ceruletide and Hypertrophy

The recent observation that the severity of pancreatitis is inversely related to the extent of apoptosis in five experimental models of the disease has suggested the possibility that apoptosis might protect against pancreatic injury in pancreatitis. This hypothesis was tested by inducing pancreatitis in mice during a phase of extensive apoptosis. Mice were fed a raw soya diet for five weeks to stimulate pancreatic growth and then switched to a regular chow diet for 27 hrs to permit involution of the hypertrophied gland. That involution is characterized by extensive apoptosis of acinar cells. Pancreatitis was induced, in either control mice or mice undergoing pancreatic involution, by repeated intraperitoneal administration of a supramaximally stimulating dose of caerulein (50 microg/kg given each hr for 12 hrs). The magnitude of hyperamylasemia, degree of inflammation, and extent of necrosis were reduced in the mice receiving caerulein during pancreatic involution. We conclude that induction of apoptosis may protect against acinar cell injury and reduce the severity of pancreatitis.

Topics: Acute Disease; Amylases; Analysis of Variance; Animal Feed; Animals; Apoptosis; Biomarkers; Ceruletide; Female; Glycine max; Hypertrophy; Mice; Mice, Inbred Strains; Necrosis; Pancreatitis

The role of exogenous and endogenous cholecystokinin has been studied in the process of pancreatic regeneration after acute pancreatitis. A mild form of pancreatitis was induced in rats by subcutaneous cerulein at 12 micrograms.kg-1, three times a day for 2 days. After 3 days of rest, the cerulein-treated rats were divided into four groups: rats with acute pancreatitis fed 20% casein, who received no treatment; rats fed 50% casein; rats fed 20% casein supplemented with 1% soybean trypsin inhibitor (SBTI); and rats fed 20% casein who received 1 microgram.kg-1 of subcutaneous cerulein, three times a day. Controls were fed 20% casein plus saline subcutaneously. Rats were killed after 5, 10, or 20 days of treatment. Pancreatitis resulted in significant decreases in pancreatic weight and contents of protein, amylase, chymotrypsin, RNA and DNA. During the regenerative process, 1 microgram.kg-1 of cerulein increased all parameters to control values within 5 days and induced pancreatic growth thereafter. SBTI restored the pancreas to normal after 10 days with cellular hypertrophy; the 50% casein diet gave a response similar to SBTI without hypertrophy. It can be concluded that cerulein and SBTI can accelerate pancreatic regeneration after an attack of acute pancreatitis.

Topics: Acute Disease; Amylases; Animals; Body Weight; Ceruletide; Cholecystokinin; Chymotrypsin; Drug Therapy, Combination; Glycine max; Hypertrophy; Male; Nucleic Acids; Organ Size; Pancreas; Pancreatitis; Proteins; Rats; Rats, Inbred Strains; Regeneration; Trypsin Inhibitors

Ornithine decarboxylase (ODC) is the rate-limiting enzyme in polyamine biosynthesis. We examined circadian variations in pancreatic ODC activity and time-course effects of caerulein in fed and fasted rats. Significant circadian variations in amount of ODC activity were observed. The highest values were obtained during the dark period (1855 +/- 406 pmoles CO2/h), and the lowest during the light period (359 +/- 84 pmoles CO2/h). Caerulein treatment induced hypertrophy and hyperplasia of the pancreas in fed rats; increases in pancreatic ODC activity preceded the rise in protein and DNA contents (447 +/- 44 pmoles CO2/h and 5573 +/- 893 pmoles CO2/h, 6 and 12 h after the first injection of caerulein, respectively). In fasted rats, pancreatic ODC activity was very low (149 +/- 37 pmoles CO2/h) and caerulein treatment induced a transient increase in this activity 12 h after the first injection; hypertrophy but not hyperplasia of the pancreas was observed. In caerulein-treated fasted rats, refeeding during the night following a 48 h fasting period was not enough to increase either ODC activity or DNA content. These findings demonstrate that nutritional status is an important factor in the regulation of ODC activity and, thereby, in caerulein-induced pancreatic growth.

