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To challenge the osmotic hypothesis of biliary NaCl secretion and bile formation, experiments were performed in anaesthetized pigs. An increase in plasma osmolality of 7 +/- 1 mosm/kg H2O induced by intravenous sucrose infusion decreased NaCl secretion, NaHCO3 secretion, and bile flow by 36 +/- 3%, 34 +/- 2%, and 34 +/- 3%, respectively. There was no change in the biliary concentration of NaCl and NaHCO3. When bile acids were infused intravenously, the secretion of 1 mmol bile acids caused an osmotic flow of 12.0 ml bile containing 0.92 mmol NaCl and 0.30 mmol NaHCO3 in an isotonic solution. Bile acids are therefore much stronger choleretic substances than NaHCO3. When the plasma sodium concentration was increased to 200 mM, bile flow increased by 31 +/- 5% and the secretion of bile acids, NaHCO3, and NaCl was increased by 63 +/- 3%, 96 +/- 4%, and 93 +/- 4%, respectively. These data are consistent with osmotic transport as the main mode of bile formation, but diffusion could be responsible for a small fraction. A raised plasma sodium concentration stimulates osmotic formation of bile by increasing both the bile acid-dependent and -independent secretion through stimulation of biliary bile acid and NaHCO3 secretion.

Three groups of rats were twice given cysteamine subcutaneously in a dose of 20 mg/100 g body weight. Nine of 10 controls developed severe duodenal ulcers. In contrast, the ulcer formation was inhibited significantly in the rats submitted, before exposure to cysteamine, to a bile diversion operation consisting of jejunopylorostomy and Roux-en-Y anastomosis without gastric resection. However, rats submitted to the same operation but drinking a solution with 5 mmol/l sodium salts of taurocholic and glycocholic acid, 1:3, developed severe duodenal ulcers after cysteamine injections (8 of 10). The conclusion is that neither the chemical cysteamine nor hydrochloric acid alone can be made responsible for cysteamine-induced duodenal ulcer in the rat, but that bile salts clearly enhance the ulcerogenic property of cysteamine.

Sodium taurocholate injected into the pancreatic duct system of the rat caused acute haemorrhagic pancreatitis. The pancreatic lesions were immediate and characterized by interstitial oedema, extensive necrotic changes of the acinar cells, and haemorrhages during the first 24 h after the injection. In animals surviving 72 h there were marked acinar atrophy and pancreatic fibrosis. The mortality increased according to the amount of sodium taurocholate injected. Except for necrosis of occasional liver cells, other organs examined were histologically normal. This investigation created an experimental model for studying the pathogenesis of acute pancreatitis. The results support the hypothesis that bile can initiate acute haemorrhagic pancreatitis.

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.

Sodium taurocholate was administered to the in situ perfused liver of male Sprague Dawley rats at various rates below (57 and 114 nmol/min -g liver) and above (228 and 456 nmol/min -g liver) its biliary transport maximum (Tm) to study its effect on bile formation. As expected, bile flow increased with increasing dose until maximal bile salt excretion was reached. By contrast, during taurocholate infusions exceeding the taurocholate-Tm, bile flow and bile salt excretion decreased. Under those conditions, a given bile salt excretion was associated with a smaller volume of bile. A relationship between these effects and the concentration of taurocholate in the perfusate (160 to 860 nmol/ml) was suggested by the observation that bile formation returned toward normal when the taurocholate concentration was lowered by exchange of the perfusate.

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.

Olsalazine is a novel compound presently under development for the treatment of ulcerative colitis. Olsalazine sometimes causes diarrhoea; one of the possible explanations could be an increased load of bile acids in the colon. Bile acid ileostomy output was therefore measured enzymatically and after oral administration of tauro-23-[75Se]selena-25-homocholic acid (SeHCAT) in eight subjects during intake of placebo or olsalazine. The bile acid output showed great individual variations during both treatment periods, but there was no indication that olsalazine interfered with bile acid handling in the terminal ileum.