16-16-dimethylprostaglandin-e2 and Pancreatitis

The aim of this work is to establish a relationship between prostanoids and oxygen free radicals in the early stages of acute pancreatitis induced by sodium taurocholate and to study the possible cytoprotective effects of exogenous prostaglandin administration. Tissue prostanoid production (6-keto-prostaglandin F1 alpha, thromboxane B2, and prostaglandin E2) was studied after induction of an acute pancreatitis by intraductal administration of 3.5% sodium taurocholate (0.1 ml/100 mg). The effect of previous administrations of 16,16-dimethyl prostaglandin E2 (0.5 microgram/kg), indomethacin (20 mg/kg), or superoxide dismutase (13 mg/kg) was evaluated. Early pancreatitis induced significant increases of the three prostanoid levels as soon as 5 min after taurocholate administration. The administration of 16,16-dimethyl prostaglandin E2 was able to maintain the tissue prostanoid production at basal levels while superoxide dismutase treatment only partially prevented the increase of 6-keto-prostaglandin F1 alpha. On the other hand, indomethacin pretreatment, as expected, prevented the taurocholate-induced early prostanoid biosynthesis but increased the mortality, suggesting that endogenous prostanoids play a role in cellular defense mechanisms. The effect of superoxide dismutase suggests that oxygen free radicals are responsible, in part, for prostanoid enhanced biosynthesis in the earlier stages of necrohemorrhagic pancreatitis.

Topics: 16,16-Dimethylprostaglandin E2; 6-Ketoprostaglandin F1 alpha; Acute Disease; Animals; Dinoprostone; Free Radicals; Indomethacin; Male; Pancreas; Pancreatitis; Prostaglandins; Rats; Rats, Wistar; Superoxide Dismutase; Taurocholic Acid; Thromboxane B2

Oxygen free radicals and prostaglandins are implicated in the pathophysiology of acute pancreatitis, although their mechanisms of action remain unclear. We have studied the effect of administration of exogenous 16,16-dimethyl prostaglandin E2 and superoxide dismutase on oxygen free radical production in acute pancreatitis. For this purpose, five experimental rat groups were studied: group I, control; group II, sodium taurocholate-induced acute pancreatitis; group III, same as group II but with previous administration of 16,16-dimethyl prostaglandin E2; group IV, same as group II but with previous administration of indomethacin; and group V, same as group II but with previous administration of superoxide dismutase. In sodium taurocholate-treated rats, xanthine dehydrogenase is completely converted to xanthine oxidase within the first 5 min with subsequent oxygen free radical production while in 16,16-dimethyl prostaglandin E2-treated rats this enzyme transformation does not occur. In the superoxide dismutase-treated group xanthine oxidase activation is partially prevented. These data suggest that xanthine oxidase is the main source of oxygen free radicals, which contribute to extending the cellular damage in sodium taurocholate-induced acute pancreatitis.

Topics: 16,16-Dimethylprostaglandin E2; Acute Disease; Animals; Edema; Enzyme Activation; Free Radicals; Indomethacin; Lipase; Lipid Peroxidation; Male; Pancreatitis; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxide Dismutase; Taurocholic Acid; Xanthine Dehydrogenase; Xanthine Oxidase

Perfusion of the main pancreatic duct in cats with a dilute solution of bile salts increases ductal permeability. Subsequent perfusion of a permeable duct with activated pancreatic enzymes results in acute edematous pancreatitis. Simultaneous infusion of 16-16 dimethyl-PgE2 converts edematous pancreatitis to acute hemorrhagic pancreatitis (AHP). AHP may be associated with a reduction in pancreatic blood flow; it is certainly associated with increases in microvascular permeability. Low dose dopamine is a splanchnic vasodilator and may also reduce pancreatic microvascular permeability through beta agonist effects. In these studies, we investigated the effect of dopamine in an established feline model of biliary AHP. We also studied its effect on blood flow in both normal pancreas and after induction of AHP. We found that dopamine significantly reduced the degree of pancreatic inflammation, even when administered up to 12 h after onset of biliary AHP. However, the drug had no significant effect on blood flow either in normal pancreas or in the gland affected by hemorrhagic pancreatitis. We concluded that the effect of dopamine was most likely due to its ability to reduce pancreatic microvascular permeability.

