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Background: We previously reported the development of pancreatic acinar cell metaplasia (PACM) in the glandular stomach of a duodenal contents reflux model (reflux model)., Aims: We aimed to investigate the characteristics and histogenesis of PACM using a reflux model., Methods: A reflux model was created using 8-week-old male Wistar rats, which were killed up to 30 weeks postoperatively. Histological examination was performed to analyze the glandular stomach-jejunal anastomosis. Furthermore, electron microscopic images of PACM samples were compared with pancreatic and gastric glands removed from rats that had not undergone surgery. Immunostaining for α-amylase, HIK1083, TFF2, and Ki-67 was performed, and double fluorescent staining was carried out using antibodies against α-amylase and HIK1083, or α-amylase and TFF2., Results: In all reflux model rats, PACM was observed proximal to the glandular stomach-jejunal anastomosis, surrounded by pseudopyloric metaplasia. The number of chief cells was decreased in the deep part of the gland, where PACM occurred. Electron microscopy showed that PACM cells had greater numbers of rough endoplasmic reticulum tubules than chief cells, and exhibited pancreatic acinar cell morphology. Upon immunochemical staining, the regenerative foveolar epithelium and part of the pseudopyloric glands stained strongly positive for TFF2, whereas PACM cells were only weakly positive. Double fluorescent staining identified early lesions of PACM in the neck, which were double positive for α-amylase and TFF2, but negative for HIK1083., Conclusions: PACM could be induced by duodenal contents reflux. PACM originates from stem cells located in the neck of oxyntic glands during gastric mucosal regeneration.

Background: Acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of other regional tissues or remote organ systems. Acute fluid collections and pseudocyst formation are the most frequent complications of acute pancreatitis., Aims: The aims of this study were to evaluate the incidence, risk factors, and clinical course of pancreatic fluid collections and pseudocyst formation following acute pancreatitis., Methods: A prospective multicenter study was conducted in five participating centers with 302 patients diagnosed with acute pancreatitis from January 2011 to July 2012., Results: The incidence of pancreatic fluid collections and pseudocyst was 42.7 and 6.3 %, respectively. Patients with fluid collections were significantly younger, compared to those without fluid collections (51.5 ± 15.9 vs. 60.4 ± 16.5 years, P = 0.000). The proportion of alcoholic etiology (54.3 %) in patients with fluid collections was significantly higher compared to other etiologies (P = 0.000). C-reactive protein (CRP) (48 h) was significantly higher in patients with fluid collections, compared to patients without fluid collections (39.2 ± 77.4 vs. 15.1 ± 36.2 mg/dL, P = 0.016). LDH (48 h) was significantly higher in patients with pseudocyst formation, compared to patients with complete resolution (1,317.6 ± 706.4 vs. 478.7 ± 190.5 IU/L, P = 0.000). Pancreatic fluid collections showed spontaneous resolution in 69.8 % (90/129) and 84.2 % of the pseudocysts disappeared or decreased in size during follow up., Conclusions: Age, CRP (48 h), and alcohol etiology are risk factors for pancreatic fluid collections. LDH (48 h) appears to be a risk factor for pseudocyst formation. Most pseudocysts showed a decrease in size or spontaneous resolution with conservative management.

Background: Little is known about the etiopathogenesis of chronic pancreatitis, due mainly to the lack of simple animal models suitable to study inflammatory and fibrogenetic processes in the pancreas., Aims: The purpose of this study was to examine whether transient congestion of pancreatic fluid flow alone or slight ductal injury alone is sufficient, or where both are required, to induce chronic pancreatic injury., Methods: Three different models of pancreatitis were tested in rats induced by retrograde intraductal infusion of 40 μl/100 g body weight of 0.01% agarose (group A), 40 μl/100 g body weight of 0.1% sodium taurocholate (group T), or a mixture of the two solutions (group M). Histological alterations of the pancreas were examined by hematoxylin-eosin staining, changes in type IV collagen structure were studied by immunostaining, and the gelatinolytic activity of latent and active matrix metalloproteinase-2 (MMP-2) was analyzed by zymography., Results: In group A and T rats, histological alterations of the pancreas and the gelatinolytic activity of MMP-2 returned to baseline levels by day 14, and immunoreactivity for type IV collagen appeared as continuous lines along the basement membrane. In group M rats, however, acinar damage, fibrosis and fatty degeneration were observed even on day 56, and type IV collagen was detected as discontinuous lines until day 56. MMP-2 was significantly elevated from day 5 to day 42., Conclusions: Co-existence of transient stasis of pancreatic fluid flow, together with mild damage to the pancreatic duct and acinar cells, exert synergistic effects on the development of persistent pancreatic injury with continuous disorganization of type IV collagen in the basement membrane of the ducts.

Direct measurement of pancreatic enzymes is the gold standard in the evaluation of exocrine pancreatic function. The purpose of our study was to evaluate the use of cholecystokinin as a single-agent secretagogue for pancreatic drainage studies. Twenty pediatric patients received cholecystokinin (group 1) and 40 patients received either secretin plus placebo (group 2) or secretin plus cholecystokinin (group 3). Duodenal fluid was collected for measurement of lipase, amylase, trypsin, chymotrypsin. The mean lipase and amylase activities were higher in group 3 and the mean trypsin and chymotrypsin activities were higher in group 1, but none of these observations were statistically significant. Group 3 had more patients with all four enzymes being normal (75%) compared to groups 1 (60%) and 2 (50%) (P = 0.262). Patients in all three groups had at least one normal enzyme. Cholecystokinin is useful as a single agent for direct pancreatic enzyme measurements in the absence of commercially available secretin.

