István Dobronyi

Effect of a new potent CCK antagonist, lorglumide, on caerulein- and bombesin-induced pancreatic secretion and growth in the rat

1 The effect of lorglumide, a new potent cholecystokinin (CCK) antagonist, on pancreatic secretion and growth induced by caerulein and bombesin was studied in the rat. 2 Pancreatic exocrine secretion was studied both in vitro (isolated and perfused pancreatic segments) and in vivo (anaesthetized animals with cannulation of the common bile duct) whereas the trophic effect was investiged after short‐term (5 days) administration of the peptides and/or lorglumide. 3 Both caerulein and bombesin stimulated amylase release from in vitro pancreatic segments in a concentration‐dependent manner. Although the efficacy of both peptides was virtually identical, the potency of caerulein was higher than that of bombesin. Lorglumide displaced the concentration‐response curves to caerulein to the right without affecting the maximum response, suggesting a competitive antagonism. The Schild plot analysis of data gave a straight line with a slope not significantly different from unity. The calculated pA2 for lorglumide was 7.31 ± 0.45. The antagonist, however, was completely ineffective when tested against bombesin‐induced amylase release. 4 In vivo experiments confirmed results from in vitro studies since lorglumide (5 and 10 mg kg−1) significantly reduced pancreatic exocrine secretion induced by caerulein without affecting the response to bombesin. 5 Administration of either peptide increased the weight of the pancreas, the total pancreatic protein and DNA, trypsin and amylase content. Lorglumide (10 mg kg−1), administered together with caerulein, reduced the peptide‐induced increase in pancreatic weight, protein and enzyme content. On the contrary, when lorglumide was given together with bombesin, all the parameters that were examined were not altered by concomitant administration of the antagonist. 6 These results have demonstrated the ability of lorglumide to antagonize the effects on the pancreas of a CCK‐analogue, caerulein, and its inability to affect bombesin‐induced pancreatic secretion and growth, suggesting that lorglumide is a potent and selective antagonist of CCK‐receptors in the pancreas.

Bombesin promotes pancreatic growth in suckling rats

The pancreatic growth promoting effect of long term administration of bombesin was investigated in suckling rats. The authors showed that bombesin given in 10 μg/kg b.wt doses s.c. every 8 h for 10 days from the day of parturition stimulated pancreatic growth: it increased pancreatic weight, protein and DNA content, trypsin and amylase activity and trypsin/DNA ratio. Conclusion: Bombesin is an effective stimulator of pancreatic growth in suckling rats.

Effect of bombesin and its mammalian counterpart, GRP, on exocrine pancreas in the rat

The effect of equimolar doses (6 nmol/kg) of bombesin and its mammalian counterpart, GRP, on pancreatic growth and secretion was studied in adult rats. Both peptides were administered intraperitoneally three times a day for 5 consecutive days. Saline-treated rats were used as controls. At the end of the treatment, animals were anaesthetized and pancreatic juice was collected in basal conditions and after caerulein (0.75 nmol/kg i.p.) stimulation. Afterwards, the rats were sacrificed and growth and composition of the pancreatic tissue were determined. Compared with the control (saline) values, either basal or stimulated secretion was significantly increased after short-term treatment with both peptides. In addition, both bombesin and GRP increased pancreatic weight, total pancreatic protein, trypsin and amylase content. The DNA content was also increased by both peptides, although only the GRP effect proved to be significant. These results demonstrate that both bombesin and GRP have a growth-promoting effect on rat pancreas and concomitantly increase its secretory capacity. The mechanism of this peculiar biological action is likely to be connected with a direct stimulatory action on the gland.

