In vivo action of bombesin on exocrine pancreatic secretion in the rat: independent of cholecystokinin and cholinergic mediation

This study evaluates the effect of bombesin on pancreatic enzyme secretion in the rat and determines whether the stimulatory action of bombesin is mediated through the release of cholecystokinin (CCK) or via a cholinergic pathway. We performed in vivo experiments on conscious rats prepared with cannulae inserted in the pancreatic duct, in the external jugular vein, and in the duodenum. Intravenous infusion of bombesin stimulated pancreatic protein output in a dose-dependent fashion. Bombesin infused at 5 micrograms/kg/h stimulated pancreatic protein secretion from a basal of 12 +/- 5 to 42 +/- 10 mg/h. Infusion of proglumide (400 mg/kg/h) did not affect the stimulatory effect of bombesin on pancreatic protein secretion (38 +/- 5 mg/h). In contrast, infusion of proglumide abolished the pancreatic protein output elicited by intravenous infusion of CCK8 (500 ng/kg/h). This suggests that bombesin does not act through CCK to mediate exocrine pancreatic secretion. In separate studies we intravenously infused rats with atropine (100 micrograms/kg/h) prior to infusion with bombesin. Administration of atropine slightly decreased secretory volume but did not affect the action of bombesin. Combined administration of atropine and proglumide also did not affect pancreatic protein output stimulated by bombesin. Since infusion of neither proglumide nor atropine inhibited the stimulatory action of bombesin, the action of bombesin in the rat is probably direct and not through the release of CCK or via a cholinergic pathway.     

Lack of cholinergic control in feedback regulation of pancreatic secretion in the rat

The effect of atropine (100 micrograms/kg/h, i.v.) on plasma cholecystokinin and pancreatic secretion during diversion of bile and pancreatic juice from the intestine was studied in 8 conscious rats equipped with jugular vein, pancreatic, biliary, and duodenal cannulas, and with pyloric ligation and gastric drainage. Diversion of bile and pancreatic juice to the exterior for 4 h significantly increased pancreatic protein and fluid secretion. Atropine delayed the pancreatic response to diversion, but during 4 h of diversion, neither total nor incremental pancreatic protein or fluid secretion was inhibited by atropine. Plasma cholecystokinin levels were elevated after diverting bile and pancreatic juice and were not significantly reduced by atropine (23.0 +/- 6.6 pM vs. 16.0 +/- 3.9 pM at 1.5 h and 17.3 +/- 5.4 pM vs. 13.1 +/- 2.9 pM at 4 h after bile and pancreatic juice diversion; atropine-treated vs. controls, respectively). These results indicate that cholinergic nerves play no important role in feedback regulation of cholecystokinin release and that the previously reported suppressive effect of atropine on the pancreatic response to diversion of bile and pancreatic juice from the intestine was secondary to inhibition of gastric secretion.     

Effects of SMS 201-995 on basal and stimulated pancreatic secretion in rats

Somatostatin (SRIF) is a potent inhibitor of most gastrointestinal and pancreatic functions. Recently, we showed that SRIF given either iv or intraduodenally (id) strongly inhibited stimulated pancreatic secretion induced by pancreatic juice diversion (PJD) from the duodenum. In this study we evaluate the effects of iv and id infusion of a long acting analog of SRIF, SMS 201-995 (SMS), on pancreatic secretion during basal conditions (pancreatic juice returned) and PJD. Conscious rats prepared with bile, pancreatic, duodenal, and jugular cannulae were studied 3-8 days postoperatively. Protein and fluid outputs were evaluated, and plasma cholecystokinin (CCK) was measured by bioassay. iv SMS infusion (5 micrograms kg-1 h-1) inhibited basal pancreatic protein and fluid secretion by 84 and 64%, respectively. Addition of atropine (500 micrograms kg-1 h-1 ip) did not cause further inhibition. During PJD, SMS iv from 0.005-1.28 micrograms kg-1 h-1 for 3 h caused a dose-dependent inhibition with maximal 90% and 75% reductions of protein and fluid, respectively, at 1.28 micrograms SMS. Plasma CCK was also reduced by 83% from 3.01 +/- 1.15 to 0.51 +/- 0.22 pM. SMS, id at 1.7 micrograms kg-1 h-1 for 1.5 h before and 2 h after PJD, caused inhibition of basal secretion by 25% and that induced by PJD by 60%. Plasma CCK, measured 1.5 h after diversion, increased from 1.55 +/- 0.06 to 5.9 +/- 1.14 pM in the presence of SMS. Intravenous SMS was 20 times more potent than SRIF in inhibiting pancreatic protein and volume secretion stimulated by PJD. Iv SMS inhibited basal and stimulated fluid and protein pancreatic secretion as well as plasma CCK levels. SMS was also effective when given id in inhibiting fluid and protein pancreatic secretion, but id SMS increased plasma CCK levels. This effect on plasma CCK may be due to the inhibition of hormonal inhibitors of CCK release.     