The importance of secretory immunoglobulin A (IgA) of local immune defense in the gastrointestinal tract has gained increasing acceptance. Bacterial contamination is a major factor related to mortality in acute pancreatitis. However, very little is known about IgA in pancreatic juice. Pure pancreatic juice was collected from 40 patients undergoing pancreatoduodenectomy. The patients were divided into three groups according to the degree of preoperative pancreatic duct obstruction, as follows: normal, narrowed, and obstructed. IgA concentration, amylase activity, and daily volume of pancreatic juice were measured. Daily IgA secretion into pancreatic juice was constant during the early period after the operation. The concentration of IgA in the control group was 5 +/- 0.8 microg/ml, and IgA daily secretion was 1.2 +/- 0.2 mg/day. Pancreatic duct obstruction resulted in a marked decrease in both amylase and pancreatic juice secretion. The concentration of IgA, however, was markedly increased in the narrowed group (11.1 +/- 2.4 microg/ml) and the obstructed group (32.5 +/- 5.4 microg/ml). The concentration of amylase increased with the increase in pancreatic juice. Conversely, the concentration of IgA increased with the decrease in volume of pancreatic juice. Similarly, the increased in IgA concentrations positively correlated with the decrease in amylase activity. In conclusion, the mechanisms that modulate IgA secretion in the human pancreas are essentially different from those that modulate digestive enzyme and fluid secretion. IgA in pancreatic juice may play an important role in pathological conditions such as pancreatic duct obstruction. As such, the measurement of IgA in pancreatic juice may potentially be used as a new marker of local immune defense and exocrine pancreatic function.

Less invasive pancreatic head resection, such as pylorus preserving pancreatoduodenectomy (PPPD) and duodenum preserving pancreatic head resection (DPPHR) has been introduced for the treatment of pancreatoduodenal lesions, especially for benign conditions, in consideration of postoperative quality of life. Surgical stress and exocrine and endocrine function of the residual pancreas were examined in 44 patients with PPPD, 10 with conventional pancreatoduodenectomy (PD) and six with DPPHR. Clinical findings including serum levels of C reactive protein (CRP), fasting blood sugar, a 120-min value of the 75-g oral glucose tolerance test (OGTT), N-benzol-L-tyrosyl-p-aminobenzoic acid (BT-PABA) excretion value (a pancreatic exocrine function test), and volume of postoperative pancreatic juice drainage were compared among the three different variants of pancreatectomy. Operation time and operative blood loss in PD were largest of the three, followed by PPPD and DPPHR. Postoperative elevation of serum CRP on postoperative day (POD) 2 or 3 was similar among the three different types of operation. Fasting blood sugar concentrations were not different among the three groups at short- and long-term after the operation, while the 120-min value of the GTT showed a marked elevation at long-term only after PPPD. The volume of pancreatic juice drainage increased up to POD 4 and became constant thereafter. The total amount of pancreatic juice drainage from POD 4 to 13 was smallest in PD (637 ml) followed by PPPD (1,255 ml) and DPPHR (1,431 ml). The BT-PABA value declined after PD (-20.3%, P = 0.0437) and PPPD (-20.2%, P = 0.0239) at short term, but not after DPPHR (8.2%). These findings suggest that the early impairment of the pancreatic exocrine function after PD and PPPD but not after DPPHR may indicate that the invasiveness of pancreatic head resection to the pancreatic functions is greater in PD and PPPD than in DPPHR.

Peptide YY (PYY) is one of several regulatory peptides reported to modulate pancreatic secretion. PYY circulates in two forms, PYY1-36 and PYY3-36, and binds to multiple receptor subtypes. We sought to determine if PYY1-36 or PYY3-36 regulates neurally mediated pancreatic secretion through the Y1, Y2, and/or Y5 receptor subtypes. Experiments were conducted in awake, surgically recovered rats. In order to determine the effects of the PYYs on basal pancreatic secretion, either PYY1-36, [Pro34] PYY1-36 (a Y1/Y5 agonist), or PYY3-36 (a Y2/Y5 agonist) were infused for 40 min at doses of 0, 12.5, 25, or 50 pmol/kg/hr while measuring pancreatic juice volume and protein. PYY1-36 increased pancreatic protein secretion at 25 and 50 pmol/kg/hr (P < 0.05) in a dose-dependent manner (P < 0.001, R2 = 0.990). The Y2/Y5 receptor agonist PYY3-36 significantly inhibited pancreatic juice volume and protein at 12.5 and 25 pmol/kg/hr, but stimulated protein secretion at higher doses (P < 0.001, R2 = 0.995). The Y1/Y5 agonist, [Pro34] PYY1-36, had no significant effect on basal pancreatic exocrine secretion. Therefore, PYY1-36, PYY3-36 and [Pro34] PYY1-36 produced different, dose-dependent changes on basal pancreatic exocrine secretion. Inhibition of pancreatic secretion by circulating PYY1-36 and PYY3-36 are primarily mediated by the Y2 receptor. Since [Pro34] PYY1-36 did not change pancreatic secretion, it can be concluded that circulating PYY1-36 or PYY3-36 does not modulate pancreatic secretion through the Y1 or Y5 receptors. Since the stimulatory effects of PYY1-36 on pancreatic secretion could not be explained by the actions of PYY3-36 or [Pro34] PYY1-36 on Y1 or Y2 receptors, and since PYY1-36 fails to bind to Y3 or Y4 receptors, we also conclude that PYY1-36 may stimulate pancreatic secretion in a dose-dependent mechanism through a PYY receptor subtype different from Y1, Y2, Y3, Y4 or Y5.

