis decreased blood glucose levels by approximately or = to 40% and increased glucagon release twofold. Aerobic glycolysis may play more important roles in the regulation of O2, metabolism, pancreatic exocrine enzyme secretion and the blood glucose level in rat pancreas.

Circulating antibodies against an exocrine pancreatic enzyme in type 1 diabetes.

In this article, we report the identification of a new autoantigen in type 1 diabetes originating from the exocrine pancreas. This antigen is a pancreatic enzyme termed bile salt-dependent lipase (BSDL). We show that antibodies present in the sera of newly diagnosed type 1 diabetic patients recognize BSDL and more specifically the COOH-terminal mucin-like region of the protein. Therefore, we engineered the COOH-terminal peptide of BSDL and demonstrated that autoreactivity was linked to specific glycosylation sites by at least two glycosyltransferases: the Core 2 beta(1-6)N-acetylglucosaminyltransferase and the alpha(1-3) fucosyltransferase FUT7. We next examined the prevalence of circulating anti-BSDL antibodies in type 1 diabetic patients and found 73.5% positivity (25 sera among 34 patients tested) at onset, whereas only 8.4% of normal individuals (7 of 83) were positive. Within a cohort of first-degree relatives of diabetic patients followed prospectively until development of diabetes, 6 of 19 (31.6%) were also positive. Interestingly, two prediabetic individuals were already positive for anti-BSDL antibodies (Abs), while islet cell cytoplasmic Abs and antibodies to GAD65, IA-2, and insulin were not detected. Anti-BSDL autoantibodies were weakly or not detected in patients suffering from pancreatitis or pancreatic adenocarcinoma or in patients with Graves' disease. Although autoreactivity to BSDL in prediabetic and newly diagnosed diabetic patients might reflect cross-reactivity, our results strongly suggest that in addition to pancreatic beta-cells, acinar cells may be also affected in type 1 diabetes.

The ontogeny of the small intestinal epithelium.

The primary factors in feeding premature infants are dependent on the development and maturation of digestion and absorption. The maturation of digestive and absorptive functions of carbohydrates, proteins, fats, minerals, and vitamins in the young premature infant were determined in relation to availability of hydrolytic enzymes, such as lipases, proteases, amylases, glucosidases, and lactase. The feeding is dependent on the ability of the premature infant to secrete salivary enzymes, gastric acid, pepsin, pancreatic exocrine enzymes, the presence of enterohepatic circulation, and the hydrolytic and absorptive capacity of the entercocyte. To evaluate the complexity of the gut maturation process, we proposed a unified concept where the ontogeny of the gastrointestinal system is the result of the following four major determinants: genetic endowment, intrinsic developmental and biological clock, endogenous regulatory mechanisms, and environmental influences. The developmental clock represents a predetermined temporal sequence of happenings in ontogeny that is inherently controlled. By 20 weeks of gestation, the anatomic differentiation of the fetal gut has progressed to the extent that it resembles that of a newborn. Secretory and absorptive functions, however, develop at different rates; the intestinal absorptive process is only partially available before 26 weeks of gestation, whereas gastric and pancreatic secretion is only basal and can be stimulated only partially even in the full-term newborn period. Regulatory mechanisms control the expression of the genetic endowment at various stages in gastrointestinal development. Neural-hormonal factors play major roles in the ontogeny of the gut. Adrenalectomy, hypophysectomy, and thyroidectomy delay the development of the gut. Administration of glucocorticoids or thyroxine at the critical stage in maturation causes early appearance of enzymes within the intestine. Other hormones that are potentially important in regulating gastrointestinal development include cholecystokinin, gastrin, secretin, which have trophic effects on the gastrointestinal tract, and insulin, insulin-like growth factors, and epidermial growth factor. The development of gastrointestinal secretory function, particularly in response to hormonal stimulation, has received considerable attention. The degree of response of the target cell is determined not only by the amount of effective hormone reaching it but also by the number and affinity of receptors on its surface. Human newborns have high levels of gastrin in their sera, yet have low acid output. Exogenous gastrin is an ineffective stimulant despite the presence of seemingly "anatomically developed" parietal cells. It seems that neither endogenous nor exogenous gastrin has an effect on the target cell. If one accepts the role of circulating gastrin levels in the regulation of its own receptor, one can hypothesize the absence of a regulatory effect of gastrin in the newborn period. It was shown that hormonal regulation of migrating activity by motilin is also absent in the preterm and term infant. Plasma levels of motilin in neonates are comparable to those found in adults, but migrating motor complexes occur in the absence of cycling of plasma concentrations. Interestingly, however, the motilin receptor appears to be present. In conclusion, the feeding mode content, concentration, and volume of the very young premature infant can be assessed by the development of digestive and absorptive capacity and gut motility. The concomitant changes in gut hormones and regulatory peptides during ontogeny and feeding will add a new dimension in the understanding of when, what, and how to feed the very young premature infant.

