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There have been numerous reports that infusion of either natural bile or bile salts into the duodenum evokes a rapid increase in pancreatic secretion through the release of the hormone secretin from the duodenal mucosa. We have extended this observation by the demonstration of an additional late increase in secretion which persisted for many hours and have sought to identify the processes underlying this increase. In anaesthetised rats, infusion of 20 mM taurocholate into the duodenum caused a staircase-like increase in the weight of pancreatic secretion which extended over many hours during which, the HCO[Formula: see text] and protein output of the secretion showed only minimal changes. This effect was also reproduced with intra-duodenal infusion of natural bile which was inferred to act though its taurocholate content. Since the stimulatory action was also obtained with superfusion of taurocholate or natural bile onto the small intestine and by intravenous injection of taurocholate, it was concluded that taurocholate acted by being absorbed into the bloodstream and then by exerting a stimulatory action on the exocrine pancreas. This action was inhibited by puromycin (a protein synthesis inhibitor), by furosemide (a Na( + )/K( + )/2Cl(-) cotransporter inhibitor), though not by SITS (an inhibitor of Cl(-)/HCO[Formula: see text] exchange). The long lasting increase in pancreatic serous secretion would be consistent with the possible activation of gene transcription by taurocholate leading to increased activity of the Na( + )/K( + )/2Cl(-) cotransporter through which the acinar cells increased their secretions.

Objectives: The outcome from acute pancreatitis depends on the severity of systemic complications. To be able to investigate mechanisms underlying the development of these systemic complications in acute pancreatitis in both wild-type and genetically engineered animal models, a mouse model of severe necrotizing pancreatitis was developed and characterized., Methods: Pancreatitis was induced by retrograde infusion of sodium taurocholate into the common bile duct in mice. After determining the optimum volume and concentration of taurocholate, the pancreatic damage and systemic inflammatory response were compared with those in cerulein-induced pancreatitis., Results: Pancreatic damage was higher in taurocholate pancreatitis than hyperstimulation-induced pancreatitis (24 hours: cerulein, 5.8 +/- 0.2 points; taurocholate, 14.8 +/- 0.8 points; P < 0.001) and mortality reached up to 60% within the first 24 hours after taurocholate administration. Pulmonary damage was detected, as measured by an increase in albumin in bronchoalveolar lavage fluid only in taurocholate-induced pancreatitis (12 hours: cerulein, 97.1 +/- 22.83 mg/g of protein; taurocholate, 234.0 +/- 32.7 mg/g of protein; P < 0.001). Furthermore, plasma interleukin 6 concentration was significantly elevated in mice with taurocholate-induced pancreatitis (12 hours: cerulein, 2.6 +/- 6.1 pg/mL; taurocholate, 2168.8 +/- 941.7 microg/mL; P < 0.001) as compared with all other groups., Conclusions: Taurocholate pancreatitis is a reliable model for severe necrotizing pancreatitis in mice with significantly greater pancreatic damage and systemic inflammatory response in comparison with cerulein-induced pancreatitis.

Bile salts are intraduodenal stimulants of basal pancreatic secretion. This study aims to show whether the three main bile salts of human bile differ in their action on pancreatic secretion, and whether they enhance or inhibit each other after combined use. Furthermore, the effect on gastroenteropancreatic peptide release is evaluated. Twelve subjects were provided with a gastroduodenal double-lumen tube. Equimolar doses (0.6 mmol) of taurocholate (322 mg), taurodeoxycholate (313 mg), and a combination of both stimuli were given intraduodenally. Another 12 subjects received taurochenodeoxycholate (313 mg) instead of taurocholate. Volume, bicarbonate, trypsin, and lipase were determined in duodenal aspirates. Cholecystokinin, pancreatic polypeptide, and somatostatin were measured radioimmunologically in plasma samples. All bile salts and combinations exerted a significant hydrokinetic and ecbolic effect. The hydrokinetic response of the combined stimuli was significantly higher as compared with taurocholate and taurochenodeoxycholate, respectively. As far as concerns the ecbolic response, the difference was significant only for trypsin output as compared with taurochenodeoxycholate. Plasma cholecystokinin rose significantly only after the combined stimuli. Pancreatic polypeptide and somatostatin increased significantly after all stimuli, except pancreatic polypeptide after taurocholate. Combined use enhances the hydrokinetic and ecbolic effects of single bile salts. Cholecystokinin may, hereby, be involved as a mediator of the ecbolic effect. Pancreatic polypeptide release indicates cholinergic mechanisms as further mediators. As demonstrated by somatostatin release, counter-regulatory mechanisms are also triggered by intraduodenal bile salts.