Caerulein stimulates pancreatic growth and somatic growth in suckling rats

SummaryThis study deals with the stimulatory effect of caerulein on pancreatic and somatic growth in CFY suckling rats before weaning. After birth, caerulein (0.25, 0.5, 1, 3, 10 and 30 μg/kg) was given subcutaneously (s.c.) 3 times daily for 10 days. Salinetreated newborn rats were used as control. Caerulein increased pancreatic weight and total pancreatic trypsin activity reaching the maximum at 1 μg/kg dose; higher doses did not cause higher values. On this basis 1 μg/kg caerulein was applied s.c. 3 times daily for 3, 5, 10 and 20 days. At the end of the treatment pancreatic weight, total pancreatic protein, DNA content, trypsin and amylase activity was measured. Increases in body weight due to caerulein treatment were found from 6 days of treatment. Caerulein treatment increased pancreatic weight, total pancreatic DNA and protein content, and trypsin and amylase activity when applied for 5, 10 and 20 days. Treatment for 3, 5, 10 and 20 days with caerulein preferentially increased pancreatic trypsin activity compared to amylase activity. Trypsin activity per mg DNA increased with time in each caerulein-treated group demonstrating that the effect of caerulein increases with duration of treatment. In the saline-treated control group, however, pronounced increase in pancreatic amylase activity compared to that of trypsin activity was found in the age between days 11 and 21. This may be explained by the observation that the plasma corticosterone level increased during this period of postnatal life. The effect of caerulein in promoting pancreatic and somatic growth of suckling rats before weaning may be attributed to a specific enhancing effect of the peptide on proteolytic (e.g. trypsin) enzyme production of the pancreas.

Excessive doses of cerulein stimulate pancreatic growth in suckling rats but damage the pancreas of weaned rats

The cerulein-stimulated pancreatic growth response was evaluated in 4- and 11-day-old female suckling CFY rats and compared with the pancreatic response of cerulein-treated 24-day-old weaned rats. Cerulein was given subcutaneously in saline in 1-, 10- and 100-micrograms/kg doses t.i.d. The increase in pancreatic DNA content was regarded as an index for hyperplasia, and the increase in pancreatic weight, protein content and enzyme activity related to milligrams of DNA as an index for hypertrophy. Three-day administration of 1- and 10-micrograms/kg doses of cerulein increased the pancreatic trypsin/DNA ratio, and doses of 100 micrograms/kg cerulein evoked pancreatic hypertrophy and hyperplasia in 4-day-old rats. Ten-day administration of 1- and 10-micrograms/kg doses induced pancreatic hypertrophy and hyperplasia, while the 100-micrograms/kg doses induced pancreatic hypertrophy in 11-day-old rats. In 24-day-old weaned rats, the 3-day administration of 1-microgram/kg doses resulted in hypertrophy of the gland, while the 100-micrograms/kg doses of cerulein evoked pancreatic aplasia and atrophy. It is concluded that the growth-promoting effect of cerulein on the newborn rat pancreas is age- and dose-dependent.

Caerulein stimulates pancreatic secretory response in conscious newborn rats

SummaryThe aim of our study was to measure age-dependent, caerulein-stimulated pancreatic enzyme secretion of conscious CFY suckling rats without pancreatic duct cannulation. Pancreatic secretory response was expressed as the decrease in specific enzyme (trypsin, amylase) activity compared to saline-injected control. The study was performed in three phases.In 10-d-old conscious newborn rats, single 1 and 3 ug/kg sc doses of caerulein induced significant decreases in specific trypsin (42 and 47 %) and amylase (34 and 33%) activity 15 min after the caerulein injection; the same doses injected at 0 and 30 min evoked a similar decrease 90 min after the first injection. The 0.5 μg/kg dose was ineffective.In 10-d-old anesthetized rats, the 90-min-decrease in total pancreatic trypsin activity, induced by graded doses (1,3,10, and 30 μ/kg) of caerulein, was compared to the 90-min output of trypsin in their bile-pancreatic juice. Each of the applied doses induced significant change in the total trypsin activity both in the pancreas (-33–57%) and juice (+ 21 ±49%) and its decrease in the gland corresponded quantitatively well (r = 0,52; p<0.01) to the increase in the simultaneous 90-min trypsin output.The age- and dose-dependent pancreatic response of 3-, 5-, 10-, and 20-d-old conscious rats was investigated under the effect of 1,3,10, and 30 μg/kg sc doses of caerulein injected at 0 and 30 min. In 3-d-old rats, the 10 and 30 μg/kg and in 20-d-old rats, the 1 and 3 μg/kg doses were effective, whereas in 5-and 10-d-old rats each caerulein dose applied evoked a significant decrease in pancreatic-specific trypsin activity. Conclusion: The pancreas of newborn rats is in vivo less sensitive to careulein between postnatal d 3 and 10 than in already weaned rats.