Topics: 16,16-Dimethylprostaglandin E2; Acute Disease; Animals; Biliary Tract Diseases; Capillary Permeability; Cats; Disease Models, Animal; Dopamine; Infusions, Intravenous; Pancreas; Pancreatitis; Regional Blood Flow

We studied the conversion of acute edematous pancreatitis (AEP) to acute hemorrhagic pancreatitis (AHP) in an experimental model in cats. In the model, 16,16 dimethyl PgE2 effects this conversion by increasing microvascular permeability. First, we induced AEP in cats and then gave PgE2 at increasing intervals after the induction of AEP to see how long an interval would still allow conversion. In 6 groups of cats, PgE2 was administered for 2 h, starting at 2, 4, 6, 8, 10, or 12 h after the creation of AEP. Twelve h later, the cats were sacrificed and the pancreases were graded for inflammation and hemorrhage. Significant pancreatic hemorrhage did not occur when the PgE2 was administered at 12 h compared to 2 h. Next, we determined that PgE2 still retained its ability to increase pancreatic vascular permeability when administered 12 h after the creation of AEP. This was done by perfusing a marker molecule through the MPD (fluorescein isothiocyanate labeled dextran: FITC-D, mol wt 20,000) and then finding it in portal venous blood (PVB). The presence of FITC-D in PVB signified increased vascular permeability, since normally none was present. We concluded that conversion of AEP to AHP was possible during the first 12 h after induction of AEP. Lack of conversion at 12 h was not caused by a lack of vascular reactivity at that time.

Topics: 16,16-Dimethylprostaglandin E2; Acute Disease; Animals; Capillary Permeability; Cats; Disease Models, Animal; Edema; Gastrointestinal Hemorrhage; Pancreatic Juice; Pancreatitis; Time Factors

Acute edematous pancreatitis was produced in rats by subcutaneous administration of caerulein. Pancreas weight, pancreas histology and plasma amylase were used as endpoints to quantitate the severity of the syndrome. A caerulein dose of 10 micrograms/kg.hour produced the most severe pancreatitis, whereas at 5 micrograms/kg.hour the values were half-maximal. The pancreatic lesions were characterized by edema, formation of cytoplasmic vacuoles, leukocytic infiltration, necrosis, and with time (12-hour caerulein infusion) dilated acini. Cholecystokinin octapeptide also produced pancreatitis when given at ten times the dose required for caerulein (50 micrograms/kg.hour instead of 5 micrograms/kg.hour). Carbachol did not induce pancreatitis. Two prostaglandins, 16,16-dimethyl prostaglandin E2 injected subcutaneously and prostaglandin E2 infused subcutaneously, dose dependently prevented caerulein-induced pancreatitis (pancreatic edema, leukocytic infiltration, and necrosis) and reduced the number and size of intracellular vacuoles. The ED50 were 15 to 25 micrograms/kg for 16,16-dimethyl prostaglandin E2 and 90 micrograms/kg.hour for prostaglandin E2. Neither prostaglandin, given at doses inhibiting the development of pancreatitis, prevented the retardation of gastric emptying caused by caerulein, a finding suggesting that the prostaglandins may act specifically on the effect of caerulein on the pancreas but not on caerulein receptors in gastric smooth muscle. Indomethacin, an inhibitor of prostaglandin synthesis, and methscopolamine bromide, an anticholinergic agent, had no effect on caerulein-induced pancreatitis. We concluded that prostaglandins of the E type prevent the development of caerulein-induced pancreatitis. The mechanism by which prostaglandins protect the pancreas may involve stabilization of lysosomes within the acinar cells and inhibition of intracellular activation of pancreatic digestive enzymes.

Topics: 16,16-Dimethylprostaglandin E2; Amylases; Animals; Carbachol; Ceruletide; Cholecystokinin; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Indomethacin; Infusions, Parenteral; Organ Size; Pancreas; Pancreatitis; Prostaglandins E, Synthetic; Rats

Acute edematous pancreatitis was induced in cats by perfusing activated pancreatic enzymes through their pancreatic ducts. The ducts had been made permeable to large molecules by one of two techniques. The cats either received ethanol (2 ml/kg every 8 h) and aspirin (25 mg/kg every 8 h) orally for 48 h or had their pancreatic ducts perfused for 1 h with 7.5 mM glycodeoxycholate. When the same procedure was followed, but using 16,16-dimethyl prostaglandin E2 (dmPGE2) (2 micrograms/kg X h infused intravenously for 1 h before and during ductal perfusion with activated enzymes), hemorrhagic pancreatitis developed instead. To investigate whether an increase in pancreatic blood flow or microvascular permeability (both caused by dmPGE2) was important in this phenomenon, we tested the effects of isoproterenol (which increased blood flow) and histamine (which increased microvascular permeability) in the model. Thus in similar experiments, either isoproterenol (0.3 micrograms/kg . min) or histamine phosphate (2 micrograms/kg . min) was infused instead of dmPGE2. The animals that received histamine also developed hemorrhagic pancreatitis. Those that received isoproterenol did not. These observations suggested that an increase in microvascular permeability in the pancreas converted edematous pancreatitis to hemorrhagic pancreatitis. These findings suggest also that clinical studies using prostaglandins to treat patients with pancreatitis should be approached with caution.