A preliminary study of the activation of endogenous pancreatic exocrine enzymes during automated porcine islet isolation.

The activation of endogenous pancreatic enzymes during automated pancreas digestion may be detrimental to islet isolation. In this report we assessed the activation of trypsin, chymotrypsin, elastase, carboxypeptidases A and B, phospholipase A2, and lipase using a porcine model. Four islet isolations were examined. Duplicate aliquots were taken from the automated circuit at 5-min time intervals up to the completion of pancreas digestion (approx 60 min). One aliquot was activated in vitro with exogenous trypsin in order to convert the enzymes into their active non-"proform," with the exception of trypsinogen, which was activated with exogenous enterokinase. This was done to assess the percentage activation of each individual enzyme (total potentially activatable enzyme release). The extent of activation between isolations was extremely variable. During the closed (recirculating) circuit phase of pancreas digestion there were both gradual and rapid increases in the levels of enzymes released. Peak activity of enzyme activation varied from 13 to 30 min; similarly, total potentially activatable peaks occurred between 13 and 38 min. Lipase and carboxypeptidase B showed greater than 70% activation, chymotrypsin, carboxypeptidase A, and phospholipase A2 between 50% and 70% activation, and trypsin and elastase less than 20%. There were up to 30-fold differences between the four islet preparations. In summary, it is unlikely that poor islet yields are soley explained by variations between collagenases; the variable activation of endogenous pancreatic exocrine enzymes is also likely to be influential to porcine islet yields.

Increased Gene Expression of Exocrine Pancreatic Enzymes Induced by Food Deprivation during Postnatal Development

Increased Gene Expression of Exocrine Pancreatic Enzymes Induced by Food Deprivation during Postnatal Development

The potential contribution of rejection to survival of transplanted human islets

Clinical islet transplantation is potentially the treatment of choice for people with type I diabetes. Rates of insulin independence in islet transplant recipients are disappointingly low, and the relative contribution of the rejection response compared with the loss of islet function is still unclear. We have compared the mixed lymphocyte islet coculture (MLIC) with the mixed lymphocyte acinar cell coculture (MLAC) and the mixed lymphocyte response (MLR) as in vitro models of allograft rejection to MHC and tissue-specific antigens expressed by human islets and acinar cells. The reduced number of MHC class II antigen-positive cells in islets and acinar tissue compared to those in the stimulator lymphocyte population of the MLR, correlated with a reduced proliferative response in the MLIC and MLAC. Enhancement of MHC class II antigen expression by islets using TNFα and IFNγ did not increase their stimulatory capacity in the islet cocultures, which may have been due to a corresponding absence of B7 expression. The lack of T cell proliferation to acinar cells despite cytokine-induced enhancement of MHC class II expression and detectable B7 expression appeared to be due to the inhibitory effect of exocrine enzymes on lymphocyte proliferation. In conclusion, we suggest that a rejection response to islets and acinar tissue is possible due to the accompanying MHC class II-positive cells and that, in this model, islet and acinar-specific antigens do not significantly contribute to that response. Acinar cells may have the potential to stimulate lymphocytes directly, but this was not evident by proliferation in the MLAC. Rejection appears to contribute to the low survival rate of human islet allografts, but it is unlikely that this is the sole explanation, and other factors should be considered.

Total parenteral nutrition influences both endocrine and exocrine function of rat pancreas.