Recent findings have suggested that oxygen-derived free radicals play an important role in the development and progression of acute pancreatitis. Therefore, the present study was designed to investigate whether metallothionein, a free radical scavenger, can protect against acute pancreatitis. Rats were injected intraperitoneally with zinc, followed by either an infusion of cerulein at 10 micrograms/kg for 4 h or a retrograde injection with 100 microliters/100 g body weight of 5% sodium taurocholate into the pancreaticobiliary duct, in order to induce acute pancreatitis. Zn administration significantly increased the levels of both metallothionein and reduced glutathione in the pancreas; the metallothionein levels reached a peak of 83-fold of normal levels after 24 h. The indications of acute pancreatitis, as well as the mortality, were improved by Zn treatment before the onset of acute pancreatitis. Immunohistochemical studies showed that metallothionein accumulated in the acini of the pancreas in the Zn-treated groups, and with strong staining around the periphery of the vacuoles in the group treated with both Zn and cerulein. These findings suggested that Zn increased both metallothionein and glutathione levels in the pancreas and exerted a beneficial effect against ceruleinor taurocholate-induced acute pancreatitis in rats.

The role of luminal bile salts (taurocholate) in regulation of rat pancreatic secretion was examined by studies on the effects of luminal stimulants on the pancreas during infusion of various concentrations of taurocholate into the duodenum of conscious rats. Rats with external bile and pancreatic fistulae were used. For 24 h before the experiment, pancreatic juice was excluded from the intestine but bile was continuously returned to the duodenum. From the beginning of the experiment, 8-200 mM of taurocholate was infused at a rate of 1 ml/h instead of returning the bile. Pancreatic juice was collected for a 2-h period and then 2 micrograms of pancreatic secretory trypsin inhibitor-61 (PSTI-61) (= monitor peptide) or partially purified putative CCK-releasing peptide from rat intestine (intestinal CCK-RP) was injected into the duodenum (1 ml/min). Continuous infusion of taurocholate maintained a constant rate of pancreatic secretion, except at a concentration of 8 mM, which resulted in a slight increase in pancreatic secretion. Both PSTI-61 and intestinal CCK-RP significantly increased pancreatic secretions during infusion of 20 or 40 mM taurocholate, but had no significant effect during infusion of 80 or 200 mM taurocholate. Therefore, higher concentrations of taurocholate in the intestine prevented the stimulatory effects of luminal stimulants, probably by preventing the latter from reaching CCK cells.

A model of acute necroto-hemorrhagic pancreatitis was prepared by injecting 5% sodium taurocholate-trypsin solution directly into the pancreatic duct of the rat. Fourty eight hours before the preparation of acute pancreatitis, intraductal injection of 0.1%, 0.2% or 0.4% sodium taurocholate-trypsin solution as mild irritant was able to decrease the mortality to 27%, 17% and 17% respectively. The maximal elevation of the serum amylase concentration in acute pancreatitis was decreased to 43%, 47% and 54%, respectively. Microscopic examination of the pancreatic tissue of the rats which were alive after pretreatment of mild irritants showed that the acute pancreatitis was milder and there was a tendency to change to chronic pancreatitis. Thus, we conclude that there is a phenomenon of adaptive cytoprotection on the exocrine pancreas in rats. The mechanisms of the phenomenon remain to be explored.