Pancreatic exocrine function was examined in rats during the early stage of acute pancreatitis induced by four subcutaneous injections of 20 micrograms/kg body weight of cerulein at hourly intervals. Basal pancreatic fluid secretion at 6 hr after the first of four cerulein injections was significantly elevated (27.6 +/- 3.7 vs 17.4 +/- 2.1 microliters/30 min in control, P < 0.01) and further increased with time, reaching the peak level at 24 hr (105.1 +/- 4.6 microliters/30 min). Intravenous infusion of loxiglumide (50 mg/kg body wt/hr), atropine (100 micrograms/kg body wt/hr), or anti-secretin serum did not modify the fluid hypersecretion observed at 24 hr after induction of acute pancreatitis. Loxiglumide, when given 30 min before the first cerulein injection, markedly reduced fluid secretion, but could not inhibit the fluid hypersecretion when applied after the last cerulein injection. Leakage of Evans blue dye into pancreatic juice was slightly but significantly increased in postpancreatitic rats compared with that in the control rats (1.30 +/- 0.17 vs 0.75 +/- 0.08 micrograms/ml, P < 0.01), whereas that in the pancreas was not different from the control rats. In vivo labeling with 5-bromo-2'-deoxyuridine showed active proliferation of acinar and ductular cells at 6 hr. In addition, the fluid was rich in chloride (137.1 +/- 2.5 at 24 hr vs 92.4 +/- 3.3 meq/liter in control, P < 0.01) but poor in bicarbonate concentration (39.0 +/- 2.0 at 24 hr vs 46.5 +/- 1.9 mmol/liter in control, P < 0.01), indicating acinar cell secretion. These results indicate that pancreatic fluid secretion during the early stage of acute pancreatitis induced by supramaximal doses of cerulein was markedly increased not by CCK-, secretin-, or cholinergic-dependent mechanisms but probably by acinar cell proliferation.

In conscious rats, bile inhibits pancreatic secretion. The role of luminal taurocholate (TC), a major component of rat bile, in the regulation of pancreatic secretion was studied in conscious rats with external bile and pancreatic fistulae. On the fourth postoperative day, after the basal collection of bile and pancreatic juice (PJ) returned to the duodenum, graded doses of TC (0, 0.4, 4, 40 mM) containing 10 mM CaCl2 were infused into the duodenum instead of bile and PJ for 2 hr (1 ml/hr), with or without 1 mg/ml of porcine trypsin. Luminal trypsin activities were not affected by any dose of TC. The increases in pancreatic secretion in response to diversion of bile and PJ were progressively inhibited with increasing doses of infused TC from 0 mM to 4 mM both with and without trypsin infusion. The effects with 4 and 40 mM TC were not significantly different. Changes in plasma cholecystokinin concentrations roughly correlated with changes in protein output in rats without trypsin infusion. We concluded that TC directly inhibited pancreatic secretion independent of the luminal trypsin activity and that its inhibitory action was concentration dependent.

In several species, bicarbonate and calcium concentrations of pancreatic juice are known to vary during the different phases of pancreatic secretion. The effects of these variations on the saturation of juice with calcium carbonate, a critical factor for the formation of pancreatic stones, are not known. In this work, we studied the saturation degree of pancreatic juice with calcium carbonate in six unanesthetized beagle dogs equipped with Thomas cannulae during basal secretion and after bolus injections of cerulein (30 ng/kg) or secretin (0.25 units/kg). In the different samples of pure pancreatic juice, pH, PCO2, bicarbonate, and proteins were measured by standard methods. Total calcium (CaT) and ionized calcium (Ca2+) were determined using calcium-specific electrodes. Saturation with calcium carbonate was calculated by reference to the solubility product of calcite at 37 degrees C. Almost all the samples were found to be supersaturated with calcium carbonate but large variations of the saturation index were observed. In basal samples, obtained during periods of low secretion rate, the mean saturation index (3.35 +/- 3.01) was significantly lower than under secretion (12.10 +/- 5.14) or cerulein (18.01 +/- 8.42). This low basal saturation index, in spite of a high Ca2+ content, was explained by a low bicarbonate concentration (37.6 +/- 18.9 mmol/liter) and a high PCO2 (13.4 +/- 7.5 kPa). In contrast, in juice obtained after hormonal stimulation, PCO2 (4.8 +/- 1.6 kPa) was similar to plasma PCO2 (5.5 +/- 1.2 kPa).(ABSTRACT TRUNCATED AT 250 WORDS)

To clarify the effect of islet hormones on pancreatic ductular cell function, we measured the exocrine secretion elicited by 10 pM secretin in the presence or absence of islet hormones using an isolated perfused rat pancreas model. Insulin significantly increased secretin-stimulated pancreatic juice secretion, but not protein secretion. The potentiating effect of insulin on pancreatic juice secretion was concentration-dependent, and the maximal effect was observed with 1 microM insulin. Ouabain, a specific Na+,K(+)-ATPase inhibitor, caused concentration-dependent inhibition of the potentiating effect of insulin without affecting secretin action. Glucagon (100 nM) significantly inhibited secretin-stimulated pancreatic juice secretion and also tended to inhibit protein secretion. A somatostatin analog, SMS 201-995 (10 nM) significantly inhibited both the pancreatic juice and protein secretion stimulated by secretin. The inhibitory effect of SMS 201-995 was concentration-dependent and was maximal at 1-10 nM. These results demonstrate that insulin potentiates the secretory response to secretin, at least partly by increasing Na+,K(+)-ATPase activity, whereas glucagon and somatostatin inhibit this response. Thus, pancreatic islet hormones regulate the secretory function of pancreatic ductular and centroacinar cells.

The development and validation of a radioimmunoassay that detects release of secretin in plasma in response to low doses of secretagogues [intraduodenal HCl (0.033 meq/min); intraduodenal sodium oleate (0.04 mmol/min)] or an oral mixed meal in conscious dogs is described. Plasma secretin levels increased significantly (P less than 0.05) in response to an oral mixed meal in conscious dogs from a basal level of 4.0 to a peak level of 12.3 pg/ml at 15 min. Infusion of graded doses of HCl (2, 4, 8, 16, meq/hr for 30 min) intraduodenally in six dogs resulted in significant elevation of plasma secretin levels in a dose-dependent manner. The pancreatic bicarbonate and volume outputs correlated with the dosage of HCl administered and with the elevations in plasma secretin concentrations. Intraduodenal infusion of increasing doses of sodium oleate (2.4, 4.8, 9.6, and 19.2 mmol in 15-min periods) resulted in a significant (P less than 0.05) elevation of plasma levels of secretin.

