Effects of glucagon on pancreatic secretion in the dog

About 85-90% of cytoplasmic protein synthesized by young reticulocytes is globin, and about 10% is a polypeptide (I) of molecular weight 64,000 daltons. Maturation of reticulocytes is accompanied by selective reduction in the synthesis of polypeptide I, relative to globin; mature reticulocytes synthesize globin at a high level but make no detectable polypeptide I. Studies in which RNA from young and old reticulocytes was translated in a wheat germ cell-free extract showed that reduction in synthesis of polypeptide I was correlated with a reduction in the amount of translatable mRNA for this protein. Differential destruction of mRNA thus is an important factor in determining the types of proteins made during the final stages of erythropoiesis.     

Intracerebroventricular neuropeptide Y increases gastric and pancreatic secretion in the dog

BACKGROUND: Neuropeptide Y (NPY), a centrally located neurotransmitter, is known to increase appetite in fasted and satiated animals. In addition to evaluating NPY's effect on eating behavior, this study was intended to determine whether intracerebroventricular (ICV) NPY would have an effect on canine gastric and pancreatic secretion. METHODS: Four dogs were prepared with cerebroventricular guides and gastric and pancreatic fistulas. ICV and intravenous NPY was administered during intragastric titration of a glucose and peptone meal. During this study, gastric and pancreatic secretion was measured, as well as insulin levels and pancreatic polypeptide (PP). An additional set of four dogs were prepared with esophageal fistulas and cerebroventricular guides, and the effect of ICV NPY on sham feeding was studied. RESULTS: ICV NPY significantly increased sham feeding, meal-stimulated gastric and pancreatic secretion, basal gastric acid, pancreatic bicarbonate, insulin levels, and PP. Vagotomy blocked the effect of ICV NPY on gastric acid secretion in a urethane-anesthetized rat model with acute gastric fistula. CONCLUSIONS: ICV NPY increased sham feeding, gastric and pancreatic secretion, insulin levels, and PP in the dogs. NPY's effect on gastric secretion was blocked by vagotomy in a rat model. NPY should be considered a candidate mediator of cephalic phase secretion.     

Similar sensitivities of pancreatic and biliary secretion to cholecystokinin plus secretin infusion

The differing sensitivities of the gallbladder and pancreas to graded doses of CCK have been claimed as important in normal digestive events. As both secretin and CCK are thought to be released in response to normal feeding, we have reexamined the sensitivities of the gallbladder and pancreas to graded increases of CCK with a constant secretin background. Under such conditions the increase in output of pancreatic trypsin and bile salt occurred simultaneously, the dose-response curves being almost superimposable. Thus, under conditions more closely approaching normal postcibal events, the previously described differing sensitivities of the pancreas and gallbladder were not observed.     

Brefeldin A inhibits the constitutive-like secretion of a sulfated protein in pancreatic acinar cells

Sulfation is a common posttranslational modification of secretory proteins and serves as a valuable marker of constitutive and regulated secretory pathways. We investigated the cellular localization and the secretory behavior of sulfated macromolecules in the mouse pancreatic acinar cell. The major sulfated proteins of the cell were present in isolated zymogen granules, as determined by metabolic labeling with [35S]sulfate and subcellular fractionation. The sulfated proteins fell into three groups: gp300 is not secreted and is a component of the zymogen granule membrane; pancreatic lipase (56 kDa) and a 40 kDa protein are soluble and exhibit regulated secretion kinetics; and p82 is initially granule membrane associated, but is released from the cell with constitutive-like kinetics as a 75 kDa protein (p75). Secretion of p75 could be stimulated for up to 4 h after pulse labeling, presumably from immature secretory granules, but not after 6 h of chase. Treatment of cells with brefeldin A (BFA) at the start of the [35S]sulfate pulse resulted in almost total inhibition of sulfation. Addition of BFA during the chase (0-2 h) allowed normal basal and stimulated secretion of regulated secretory proteins, but reversibly inhibited the constitutive-like secretion of p75. In this case, the behavior of p75 was maintained as that of a regulated secretory protein for up to 6 h of chase. In untreated cells, immunofluorescence of p82/p75 was along the acinar lumen, and in small punctate structures in the apical cytoplasm. In BFA-treated cells, immunolabeling of p82/p75 was lost from the acinar lumen, and cytoplasmic labeling was finer and appeared to be associated with the secretory granule membranes. These data suggest a role for brefeldin A-sensitive coat formation in maturation of secretory granules after they bud from the TGN.     

Feedback regulation of pancreatic enzyme secretion by intestinal trypsin in man

In a patient a papilla Vateri tumor completely prevented the bile-pancreatic flow into the intestine although the pancreatic juice was secreted into the bile duct via a common channel. Consequently, the bile-pancreatic juice was possible to sample via a percutaneous transhepatic cholangiography (PTC) catheter. This made it possible to study the effect of duodenal infusion of different substances on the bile-pancreatic secretion. In repeated experiments a suppression of the secretion was observed by intraduodenal trypsin as well as the patient's own bile-pancreatic juice. In the presence the bile-pancreatic juice intraduodenal trypsin inhibitor infusion caused a marked stimulation of the secretion. The results are in accordance with the hypothesis that trypsin in the upper part of the intestine exerts a negative feedback regulation of the pancreatic secretion in man.     