Acute hemorrhagic pancreatitis was induced in rats by injecting sodium taurocholate into the common biliopancreatic duct. The extent of pancreatic necrosis was quantified in histological sections during the course of the disease. The proportion of necrotic acini was low, although the amount of necrosis increased from 3.3% of pancreatic parenchyma at 15 min to 10.5% at 12 h. The degree of ischemia in the inflamed pancreas was estimated by extracting intravenously injected toluidine blue from the gland. The amount of the dye in the gland decreased progressively during 12 h to 58.8% of the amount in normal pancreas. The development of pancreatic edema was studied by recording the water content of the gland. The edema was maximal at 3 h and resolved partly in 12 h after the induction of the disease. Necrosis and ischemia become progressively more pronounced in the edematous pancreas during sodium taurocholate-induced acute hemorrhagic pancreatitis. This kind of pathophysiologic course is also thought to characterize human pancreatitis. The present simple model of acute hemorrhagic pancreatitis in the rat is suitable for quantitative observations on the development of pancreatic damage under various experimental conditions.

Necrotic lesions caused by the intraductal injection of sodium taurocholate in rat pancreas were studied by electron microscopy. The early (1 and 15 min after the injection) ductal cells were often necrotic. The acinar cell damage was characterized by mitochondrial swelling, vesiculation of the granular endoplasmic reticulum, and dissolution of cellular membranes. At later time intervals (1, 3, and 6 h) there were necrotic acinar cells with heterogeneous cytoplasmic inclusions representing degenerative cell organelles and their remnants. At 6, 12, and 24 h there were autophagic vacuoles in sublethally damaged acinar cells. The zymogen granules seemed relatively well preserved throughout the experiment. The vascular lesions consisted of endothelial detachment, extravasation of erythrocytes, thrombosis, and poikilocytosis. It was concluded that the initial cell injury was caused by the detergent action of the injected bile salt.

In the anesthetized cat duodenal perfusion with Na-taurocholate (TC, 0.2 M, pH 6.1, 290 mosmol, 45 ml x h-1) stimulated pancreatic volume (0 to 326 +/- 236 mg x 10 min-1) and bicarbonate secretion (0 to 34.2 +/- 4.1 mumol x 10 min-1), whereas pancreatic enzyme output was sparse. Simultaneously with the pancreatic response, bile flow increased from 139 +/- 74 mg to 484 +/- 146 mg x 15 min-1 (p < 0.05). During perfusion of the upper jejunum both pancreatic and biliary responses were significantly lower than the responses to duodenal TC perfusion (p < 0.05). During TC perfusion of the terminal ileum there was no response from the pancreas, whereas the increase in bile flow accounted only for an increase in the bile-acid-dependent fraction. The concomitant stimulation of both the hydrokinetic function of the pancreas and the bile-acid-independent bile flow might be mediated by a release of secretin.

Luminal sequestration of bile salts with cholestyramine and the oral administration of bile salts represent current forms of therapy for some diseases. We have recently reported that secretion of these salts exerts negative feedback control on the release of cholecystokinin (CCK). The purpose of this study was to examine the effects of long-term alterations of luminal concentrations of bile salts on CCK target organs, the pancreas and gallbladder. The bile salt pool in adult guinea pigs was either enriched by feeding 0.5 percent sodium taurocholate or depleted by feeding 2 percent cholestyramine. Pancreatic growth, gallbladder contractility, the concentration of cholecystokinin receptors in the gallbladder muscle, and meal-stimulated plasma levels of cholecystokinin were significantly stimulated by feeding the bile salt sequestrant cholestyramine to guinea pigs. Administration of the bile salt taurocholate produced the opposite effects. Inhibition of CCK release by bile salts and up-regulation of CCK receptors by CCK may be the mechanisms responsible for the actions of bile salts on CCK target organs.