The effects of intraluminal bile on cholecystokinin release and pancreatic exocrine secretion were studied in conscious rats. Since it has been suggested that bile acid may influence pancreatic secretion indirectly by interacting with luminal protease activities, intraduodenal protease activities were eliminated by pancreatic juice diversion accompanied with simultaneous intraduodenal infusion of aprotinin. This treatment resulted in gradual increases in pancreatic juice flow, bicarbonate and protein outputs, and an increase in plasma cholecystokinin levels, reaching plateau levels 2 hr after the start of the treatment. When endogenous bile was excluded from the intestine, the pancreatic secretion and plasma cholecystokinin concentrations further increased. The intraduodenal infusion of sodium taurocholate during bile pancreatic juice diversion inhibited cholecystokinin release, while pancreatic protein output was only transiently decreased. The results indicate that bile in the duodenum directly regulates cholecystokinin release, probably through its major components, bile salts.

The effects of L-364,718, a new CCK receptor antagonist, on food-stimulated exocrine pancreatic secretion and plasma levels of PP, insulin, CCK, and gastrin were examined in four conscious dogs with pancreatic fistulas. Intravenous injections of L-364,718 (20 nmol/kg) significantly inhibited pancreatic protein and enzyme responses by food (33% inhibition) but not juice volume output. Both rapid and secondary prolonged postprandial rises of plasma PP were also significantly suppressed by L-364,718 (50% inhibition); however, plasma levels of insulin were not altered. Postprandial levels of gastrin were not affected by L-364,718 administration, whereas 3-hr integrated CCK response was significantly enhanced by L-364,718. This study indicates that L-364,718 inhibits pancreatic protein and enzyme secretion and the release of pancreatic polypeptide stimulated by food in conscious dogs. This inhibition might be due to the selective blockage of receptor binding of circulating CCK molecules. The results suggest that L-364,718 may be useful for the physiological and pathophysiological studies associated with CCK.

Sulpiride is a nonsedative neuroleptic, pharmacologically related to metoclopramide, which has previously been shown to affect various gastric functions and to exert a beneficial effect in the treatment of duodenal ulcer. In the present study the authors investigated the effects of sulpiride on pancreatic exocrine secretion. The intravenous injection of sulpiride (100 mg) during a constant infusion of secretin (0.5 CU/kg/hr) and cholecystokinin (0.5 IDU/kg/hr) significantly increased outputs of bicarbonate and enzymes in nine healthy subjects. The increase was maximal 20-30 min after sulpiride administration and lasted for the duration of the study (1 hr). Compared to presulpiride control levels, the mean maximum percent increase was 35% for bicarbonate, 39% for lipase, and 32% for chymotrypsin. It is concluded that sulpiride augments pancreatic secretion stimulated by submaximal doses of secretin and cholecystokinin. The mechanism of this effect is unknown.

The effect of chronic alcohol abuse on the secretion of pancreatic exocrine proteins was studied. Pure pancreatic juice (PPJ) was obtained by endoscopic cannulation of the pancreatic duct from 21 healthy, nonalcoholic volunteers and 25 chronic alcoholics. Peak concentration and output of total proteins after sequential stimulation with secretin and cholecystokinin was elevated significantly in chronic alcoholics when compared to nonalcoholic subjects. The most striking change in the secretory proteins investigated was exhibited by the trypsinogens. Although the concentrations of all three trypsinogen variants were elevated significantly in PPJ of chronic alcoholics, most of the increase resulted from an approximately fivefold increase of the anionic variant, suggesting nonparallel alterations in the synthesis of pancreatic exocrine proteins. Whereas the ratio of cationic-anionic trypsinogen in the control group was consistently greater than one, it was, without exception, below one in the chronic alcoholics group. As there was no significant increase in trypsin inhibitor in PPJ of alcoholics, the ratio of trypsinogen-trypsin inhibitor showed a highly significant increase in this group. This distortion of the normal ratio in favor of trypsinogen may facilitate premature activation of pancreatic zymogens as postulated in acute pancreatitis. The concentrations of other zymogens and lysosomal hydrolases in PPJ of chronic alcoholics showed small, but not significant, increases, with the exception of leucine naphthylamidase which was significantly elevated. Nonparallel secretion of some exocrine proteins previously described in healthy nonalcoholic subjects was affected selectively by chronic ethanol ingestion. Thus, in chronic alcoholics the secretory kinetics of trypsinogen and chymotrypsinogen were altered, but trypsin inhibitor secretion remained apparently unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

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, 1 microgram/kg) was infused intravenously as a bolus under background infusion of secretin (1 unit/kg/hr) in combination with cholecystokinin-octapeptide (0.1 microgram/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 microgram/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 less than 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.

Biochemical, histological, and crystallographic studies were carried out on basal pancreatic secretion of 4 dogs fed alcohol for 12-15 months and 11 control dogs. The results in alcohol-fed dogs when compared to normals showed that: (1) protein concentration was higher, (2) fluid was decreased; (3) conductivity was decreased leading to differences in ionic distribution: Cl- and H+ ion concentrations increased, HCO3 concentrations and output decreased, total Ca, Mg, and Zn soluble in the juice did not change and therefore Ca, Mg, and Zn to protein ratios decreased. In the basal secretion of alcoholic dogs, numerous plugs were found of which three components were identified: (1) cells mostly of ductal origin; (2) calcium already crystallized; (3) protein material in the center of these plugs. Thus a change in Donan equilibrium led to modifications of protein and calcium solubilities with formation of precipitates. These findings are relevant to the study of chronic pancreatitis due to alcohol consumption.

The effects of natural peptide YY on pancreatic secretion under different stimulatory conditions and on fatty acid-induced cholecystokinin release were examined in five conscious dogs with pancreatic and gastric fistulas. Intravenous infusion of natural peptide YY at 1 and 0.2 microgram/kg/hr caused 60 and 40% inhibition of secretin- and cholecystokinin-stimulated secretion, respectively, and 40-50 and 20-40% inhibition of intraduodenal oleate stimulated secretion, respectively. A significant but transient decrease in the plasma cholecystokinin level was observed in response to peptide YY under oleate stimulation. The present study demonstrates that peptide YY has a potent inhibitory effect on both exogenously and endogenously stimulated pancreatic secretion and has a mild suppressive effect on fatty acid-induced cholecystokinin release suggesting that this peptide is an important colonic inhibitor of pancreatic secretion.