Role of secretin in basal and fat-stimulated pancreatic secretion in conscious rats

The role of endogenous secretin in basal and fat-stimulated pancreatic exocrine secretion was investigated in conscious rats. Rats were prepared with chronic fistulas draining bile and pancreatic juice, which was collected and returned to the duodenum at all times. Six days postoperative rats were fasted overnight, and pancreatic protein and fluid secretion were monitored for 3 h under basal conditions (0.15 M NaCl, intraduodenally) and during 2 h of intraduodenal infusion of a 20% triglyceride emulsion (Liposyn). Solutions were infused at 4.6 ml/h. Rats received a single bolus injection of 0.1 ml antisecretin serum or normal rabbit serum starting in the second hour of the basal period, and the effect on basal and fat-stimulated pancreatic protein and fluid secretion was determined. Antisecretin serum significantly inhibited basal interdigestive pancreatic protein and fluid secretion by 43% and 36%, respectively. Infusion of 20% fat emulsion stimulated a 2.1-fold increase in pancreatic protein and fluid secretion. The stimulation of both protein and fluid secretion was significantly inhibited by 60% by antisecretin serum. Plasma secretin after 2 h of fat infusion was 17.7 +/- 1.8 pM and was greatly reduced by the presence of secretin antiserum. The results support the hypothesis that secretin released by fatty acids is an important mediator of the pancreatic protein and fluid secretory response to dietary fat in the rat.     

Role of cholecystokinin in bombesin-stimulated pancreatic enzyme secretion in conscious rats

Since bombesin is a potent stimulus of cholecystokinin (CCK) secretion, it is assumed that the stimulatory effect of bombesin on pancreatic protein secretion is mediated by CCK. This study was undertaken to determine in the conscious rat with a cannulated pancreatic duct the role of CCK in the stimulation of pancreatic protein secretion by bombesin. Infusion of 18 pmol/kg/30 min of bombesin into rats stimulated pancreatic protein secretion from 6.7 +/- 1.1 to 9.9 +/- 0.4 mg/30 min (p less than 0.05). This stimulation of pancreatic protein secretion was accompanied by a significant increase in plasma CCK, measured by a specific and sensitive radioimmunoassay, from 3.2 +/- 0.2 to 4.7 +/- 0.2 pM (p less than 0.01). When a similar plasma CCK increment as during infusion of bombesin (1.5 +/- 0.2 pM) was achieved by infusion of 6 pmol/kg/30 min of exogenous CCK (1.6 +/- 0.3 pM), pancreatic protein secretion increased only from 6.9 +/- 0.7 to 7.6 +/- 0.7 mg/30 min (p less than 0.05). To achieve a pancreatic protein secretion similar to that during bombesin, large doses of exogenous CCK (24 pmol/kg/30 min) were needed, resulting in considerably higher plasma CCK concentrations of 10.9 +/- 0.7 pM. It is concluded that CCK is unlikely to play a significant role in the stimulation of pancreatic protein secretion by bombesin in the rat.     

Inhibitory effect of somatostatin on cholecystokinin release is independent of luminal cholecystokinin-releasing factor content in conscious rats.