The aim of this study was to examine the effect of total parenteral nutrition (TPN) on the endocrine and exocine function of the pancreas. Endocrine function was investigated using an intravenous glucose tolerance test (IGTT) in rats with TPN for 7 or 14 days. Exocrine function was evaluated by measuring amylase secretion from isolated acini as well as pancreatic weight, water content, protein, and enzymes after 7 days of TPN. When the TPN rats were compared with the controls, the glucose tolerance curve after an IGTT was unchanged, the basal plasma insulin levels were slightly lower and the insulin secretory response to intravenous glucose was markedly impaired. No differences could be seen between the insulin response after 7 days and that after 14 days of TPN. The weight of pancreas, the total content and concentration of pancreatic protein, and the total amylase content of the pancreas were lower, whereas the total content of both chymotrypsin and trypsin was higher. The concentration of DNA remained intact, whereas the total DNA content decreased. The levels of lipolytic enzymes, except for carboxylesterlipase, were unaffected. After TPN treatment, the insulin secretory response to glucose is impaired, the exocrine pancreas is hypoplastic and the storage pattern of pancreatic exocrine enzymes is altered.

Effect of thyroxine on pancreatic digestive enzymes and ornithine decarboxylase gene expression in neonatal rats.

Thyroxine has been shown to play a role in the development of exocrine pancreatic enzymes in neonatal rats. To further evaluate the regulatory mechanisms for thyroxine in pancreatic development, we examined the changes in the expression of pancreatic enzymes (amylase and trypsinogen) and ornithine decarboxylase (ODC) genes following daily injection of thyroxine for 5 and 10 days to neonatal rats (5 days old). Total pancreatic proteins and DNA contents as well as the activity of ODC and exocrine enzymes were significantly increased after 5 and 10 days of thyroxine treatment. These increases were associated with parallel alterations (to three to fourfold rise) in steady-state mRNA levels of both amylase and trypsinogen. In contrast, thyroxine only produced a 57-68% increase in steady-state ODC mRNA levels. These data suggest that thyroxine stimulated the express of amylase and trypsinogen genes partly due to increased transcriptional rate and/ or decreased mRNA turnover. Thyroxine also stimulated ODC gene expression. However, the stimulatory mechanisms may involve transnational or posttranslational regulation of ODC and are independent of thyroxine effects.

Expression of inter-alpha-trypsin inhibitor light chain (bikunin) in human pancreas.

Expression of inter-alpha-trypsin inhibitor light chain (ITI-LC, also known as bikunin or urinary trypsin inhibitor) was examined in various human tissues. By reverse-transcription polymerase chain reaction, the mRNA was detected not only in the liver, a known site of ITI-LC production, but also in the kidney, heart, lung, and pancreas. By RNA blot analysis, the mRNA was also detected in the pancreas and liver, but not in the kidney, heart, or lung. The ITI-LC protein was immunohistochemically detected along the surface of pancreatic acinar cells. These results indicate the apparent expression of the gene for ITI-LC in the pancreas. ITI-LC protein on the surface of pancreatic acinar cells may play an important role in preventing autodigestion by exocrine enzymes such as trypsinogen and chymotrypsinogen.

Does high pancreatic duct pressure compromise the duct mucosal barrier function to pancreatic exocrine proteins?

The effect of duct pressure on the barrier function of the pancreatic duct mucosa to both activated and nonactivated pancreatic exocrine enzymes was studied in a feline model. The cat main pancreatic duct was perfused from the tail to the head of the gland with rat pancreatic juice at high duct pressure (40 cm H2O). In a first experiment, nonactivated pancreatic juice was perfused. Analysis of the juice for loss of fluid volume (measurement by weight) and for loss of individual proteins (two-dimensional isoelectric focusing/sodium dodecyl sulphate gel electrophoresis, reversed phase-high performance liquid chromatography) after duct passage showed that pancreatic secretions were completely recovered from the duct lumen. In another experiment, applying the same pressure, the duct was perfused with activated pancreatic juice. Morphologic analysis showed a preservation of the pancreatic duct mucosal integrity immediately after duct perfusion and absence of pancreatic inflammatory lesions 24 h after duct passage. We conclude that the pancreatic duct mucosa is impermeable to the leakage of pancreatic exocrine proteins from the duct lumen at duct pressure < or = 40 cm H2O. Flow of activated pancreatic juice along the pancreatic duct at duct pressure < or = 40 cm H2O does not cause acute pancreatitis. These data do not support the hypothesis that leakage of pancreatic juice from the duct lumen caused by high intraductal pressure due to duct obstruction initiates acute pancreatitis.

