ABSTRACT
Experimental porcine pancreatitis was induced by the injection of taurocholate into the pancreatic duct. Recombinant human pancreatic secretory trypsin inhibitor (25 mg) was administered to each animal in one of three different ways: into the pancreatic duct (n = 5), into the abdominal cavity adjacent to the pancreas (n = 2) or intravenously (n = 2). The intrapancreatic turnover was assessed during 6 h using a microdialysis technique. The intraglandular concentration, measured by enzyme-linked immunosorbent assay, was highest after injection of rhPSTI into the pancreatic duct and substantially lower after intravenous and intraperitoneal administration. The intrapancreatic half-life of the inhibitor after intraductal administration was considerably longer (3-6 times) in pigs with pancreatitis than has previously been found in the normal gland. These facts argue in favour of the intraductal administration route in future trials of antiprotease treatment in acute pancreatitis.
Subject(s)
Pancreas/metabolism , Pancreatitis/metabolism , Trypsin Inhibitor, Kazal Pancreatic/administration & dosage , Trypsin Inhibitor, Kazal Pancreatic/pharmacokinetics , Abdomen , Animals , Female , Injections, Intravenous , Male , Microdialysis , Pancreatic Ducts , Pancreatitis/chemically induced , Pancreatitis/drug therapy , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacokinetics , Swine , Taurocholic AcidABSTRACT
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.
Subject(s)
Cholecystokinin/metabolism , Gastrointestinal Hormones/pharmacology , Growth Substances , Intercellular Signaling Peptides and Proteins , Pancreas/metabolism , Taurocholic Acid/pharmacology , Trypsin Inhibitor, Kazal Pancreatic/pharmacology , Animals , Gastrointestinal Hormones/administration & dosage , Intestinal Mucosa/anatomy & histology , Intestinal Mucosa/chemistry , Intestinal Mucosa/drug effects , Male , Pancreas/drug effects , Rats , Rats, Inbred Strains , Taurocholic Acid/administration & dosage , Trypsin/metabolism , Trypsin Inhibitor, Kazal Pancreatic/administration & dosageABSTRACT
We examined the protective effect of human pancreatic secretory trypsin inhibitor (PSTI), a specific trypsin inhibitor secreted from pancreatic acinar cells into the pancreatic duct, on cerulein-induced acute pancreatitis in conscious rats. The protective effect of human PSTI-RS, an analogue of PSTI with Arg-44 to Ser substitution which has a longer half-life in vitro, was also examined. Intraperitoneal administration of a pharmacological dose of cerulein to conscious rats induced acute pancreatitis, characterized by light microscopy as cellular disorganization of the acini and interstitial edema. Intravenous infusion of human PSTI (10, 50 or 250 micrograms/rat/h) into rats with cerulein-induced acute pancreatitis decreased their pancreatic wet weight and plasma amylase concentration. It also caused a dose-dependent decrease in vacuoles in acinar cells and interstitial edema. Human PSTI-RS, which has a longer half-life in vivo, was more effective than native PSTI at the same dose rate (10 micrograms/rat/h) in reducing pancreatitis. These results suggest that human PSTI may have a beneficial effect on acute pancreatitis.