Effects of autonomic denervation on canine exocrine pancreatic secretion and blood flow

Summary The effect of autonomic denervation on the exocrine pancreatic secretion and blood flow was studied in a group of dogs. Pancreatic secretion was collected and analyzed for volume and bicarbonate by direct cannulation of the main papilla through a duodenotomy prior to and following truncal vagotomy and celiac plexus denervation. Pancreatic blood flow was determined by the radioisotope distribution method (¹⁴¹Ce). Truncal vagotomy causes a reduction in pancreatic secretion of volume and bicarbonate by 25–30%, while celiac denervation caused a reduction of 70% in the secretion. The mean baseline pancreatic blood flow was 0.5 ml/g pancreas/min. Truncal vagotomy did not cause any significant flow changes, while celiac denervation caused a significant increase in blood flow of 350% (to 1.75 ml/g/min). These results suggest that both the parasympathetic and the sympathetic system affect pancreatic secretion independently of their effect upon pancreatic blood flow.     

Effect of natural peptide YY on blood flow and exocrine secretion of pancreas in dogs

Little is known regarding the mechanism by which peptide YY exerts an inhibitory effect on exocrine pancreatic secretion. The purpose of this study is to determine if peptide YY affects pancreatic blood flow with simultaneous measurement of exocrine pancreatic secretion in dogs. Pancreatic blood flow was measured by a laser Doppler flowmeter which allows continuous measurement of tissue blood flow. Natural peptide YY (0.1, 0.5, 1g/kg) was infused intravenously as a bolus under background infusion of secretin (1 unit/kg/hr) in combination with cholecystokinin-octapeptide (0.1g/kg/hr). Peptide YY caused a reduction of pancreatic blood flow in a dose-dependent manner as well as inhibition of pancreatic protein output, attaining the maximal reduction (28±4%) and inhibition (45±9%) at a dose of 1 g/kg, respectively. Simultaneous and continuous observation on tissue blood flow and exocrine secretion of the pancreas revealed that there was a highly significant correlation between the percent reduction of pancreatic blood flow and that of volume of pancreatic juice in response to peptide YY (r=0.849, P < 0.001). This study provides evidence that the mechanism of peptide YY-induced inhibition of exocrine pancreatic secretion is mediated, at least partly, through the decreased pancreatic blood flow.This study was supported by a grant from the Ministry of Education, Japan (A,61440060).A portion of this work was presented at the American Gastroenterological Association Meeting in New York in May 1985.     

Duration and potency of anticholecystokinin action of subcutaneous and oral loxiglumide on cerulein-stimulated pancreatic exocrine secretion

Summary The duration and the potency of the antiCCK activities of loxiglumide given by sc and oral routes were examined in rats. Pancreatic juice flow and protein output in response to an iv bolus injection of cerulein (100 ng/kg body wt) were measured at specified time intervals from 1–12 h after loxiglumide administration. Subcutaneous loxiglumide (10 g/kg body wt) effectively suppressed cerulein-stimulated protein output for 4 h and pancreatic juice volume for 6 h, when total outputs during a 60-min period after cerulein stimulation were compared with the control value without loxiglumide pretreatment. Oral dose of loxiglumide exerted longer-term anti-CCK activity (protein output: 6 h, pancreatic juice: 8 h) than the same sc dose. In addition, oral loxiglumide showed more potent suppression of protein output than the same sc dose at the corresponding time interval. Higher oral dose of loxiglumide (50 mg/kg body wt) caused longer inhibition on both protein (8 h) and pancreatic juice secretion (12 h). These results suggest that the half-life of loxiglumide given by oral route is longer than that by sc route or that the bioavailability of oral loxiglumide is higher than that of sc dose. The present study demonstrates that loxiglumide, given either by sc or by oral route, has long duration of action in antagonizing responses to exogenously administered cerulein.     