INTRODUCTION: Exclusion of bile-pancreatic juice from the intestine increases pancreatic secretion via cholecystokinin (CCK) release in conscious rats. Luminal CCK-releasing factor (LCRF), purified from rat intestinal secretions, is an intraluminal regulator of CCK secretion during bile-pancreatic juice diversion. AIMS: Because somatostatin is a potent inhibitor of CCK release and pancreatic secretion, the inhibitory effect of somatostatin on LCRF was examined. METHODOLOGY: Rats were prepared with bile and pancreatic cannulae and two duodenal cannulae and with an external jugular vein cannula. The experiments were conducted without anesthesia. After 1.5-hour basal collection of pancreatic juice with bile-pancreatic juice return, bile-pancreatic juice was diverted for 2 hours, during which time somatostatin (2, 10 nmol/kg/h) was infused intravenously. The rats were killed before and 1 and 2 hours after bile-pancreatic juice diversion. To examine the effect of luminal somatostatin, 50 or 200 nmol/kg/h of somatostatin was infused into the duodenum. The plasma CCK and luminal content of LCRF were measured by specific radioimmunoassays. RESULTS: Bile-pancreatic juice diversion significantly increased pancreatic secretion, plasma CCK, and LCRF levels. Intravenous infusion of somatostatin inhibited CCK release and pancreatic secretion, but not LCRF content. Luminal administration of somatostatin did not show any effect. CONCLUSION: Inhibitory effect of circulating somatostatin on CCK release and pancreatic secretion is independent of LCRF content.     

Effect of taurocholate on CCK release and pancreatic secretion produced by two CCK-releasing peptides in conscious rats.

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.     

Inhibitory effects of octreotide on luminal cholecystokinin-releasing factor, plasma cholecystokinin, and pancreatic secretion in conscious rats

INTRODUCTION: Luminal cholecystokinin-releasing factor (LCRF), purified from rat intestinal secretions, is an intraluminal regulator of cholecystokinin (CCK) secretion during bile and pancreatic juice diversion. AIM: Because the LCRF content was not influenced by intravenous administration of atropine or somatostatin, the inhibitory effect of a potent somatostatin analog octreotide on LCRF content, the plasma CCK level, and pancreatic secretion was examined. METHODOLOGY: Rats were prepared with bile and pancreatic cannulae and two duodenal cannulae and with an external jugular vein cannula. After 1.5-hour basal collection, bile and pancreatic juice was diverted for 2 hours, during which octreotide was infused intravenously or into the duodenal lumen. The changes in pancreatic secretion were recorded for 2 hours, and the plasma CCK level and LCRF content 2 hours after the treatment were measured. RESULTS: Bile and pancreatic juice diversion significantly increased pancreatic secretion and plasma CCK and LCRF levels. Intravenous infusion of octreotide (0.2 and 0.5 nmol/kg/hour) inhibited all parameters. Intraduodenal infusion of a lower dose of octreotide (33 nmol/kg/hour) inhibited pancreatic secretion, but did not inhibit CCK release or LCRF content. The higher doses (100 and 300 nmol/kg/hour) inhibited all parameters. CONCLUSION: Intravenous and intraduodenal administrations of octreotide inhibited CCK release and LCRF content and pancreatic secretion induced by bile and pancreatic juice diversion.     

CCK-releasing activity of rat intestinal secretion: effect of atropine and comparison with monitor peptide

A bioassay for studying the cholecystokinin (CCK)-releasing activity of intraluminal protease-sensitive bioactive peptides was developed. In conscious rats, bile and pancreatic juice were chronically diverted from the proximal intestine to the ileum to cause chronic stimulation of CCK release and pancreatic protein secretion. CCK-releasing activity of test substances was assayed during transient inhibition of CCK release by intraduodenal sodium taurocholate (78 mumols/h). Intestinal secretion as a source of the putative trypsin-sensitive intestinal CCK-releasing peptide was obtained by rapid intestinal perfusion of isolated Thiry-Vella fistulae of jejunum in conscious rats, collected with or without atropine pretreatment. Partially purified rat pancreatic secretory trypsin inhibitor (PSTI, or "monitor peptide") was compared with ovomucoid trypsin inhibitor (OMTI) and with concentrated jejunal secretions for CCK-releasing activity and trypsin inhibitor activity. Concentrated, heat-treated jejunal secretions were the strongest stimulants of CCK release and pancreatic protein secretion in this model. OMTI had no CCK-releasing activity in this model, whereas a larger amount (approximately 5x, based on trypsin inhibitor activity) of PSTI weakly but significantly stimulated CCK release. CCK-releasing activity manifested by pancreatic protein secretion was equivalent in intestinal washes from atropine-treated and control Thiry-Vella fistula donor rats. Concentrated jejunal secretions had no trypsin inhibitory activity, indicating that the putative intestinal CCK-releasing peptide and "monitor peptide" are different substances.     