Topics: Animals; Cell Division; Ceruletide; Circadian Rhythm; DNA; Eating; Fasting; Hyperplasia; Hypertrophy; Male; Ornithine Decarboxylase; Pancreas; Rats; Rats, Inbred Strains; Time Factors

The effect of proglumide (400 mg/kg), spantide (400 g/kg) and ranitidine (20 mg/kg) on pancreatic secretory and trophic response to bombesin (10 micrograms/kg) was studied in the rat. Drugs were administered alone or combined with bombesin three times daily for 5 days. Saline-treated rats were used as controls. At the end of treatment, animals were anaesthetized and pancreatic juice was collected for 1 h after caerulein stimulation (1 microgram/kg intraperitoneally). Afterwards, rats were sacrificed and the weight and composition of pancreatic tissue were determined. As compared with control (saline) values, the volume of pancreatic juice and the output of trypsin and amylase were increased by treatment with bombesin. Neither proglumide nor spantide affected basal and caerulein-stimulated pancreatic exocrine secretion. Ranitidine, although unable to modify protein and enzyme content of pancreatic secretion, significantly reduced the volume of pancreatic juice in both basal conditions and after caerulein stimulation. Bombesin increased pancreatic weight as well as the protein and enzymatic contents of the gland. Neither the weight of the pancreas nor its composition were significantly affected by CCK-antagonist proglumide, the putative bombesin antagonist spantide or the H2-receptor antagonist ranitidine. These results show that bombesin has a trophic effect on rat pancreas and concomitantly increases its secretory capacity. Both effects are likely to be mediated through a direct action of the peptide on the pancreatic gland.

Topics: Animals; Bombesin; Ceruletide; Hypertrophy; Male; Pancreas; Proglumide; Ranitidine; Rats; Rats, Inbred Strains; Substance P

The in vivo effects of epidermal growth factor (EGF) on pancreatic growth and digestive enzyme concentrations were compared with the actions of the pancreatic secretagogue caerulein in the adult rat. EGF (10 micrograms/kg BW) did not alter pancreatic weight or protein content. However, this concentration of EGF inhibited [3H]thymidine incorporation into DNA by 44%, decreased DNA content by 20%, and increased the concentrations of amylase, chymotrypsinogen, and protein by 106%, 232%, and 42%, respectively. Pancreatic acini prepared from EGF-treated rats exhibited a characteristic secretory response to caerulein that was superimposable to that obtained in acini from saline-treated rats. In both groups of acini half-maximal and maximal stimulation of amylase release occurred at approximately 5 pM and 50 pM caerulein, respectively. In contrast to EGF, caerulein (1 microgram/kg BW) increased pancreatic weight by 29% and protein content by 59%, and enhanced [3H]thymidine incorporation into DNA by 70%. Although caerulein increased the concentrations of pancreatic amylase and chymotrypsinogen by 38% and 297%, respectively, pancreatic acini prepared from caerulein-treated rats were less sensitive to the actions of caerulein in vitro when compared with acini from control rats. Indeed, the EC50 was shift from 4.8 pM to 9.8 pM after 4 days of treatment. EGF potentiated the actions of caerulein on pancreatic weight, protein content, and chymotrypsinogen concentration, and prevented the caerulein-induced alteration in the secretory responsiveness of the acinar cell. Conversely, caerulein reversed the inhibitory effect of EGF on thymidine incorporation. These findings suggest that EGF may modulate the trophic effects of certain gastrointestinal hormones, and may participate in the regulation of pancreatic exocrine function in vivo.