Topics: 16,16-Dimethylprostaglandin E2; Animals; Aspirin; Capillary Permeability; Cats; Ethanol; Glycodeoxycholic Acid; Hemorrhage; Histamine; Isoproterenol; Pancreas; Pancreatic Juice; Pancreatitis; Prostaglandins E, Synthetic; Regional Blood Flow

In a model of acute pancreatitis which requires that pancreatic enzymes leak from a permeable duct, we studied the role of intravenous enterokinase (195,000 daltons) in pancreatic enzyme activation. Anesthetized cats were given intravenous 16,16-dimethyl prostaglandin E2 to increase pancreatic blood flow and microvascular permeability. In some animals the permeability of the pancreatic duct was increased by perfusion of the duct with glycodeoxycholic acid (7.5 mM). Endogenous enzyme secretion was stimulated by IV CCK and secretin. Some cats also received enterokinase intravenously. Those animals that received PGE2, glycodeoxycholate, and enterokinase all developed pancreatitis. When any of these agents were not given the pancreases appeared normal. These findings were consistent with the hypothesis that intravenous enterokinase leaked from small pancreatic blood vessels into the pancreatic parenchyma and/or ducts where activation of pancreatic enzymes occurred. The development of pancreatitis appeared to require an increase in both microvascular and ductal permeability.

Topics: 16,16-Dimethylprostaglandin E2; Acute Disease; Animals; Capillary Permeability; Cats; Disease Models, Animal; Enteropeptidase; Glycodeoxycholic Acid; Pancreas; Pancreatic Ducts; Pancreatitis; Particle Size; Permeability

Pharmacological attempts to alter the course of experimental pancreatitis in the opossum were made using synthetic 16, 16-dimethyl prostaglandin E2 (16, 16-dm PGE2). Anatomically, the opossum has an elongated ampulla resulting in a supraduodenal pancreatic duct-common bile duct junction allowing for bile reflux pancreatitis to be produced by ligating the distal common bile duct. Preliminary evaluation demonstrated that at 72 hours common bile duct ligation distal to the pancreatic duct orifice produced pancreatitis comparable in severity to that produced by a Pfeffer loop. When the oppossum distal common bile duct was ligated, serum amylase concentrations progressively increased from control values of 182 +/- 43 to 742 +/- 62 Somogyi units/dl at 5 hours. Administration of 0.2 microgram-kg-1-min-1 16, 16-dm PGE2 significantly decreased the hyperamylasemia associated with bile reflux pancreatitis and, in addition, decreased the pancreatic gland weights when compared to control values. Subsequent evaluation of the administration of 75 micrograms-kg-1 16, 16-dm PGE2 every 12 hours for 72 hours to opossums with distal common bile duct ligation demonstrated no significant differences in serum amylase concentrations when compared to control values. Histologic evaluation of the pancreas glands at 72 hours demonstrated increased glandular integrity when the pancreas glands from the opossums receiving 16,16-dm PGE2 were compared to the glands subjected to distal common bile duct ligation alone. This report identifies several favorable characteristics in the course of experimental pancreatitis associated with the administration of a synthesis PGE analog at the onset of the inflammatory process.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 16,16-Dimethylprostaglandin E2; Amylases; Animals; Bile Reflux; Biliary Tract Diseases; Disease Models, Animal; Female; Male; Opossums; Pancreatitis; Prostaglandins E, Synthetic

This study was performed to determine the effects of exogenous prostaglandin and a prostaglandin synthetase inhibitor on experimental pancreatitis in mice. An ethionine-supplemented choline-deficient diet was used to induce pancreatitis in 4-6-wk-old Swiss Webster mice. Mice were injected subcutaneously with 16,16-dimethyl prostaglandin E2 (0.1, 1.0, 10 micrograms X kg-1 X day-1), indomethacin (0.05, 0.5, 5 mg X kg-1 X day-1), or saline for 7 days. The ethionine-supplemented choline-deficient diet was introduced 24 h after the first injection, and animals ate the test diet for 48 h. A 55% mortality was observed in control animals (n = 100) treated with carrier alone. Treatment with 10 micrograms X kg-1 X day-1 of 16,16-dimethyl prostaglandin E2 significantly decreased (p less than 0.01) mortality to 12% (n = 100). Improved survival was accompanied by a significant (p less than 0.05) decrease in the pancreatic content of free chymotrypsin and a decrease in histologic damage. Treatment with 5 mg X kg-1 X day-1 of indomethacin (n = 30) significantly (p less than 0.01) increased mortality in diet-treated rats from a control rate of 55% to 100%. These studies demonstrate a protective effect of prostaglandin on the pancreas and suggest a role for endogenous prostaglandins in the pathophysiology of pancreatitis.

Topics: 16,16-Dimethylprostaglandin E2; Acute Disease; Animals; Chymotrypsin; Diet; Female; Indomethacin; Mice; Pancreas; Pancreatitis; Prostaglandins E, Synthetic; Trypsin; Trypsinogen