Regulation of pancreatic secretion by vagal nerve during short-term duct occlusion in conscious rats

The basal exocrine secretion of the pancreas is maintained at a constant level in conscious rats. We examined the changes in basal secretion with respect to the effect of various time periods of pancreatic duct occlusion (PDL). Male Wistar rats were prepared with cannulae that separately drained bile and pancreatic juice as well as with a duodenal cannula. Rats were placed in restraint cages, and experiments were conducted without anesthesia 4 days after the operation. Cholecystokinin (CCK) release was artificially prevented by the continuous infusion of bile with trypsin into the duodenal lumen throughout the experimental period to avoid the modification of pancreatic response by CCK. After 2-h basal collection, a pancreatic secretion was interrupted for 0.5-4 h, and then the collection of pancreatic juice was initiated again for an additional 2-4.5 h. The pancreatic secretion after the reopening of the 0.5-to 3-h PDL was comparable to basal secretion levels. However, protein secretion was significantly inhibited after the removal of 4-h PDL. Both vagotomy and capsaicin treatment abolished this inhibition, and the protein secretion after 1-h PDL in vagotomized rats increased 1.5-fold high compared with the basal value. These observations indicate that protein secretion was ceased during PDL via vagal nerve, and this may be a self-protective mechanism.     

Cholinergic component in the human pancreatic secretory response to intraintestinal oleate.

To determine the role of cholinergic reflexes on pancreatic secretory response to food, we studied the effect of atropine on amylase secretion in response to the octapeptide of cholecystokinin (CCK8) and to intraintestinal oleate. Four studies were done in six healthy volunteers. The duodenal content was aspirated by a double lumen tube while synthetic secretin (41 pmol/kg/h) was infused as a background in all the studies. Graded doses of CCK8 IV or 0.42 M oleate pH 9.4 at 25 ml/h into the intestine with and without atropine 1.8 mg were given on different days. CCK-like immunoreactivity (LI) in the plasma was measured by RIA during the intraintestinal oleate studies. CCK8 stimulated pancreatic enzyme secretion in a dose related fashion, an effect that was not modified by atropine. Intraintestinal oleate also stimulated pancreatic secretion and increased the CCK-LI in the plasma. Atropine significantly (p less than 0.05) decreased the pancreatic enzyme secretion before and during intraintestinal oleate, without effect on the CCK-LI levels. We conclude: (1) that the effect of exogenous CCK on pancreatic secretion of enzymes is not affected by atropine; (2) intraintestinal oleate stimulates pancreatic enzyme secretion significantly by an atropine-sensitive mechanism; (3) probably the atropine effect is a blockade of a cholinergic enteropancreatic reflex.     

Inhibition of cholecystokinin-stimulated pancreaticobiliary output in man by the cholecystokinin receptor antagonist MK-329.

MK-329 (formerly L-364,718) is a new nonpeptide antagonist for the peripheral (type-A) cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. To evaluate the effect of MK-329 on CCK-stimulated pancreaticobiliary output in man, six normal subjects received 10 mg MK-329 or placebo orally in a randomized, crossover fashion, before a background intravenous infusion of secretin (5 pmol/kg/h) and two doses of CCK-8 (approximately 15 and 40 pmol/kg/h, each for 1 h). Gastric and duodenal juice were aspirated separately via two double-lumen tubes, with 51Cr-ethylene-diaminetetraacetic acid as a duodenal marker. After placebo treatment the background infusion of secretin produced maximum plasma concentrations of secretin similar to postprandial values, averaging about 5 pM. After placebo treatment the low dose CCK-8 infusion (15 pmol/kg/h) increased circulating CCK concentrations from basal levels of 1.8 +/- 0.2 pM to levels similar to those observed postprandially, averaging 9.2 +/- 1.3 pM, and the high dose of CCK-8 (40 pmol/kg/h) induced supraphysiologic levels of CCK, averaging 23.4 +/- 3.2 pM. Plasma concentrations of secretin and CCK were not significantly different during MK-329 treatment. As expected, infusion of CCK-8 at both doses stimulated pancreatic exocrine secretion and gallbladder contraction in placebo controls, as indicated by increases in the output of trypsin, amylase, bicarbonate, and bilirubin. Whereas MK-329 did not significantly reduce basal pancreatic secretion, the integrated incremental output of trypsin, amylase, and bicarbonate in response to stimulation with the low (physiologic) CCK dose was inhibited by 74% (p less than 0.01), 89% (NS), and 75% (p less than 0.05), respectively. Basal bilirubin output was virtually abolished after treatment with MK-329, and the response to the low dose of CCK was reduced by 98% (p less than 0.01), indicating almost complete inhibition of gallbladder contraction at physiologic circulating concentrations of CCK. It is concluded that MK-329 is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man and could thus be utilized to explore the physiologic regulation of the exocrine pancreas and gallbladder by CCK.     