Effect of diabetes mellitus on pancreatic exocrine secretion from isolated perfused pancreas in rats

We studied pancreatic exocrine function in response to cerulein and carbamylcholine in isolated perfused pancreas obtained from control, streptozotocin-induced diabetic, and insulin-treated diabetic rats. The time course of pancreatic juice, protein, amylase, and trypsinogen secretion in response to cerulein or carbamylcholine in diabetic rats was similar to that in control rats. Basal as well as cerulein- or carbamylcholine-stimulated output of amylase from diabetic rat pancreas was significantly reduced, whereas that of trypsinogen was similar to the control. Amylase and trypsinogen outputs in response to 620 pM (1.0 ng/ml) cerulein from insulin-treated diabetic rat pancreas were significantly lower than those from control rat pancreas, although the pancreatic contents of these enzymes were similar to or greater than those in control rats. The dose-response curves of pancreatic juice, protein, amylase, and trypsinogen for cerulein and carbamylcholine were biphasic in both control and diabetic rats. The minimal and the maximal release in response to cerulein occurred with higher concentrations in diabetic rats compared with control rats. In contrast, the maximal responses were obtained with 1 M carbamyl-choline in control rats and with 0.1–1 M carbamylcholine in diabetic rats. The present study demonstrates that the concentration of cerulein required to elicit maximal response was increased, whereas that to carbamylcholine was reduced in diabetic rat pancreas, and that the protein and enzyme outputs in response to cerulein were significantly reduced in insulin-treated diabetic rat pancreas despite restoration of the pancreatic enzyme contents to control levels.     

Effect of intraduodenai infusion of tocamphyl on pancreatic exocrine secretion and gastrointestinal hormone release in rats

Tocamphyl is a synthetic choleretic that is derived from a root extract ofCurcuma longa, L. We investigated the effect of tocamphyl on pancreatic exocrine secretion and bile flow, and on the release of some gastrointestinal hormones, by administering it intraduodenally using anesthetized rats. Tocamphyl stimulated pancreatic exocrine secretion in terms of volume and amylase output in a dose-related manner. Neither a CCK-receptor antagonist, CR1505 (loxiglumide), nor atropine sulfate infused intravenously suppressed the stimulatory effects of tocamphyl on pancreatic exocrine secretion and bile flow. The stimulatory effect on bile flow was stronger than that on pancreatic exocrine secretion. Plasma secretin levels were augmented with the increasing doses of tocamphyl, but CCK levels were not. These results indicate that intraduodenally administered tocamphyl stimulates pancreatic exocrine secretion and bile flow, and suggest that the stimulatory action is, at least in part, mediated by secretin, but not by either CCK or the cholinergic pathway.     

Plasma osmolality and exocrine pancreatic secretion

To confirm the influence of plasma osmolality on exocrine pancreatic secretion, hypertonic saline (4% saline) was given intravenously to dogs with gastric and pancreatic fistulae. Intravenous administration of hypertonic saline caused a reduction of pancreatic juice flow and bicarbonate output, but did not alter protein output stimulated by secretin and cerulein. The changes of pancreatic juice flow(X) exhibited negative correlations with the changes in plasma osmolality(Y)(Y = -2.2X + 6A, r = -0.74,p < 0.01). Plasma osmolality and plasma vasopressin level were measured simultaneously. Plasma osmolality was elevated from 292 to 315 mOsm/kg with concurrent increase of plasma vasopressin level from 2.4 to 19.6 pg/ mL. On the other hand, exogenous administration of vasopressin inhibited pancreatic juice flow and bicarbonate output dose-dependently. In conclusion, elevation of plasma osmolality decreased exocrine pancreatic secretion stimulated by secretin and cerulein, and vasopressin may play an important role in its mechanism.     

Effects of tetraprenylacetone on pancreatic exocrine secretion and acute pancreatitis in two experimental models in rats

