Injection Of Sodium Taurocholate Research Articles

Local administration of human pancreatic secretory trypsin inhibitor prevents the development of experimental acute pancreatitis in rats and dogs.

The objective of this investigation was to test the capacity of recombinant human pancreatic secretory trypsin inhibitor (rhPSTI) to provide prophylaxis against experimental pancreatitis. Acute hemorrhagic pancreatitis was induced by intraductal injection of sodium taurocholate in rats and by intraductal injection of bile in dogs. In one treatment group of rats the injection of taurocholate was preceded by injection of rhPSTI. In a second group of rats the rhPSTI was given intraperitoneally starting 15 min after the induction of acute pancreatitis. The survival rate in a control group of rats was 13%. In contrast, the survival rate in groups receiving rhPSTI intraductally or intraperitoneally was 80% and 63%, respectively. The survival rate in a control group of dogs was 40% at 24 h and 0% at 48 h. In contrast, all the dogs receiving a single intraductal dose of rhPSTI, either immediately before the bile injection or mixed with the bile, survived for up to 6 weeks. Detailed biochemical and immunohistologic studies in the dog indicate that, whereas rhPSTI cannot prevent the initial bile-induced injury, it does prevent the subsequent development of that injury to the point where there is massive damage to the pancreas and the surrounding tissues, and changes in blood chemistry. The development of the initial injury is, therefore, presumed to involve activation of trypsinogen. Since rhPSTI prevents the serious consequences of experimental pancreatic injury by blocking the action of trypsin, and since the pathobiochemistry of human acute pancreatitis also implies an important role for trypsin, it is possible that rhPSTI could protect humans from the pancreatitis that complicates endoscopic retrograde cholangiopancreatography and endoscopic papillotomy.

Bile salt related secretion of acid phosphatase in rat bile.

The biliary excretion of bile salts, lysosomal acid phosphatase, and total proteins were studied in rats under different experimental conditions: during bile salt loss through a bile fistula and after loading with exogenous sodium taurocholate. The experimental models were suitable to demonstrate that variations in the excretion of bile salts were associated with those of acid phosphatase output. During bile salt depletion, acid phosphatase output showed a decrease parallel to that of bile salts. Following a single i.v. injection of sodium taurocholate and during its i.v. infusion, a rapid increase of acid phosphatase excretion in bile was seen. The patterns of enzyme outputs observed after administration of sodium taurocholate suggested a bulk discharge in bile of lysosomal contents. The profiles of protein output were similar to those of acid phosphatase suggesting an association between the secretory mechanism of these bile constituents. In contrast to sodium taurocholate, 4-methylumbelliferone, which also increases canalicular bile flow, did not produce changes in the excretory patterns of the bile components studied. Therefore, the results suggested a bile salt related secretion of acid phosphatase in the rat, which may involve protein secretion in bile.

Experimental pancreatitis in the rat. — Ductal factors in sodium taurocholate-induced acute pancreatitis

Spreading of injected material and ductal resistance were studied in the rat pancreas after intraductal injection of Indian ink, human serum or sodium taurocholate. Indian ink filled the main pancreatic duct and small ductules revealing the lobular structure in macroscopic preparation. Escape into the interstitium was observed both in the macroscopic preparations and in histologic sections. Human IgG was demonstrated immunohistochemically in single acinar cells and around acinar cells after intraductal injection of human serum. The changes were most pronounced at 15 min and at 6 h after the injection but were almost resolved at 24 h. The intraductal pressure was registered during sodium taurocholate infusion. The pancreatic duct ruptured at the pressure of 82 mm Hg in average. It was concluded that in the ductal model of experimental acute pancreatitis the infusion causes ruptures in pancreatic ducts and the infusate escapes into the interstitium where it remains for several hours.

Experimental pancreatitis in the rat. Changes in pulmonary phospholipids during sodium taurocholate-induced acute pancreatitis.

Acute haemorrhagic pancreatitis was induced in rats by injecting aqueous solution of sodium taurocholate into the common biliopancreatic duct. Lecithin and lysolecithin were separated from pulmonary homogenate by thin layer chromatography and quantified by phosphorus determination. The ratio of lysolecithin to lecithin increased after the sodium taurocholate injection as well as after i.v. administration of porcine pancreatic phospholipase A2. It was concluded that phospholipase A2, released from pancreatic acinar cells into blood, may convert pulmonary lecithin into lysolecithin during acute pancreatitis. Destruction of pulmonary surfactant may contribute to the development of the adult respiratory distress syndrome as seen in patients suffering from severe acute pancreatitis.

Excretion of azlocillin and mezlocillin by the normal pancreas and in acute pancreatitis in dogs and rats.