Intraileal carbohydrate regulates canine postprandial pancreaticobiliary secretion and upper gut motility

Background & Aims: The effect of nutrients in the distal small intestine or colon on postprandial upper gut function is incompletely understood. The aim of this study was to determine if carbohydrate in the ileum or proximal colon of dogs affects postprandial pancreaticobiliary secretion, gastrointestinal transit, and circulating concentrations of certain gastrointestinal regulatory peptides. Methods: Seven dogs were prepared with permanent infusion and aspiration catheters in the duodenum and ileum and an infusion catheter in the cecum. Coincident with eating a meal containing liquid and solid markers, ileal or colonic (n = 5 dogs for each) infusions were begun of isosmolar 0.9% NaCI or carbohydrate in a 3:1 ratio of starch to glucose. Pancreatic enzyme output, bile acid delivery, gastrointestinal transit, and plasma concentrations of pancreatic polypeptide, neurotensin, and peptide YY were measured for 6 hours postprandially. Results: Carbohydrate infusion in the ileum, but not in the proximal colon, increased amylase secretion and plasma peptide YY, slowed gastric emptying of liquids and solids, slowed small intestinal transit, and decreased bile acid delivery into the duodenum ( P < 0.05 in each). Conclusions: Carbohydrate in the ileum regulates postprandial exocrine pancreatic enzyme secretion and other postprandial upper gut functions. Peptide YY may play a role in this regulation.

Normalization of pancreatic exocrine enzymes by islet transplantation in diabetic rats.

In an effort to evaluate the effectiveness of islet transplantation in correcting exocrine dysfunction, young male Lewis rats were made diabetic by i.v. streptozotocin injection. Diabetes status was confirmed by decrease in insulin and increase in blood glucose and glycosylated hemoglobin levels. Pancreatic islets were isolated from age-matched control syngeneic rats by collagenase digestion followed by purification through a Ficoll gradient. Islets (approximately 1200) were grafted to the liver by intraportal injection to animals at 8 weeks after diabetes was established. Transplanted rats were sacrificed 4 weeks after correction of hyperglycemia. Diabetes resulted in decrease in body weight. Transplantation reversed the body weight loss and led to a body weight gain. Diabetes resulted in a decrease in pancreatic amylase (1.4 +/- 0.4 U/mg protein compared with a control value of 121.9 +/- 3.2 U/mg protein) and a slight increase in lipase (87.3 +/- 5.5 U/mg protein compared with a control value of 69 +/- 4.7 U/mg protein). Transplantation completely normalized amylase (132.2 +/- 25.0 U/mg protein) and lipase (56.3 +/- 3.9 U/mg protein) in spite of an imperfect correction of blood insulin, glucose, and glycosylated haemoglobin levels in these rats. These data demonstrated that islet transplantation is very effective in correcting the exocrine enzyme changes resulting from diabetes. Evaluation of steady-state levels of amylase mRNA in these groups of animals by Northern blots showed a decrease in the amylase mRNA level in diabetes and a return to that of control in transplanted rats, indicating that the control of amylase expression is most likely at the pretranslational level.

Pancreas Transplantation and Dysuria

Bladder drainage of the pancreatic graft remains the most common technique in pancreatic transplantation. Graft and patient survival is superior to duct injection and bowel drainage techniques. However, several urological complications develop as a result of bladder drainage. We report 6 cases of the dysuria syndrome after combined kidney/pancreas transplantation. Retrograde urethrography or cystoscopy showed extravasation from the bulbous urethra in all cases, which was most likely caused by activated proteolytic exocrine enzymes from the transplanted pancreas. Minor urethral trauma due to Foley catheterization or cystoscopy may pre-dispose patients to this syndrome. Short-term urethral catheterization or suprapubic catheter drainage led to resolution in all cases. A high index of suspicion coupled with early intervention is recommended for patients with the dysuria syndrome.