Topics: Amylases; Animals; Cell Division; Ceruletide; Chymotrypsin; DNA Replication; Epidermal Growth Factor; Hyperplasia; Hypertrophy; Male; Organ Size; Pancreas; Rats; Rats, Inbred Strains; Reference Values

It is well established that repeated injections of the cholecystokinin (CCK) analogue caerulein induce pancreatic hypersecretion and growth, but so far the time-specific development of hypersecretory capacity has not been studied. Rats were given intraperitoneal injections of caerulein (1 microgram/kg) three times daily for 0-7 days. On the day after the last injection a secretory test was performed with the rats under urethane anaesthesia. Subsequently, pancreatic tissue composition was analysed. Basal and caerulein-stimulated secretion rates of fluid and trypsin were elevated after as little as 1 day of caerulein treatment. These values remained significantly greater than those of the controls after 2-7 days' administration of the peptide. Pancreatic tissue hypertrophy (increases in absolute pancreatic weight, protein and trypsin contents, and also in these values normalized to DNA) appeared after 2 days' pretreatment. Tissue growth turned to hyperplasia (increase in tissue DNA content) after 5 days' caerulein administration. We conclude that chronic administration of the CCK analogue caerulein induces adaptation of the pancreas in a sequential order. First, the hypersecretory state appears, followed by hypertrophy, and, finally, pancreatic growth turns into hyperplasia.

Topics: Animals; Ceruletide; DNA; Hypertrophy; Male; Pancreas; Rats; Rats, Inbred Strains; Secretory Rate; Time Factors; Trypsin

Glucagon is structurally related to secretin but inhibits the effects of secretin and cholecystokinin (CCK) on pancreatic secretion in vivo. Because secretin is a weak stimulant of pancreatic growth and potentiates the trophic effects of CCK, we hypothesized that glucagon might inhibit CCK-induced pancreatic growth. Four groups of 10 rats were injected with saline, glucagon (30 micrograms/kg, equimolar to a known trophic dose of secretin), cerulein (0.67 microgram/kg), or glucagon plus cerulein every 8 h for 5 days. The pancreas was excised, weighed, and assayed for total content of DNA, protein, amylase, chymotrypsinogen, and lipase. In control and glucagon-alone groups, the small intestine was also removed, weighed, and assayed for DNA, protein, and disaccharidase content. Glucagon alone decreased pancreatic DNA and increased lipase content. Compared with cerulein-treated animals, animals treated with glucagon and cerulein showed significant decreases in pancreatic weight and content of protein, amylase, and chymotrypsinogen. Although glucagon had significant effects on intestinal protein, maltase, and sucrase contents in certain segments, there was no clear pattern of response. The data suggest that glucagon may be an inhibitory regulator of pancreatic growth, acting to block the effects of CCK on pancreatic hypertrophy.

Topics: Animals; Ceruletide; Glucagon; Hypertrophy; Intestine, Small; Male; Pancreas; Rats; Rats, Inbred Strains

Pancreatic hypertrophy and hyperplasia following chronic joint (CA + SE), or separate, caerulein (CA: 1 microgram . kg-1) and secretin (SE: 75 micrograms . kg-1) administration were studied in parallel with pancreatic somatostatin (SRIF) contents following 2, 4, 7 and 10 days of treatment. Parameters indicative of pancreatic growth (tissue weight, DNA and protein contents, cellular protein concentrations) increased significantly after 2 days of CA or CA + SE and reached a plateau between days 4 and 10. SE merely induced a mild hypertrophy after 4 days. Endogenous pancreatic SRIF contents varied upon treatment, differently so with each peptide regimen. Indeed, CA and CA + SE treatments decreased total SRIF contents after 2 days with no effect thereafter. SE also decreased the latter after 2 days while significant increases were observed after 7 and 10 days. The inverse relationship seemingly existing between SRIF contents and the amplitude of hormonally-induced pancreatic growth supports the hypothesis that endogenous pancreatic SRIF, operating as an 'antigrowth' factor, may participate in the exogenous CA, SE and CA + SE stimulated pancreatic growth phenomena.