Dogs and rats were studied to evaluate the excretion of two new acyl-ureidopenicillins, azlocillin and mezlocillin, in the pancreatic fluid. After intravenous administration of 55 mg X kg-1 of either drug, an extremely low concentration (less than 3.0 micrograms X ml-1) of both antibiotics was measured in pancreatic juice of conscious dogs. In rats, both azlocillin and mezlocillin were excreted by the pancreas in bactericidal concentrations (greater than 10 micrograms X ml-1) during the first 15 min following their injection. In anesthetized dogs and rats in which acute pancreatitis was induced by injection of sodium taurocholate into the main pancreatic duct, the tissue concentration of mezlocillin (55 mg X kg-1 i.v.) was significantly higher than in the pancreatic tissue of control animals. In both instances, bactericidal concentrations of mezlocillin were measured in the pancreatic tissue. During the first 30 min following its injection, the concentration of mezlocillin was about five times higher in inflammed pancreatic tissue than in the normal pancreas (dogs: 44 +/- 14 vs. 5 +/- 3 micrograms X g-1 tissue; rats: 67 +/- 10 vs. 13 +/- 2 micrograms X g-1). These data indicate that (1) azlocillin and mezlocillin are excreted in bactericidal concentrations by the normal pancreas only in rats but not in dogs, and (2) in both species, bactericidal concentrations of mezlocillin can be observed in the normal pancreatic tissue and in acute pancreatitis; its concentration being significantly higher in acute pancreatitis than in controls.

Effect of acute pancreatitis on pulmonary transvascular fluid and protein exchange.

We used the anesthetized sheep lung lymph preparation to examine the effects of acute hemorrhagic pancreatitis on pulmonary transvascular fluid and protein exchange. Induction of acute pancreatitis by injection of trypsin and sodium taurocholate into the pancreatic duct caused significant increases (p less than 0.05) in lung lymph flow, ratio of lymph to plasma protein concentration (L/P ratio), and transvascular protein clearance. Pulmonary arterial and pulmonary arterial wedge pressures did not change significantly, but pulmonary blood flow decreased (p less than 0.05) and pulmonary vascular resistance increased (p less than 0.05). In contrast to the effects of acute pancreatitis, left atrial hypertension caused increases in lung lymph flow that were associated with decreases in the L/P ratio. Extravascular lung water content was increased after acute pancreatitis by 25% from the value obtained in sham-operated animals in which saline was injected into the pancreatic duct. These findings indicate that acute hemorrhagic pancreatitis causes an increase in pulmonary vascular permeability to proteins. Because pulmonary vascular pressures did not change, the increased permeability may be due to the cellular and humoral factors rather than hemodynamic mechanisms.

Experimental pancreatitis in the rat. Ultrastructure of sodium taurocholate-induced pancreatic lesions.

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.

Proteolytic proenzymes in the pancreas in the course of experimental bile-induced pancreatitis in the guinea pig.

The levels of the proenzymes trypsinogen and chymotrypsinogen were studied in guinea pigs with pancreatitis induced by injection of sodium taurocholate containing the antibiotic cephalothin. This treatment inhibited the enzyme activities and prolonged the activation times of the proenzymes. Both trypsinogen and chymotrypsinogen content decreased after induction of pancreatitis, but there were no significant changes in the proenzyme contents in relation to injection-to-excision times. Sodium taurocholate and cephalothin were cleared from the pancreas in 2 h. Administration of chlorophyll-a together with the inducer caused a slight increase in proenzyme levels.

Chemical composition of fat necrosis in experimental pancreatitis in the rat.

Experimental acute pancreatitis was produced in rats by injection of sodium taurocholate into the pancreatic ducts. The intra-abdominal fat necroses produced were collected after 12 hours to 16 days for analysis of water content, free fatty acids (FFA), triglycerides, calcium, inorganic phosphate, and carbonate. Calcium was also determined in the serum at these times. High concentrations of FFA were found in the necroses, whereas the control tissue contained for the most part triglycerides and only traces of FFA. Calcium contents were initially low but increased to a molar ratio of calcium/FFA of about 0.5 at about the second day. Thereafter somewhat higher ratios were found, together with increasing amounts of phosphate and some carbonate. Water content increased successively. The findings are compatible with an initial hydrolysis of triglycerides in the necrotic areas, followed by a calcium deposition during the first 1 to 2 days. This is also supported by the fact that serum calcium was decreased durin...

ANIMAL EXPERIMENTS ON THE INHIBITION OF HÆMOLYSIS BY BLOOD SERUM. II

Repeated injection of sodium taurocholate into rabbits does not result in any increase in the inhibitory power of their serum to taurocholate hænolysis.