Inhibition of rat basal pancreatic secretion by intraduodenal bile

The effect on basal exocrine pancreatic secretion of diversion from and reintroduction into the duodenum of bile has been studied on conscious rats provided with pancreatic, biliary and duodenal fistulae. Diversion of bile from the intestine augmented protein output by 30%. After an eight-hour diversion recirculation of bile into the duodenum reduced pancreatic protein output by 30%; volume being not significantly modified. When either bile was diverted or the main bile duct was ligated, a similar inhibition of protein secretion was observed after intraduodenal injections of 20 mM solutions of taurocholate, taurochenodeoxycholate, chenodeoxycholate, and cholate, and of synthetic mixed micelles (bile salts, lecithin). Inhibitory action of bile salts on pancreatic secretion was seen equally whether or not the bile salts were in free or conjugated form or pancreatic juice returned to the intestine. We conclude that unlike man and the dog, bile as well as pancreatic juice inhibits the basal pancreatic exocrine secretion of the rat.     

Role of local motility changes in the pathogenesis of duodenal ulcers induced by cysteamine in rats

The possible role of local motility in the pathogenesis of duodenal ulcers was investigated in rats using cysteamine. Duodenal motor activity was measured as intraluminal pressure recordings by means of a balloon positioned in the proximal duodenum. Subcutaneous administration of cysteamine (100 mg/kg) produced two linear bandlike lesions in the proximal duodenum within 6 hr. This dose of cysteamine significantly increased gastric acid secretion in acute fistula rats, and decreased duodenal HCO₃ ^– secretion caused by acid. During this period, this agent inhibited gastric motility but did produce markedly enhanced contractions in the duodenum. The changes in duodenal motility appeared within 5–10 min and were dose-dependent for cysteamine (10–100 mg/kg). Pretreatment with subcutaneously administered atropine (10 mg/kg), 16,16-dmPGE₂ (30 g/kg) or dopamine (10 or 30 mg/kg) significantly reduced the development of duodenal lesions caused by cysteamine, the inhibition being 86.8%, 49.7%, 54.5% or 67.8%, respectively. In the presence of cysteamine, dopamine had minimal effect on both acid and HCO₃ ^– secretion, while atropine or 16,16-dmPGE₂ markedly inhibited acid secretion or increased HCO₃ ^– secretion, respectively. The enhanced duodenal motility induced by cysteamine was blocked partially by atropine and only slightly by 16,16-dmPGE₂. Dopamine showed a dose-dependent inhibition on the duodenal hypermotility following cysteamine, and at 30 mg/kg almost completely abolished the development of contractions. These results suggest that abnormal hypermotility in the duodenum may be partly involved in the pathogenesis of cysteamine-induced duodenal ulcers.     

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-8 AM) and by darkroom housing at daytime (8 AM-8 PM). During a 24-h fasting period, samples of bile (100 microL) and pancreatic juice (20 microL) 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) pancreatic 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.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathogene sis of digitoxin-induced duodenal ulcers in pregnant rats

Late-stage pregnant rats (day 17) had higher rates of gastric acid secretion (45–55 eq/15 min) as compared to nonpregnant and middle-stage pregnant (day 10) rats (20–25eq/15 min). In contrast, basal rates of duodenal alkaline secretion were significantly lower (2–3 eq/15 min) in pregnant rats (day 10 and 17) than those in nonpregnant rats (5 eq/15 min), although the duodenal mucosa responded to acid with a significant rise in HCO₃ ^} output in these three groups of rats. In pregnant rats (day 17), a single injection of digitoxin, a Na⁺K⁺-ATPase inhibitor (10 mg/kg, subcutaneously), had no effect on basal acid and alkaline secretions, but significantly blocked the acid-induced HCO₃ ^}-secretion for more than 18 hr from 6 hr after administration. This drug, when given once daily for four days (10 mg/kg, subcutaneously), produced well-defined ulcers in the proximal duodenum with few lesions in the stomach of female rats, and the severity and incidence were significantly higher in late-stage pregnant rats than in the other two groups of rats. Following repeated administration of digitoxin (10 mg/kg) to late-stage pregnant rats (days 17–20), acid secretion significantly declined after two days of treatment, while the acid-induced HCO₃ ^}-secretion was significantly attenuated after one day of treatment and remained inhibited during the whole period. These results suggest that an impairment of the mechanisms related to acid-induced HCO₃ ^}secretion may be associated with the induction of duodenal ulcers caused by digitoxin in female rats, and the high incidence of these ulcers in late-stage pregnant rats may be due to acid hypersecretion.     