Summary The effects of tetraprenylacetone (TPN), an acyclic polyisoprenoid with antiulcer actions, on pancreatic exocrine secretion, and its preventive and therapeutic effects on acute pancreatitis in two experimental models were studied in rats. Intraduodenal administration of TPN (0, 100, 200 and 400 mg/kg/h) caused dose-dependent increases in pancreatic juice and bicarbonate output without increasing protein output and plasma cholecystokinin (CCK) concentrations. TPN-stimulated pancreatic exocrine secretion was completely abolished by antisecretin serum but it was not by CCK receptor antagonist loxiglumide (50 mg/kg/h). In acute pancreatitis induced by four subcutaneous injections of 20 μg/kg cerulein at hourly intervals over, 3 h, TPN (400 mg/kg) given by an oral route either 1 h before the first cerulein injection or immediately after the last injection significantly reduced the increases in serum amylase and lipase activities and pancreatic wet wt. Pretreatment with TPN caused histologic improvements, whereas posttreatment failed to ameliorate histologic alterations. In severe type of acute pancreatitis induced by retrograde intraductal injection of 1.0 mL/kg of 4% sodium taurocholate, TPN exerted no apparent beneficial effects on biochemical and histologic alterations of acute pancreatitis. It is concluded that TPN given by an oral route stimulates pancreatic exocrine secretion through an increase in endogenous secretin release and causes beneficial effects on the experimental model of mild acute pancreatitis in rats.     

The influence of cutting the pancreatic nerve plexus on exocrine function in the pancreas of rats

This study was performed to clarify changes in protein synthesis and exocrine enzymes of the pancreas after cutting the pancreatic nerve plexus of Wistar rats. The rats were divided into two groups, consisting of a group that underwent cutting of the pancreatic nerve plexus (neurotomy group) and a group that underwent a sham operation (control group).³H-leucine uptake in the pancreatic protein fraction of the neurotomy group at 3, 5 and 7 days after the operation was significantly lower than that of the control group (P<0.05-0.01), and this low uptake returned to the normal range at 14 days. Amylase, lipase and trypsin values in pancreatic tissue of the neurotomy group decreased during the period of from 1 to 7 days, and there were significant differences in the values of the respective enzymes at 5 or 7 days between the neurotomy and the control group (P<0.05). Thereafter, all enzyme values increased to within the normal range. Upon examination of pancreatic blood flow using a microsphere, the neurotomy group showed a significant reduction at 7 days compared with the control group (P<0.05), and thereafter exhibited recovery of blood flow. These results indicate that after cutting the pancreatic nerve plexus, exocrine function in the pancreas is reduced immediately but recovers within a short period of time, and that these changes in exocrine function are affected by blood flow in the pancreas. Supported partially by the grants from the Japanese Ministry of Health & Welfare.     

Stimulated pancreatic exocrine secretion does not require pancreatic hyperemia in rats

Although blood flow and cholinergic tone influence gastric and salivary gland secretion, their role in pancreatic secretion is poorly defined. The purpose of the present study was: (1) to test the hypothesis that an increase in pancreatic blood flow accompanies stimulated pancreatic exocrine secretion, and (2) to examine the effects of cholinergic agents on basal and stimulated blood flow using hydrogen gas clearance. Stimulated pancreatic exocrine secretion (secretin 0.4, 0.8, ..6 g/kg/hr) resulted in a significant (P<0.005) increase in secretory volume; however, pancreatic blood flow was not significantly changed, and a negative correlation between blood flow and secretion was observed. A pharmacologic dose of secretin (5.0 g/kg/hr) resulted in a significant (P<0.05) increase in pancreatic blood flow, which was inhibited by atropine (5.0 g/kg/hr) infusion. Although 2-deoxyglucose caused a significant decrease (P<0.03) in basal pancreatic blood flow, atropine had no effect on basal blood flow levels. These observations suggest that: (1) under physiologic conditions, secretin- or 2-deoxyglucose-stimulated pancreatic secretion does not require pancreatic hyperemia; (2) a pharmacologic dose of secretin does produce pancreatic hyperemia, perhaps through a local cholinergic mechanism; (3) peripheral cholinergic tone does not contribute significantly to basal pancreatic blood flow; and (4) basal pancreatic blood flow may be influenced by central mechanisms.A portion of this work was presented at the annual meeting of the American Gastrointestinal Association, 1989, Washington, DC, and published in abstract from inGastroenterology 96:A97, 1989.     