Pancreatic secretions were collected during endoscopic retrograde cholangiopancreatography from 15 subjects without pancreatic, biliary, or hepatic diseases, 11 patients with non-insulin-dependent diabetes, and 11 patients with insulin-dependent diabetes. Pancreatic secretion was stimulated by the intravenous administration of one unit of secretin per kilogram of body weight. Immunoreactive somatostatin (IRS) in the pancreatic juice of the nondiabetic subjects ranged from 43 to 97 pg/ml, in non-insulin-dependent diabetics from 5 to 3872, and in the insulin-dependent diabetics from 0 to 2093. IRS in insulin-dependent diabetics under good plasma glucose control ranged from 0 to 281 pg/ml, compared to those under poor control who ranged from 518 to 2093 pg/ml. These results indicate that IRS in pancreatic juice is higher in poorly controlled insulin-dependent diabetics than in well controlled insulin-dependent diabetics and nondiabetics. Whether these changes in IRS are purely secondary phenomena or play some pathogenetic role in the disturbed metabolism of diabetes remains to be proven. The chromatographic profile of IRS in pancreatic juice on both gel filtration and high-performance liquid chromatography has indicated that these IRS moieties represent somatostatin 14 and somatostatin 28.

The effects of a new H2-receptor blocker, ranitidine, given intravenously (for comparison with cimetidine) or orally an gastric and pancreatic secretion have been studied in duodenal ulcer patients. Ranitidine appears to be several times more potent and a longer-acting inhibitor of gastric secretion than cimetidine. This H2 blocker does not affect pancreatic bicarbonate and enzyme secretion.

The mechanism by which oxethazaine inhibits hydrochloric acid stimulation of pancreatic secretion and the endogenous release of secretin was studied in six dogs prepared with pancreatic and gastric fistulae. Oxethazaine reduced both pancreatic secretion and plasma secretin concentration evoked by duodenal acidification, and the degree of inhibition was proportional to its dose. This drug did not inhibit the pancreatic secretion stimulated by the exogenous secretin. From kinetic analyses, it seems that oxethazaine acted as noncompetitive inhibitor of hydrogen ion on the chemoreceptors of the secretin-releasing cells in the duodenal mucosa. This may result in a decrease of secretin release from these cells and consequently of pancreatic secretion.

To study whether the secretory state of the in vivo pancreas affects its response to ethanol, we administered ethanol intravenously to conscious rats in the presence and absence of exogenous secretin. In the absence of secretin when pancreatic secretion was maintained at basal levels, intravenous ethanol produced a significant stimulation of the flow rate, bicarbonate concentration, and protein concentration. This response persisted despite elimination of gastric acid production by infusion of the H2 receptor antagonist cimetidine. In contrast, intravenous ethanol inhibited the flow rate and bicarbonate concentration when pancreatic secretion was augmented by the infusion of GIH secretin. Thus, the rat pancreas responds differently to intravenous ethanol in the basal and secretin-stimulated states. These results may account for the lack of agreement regarding the pancreatic effects of systemic ethanol.

The possibility of the involvement of pancreatic polypeptide (PP) release in luminal feedback regulation in the conscious rat was examined. Pancreatic secretion in the intestinal phase in the rat is regulated by negative feedback control so that a decrease in luminal protease activities produced by a diversion of bile-pancreatic juice (BPJ) from the intestine stimulates pancreatic secretion. Plasma concentration of rat PP and the effect of exogenous infusion of rat PP on pancreatic secretions during BPJ diversion were determined. Plasma PP concentration significantly increased with BPJ diversion and peaked at 90 min after BPJ diversion began, almost paralleling changes in protein output. Exogenous PP infusion (1, 2 and 10 micrograms/kg/hr) inhibited pancreatic protein and fluid outputs but not the bicarbonate output during BPJ diversion. PP was shown to be physiologically released in the intestinal phase of pancreatic secretion; however, the physiological role of endogenous PP remains unknown.

Previous studies have suggested that chronic alcohol consumption in man is associated with an increased secretion of pancreatic enzymes. Precise quantitation of the output of protein and trypsin in the interdigestive state has not been possible because of large variations and small volume of pancreatic juice. We utilized a multilumen, marker-perfused duodenal catheter to simultaneously monitor intraluminal pressures and collect mixed duodenal juice at the ligament of Treitz in five groups of patients: normal volunteers (group I), alcoholics without pancreatitis (group II), alcoholics who had recovered from acute pancreatitis (group III), alcoholics with chronic pancreatitis (group IV), and nonalcoholics who had recovered from acute pancreatitis secondary to biliary tract disease (group V). The output of trypsin and protein during 30 min of phase II and 60 min of CCK-OP 40 ng/kg/hr was determined in each group. The output of trypsin during phase II was 1.3 +/- 1.2 and 3.0 +/- 2.5 mg/kg/hr in groups II and III, respectively, compared to 0 +/- 0.1 in group IV (normal = 0.6 +/- 0.5). The outputs in group V were similar to normals. The output of protein during the interdigestive state was 15.7 +/- 13.7 mg/min in group III, compared to 4.5 +/- 3.6 in normals (group I). The duodenal contraction rate was 4.6 +/- 3.0 and 3.3 +/- 2.7 contractions/min in groups III and II, respectively (significantly greater than the normal rate of 2.2 +/- 1.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Profiles of pancreatic secretory proteins (zymogens, lysosomal enzymes) were studied in Syrian golden hamsters after sequential stimulation of the pancreas with secretin and cholecystokinin-octapeptide (CCK). The flow rate of pancreatic juice after secretin (0.2 CU/100 g) was approximately 2.7 microliters/min/100 g animal (about 55% of that in human subjects). The half-life of the secretin effect was about 60 min. The initial concentration of protein in pancreatic juice (minute-to-minute collection) in response to secretin was over 10 times larger than that in human subjects and the "wash-out" phase required greater than 1 hr vs less than 10 min in humans. CCK (4 ng/100 g) in minute-to-minute collections of juice produced an approximately eightfold increase in concentration of secretory products over baseline values, and the half-life of its effect was about 2 min, similar to that found in human subjects. Digestive as well as lysosomal enzyme activities in hamster pancreatic juice were 10-15 times higher than those found in human pancreatic secretions. This species difference may be relevant to the susceptibility of the hamster pancreas to carcinogens.