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.     

Phospholipid degradation in, and protein content of, rat fistula bile. Contamination of bile with pancreatic juice

The extent to which pancreatic juice can contaminate bile collected from a rat with a biliary fistula has been investigated by cannulating the bile duct proximal to either the duodenum or the liver, and by stimulating pancreatic flow with secretin. Bile collected via a fistula proximal to the duodenum showed marked pancreatic contamination. Thus, bile collected via a fistula proximal to the duodenum has a higher flow rate, a greater total protein and amylase content and a different polypeptide profile than bile collected via a fistula proximal to the liver. The phospholipid content also differed in that phosphatidylcholine was converted enzymically to lysophosphatidylcholine. Secretin increased bile flow and the biliary output of total protein and amylase when the fistula was proximal to the duodenum, but had no effect upon these parameters when the fistula was proximal to the liver, or in the isolated perfused rat liver.     

Inhibition of cysteamine-induced duodenal ulcer in the rat by bile diversion. Enhancement of the ulcerogenic effect of cysteamine by taurocholic and glycocholic acids

Three groups of rats were twice given cysteamine subcutaneously in a dose of 20 mg/100 g body weight. Nine of 10 controls developed severe duodenal ulcers. In contrast, the ulcer formation was inhibited significantly in the rats submitted, before exposure to cysteamine, to a bile diversion operation consisting of jejunopylorostomy and Roux-en-Y anastomosis without gastric resection. However, rats submitted to the same operation but drinking a solution with 5 mmol/l sodium salts of taurocholic and glycocholic acid, 1:3, developed severe duodenal ulcers after cysteamine injections (8 of 10). The conclusion is that neither the chemical cysteamine nor hydrochloric acid alone can be made responsible for cysteamine-induced duodenal ulcer in the rat, but that bile salts clearly enhance the ulcerogenic property of cysteamine.     

Relative importance of biliary and pancreatic secretions in the genesis of esophagitis in rats

Summary Esophagitis in rats with esophagojejunostomy is due to biliary and pancreatic reflux. Respective roles of these two secretions in the genesis of this esophagitis are clarified by the following. By limiting reflux of these secretions to one or the other in 64 rats, we found a 79% incidence of esophagitis in rats with pancreatic reflux and an incidence of 28% when reflux was limited to bile. Therefore, pancreatic juice appears responsible for this type of esophagitis. Although bile alone did not cause esophagitis, it appeared to potentiate the action of pancreatic juice.Development of esophagitis after esophagojejunostomy was partially prevented by trypsin-inhibiting agents.     

Hyperplasia of Gastric Antral ß-Microseminoprotein Endocrine-like Cells and Increased Serum Levels of ß-Microseminoprotein in Atrophic Corpus Gastritis

The effect of fat emulsion in the upper intestine on the maximal gastric acid response to pentagastrin was studied in chronic gastric fistula (GF) mts with a 4-cm blind loop of the duodenum anastomosed to the jejunum (Roux-en-Y). Fat emulsion in the loop inhibited the acid response by 85%. To localize the site of the inhibitory mechanism, GF rats were provided with Thiry-Vella loops of the duodenum (bile and pancreatic ducts transplanted to the proximal jejunum) or with Thiry-Vella loops of the proximal jejunum and a Roux-en-Y loop of the duode* to prevent gastric juice from entering the duodenum. Perfusion of the duodenal loop with fat emulsion mixed with bile and pancreatic juice reduced the acid response by 49%, but perfusion of the proximal jejunal loop did not alter the response. It is concluded that the intestinal mechanism for inhibition of acid secretion by fat is located in the duodenum in rats.     