Effect of somatostatin 14 on pure human pancreatic secretion

While it is well known that large doses of somatostatin inhibit human pancreatic enzyme secretion, it is still unknown whether low doses are also effective and whether the peptide is able to inhibit bicarbonate production. Eight subjects with external transduodenal drainage of the main pancreatic duct performed after biliary tract surgery were studied. Somatostatin was infused at progressively increasing rates of 0.05, 0.15, 0.45, and 1.35 g/kg/hr, for 30 min/dose, during pancreatic stimulation with secretin, 25 ng/kg/hr, and cerulein, 10 ng/kg/hr. Somatostatin, at the dose of 0.05 g/kg/hr (shown to produce blood levels similar to those measured after a meal) did not affect pancreatic secretion in any of the subjects. The successive three higher doses caused a significant and dose-dependent inhibition of protein concentration and output and of bicarbonate output. Bicarbonate concentration was slightly but significantly reduced only by the two highest doses of somatostatin. At each dose level, the inhibition of protein output was much more marked than the inhibition of bicarbonate output. The maximal inhibition of protein output (at 1.35 g/kg/hr somatostatin) was 73.9±5.4%, and that of bicarbonate output was 55.9±6.4%. The results demonstrate that: (1) the administration of somatostatin at a low dose level does not affect human exocrine pancreatic secretion, at least under the experimental conditions of this study; and (2) the administration of larger doses of somatostatin inhibits pancreatic secretion of both protein and bicarbonate dose-dependently. The inhibitory effect on protein output is significantly greater than that on water and bicarbonate production.     

Reduced reactivity of pancreatic exocrine secretion in response to gastrointestinal hormone in WBN/Kob rats

We compared pancreatic exocrine secretion in 5-month-old WBN/Kob rats, a model of chronic pancreatitis, with that in Wistar rats of the same age in a conscious state. Basal pancreatic secretion and pancreatic wet weight in WBN/Kob rats were lower than the values for Wistar rats. There was no difference in plasma cholecystokinin (CCK) concentration between the two types of rats. When CCK-8 was intravenously administered, the stimulation of pancreatic protein secretion in WBN/Kob rats was weaker than that in Wistar rats. When bile and pancreatic juice were diverted from the duodenum, the resulting increase in the plasma CCK concentration was similar in both types of rats, but stimulation of the volume and protein output of pancreatic juice in WBN/Kob rats was weaker than that in Wistar rats. In addition, WBN/Kob rats exhibited little increase in pancreatic wet weight because of this diversion. When secretin was intravenously administered, the stimulation of fluid secretion in WBN/Kob rats was also weaker than that in Wistar rats. The binding of CCK-8 to pancreatic membrane fractions in WBN/Kob rats was much weaker than that in Wistar rats. Histological findings in WBN/Kob rat pancreas showed proliferation of fibrous tissue and atrophy of acinar cells. In conclusion, pancreatic exocrine secretion in response to the gastrointestinal hormones, CCK and secretin, was lower in WBN/Kob rats than in Wistar rats. These findings suggest that the hyposecretion of pancreas in WBN/Kob rats is hyporeaction of pan-creatic membrane to gastrointestinal hormones. (Received Feb. 5, 1997; accepted July 25, 1997)     

Effect of synthetic porcine neuropeptide Y (NPY) on splanchnic blood flows and Exocrine pancreatic secretion in dogs

This study examined the effect of synthetic porcine neuropeptide Y on the splanchnic blood flows and the exocrine pancreatic secretion in dogs. Graded doses of neuropeptide Y (0.1–5 g/kg, intravenous) caused dose-dependent reduction of the secretin-stimulated exocrine pancreatic secretion and of the blood flows in the superior mesenteric artery, the portal vein, and the pancreatic tissue. Neuropeptide Y at 5 g/kg reduced the blood flows to 45.9±13.3% (superior mesenteric artery), 63.0±10.5% (portal vein), and 77.9±4.8% (pancreatic tissue), respectively. This dose also reduced secretin-stimulated pancreatic juice volume and CCK-8 plus secretin-stimulated protein output to 65.2±9.3 and 63.3±14.0%, respectively. This study shows a potent vasoconstrictor effect of neuropeptide Y on splanchnic vessels. Neuropeptide Y also inhibited exocrine pancreatic secretion in a significant correlation with the reduction in pancreatic tissue blood flow, which suggests that reduction in the blood flow may be one of the possible mechanisms of the inhibitory action of neuropeptide Y on exocrine secretion.This work was supported by a grant from the Ministry of Education, Japan (A-61440060).     