The effect of aclatonium napadisilate, a choline sulfonate derivative, on exocrine and endocrine pancreatic functions was compared with that of carbamylcholine in both isolated pancreatic acini and the isolated perfused pancreas of rats. In the isolated acini, aclatonium napadisilate and carbamylcholine stimulated amylase release. While the relative efficacy of aclatonium napadisilate was the same as that of carbamylcholine, aclatonium napadisilate was about 20-fold less potent. In the isolated perfused pancreas, 0.1 microM or higher concentrations of aclatonium napadisilate elicited a significant insulin release in the presence of 8.3 mM glucose, whereas an appreciable increase in pancreatic exocrine secretion was obtained with a 10 times higher concentration (1.0 microM). In contrast, carbamylcholine did not stimulate insulin release at a dose (0.1 microM) that stimulated pancreatic exocrine secretion. The insulin-releasing effect of aclatonium napadisilate depended on the glucose concentration. These stimulatory effects of aclatonium napadisilate on endocrine and exocrine pancreatic secretion were inhibited by the muscarinic receptor antagonist pirenzepine but were not affected by the cholecystokinin receptor antagonist proglumide. These results indicate that aclatonium napadisilate stimulates both endocrine and exocrine pancreatic secretion via muscarinic receptors and that its action on B cells is more potent than on the exocrine pancreas.

Pharmacological doses of ceruletide administered intravenously to unconscious rats uniformly induces acute pancreatitis (AP) as well as a striking reduction in pure pancreatic juice (PPJ) and protein output. High-dose intravenous secretin administered to rats with ceruletide-induced AP effects a reestablishment of PPJ flow and a significant increase in PPJ protein output. Light microscopy of the pancreas in ceruletide-induced AP rats revealed marked acinar cell vacuolization and intense interstitial edema. By contrast, pancreatic histology in AP rats treated with high-dose secretin revealed a distinct lessening of acinar cell vacuolization and interstitial edema. We have established that high-dose intravenous secretin given to rats with ceruletide-induced AP is (1) not harmful, (2) reestablishes PPJ flow and evokes a partial restoration of protein output, and (3) appears to reduce pancreatic histopathology when compared to non-secretin-treated rats with AP.

Pancreatic secretions from the hamster model for pancreatic ductal adenocarcinoma were analyzed to determine whether alterations had occurred in the protein composition. CCK-and secretin-stimulated secretions were collected from 13 animals with cancer and 16 normal controls. Subsequent separation of the proteins by isoelectric focusing showed the following: (1) Significant changes occurred in the protein composition from animals with carcinoma. An unusually dark band was present at pH 7.5 just below amylase (pH 7.65); two unidentified bands, present in the normals at pH 6.9 and 7.0, were missing; and marked decreases occurred in the cathodic proteins with isoelectric points above pH 9, (2) CCK provided the optimal stimulus for differentiating specimens from animals with carcinoma from the normal controls. (3) The protein concentrations of CCK-stimulated secretions of animals with carcinoma were significantly lower than the controls. We have concluded that the protein alterations which have occurred in the hamster model for pancreatic ductal adenocarcinoma warrant further investigation.

Basal pancreatic and biliary outputs were examined in seven healthy volunteers during intravenous infusion of bovine pancreatic polypeptide (BPP) at a mean dose of 320 pmol/kg/hr. BPP significantly (P less than 0.02) inhibited outputs of trypsin and bilirubin, without affecting bicarbonate. These studies suggest the possibility that pancreatic polypeptide may have a role in the regulation of biliary and pancreatic enzyme secretion in man.

Pancreatic secretory profiles for 11 pancreatic enzymes and proteins were established in nine patients with cancer of the pancreas by analysis of minute-to-minute collections of pure pancreatic juice after sequential administration of secretin and cholecystokinin. Aspiration of pancreatic fluid sufficient for this study was successful in less than one quarter of the patients investigated because of ductal obstruction and/or the effect of the disease on pancreatic exocrine function. Flow rates in patients generally were lower than in healthy individuals, and secretion of total protein, trypsin inhibitor, and activity of digestive enzymes were in the lowest part of or below the normal range. Normal flow rates in four patients precluded ductal obstruction as the sole cause of impaired enzyme secretion. Activity of lysosomal hydrolases in pancreatic juice of these patients, in contrast to that of digestive enzymes, remained within or rose above the normal range. The tumor appeared to have a diametrically opposite effect on the two different groups of enzymes. This is illustrated most dramatically in the form of ratios of lysosomal to digestive enzymes. Virtually all of 10 such ratios were far above the normal average in all patients, and none was below. In an analogous investigation of 25 patients with chronic pancreatitis only three exhibited the ratio pattern characteristic of pancreatic cancer patients. Pancreatic secretory profiles appear to be capable of discriminating between cancer of the pancreas and chronic pancreatitis in a high percentage of cases. Extension and refinement of this approach may facilitate early detection of cancer of the pancreas.

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 micrograms/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 microgram/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 micrograms/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.