Effect of intraluminal bile on the feedback regulatory mechanism of pancreatic enzyme secretion in conscious rats

The effect of intraluminal bile on the well-known feedback regulatory mechanism of exocrine pancreatic secretion exerted by intraluminal trypsin was investigated in conscious rats with pancreatic, biliary and duodenal fistulae. The stimulated pancreatic enzyme secretion caused by diversion of bile-pancreatic juice from the intestine was apparently suppressed by intraduodenal reintroduction of pancreatic juice or bile-pancreatic juice, while it was slightly suppressed by intraduodenal reintroduction of bile. Although additional reintroduction of bile did not alter the already suppressed pancreatic enzyme secretion by the presence of pancreatic juice in the intestine, diversion of bile stimulated the suppressed pancreatic enzyme secretion by intraluminal bile-pancreatic juice. Infusion of sodium taurocholate into the duodenum with diversion of bile-pancreatic juice effectively inhibited pancreatic enzyme secretion. The inhibitory effect seemed to be dependent on the concentration of taurocholate infused into the duodenum. The results suggest that bile and bile acid have an important role in the feedback regulatory mechanism of pancreatic enzyme secretion, at least partly directly inhibiting the secretion.     

Effect of ethanol on pancreatic and biliary secretions in humans

The effect of various doses of ethanol on pancreatic and biliary secretions was studied in normal subjects and in patients with alcoholic pancreatitis. The composition of duodenal aspirates after ethanol administration was compared to that obtained after isotonic saline administration. A multilumen tube was used to perfuse a nonabsorbable marker (phenol red) into the duodenum, to collect duodenal secretions, and to perfuse saline or ethanol 45 cm beyond the ligament of Treitz. After the equilibration period, three 20-minute basal collections were obtained, followed by nine more collections after ethanol was started. Jejunal perfusion of isotonic (1.39%) alcohol, at rates at which no significant blood ethanol levels could be detected, did not cause changes in pancreatic or biliary secretions in either group. On the other hand, jejunal or intravenous alcohol administration in doses of 1 g/kg body weight caused marked reductions in volume and outputs of pancreatic enzymes, bicarbonate, and bile salts. The decrease in outputs was accompanied by a corresponding diminution in concentrations. The changes observed indicate that acute administration of large doses of ethanol causes rapid changes in the composition of duodenal aspirates in humans, which cannot be totally explained by postulating a spasm of the sphincter of Oddi.This study was supported in part by Clinical Research Center Grant FR-0107 from the National Institutes of Health, United States Public Health Service, Bethesda, Maryland; and Philadelphia General Hospital Research Fund Grants 7114 and 7301, Philadelphia, Pennsylvania.     

Effect of EM574 on Postprandial Pancreaticobiliary Secretion, Gastric Motor Activity, and Emptying in Conscious Dogs