Topics: Animals; Ceruletide; DNA; Drug Interactions; Hyperplasia; Hypertrophy; Male; Organ Size; Pancreas; Rats; Rats, Inbred Strains; Secretin; Somatostatin

Topics: Animals; Ceruletide; Dose-Response Relationship, Drug; Hypertrophy; Male; Pancreas; Rats; Rats, Inbred Strains

We studied the effects of acute and chronic administration of secretin and caerulein, alone and in combination, on RNA and protein synthesis in the duodenum and oxyntic gland area as well as content of DNA, RNA and protein in rats. Secretin, 100 micrograms . kg-1, three times a day for 5 days, was associated with duodenal hypertrophy after the first 24 h of treatment and hyperplasia at the end of days 2 and 4; hypertrophy of the oxyntic gland area was observed only at 4 h after the first injection. Caerulein, 1 microgram . kg-1, also promoted duodenal hyperplasia after 2 and 4 days of treatment. The oxyntic gland area showed hypertrophy only at 4 h after the second injection of caerulein. These data indicate that both hormones can induce duodenal hyperplasia, probably by an amplification of the normal renewal cycle of the epithelial cells. They also demonstrated that growth of the oxyntic gland area is not promoted by these two peptides at the doses studied.

Topics: Animals; Ceruletide; DNA; Dose-Response Relationship, Drug; Duodenum; Hypertrophy; Male; Organ Size; Protein Biosynthesis; Rats; RNA; Secretin; Stomach

Rat exocrine pancreatic function was studied structurally and biochemically after the in vivo production of actue interstitial pancreatitis by supramaximal stimulation with caerulein. Two major phases in the reaction of the gland were observed: During the first two days after cessation of the supramaximal stimulation a progressive infiltration of the interstitium and the pancreatic tissue with polymorphonuclear leucocytes, lymphocytes and macrophages occurred which led to further destruction of the gland and to decreased functional response. From two days after the cessation of the treatment, hypertrophy of centro-acinar cells and an increased rate of mitotic activity indicated regeneration of the pancreas. This was combined with an accelerated in vitro discharge of newly synthesized proteins over a period of four days. Between days three and six after the initial treatment mitotic activity was also observed in fully differentiated exocrine cells. Total structural and functional recovery of the pancreas was achieved nine to tweleve days after the cessation of the supramaximal stimulation.

Topics: Acute Disease; Animals; Ceruletide; Hypertrophy; Leukocytes; Lymphocytes; Macrophages; Male; Mitosis; Pancreas; Pancreatitis; Rats; Regeneration; Remission, Spontaneous; Time Factors

Topics: Animals; Ceruletide; Cholecystokinin; Hypertrophy; Insulin; Islets of Langerhans; Male; Pancreas; Rats; Trypsin Inhibitors

Rats were given injections of caerulein, secretin, or a combination of these two peptides subcutaneously 3 times daily for 5, 10, or 15 days. Caerulein produced significant dose- and time-dependent increases in pancreatic weight and content of DNA, RNA, protein, amylase, and trypsinogen. Secretin produced significant increases in pancreatic weight and content of RNA and lipase after 15 days of treatment. After only 5 days of treatment with a combination of secretin plus caerulein, pancreatic weight and content of RNA and protein more than doubled, and trypsinogen content increased more than fivefold. Comparing the averages across the 5-, 10-, and 15-day values, increases in weight, protein, and trypsinogen with the combination of secretin plus caerulein were significantly greater than the sum of the effects of the peptides given singly. Using increase in DNA content as an index of hyperplasia and increases in the ratios of pancreatic weight, RNA content, and protein content to DNA content as indices of hypertrophy, we concluded that caerulein produced both hyperplasia and hypertrophy of rat pancreatic acinar cells. Secretin markedly augmented the hypertrophic action of caerulein but did not alter its hyperplastic action.

Topics: Amylases; Animals; Cell Division; Ceruletide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hyperplasia; Hypertrophy; Lipase; Male; Pancreas; Rats; Secretin; Trypsinogen