The effects of intravenous infusion of amino acids, fat, or glucose on unstimulated pancreatic secretion were studied in 31 healthy male volunteers. Each subject was studied twice on two separate days. On both days pancreatic outputs were measured during a 4-hr basal period that was followed by a 4-hr test period. During the test period either one of the digestive end products (100 ml/hr 10% amino acids in 13 subjects; 100 ml/hr 10% fat in 8 subjects; 150 ml/hr 10% glucose in 10 subjects) or saline was intravenously infused. The infusion of the digestive end products or saline on the two separate days was done in a randomized order. Six of the 10 subjects that had already been studied for glucose received a higher glucose dose (100 ml 20% glucose as a bolus followed by 300 ml/hr 10% glucose) in a third additional experiment. Intravenous infusion of amino acids significantly stimulated pancreatic outputs of trypsin and chymotrypsin, but left the outputs of amylase, lipase, bicarbonate, and volume unaffected. The low-glucose dose, as well as the fat infusion did not alter any of the pancreatic outputs. To analyze the relationships between different enzymes during the infusion of digestive end products, regression lines were calculated from the scatter of all individual pairs of enzyme measurements. Significantly different regression functions found for each condition (NaCl control, amino acids, fat, glucose) when trypsin and chymotrypsin were plotted versus lipase and amylase: amino acids shifted the function to a trypsin- and chymotrypsin-dominant pattern of secretion, glucose to an amylase-dominant pattern, and fat to a lipase-dominant pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

Portal plasma immunoreactive secretin (IRS) concentrations, pancreatic juice flow, and amylase output were simultaneously measured in response to intraduodenal infusion of 1-phenyl-1-hydroxy-n-pentane (PHP), as well as infusion of hydrochloric acid (HCl). These data were compared with those obtained from intravenous bolus injections of synthetic porcine secretin in anesthetized rats. The intraduodenal infusion of PHP or HCl at a rate of 2 ml/min for 2 min produced a dose-related increase in portal plasma secretin concentrations, pancreatic juice flow, and amylase output. However, the mechanism of secretin release by PHP seems to differ from that of HCl. The secretin response to 0.1 N HCl infused at a rate of 0.1 ml/min for 30 min was complete after 10 min, despite continued infusion, while PHP stimulated a secretin release which persisted for 10 min after cessation of infusion. The pH in the second portion of the duodenum, following PHP infusion, remained consistently greater than 6.3. PHP-stimulated pancreatic exocrine secretions were only partially suppressed by somatostatin, while secretin release was almost completely inhibited. However, intraduodenal PHP may stimulate the release of secretin along with other gastrointestinal hormones, and the endogenous release of these hormones may not be inhibited by somatostatin.

The possibility that pancreatic secretory abnormalities might precede the appearance of pancreatic neoplasms and thus provide clues to early detection of this malignancy has been investigated in an animal model. Syrian golden hamsters were treated with bis-(2-oxopropyl)-N-nitrosamine on two successive weeks (2 mg/100 g body weight/week). Pancreatic secretions from treated and untreated control animals were studied at approximately monthly intervals. The animals were anesthetized, their pancreatic ducts cannulated, and basal pancreatic juice collected for 30 min. Pancreatic secretion was then stimulated by sequential intravenous injection of secretin (50 ng/100 g) and C-terminal octapeptide of cholecystokinin (4 ng/100 g) 1 hr later. Four consecutive 15-min collections of fluid were made following secretin stimulation and four additional collections after CCK administration. Each collection was examined for volume, total protein, trypsin, chymotrypsin, elastase, arylsulfatase, beta-D-glucuronidase, alpha-D-glucosidase, and leucine naphthylamidase. In addition two trypsinogen variants present in pancreatic secretions were determined. The pancreas and other organs were removed and examined histologically at the end of each experiment. Cytological atypia appeared 3 months, ductal hyperplasia 4 months, and pancreatic neoplasms 6 months after the last injection of carcinogen. Striking decreases in flow rate and output of trypsin and chymotrypsin were observed several months prior to the appearance of histologically recognizable pancreatic tumors. By contrast, output of beta-D-glucuronidase and alpha-D-glucosidase in pancreatic juice increased markedly in the last 2 months preceding the emergence of neoplasms. The diagnostic significance of these premalignant abnormalities is illustrated most dramatically in the form of ratios of lysosomal to digestive enzymes, such as beta-D-glucuronidase-trypsin or alpha-D-glucosidase-chymotrypsin. Highly significant increases in these ratios were observed consistently, not only in hamsters with pancreatic neoplasms, but also in animals with preneoplastic lesions (ductular hyperplasia) which preceded malignancies by about 2 months.

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.

Regulation of the exocrine pancreatic secretion elicited by a meal in man is incompletely understood. In this study, we attempted to localize in the gastrointestinal tract areas that control postprandial trypsin secretion and to determine the effects of individual components of jejunal chyme on the meal-stimulated trypsin secretion. Trypsin outputs elicited by ingesting a mixed-nutrient meal and diverting it at the ligament of Treitz proximal to an occlusive balloon were compared with those occurring when the same meal was ingested, diverted at the ligament of Treitz, and immediately reinfused distal to the balloon, a procedure that exposed the entire gastrointestinal tract to chyme. Two different meals, one of semielemental and one of complex nutrients, were used with similar results. Trypsin outputs were similar whether or not jejunal chyme was diverted. In addition, no component--exogenous nutrients or endogenous secretions--of chyme reaching the jejunum after a meal further modified the trypsin secretion elicited by the gastroduodenal segment. This finding suggests that the gastroduodenal segment is sufficient to elicit the entire postprandial trypsin output and is the physiologic determinant of meal-stimulated trypsin secretion.

This study was undertaken to determine the effect of synthetic chicken vasoactive intestinal peptide (VIP) on pancreatic blood flow, exocrine and endocrine secretions of the pancreas, and biliary secretion in dogs. The effect of synthetic chicken VIP on pancreatic blood flow and systemic arterial pressure was identical to that of natural chicken VIP in dogs. The present study demonstrated that synthetic chicken VIP induces significant increases in pancreatic blood flow, pancreaticobiliary secretion, and blood levels of insulin and glucose in dogs. Both the volume of pancreatic juice and blood levels of insulin were increased in consonance with the increase of pancreatic blood flow. This study suggests that the stimulatory effects of synthetic chicken VIP on exocrine and endocrine secretions of the pancreas may be related to the increased pancreatic blood flow elicited by synthetic chicken VIP.