The role of gastrointestinal peptides on pancreatic secretion in response to different stimulants in conscious rats

Summary Effects of intragastric food, intraduodenal amino acids, and intravenously administered bombesin and gastrin-releasing peptide (GRP) were examined in conscious rats with pancreatic fistula in terms of responses of exocrine pancreatic secretion, plasma levels gastrin, and cholecystokinin (CCK). Pancreatic juice and blood samples were collected at regular intervals before and after the stimuli. Intragastric food increased pancreatic secretion and plasma levels of gastrin and CCK. Intraduodenal infusion of amino acids had no effect on pancreatic secretion and plasma levels of gastrin and CCK. Intravenous infusion of bombesin at 1 μg/kg/h induced significant increases in pancreatic volume and protein outputs, but had no effect on plasma levels of gastrin and CCK. Bombesin infusion at 10 μg/kg/h resulted in significant increases in pancreatic volume and protein outputs as well as plasma gastrin levels, but had no effect on plasma CCK levels. Intravenous infusion of GRP induced increases in pancreatic volume and protein outputs and plasma gastrin levels, but had no effect on CCK levels. Antrectomy resulted in significant decreases in basal levels of plasma gastrin. GRP-stimulated pancreatic volume and protein outputs were not significantly changed by antrectomy. In rats that underwent antrectomy, GRP infusion significantly increased pancreatic volume and protein outputs, but had no effect on plasma levels of gastrin and CCK. Food-stimulated pancreatic secretion and plasma levels of gastrointestinal peptides of rats were similar to other species, but amino acids, bombesin, or GRP may not be the stimulants for CCK release in rats. The stimuli that release CCK from duodenal mucosa probably varies among species.     

Trypsin suppression of pancreatic enzyme secretion. Differential effect on cholecystokinin release and the enteropancreatic reflex

We have recently demonstrated that intraduodenal perfusion of trypsin inhibits phenylalanine-stimulated pancreatic enzyme secretion by suppression of release of cholecystokinin (CCK). It is not known whether trypsin in the duodenum inhibits pancreatic secretion stimulated by a cholinergic mechanism. To investigate this question gastrointestinal intubation and perfusion were performed in 12 healthy subjects. Volume and osmoreceptors in the duodenum, which are known to elicit pancreatic secretion through cholinergic pathways, were stimulated by infusing increasing volumes (1.0, 2.5, and 5.0 ml/min) of normal saline or increasing osmolality (300, 400, 500 mosmol) of NaCl solution. Increasing the rates of intraduodenal perfusion of normal saline or increasing the osmolality of the duodenal perfusates caused a dose-related increase in pancreatic trypsin and chymotrypsin outputs without affecting basal plasma CCK levels (0.9 +/- 0.1 pM). The volume- or osmolality-stimulated pancreatic secretions were abolished by atropine, but not by intraduodenal perfusion of trypsin. In contrast, intraduodenal perfusion of phenylalanine (10 mM) produced a significant increase in plasma CCK levels (6.7 +/- 0.8 pM) and a three- to fourfold increase in pancreatic enzyme outputs. Perfusion of the duodenum with bovine trypsin (1 g/L) reduced the plasma CCK levels to basal values and significantly attenuated the phenylalanine-stimulated enzyme secretion to 63% +/- 4% of control. Simultaneous administration of atropine and intraduodenal perfusion of trypsin completely abolished the pancreatic enzyme response to phenylalanine stimulation. These studies indicate that the intestinal phase of human pancreatic enzyme secretion is under both hormonal and neural control. Intraduodenal trypsin inhibits only pancreatic secretion mediated by CCK release, and not that mediated by cholinergic mechanisms. These observations suggest that feedback regulation of pancreatic enzyme secretion is stimulus specific.     

Comparison between the synthetic cholecystokinin analogues caerulein and Thr28NlE31CCK25-33(CCK9) with regards to plasma bioactivity, degradation rate and stimulation of pancreatic exocrine function.