Transitional cells in the regenerating pancreas.

We examined the spectrum of intermediate cell types in the regenerating pancreas as duct epithelial cells progressed through their differentiation pathway to become mature endocrine cells. The model used was transgenic mice in which the pancreatic islets continue to grow during adulthood, unlike normal mice whose islet cell formation ceases early in life. Because the intermediate cells migrated into islet-like clusters at specific locations, we propose a specific pathway for islet development. Endocrine cells are derived from duct cells co-expressing a duct cell antigen, carbonic anhydrase II (CA II) and an exocrine enzyme, amylase. The CA II/amylase cells become amylase/endocrine intermediate cells as they exited from their lumenal location. The abluminal amylase/endocrine cells continue to differentiate to multihormone-bearing young endocrine cells, which migrated to form clusters with other differentiating endocrine cells.

High Strength Pancreatic Exocrine Enzyme Capsules Associated with Colonic Strictures in Patients with Cystic Fibrosis

High Strength Pancreatic Exocrine Enzyme Capsules Associated with Colonic Strictures in Patients with Cystic Fibrosis

Enhancement of pancreatic secretion by dietary protein in rats with chronic diversion of bile-pancreatic juice from the proximal small intestine.

The regulation of exocrine pancreatic enzyme secretion by dietary protein is known to depend on pancreatic protease activity in the lumen of the proximal small intestine in rats, which is a negative feedback mechanism. We observed whether dietary protein stimulates pancreatic secretion in rats with a 7-day diversion of bile-pancreatic juice (BPJ) from the proximal small intestine under unrestrained and unanesthetized conditions. In the chronically BPJ-diverted rats, hypersecretion of proteases in the fasting state were observed, and pancreatic enzyme secretion was significantly increased after feeding of a 25% casein diet over the hypersecretion in the fasting state. The amplitude of the increments of the secretion after feeding in diverted rats was comparable to that in normal rats. Dietary fat decreased stimulated secretion by the protein diet in the diverted rats, but not in the normal rats. We conclude that there is an upper small intestinal BPJ-independent mechanism for response of pancreatic enzyme secretion to dietary protein, and that dietary fat inhibits pancreatic secretion in diverted rats. The distal small intestine or colon may contribute to the inhibition.

Cyclosporine A Inhibits Protein-Kinase-C-Mediated Amylase Release from Isolated Rat Pancreatic Acini

The present study was performed to characterize a direct influence of cyclosporine A (CsA) on exocrine pancreatic enzyme secretion. CsA inhibited dose-dependently amylase release from isolated rat pancreatic acini in response to carbachol or cholecystokinin octapeptide (CCK-8). A significant reduction in amylase release by 17% was observed at 0.2 mumol/l CsA (p < 0.001) when compared to controls. At 0.2 mmol/l, CsA reduced amylase release in response to both secretagogues by maximally 45%, whereas basal secretion was not affected. CsA had no influence on CCK-8-stimulated increase in intracellular Ca2+ concentrations or amylase release in response to the Ca2+ ionophore A 23187. In contrast, the dose-response curve for amylase secretion induced by the phorbol ester phorbolmyristate-13-acetate was shifted to the right without a reduction of the maximal secretory response. Unexpectedly, vasoactive-intestinal-polypeptide- and secretin-stimulated acinar secretion was not diminished by CsA. In isolated pancreatic lobules exposed to 0.1 mmol/l CsA, amylase release stimulated by cerulein or veratridine was reduced by 26.7 +/- 2 or 28.3 +/- 4%, respectively. CsA had no influence on the displacement of 125I-Bolton-Hunter-labeled CCK-8 from acinar CCK receptors. The ultrastructure of cellular organelles in isolated lobules was not altered after incubation with 0.1 mmol/l CsA for 60 min. Our data suggest that CsA interferes with protein-kinase-C-mediated signal transduction in isolated rat pancreatic acini, without affecting cAMP-dependent signalling.