Effect of pancreastatin on pancreatic endocrine and exocrine secretion

Pancreastatin is a novel peptide that was recently purified from extracts of the porcine pancreas. The present study shows that pancreastatin (10(-9)-10(-8) M) can stimulate release of insulin from both the isolated perfused rat pancreas and from cultured rat islet cells in the presence of a low, non-insulinotropic concentration of glucose (4.2 mM). Pancreastatin (10(-9) M) can also inhibit release of insulin stimulated by a high concentration of glucose (16.7 mM). Pancreastatin, at 10(-8) M, can enhance glucose (8.3 mM) induced release of insulin in the static islet cell incubation. In addition, pancreastatin (10(-9)-10(-8) M) can inhibit, in a dose-dependent fashion, cholecystokinin (CCK)-8 stimulated release of amylase from dispersed guinea pig pancreatic acini. Pancreastatin alone, however, did not affect basal release of amylase. Our study shows that pancreastatin can exert a direct effect on both pancreatic endocrine and exocrine secretion.     

Duodenum preservation in pancreatic head resection to maintain pancreatic exocrine function (determined by pancreatic function diagnostant test and cholecystokinin secretion)

Background/Purpose

Organ-preserving surgery, such as pylorus-preserving pancreatoduodenectomy (PPPD), duodenum-preserving pancreatic head resection (DPPHR), or medial pancreatectomy (MP), is one of the recent advances in pancreatic surgery. There was a previous report that preservation of the duodenum maintained pancreatic function. However, concerning the resected pancreas, patients were divided into two groups; one group included pancreatic head resections such as Whipple, PPPD, and complete DPPHR, and the other group included MP that removed only the pancreatic neck and preserved the pancreatic head and distal pancreas. The present study was designed to clarify the significance of duodenum preservation, in comparison with duodenum removal, in patients with pancreatic head resection, in terms of pancreatic function, determined by a pancreatic function diagnostant (PFD) test and cholecystokinin (CCK) secretion.

Methods

The subjects were 61 patients (10 with Whipple, 41 with PPPD, and 10 with complete DPPHR). PFD tests and postprandial plasma CCK secretion were used for evaluation.

Results

There was a significant difference between pre- and postoperative PFD values in the patients who received Whipple or PPPD; however, there was no difference in those who had complete DPPHR. Concerning the postoperative PFD value, complete DPPHR was superior to Whipple and PPPD. Regarding postprandial CCK secretion, the pre- and postoperative values were significantly different in the patients with Whipple or PPPD, but there was no difference in those with complete DPPHR. Comparing the three kinds of operations, complete DPPHR was superior to the other two procedures in its maintenance of pancreatic function. There was the significant correlation between CCK and PFD in our patients in the Spearman Rank Correlation (P < 0.0029) and Fisher’s r to z (P < 0.0058).

Conclusions

When pre- and postoperative pancreatic exocrine function and postprandial CCK secretion were measured in patients with pancreatic head resection, it was found that preservation of the entire duodenum was an important factor for maintaining pancreatic function.     

Role of secretin and cholecystokinin in oleic acid-stimulated pancreatic secretion in rats

We investigated the possible role of endogenous secretin and cholecytokinin (CCK) on oleic acid-stimulated pancreatic exocrine secretion in anesthetized rats. Intraduodenal infusion of oleic acid (pH 6.5) in three different doses (0.06, 0.25 and 1 mmole/hr) resulted in dose-related increases in pancreatic juice volume, bicarbonate and amylase outputs (r=0.665, 0.736 and 0.517, respectively) (P<0.001). Plasma secretin and CCK concentrations also elevated significantly in response to oleic acid, in a dose-related manner (r=0.721 and 0.546, respectively) (P<0.001). There were statistically significant correlations between plasma secretin concentrations and bicarbonate outputs, and between plasma CCK concentrations and amylase outputs in response to oleic acid (P<0.01). Potent CCK antagonist, CR 1409 (5 mg/kg.hr) administered intravenously suppressed completely increase in amylase output induced by oleic acid, and partially in juice volume and bicarbonate output. It is concluded that both endogenous secretin and CCK play important roles on oleic acid-induced pancreatic secretion in rats. The results of this study were presented at The 7th International Symposium of Gastrointestinal Hormones in Shizuoka, Japan, Nov. 1–4, 1988, and appeared in abstract form in Biomedical Research 1988;9(Suppl. 1):114. This work was supported in part by grants from the Japanese Ministry of Education and the Ministry of Welfare. The authors are grateful to Y. Hirasawa, B.S. and M. Takeda, B.S. for their technical assitance.     