EM574, an erythromycin derivative and a potentmotilin receptor agonist, is now under clinical trial asa gastroprokinetic drug. The aim of this study was toestimate the effect of EM574 on postprandial pancreaticobiliary secretion, gastric motoractivity, and emptying in conscious dogs. Five mongreldogs were prepared. Indwelling cannulas for bothinfusion of phenolsulfonphthalein and aspiration ofluminal samples were inserted into the proximal anddistal duodenum, respectively. EM574 (3-30 g/kg) wasgiven intraduodenally through the indwelling distalduodenal cannula at the start of feeding. Postprandial pancreatic and biliary secretions were assessedby measuring the outputs of amylase and bile acid intothe duodenum, respectively. Gastric motor and emptyingactivity were measured by means of a force transducer method and our own freeze-drying method,respectively. One hundred grams of a freeze-driedstandard meal was given as a solid marker after beingmixed with 100 ml of normal saline containing 15 g ofpolyethylene glycol as a liquid marker. EM574 at doses of 10and 30 g/kg significantly increased the meanintegrated postprandial amylase output into theduodenum, but the mean integrated postprandial bile acidoutput was not significantly increased. EM574increased postprandial gastric antral motor activitydosedependently. EM574 at doses of 10 and 30 g/kgsignificantly accelerated gastric emptying of liquidsand solids, respectively. EM574 enhances gastricantral motor activity and accelerates gastric emptyingof solids and liquids with a concomitant increase inpostprandial pancreatic amylase, but not bile acid, output in normal dogs.     

Relative importance of pancreatic, hepatic, and mucosal bicarbonate in duodenal neutralization of acid in anaesthetized pigs.

Pancreatic and hepatic bicarbonate secretion and the disappearance rate of acid during duodenal acidification were measured simultaneously in anaesthetized pigs. Perfusion of the duodenum with HCl resulted in an increase in both hepatic and pancreatic bicarbonate secretion. During all acid loads hepatic bicarbonate secretion was significantly greater than pancreatic secretion. Furthermore, the disappearance rate of acid in the duodenum during diversion of both bile and pancreatic juice was significantly greater than the amount of acid which could be neutralized by the concomitant pancreatic bicarbonate secretion. Diversion of pancreatic juice from the duodenum did not affect the disappearance rate of acid at any acid load, whereas diversion of bile caused a significant decrease. Thus, in the anaesthetized pig the liver and the duodenal mucosa are of greater importance than the pancreas for the neutralization of acid in the duodenum. It is suggested that the importance of the pancreatic contribution to duodenal neutralization should be reevaluated in other species, including man.     

Relative Importance of Pancreatic,Hepatic, and Mucosal Bicarbonate in Duodenal Neutralization of Acid in Anaesthetized Pigs

Pancreatic and hepatic bicarbonate secretion and the disappearance rate of acid during duodenal acidification were measured simultaneously in anaesthetized pigs. Perfusion of the duodenum with HCI resulted in an increase in both hepatic and pancreatic bicarbonate secretion. During all acid loads hepatic bicarbonate secretion was significantly greater than pancreatic secretion. Furthermore, the disappearance rate of acid in the duodenum during diversion of both bile and pancreatic juice was significantly greater than the amount of acid which could be neutralized by the concomitant pancreatic bicarbonate secretion. Diversion of pancreatic juice from the duodenum did not affect the disappearance rate of acid at any acid load, whereas diversion of bile caused a significant decrease. Thus, in the anaesthetized pig the liver and the duodenal mucosa are of greater importance than the pancreas for the neutralization of acid in the duodenum. It is suggested that the importance of the pancreatic contribution to duodenal neutralization should be reevaluated in other species, including man.     

Duodenal ulcerogens cysteamine and propionitrile decrease duodenal neutralization of acid in the rat

Neutralization of acid was evaluated in rat proximal duodenal segments isolated from biliary and pancreatic secretions. Duodenal ulcerogenic doses of cysteamine produced a significant decrease in acid disposal 0.5–2 hr after treatment. Oral or subcutaneous administration of the duodenal ulcerogen was effective. The potent ulcerogen cysteamine produced a more pronounced decrease than propionitrile (a weak duodenal ulcerogen). The failure of ethanolamine, a nonulcerogenic structural analog of cysteamine to significantly alter acid disposal suggests that the effect is not due to the toxic properties of the duodenal ulcerogen. The results reinforce the concept that the duodenum is able to dispose of significant quantities of acid. The decrease in acid-handling may contribute to duodenal susceptibility to acid after treatment with ulcerogens and possibly reflects pathophysiologic changes early in duodenal ulceration.     