A new synthetic analogue of cholecystokinin, Thr28Nle31CCK25-33(CCK9) is compared with caerulein with regards to plasma bioactivity, degradation rate, side effects, and stimulation of pancreatic secretion. 24 healthy male volunteers were intubated with a double lumen Lagerl?f-tube. 30 min after correct positioning of the tube subjects received a continuous intravenous infusion of synthetic secretin (1 U/kg) together with either ceruletide (61.5 pM/kg) or CCK9 (30 pM/kg) both for 45 min. 30 pM/kg of CCK9 have been shown by others to cause maximal enzyme secretion (1). 61.5 pM/kg (= 100 ng) of caerulein are probably supramaximal but used by many centers for direct pancreatic function tests. Plasma CCK was measured by bioassay which compares amylase release of isolated rat pancreatic acini stimulated by plasma extracts with known standards of CCK8. Lipase, amylase, trypsin, chymotrypsin, and bicarbonate were measured in 15 min fractions after the onset of CCK infusion. Both drugs caused a similar stimulation of pancreatic enzyme secretion during infusion of the respective analogue which declined after termination. After the onset of CCK9 infusion plasma bioactivity reached a plateau around 20 pM at 15 min. Values declined after 30 min. After termination of infusion bioactivity rapidly declined within 3 min but still remained slightly elevated after further 15 min as compared to basal values (3.9 vs 0.6 pM). Plasma kinetics of caerulein were quite similar. However, despite a dose which was only twice as high as compared to CCK9, plasma bioactivity was six times higher with plateau values of about 120 pM.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation of plasma cholecystokinin levels by bile and bile acids in the rat

To determine whether intraduodenal bile acids inhibit pancreatic secretion and cholecystokinin (CCK) release independent of pancreatic proteases, experiments were conducted in rats with bile and pancreatic juice chronically diverted to the ileum. Diversion of bile and pancreatic juice increased plasma CCK concentration to 19.1 +/- 4.0 pmol/L. Intraduodenal sodium taurocholate (78 mumol/h) reduced plasma CCK concentration to 6.6 +/- 1.5 pmol/L after 1 hour, but values increased to 17.3 +/- 2.3 pmol/L after 13.5 hours despite continued taurocholate infusion. Pancreatic protein secretion was also significantly but transiently inhibited by taurocholate. However, neither acute nor chronic intraduodenal bile infusion significantly reduced plasma CCK concentration compared with sodium bicarbonate infusion (13.4 +/- 1.9 pmol/L vs. 15.0 +/- 1.7 pmol/L, respectively). Chronic (13.5 hours) intraduodenal infusion of taurocholate plus pancreatic juice caused a sustained reduction of plasma CCK level to 3.1 +/- 0.5 pmol/L, which significantly increased to 9.4 +/- 1.1 pmol/L after cessation of taurocholate but with continued infusion of pancreatic juice. The results indicate that bile does not inhibit CCK release and that bile acids do not physiologically inhibit pancreatic secretion or CCK release independent of the presence of pancreatic proteases.     

Release of pancreatic polypeptide and its mechanism in luminal feedback regulation in the conscious rat

Exclusion of bile and pancreatic juice (BPJ) from the proximal intestine increases the release of pancreatic polypeptide (PP) from 4.4 to 14.3 pM and its increase was diminished by the intravenous infusion of atropine (100 micrograms/kg/h) in conscious rats. Neither intravenous bolus injection nor continuous infusion of cerulein did increase plasma PP concentration. It is suggested that the increase in plasma PP concentration produced by BPJ diversion is regulated by cholinergic mechanism, but not by cholecystokinin (CCK) released despite the known fact that BPJ diversion increases plasma CCK concentration.     