Porcine pancreastatin has no effect on endocrine secretion from the pig pancreas

Summary We investigated the effects of porcine pancreastatin on the endocrine and unstimulated exocrine secretion of isolated, perfused porcine pancreas. Pancreastatin in a concentration of 10^–8mol/l had no effect on basal secretion of insulin, glucagon and somatostatin at a perfusate glucose concentration of 5 mmol/l (n=4) and neither at 10^–8 nor 10^–7 mol/l influenced the hormone responses to acute elevations of perfusate glucose concentration from 3.5 to 11 mmol/l (n=7). This elevation strongly stimulated insulin secretion and inhibited glucagon secretion. Exocrine secretion was not affected by pancreastatin. The results suggest that pancreastatin does not directly influence pancreatic secretion.     

Contrasting effects of circulating nitric oxide and nitrergic transmission on exocrine pancreatic secretion in rats

Background—Nitric oxide (NO) blockade byL-nitroarginine methyl ester (L-NAME) inhibitspancreatic secretion in vivo and aggravates caerulein inducedpancreatitis. Nitric oxide synthase (NOS) is present in pancreaticislets, endothelium, and nerve fibres. L-NAME blocks allknown NOS isoforms.
Aim—To investigate the source of NO blocked byL-NAME that inhibits amylase secretion.
Methods—Amylase output was measured in rats inresponse to caerulein (0.1-50 µg/kg) alone or with indazole.Baseline secretion and the response to supramaximal caerulein were alsoexamined after administration of indazole, L-NAME,haemoglobin, or aminoguanidine under continuous blood pressuremeasurement. In separate experiments, pancreatic secretion was measuredafter blockade of afferent nerve fibres by either systemic or localcapsaicin. The effect of neural NOS inhibition on caerulein inducedpancreatitis was also investigated.
Results—L-NAME, haemoglobin, andsupramaximal caerulein (10 µg/kg) increased blood pressure, whereasindazole and suboptimal caerulein (0.1 µg/kg) did not. Indazole andcapsaicin decreased basal amylase output. L-NAME andhaemoglobin reduced basal amylase output to a lesser extent andpotentiated the inhibitory response to supramaximal caerulein. Incontrast, full neural NOS inhibition by L-NAME partiallyreversed the expected caerulein induced suppression of amylase output.This effect was reproduced by indazole and capsaicin. Indazole did notalter responses to either optimal (0.25 µg/kg) or suboptimal (0.1 µg/kg) caerulein, nor, in contrast with L-NAME, aggravatethe outcome of caerulein induced pancreatitis.
Conclusions—Reduction of circulating NOavailability, probably of endothelial origin, is responsible for thedecrease in amylase secretion observed in the early response toL-NAME. Nitrergic neurotransmission plays an important rolein the control of pancreatic secretion and may induce opposite effectsto endothelial NOS activity.

     

Nonparallel patterns of circadian pancreatic and biliary secretions in fasting rats