We have compared responses to an ordinary solid-liquid (S) meal and to a homogenized (H) meal of identical composition (sirloin steak, bread, butter, ice cream with chocolate syrup, and water) by measuring simultaneously postprandial gastric, pancreatic, and biliary functions by marker-perfusion techniques. Responses to each (S or H) meals differed strikingly both in magnitude and pattern. S meals elicited a stronger early gastric secretory response (acid, pepsin, and volume) which compensated for faster initial emptying and resulted in higher gastric acidity and volume than after H meals. Further, nutrients ingested with S meals were emptied at a slower rate than H (as evidenced by a more gradual decline in intragastric buffer and osmolality, as well as time required for complete emptying of the meal). This, in turn, prolonged pancreatic and biliary responses since stimulation of these organs continued for as long as meal was delivered into the duodenum. However, early biliary outputs (gallbladder response) were less after S than H, probably because nutrients entered the duodenum more slowly and were initially diluted by rapidly emptying water. The physical characteristics of each meal (encompassing appearance, taste, and form of ingestion) probably accounted for early differences in digestive responses. Later, interactions between gastric (motor and secretory), pancreatic, and biliary functions played a major role. Our findings suggest that gastric, pancreatic, and biliary responses to liquid test meals introduced into the stomach may differ substantially from the presumably more physiological response to ordinary solid-liquid meals.

Basal pancreatic exocrine functions as well as responses to endogenous (BPJ diversion) and exogenous (injection of CCK-8 or secretin) stimulations were examined in young (6- and 12-month-old) and old (24- to 26-month old) female Fischer 344 rats. Basal secretions were not significantly different between young and old rats. BPJ diversion significantly stimulated pancreatic secretions of fluid, bicarbonate, and protein in all animals. The pancreatic protein response (mg/kg/hr) to BPJ diversion was significantly attenuated with respect to age [57.59 +/- 16.16, 43.73 +/- 6.94, and 20.75 +/- 3.95, for 6-, 12-, 24- to 26-month-old rats, respectively, mean +/- SE, F(2,20) = 3.49, P less than 0.05]. The pancreatic responses to secretin (0.086, 0.432, and 1.728 nmol/kg) were not significantly different between young and old rats. Intravenous injection of CCK-8 (0.033, 0.167, and 0.667 nmol/kg) produced a significant increase in protein output in all age groups. In young animals, stepwise increases in protein output were observed, whereas, in old rats, increments in response to the larger two doses of CCK-8 (0.167 and 0.667 nmol) were smaller than that produced by 0.033 nmol/kg of CCK-8. In conclusion, the basal secretions in old rats were comparable with those in young ones, but the reserve capacity for protein secretion appears to decrease in old compared to young rats.

A single oral dose of synthetic trypsin inhibitor (TI, 20 mg/100 g) was given to rats by orogastric tube 6, 12, 18, or 24 hr before the removal of the pancreas and the preparation of isolated perfused pancreas. TI treatment induced no significant changes in body weight and total amount of DNA content in the pancreas, but pancreatic wet weight, total pancreatic protein and amylase, and the concentration of total protein and amylase relative to DNA were significantly decreased at 6 or 12 hr posttreatment, with a partial return toward control values at 18-24 hr after TI treatment. In isolated perfused pancreas, basal amylase output was similar in the control and in all 4 groups of TI-pretreated rats, while basal rate of flow of pancreatic juice was significantly increased at 12-24 hr posttreatment. Caerulein (0.1 ng/ml; 64 pM) stimulated pancreatic juice flow was greatly increased in rats pretreated with TI 12-24 hr earlier. In contrast, caerulein-stimulated amylase output was significantly lower in TI-pretreated groups compared with the control. However, when amylase output was related to the total content in the pancreas, the secretory responsiveness for amylase release was significantly higher in rats at 6-18 hr posttreatment compared with the control. The present study indicates that a single oral administration of TI modulates biological response to caerulein in the isolated perfused pancreas. The enhanced responsiveness of amylase release to subsequent stimulation is seen in early periods, while that of pancreatic juice flow is observed in late periods.

This is a critical review of papers published on definition, classification, etiology, and pathogenesis of chronic pancreatitis from 1981 to 1985. Articles published earlier will only be mentioned when they are necessary to the understanding of the present knowledge or when they are insufficiently known. The more ancient literature has been reviewed elsewhere. The etiology and pathogenesis section will be limited to calcifying pancreatitis which is the most frequent form of chronic pancreatitis. The etiology of chronic obstructive pancreatitis has been studied in another review. The simple fibrosis of the pancreas is excluded from this chapter.

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 microM carbamylcholine in control rats and with 0.1-1 microM 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.

Modifications of pancreatic secretion induced by the infusion of alcohol were investigated in seven Thomas fistula dogs. Acute intravenous injections of low doses of alcohol induced a significant increase of all parameters of pancreatic secretion. On the contrary the acute intravenous injection of high doses of alcohol induced a significant decrease of pancreatic secretion. A prolonged-alcohol intravenous infusion producing a stable blood alcohol level provoked at first a decrease of pancreatic secretion, significant only for protein output, followed by a significant increase of all parameters of pancreatic secretion. A spontaneous return to prealcohol values of pancreatic secretion was observed in all cases even if the blood alcohol level remained high and stable and despite four hours of experimentation. Upon the background of a stable blood alcohol level, pentolinium did not suppress alcohol-induced stimulation of water and bicarbonate outputs but did abolish the postalcohol changes in protein secretion. Furthermore, atropine abolished all postalcohol changes in pancreatic secretion. Consequently, there are two responses (inhibition and stimulation) to alcohol which coexist in normal dogs. They are related to the blood alcohol levels and are transitory. These responses involve the vagus nerves. Alcohol appears to stimulate the exocrine pancreas through receptors at different levels of the nervous system.