Endogenous nitric oxide mediates pancreatic exocrine secretion stimulated by secretin and cholecystokinin in rats

Nitric oxide (NO) is one of the important biologic mediators in regulation of gastrointestinal (GI) functions, but the influence of NO on the release of secretin and cholecystokinin (CCK) and exocrine pancreatic secretion has not been adequately investigated in the rat. The aim of this study was to determine the role of NO on endogenous and exogenous secretin- or CCK-stimulated pancreatic exocrine secretion both in anesthetized and conscious rats. Experiments were carried out in four different groups of rats with duodenal pancreatobiliary cannulas and jugular vein catheters. Group 1: During duodenal infusion of 0.05N HCl or 15% casein (pH 7.0), N-nitro-L-arginine (NNA), an inhibitor of NO-synthase in graded doses (2.5, 5, 10 mg/kg/h), was infused intravenously. Group 2: One hour after starting intravenous secretin at 5 pmol/kg/h or intravenous CCK-8 at 0.06 microg/kg/h, NNA in graded doses was administered intravenously. Group 3: In conscious rats, NNA (5 mg/kg/h) was given intravenously for 1 hour after a meal. Group 4: L-Arginine at 100 mg/kg/h was infused intravenously during the period of NNA (5 mg/kg/h) infusion in groups 1, 2, and 3. Pancreatic juice was collected at 30-minute intervals to measure volume, as well as output of bicarbonate and protein. At the end of the experiment, plasma secretin, vasoactive intestinal polypeptide (VIP) and CCK levels were determined by radioimmunoassay (RIA). NNA dose dependently inhibited the pancreatic secretion of fluid and bicarbonate stimulated by duodenal acidification, exogenous secretin, and a meal. NNA dose dependently inhibited the pancreatic secretion of protein stimulated by duodenal infusion of casein, exogenous CCK, and a meal. L-Arginine significantly reversed the NNA-induced inhibition of pancreatic secretion in all experiments. NNA did not alter significantly the plasma levels of secretin, VIP, and CCK. Our results indicated that endogenous NO plays a significant role in the regulation of pancreatic exocrine secretion stimulated by secretin and CCK. However, NO does not influence the release of secretin, VIP, or CCK in the rat.     

Comparison of loxiglumide, a cholecystokinin receptor antagonist, and atropine on hormonal and meal-stimulated pancreatic secretion in man

The effects of loxiglumide, a potent cholecystokinin (CCK)-receptor antagonist, and atropine, a muscarinic receptor blocker, on exocrine pancreatic secretion stimulated by hormones (secretin plus CCK) and a Lundh test meal were studied in healthy young volunteers. Loxiglumide infused intravenously in gradually increasing doses (2-16 mumol/kg-h) caused a dose-dependent inhibition of pancreatic enzyme secretion induced by intravenous infusion of a constant dose of secretin (82 pmol/kg-h) plus CCK-8 (85 pmol/kg-h) but had relatively smaller influence on duodenal volume flow and bicarbonate output. Atropine (20 nmol/kg) also caused a significant reduction in pancreatic enzyme secretion but failed to affect the volume flow or bicarbonate secretion induced by secretin plus CCK, possibly owing to the high doses of secretin and CCK used in these tests. Both loxiglumide and atropine inhibited the pancreatic enzyme response to a Lundh meal, but atropine was more effective in the early phase and loxiglumide in the late phase of the postprandial secretion. Neither loxiglumide nor atropine affected the plasma gastrin and CCK levels, but both antagonists reduced plasma pancreatic polypeptide responses to the Lundh meal. We conclude that 1) loxiglumide results in a relatively stronger suppression of the pancreatic enzyme than aqueous-alkaline secretion induced by secretin plus CCK, whereas atropine inhibits only enzyme secretion; and 2) both loxiglumide and atropine suppress the pancreatic enzyme responses to the meal stimulation without affecting the postprandial plasma gastrin and CCK responses.     

Effect of atropine on feedback regulation of pancreatic enzyme secretion in rats

The effect of atropine on the feedback regulatory mechanism of pancreatic enzyme secretion exerted by intraluminal trypsin was investigated in conscious rats. Intravenous atropine infusion (50 micrograms/kg/h) suppressed pancreatic enzyme secretion to the same extent in both the presence and the absence of pancreatic juice in the intestine. However, with or without atropine infusion, pancreatic secretory rate was higher throughout diversion of pancreatic juice than during intraduodenal return of the juice. Atropine also inhibited the stimulatory response to intraduodenal trypsin inhibitor and intravenous caerulein. The atropine-induced inhibitory effect was not significantly different between the two experimental conditions. Regardless of atropine administration, both trypsin inhibitor and caerulein caused a significant increase in pancreatic secretion. The results suggest that cholinergic mechanisms have little influence on the feedback regulation. Cholinergic mechanisms may play an important role in maintaining the physiologically basal secretion because the basal secretion is atropine-sensitive.