We compared the circadian patterns of pancreatic and biliary secretions in fasting rats. For this purpose, indwelling plastic catheters were placed in 10 male Wistar rats (300-320 g) for the collection of biliary and pancreatic secretions. After small samples were taken for analysis, pancreatic and biliary secretions were recirculated into the duodenum by an additional connecting system. The rats were adapted to an inverse night-day cycle by artificial light during the night (8 pm-8am) and by darkroom housing at daytime (8 am -8 pm ). During a 24-h fasting period, samples of bile (100 μL) and pancreatic juice (20 μL) were taken every hour for determination of the following parameters: pancreatic and biliary flow rate, protein, amylase, lipase, trypsin, and bile acid output. Peak pancreatic flow rate (1.96 ± 0.05 mL/h-kg) was achieved toward the end of the dark period at 7 pm. A significant increase of pancreatic secretion could be achieved merely by turning the lights off, a significant decrease by turning the lights on. Similar circadian patterns were found for pancreatic protein, amylase, and lipase output with peak secretions at 7 PM. An increase of nearly 5x was found between minimal (15.64 ± 0.65 mg/h-kg) and maximal (72.43 ± 2.83 mg/h-kg) pan-creatic protein output. The amplitude was highest for amylase; peak amylase output (13740 ± 832 U/h-kg) was about 18-fold above minimal output (758 ± 44.3 U/h-kg). Conversely, the peak of trypsin concentration in pancreatic juice (1095 ± 17.8 U/mL) occurred during the light period when flow rates were lowest. Circadian patterns of biliary vol flow rate and bile acid output were also present, with peak secretions after 4 and 5 h of the dark phase, respectively (9.22 ± 0.31 mL/h-kg; 440 ± 9,53 μmol/h-kg). No acute alterations in biliary secretion resulted from turning the lights on or off. We conclude that pancreatic and biliary secretions are nonparallel in fasting rats and that distinct mechanisms are likely to be involved in the regulation of these different circadian patterns.     

Effects of a new benzodiazepine derivative cholecystokinin receptor antagonist FK480 on pancreatic exocrine secretion in anesthetized rats

Inhibitory effects of a newly developed benzodiazepine derivative (S)-N-[1-(2-fluorophenyl)-3,4,6,7-tetrahydro-4-oxo-pyrrolo-[3,2,1-jk][1,4] benzodiazepine-3yl]-1H-indole-2-carboxamide (FK480), a cholecystokinin (CCK) -A receptor antagonist, on pancreatic exocrine secretion were examinedin vivo in anesthetized rats. The antagonism produced by FK480 was competitive in nature because intraduodenal as well as intravenous infusion of FK480 (50–250 nmol/kg/hr) caused a parallel rightward shift of the entire dose-response curve for cerulein-stimulated pancreatic exocrine secretion without altering the maximal increase. The magnitude of the shift was proportional to the dose of FK480. The mean pA2 and ID₅₀ values of intravenously administered FK480 were 8.2 and 24 nmol/kg/hr, respectively, and those of intraduodenally infused FK480 were 7.7 and 168 nmol/kg/hr, respectively. Thus, FK480 given by the intravenous route was about sevenfold more potent than that given by the oral route. The antagonistic effects produced by intravenous FK480 were specific for CCK receptor in that the stimulatory effects of cerulein were inhibited whereas those of bombesin and secretin were not altered. In addition, intravenous administration of 50 nmol/kg/hr FK480 completely suppressed pancreatic exocrine secretion in response to intraduodenal infusion of 10% casein (400 mg/hr). FK480 was active as a CCK receptor antagonist for more than 12 hr because oral administration of FK480 (1.0 mg/kg) had significant inhibitory effects even after 12 hr on cerulein-stimulated pancreatic exocrine secretion. These results indicate that FK480 is a potent, competitive, and specific CCK receptor antagonist on the exocrine pancreasin vivo, having oral bioavailability and a long biological half-life.This work was supported in part by a grant from the Japanese Ministry of Health and Welfare (Intractable Disease of the Pancreas).     

The effect of chronic intraperitoneal infusion of bacterial endotoxin on exocrine pancreas function in rats

Summary Conclusion This study demonstrated that LPS infusion can induce tissue lesions and impair the exocrine protein secretion of the pancreas in rats. Background The effect of chronic ip infusion of lipopolysaccharide (LPS) on the exocrine pancreas function was studied in rats. Methods Four milligrams per kilogram per day ofSalmonella typhi LPS were infused intraperitoneally by means of surgically implanted osmotic pumps. Rats were studied after 7-d LPS infusion. Results Plasma fibrinogen and amylase activity increased significantly in LPS-treated rats when compared with control rats. Histological examination of the pancreas showed congestion, infiltration, and focal necrosis in LPS-treated rats. The pancreas wet weight, as well as DNA and total soluble protein contents were significantly increased in LPS-treated animals when compared with controls. The pancreas protein output was significantly decreased in pure pancreatic juice, whereas the pancreatic juice flow rate was significantly increased in LPS-treated animals, when compared with controls. Electrophoretic patterns showed a marked decrease in digestive enzyme contents, whereas there was an increased content of 15 kDa protein.