Influence of bile flow obstruction vs bile diversion on pancreatic secretion in the conscious rat

Changes in pancreatic exocrine functions were compared between conscious rats with bile duct ligation and bile diversion from the duodenum on the first, third, fifth, and seventh postoperative days. Body weight was significantly decreased with time in both groups. Basal secretions of fluid, bicarbonate, and protein remained unchanged throughout the experimental period in bile duct ligated rats, whereas in bile diverted rats, the basal bicarbonate secretion with returning of pancreatic juice to the duodenum increased on the third postoperative day, and the basal protein output significantly increased with time. Basal secretions with returning of pancreatic juice to the duodenum in both groups were higher than that in control (bile and pancreatic juice returned to the intestine) rats. Stepwise increases in fluid and bicarbonate outputs responding to the graded doses of secretin were observed in bile duct ligated rats on the first and third postoperative days, as has been observed in bile diverted rats. However, on the fifth and seventh postoperative days, stepwise responses to graded doses of secretin were no longer observed in bile duct ligated rats. The pancreatic response to cerulein was greater in bile diverted rats than in bile duct ligated rats. Plasma CCK concentration in 7-d bile duct ligated rats (4.7 pM) was significantly higher than that in 7-d bile diverted rats (1.6 pM), although the pancreatic wet weight, protein concentration, and total content were comparable for the two groups. It was suggested that the presence of bile in the duodenum is required to maintain normal pancreatic secretion, and that the removal of bile from the intestine has quite different effects, depending on whether the bile flow is obstructed or diverted.     

Influence of bile flow obstruction vs bile diversion on pancreatic secretion in the conscious rat

Changes in pancreatic exocrine functions were compared between conscious rats with bile duct ligation and bile diversion from the duodenum on the first, third, fifth, and seventh postoperative days. Body weight was significantly decreased with time in both groups. Basal secretions of fluid, bicarbonate, and protein remained unchanged throughout the experimental period in bile duct ligated rats, whereas in bile diverted rats, the basal bicarbonate secretion with returning of pancreatic juice to the duodenum increased on the third postoperative day, and the basal protein output significantly increased with time. Basal secretions with returning of pancreatic juice to the duodenum in both groups were higher than that in control (bile and pancreatic juice returned to the intestine) rats. Stepwise increases in fluid and bicarbonate outputs responding to the graded doses of secretin were observed in bile duct ligated rats on the first and third postoperative days, as has been observed in bile diverted rats. However, on the fifth and seventh postoperative days, stepwise responses to graded doses of secretin were no longer observed in bile duct ligated rats. The pancreatic response to cerulein was greater in bile diverted rats than in bile duct ligated rats. Plasma CCK concentration in 7-d bile duct ligated rats (4.7 pM) was significantly higher than that in 7-d bile diverted rats (1.6 pM), although the pancreatic wet weight, protein concentration, and total content were comparable for the two groups. It was suggested that the presence of bile in the duodenum is required to maintain normal pancreatic secretion, and that the removal of bile from the intestine has quite different effects, depending on whether the bile flow is obstructed or diverted.     

An experimental study of adrenalin-stimulated gastric acid secretion and gastrin secretion in rats of cysteamine-induced duodenal ulcer]

It is known that cysteamine-induced duodenal ulcers in rats are similar to the human duodenal ulcers in some aspects. We investigated their similarities in view of adrenalin-stimulated gastric acid secretion and gastrin secretion in these rats. Acid outputs decreased in the control group by the administration of adrenaline, but in the cysteamine-administered group acid outputs increased dose dependently. Serum gastrin levels and plasma noradrenaline levels increased by cysteamine administration. The abnormal gastric acid secretion by the adrenalin infusion in the process of cysteamine-induced duodenal ulcers in rats, which was resembled to that of duodenal ulcer patients, was recognized.     

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.