Inhibition of stimulated amylase secretion by adrenomedullin in rat pancreatic acini

Adrenomedullin is a novel hypotensive peptide originally isolated from human pheochromocytoma and recently localized to PP cells of the pancreatic islets of Langerhans. Based on the pancreatic islet-acinar axis model, we investigated the effect of adrenomedullin on regulated exocytosis of exocrine pancreas. Using rat [125I]-adrenomedullin, specific binding sites were localized to rat pancreatic acini. We next examined the effect of adrenomedullin on 100 pM cholecystokinin (CCK)-stimulated amylase release from pancreatic acini. Adrenomedullin inhibited amylase secretion in a dose-dependent manner by approximately 50% at maximum, and the IC50 was 1.1 pM. However, adrenomedullin did not affect rat [125I]CCK binding to isolated acini or reduce the intracellular free Ca2+ concentration increased by CCK. Adrenomedullin also inhibited amylase secretion induced by 1 microM calcium ionophore A23187, suggesting that adrenomedullin inhibits stimulated amylase secretion by functioning at a step(s) distal to the ligand-receptor binding system and intracellular calcium mobilizing mechanism. In streptolysin-O permeabilized acini, 10 nM adrenomedullin shifted the calcium dose-response curve to the right, indicating that adrenomedullin inhibits calcium-induced amylase secretion by reducing calcium sensitivity of the pancreatic exocytotic machinery. In addition, pretreatment of pancreatic acini with pertussis toxin abolished the inhibitory effect of adrenomedullin on CCK-stimulated amylase secretion. These results indicate that adrenomedullin inhibits stimulated amylase secretion by reducing the calcium sensitivity of the exocytotic machinery of the pancreatic acini. A pertussis toxin-sensitive GTP-binding protein(s) is also involved in this mechanism.     

Influence of hyperglycaemia on maximal gastric secretion in healthy subjects

The influence of a single intravenous glucose load on maximal gastric acid secretion in 25 healthy men when stimulated with pentagastrin was studied. Under the influence of hyperglycaemia, a highly significant decrease of maximal acid output was found. Moreover, in the gastric juice an increase of chloride and calcium concentrations was noted. On the other hand, the output of potassium, chloride and magnesium was lowered. The above differences were statistically significant.     

Effect of histamine on intestinal fluid secretion in the dog

Intra-arterial infusion of histamine into the small intestine caused about a onefold increase of blood flow, edema of the intestinal tissues and mesentery, and produced a copious secretion of fluid. The jejunal secretions had an ionic composition similar to that of plasma, whereas ileal secretions contained high concentrations of HCO3 with relative low concentrations of Cl. The secretions contained protein (1.5 +/- .2 g/100 ml, range 0.5-2.4) with a similar electrophoretic pattern of plasma protein. When lissamine green was present in the blood, it also appeared in the secretion to a considerable concentration. It is inferred from these findings that a major mechanism of fluid secretion by the action of histamine involves a filtration process across the mucosal epithelium by the incrreased tissue fluid pressure due to extensive capillary leak.     

High uptake of myo-inositol by rat pancreatic tissue in vitro stimulates secretion

A recent study by Hokin-Neaverson, M., Sadeghian, K., Majumder, A.L., and Eisenberg, F. (1975) Biochem. Biophys. Res. Commun. 67, 1537-1544, demonstrates that free myo-inositol in the pancreas is significantly increased during intense cholinergic stimulation of secretion. Incubation of rat pancreatic tissue in medium with 100 mM myo-inositol increases 10-fold the endogenous content of free myo-inositol and elicits a prompt and sustained 50% increase in the rate of release of amylase activity. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis reveals that the electrophoretic pattern of the protein mixture released in the presence of 100 mM myo-inositol is the same as that of the secretory output released in the presence of 10 muM carbamylcholine. Microscopic examination of tissue pieces indicates that there is no significant decrease in zymogen granule content of the pancreatic acinar cells during incubation in medium with 100 mM myo-inositol. Jamieson, J.D., and Palade, G.E. (1967) J. Cell Biol. 34, 597-615, have shown that pulse-labeled secretory proteins in guinea pig pancreas first appear in zymogen granules 1 hour postpulse, becoming maximally accumulated in these storage sites by 2 hours postpulse. myo-Inositol (100 mM) stimulates release of pulse-labeled secretory proteins only if incubation in medium with 100 mM myo-inositol is initiated anytime during the first 80 min postpulse. The findings thus indicate that a high uptake of myo-inositol by rat pancreatic tissue in vitro selectively stimulates the release of just those secretory proteins being packaged in newly forming zymogen granules.     

Influence of ruminal or abomasal starch hydrolysate infusion on pancreatic exocrine secretion and blood glucose and insulin concentrations in steers

Seven Holstein steers (234 +/- 6.4 kg) surgically fitted with pancreatic cannulas, ruminal and abomasal infusion cannulas, and hepatic-portal vein catheters were used in a 4 x 7 incomplete Latin square design experiment to examine the influence of ruminal and abomasal carbohydrate infusion on enzyme secretion and composition of pancreatic juice. Four treatments were arranged in a 2 x 2 factorial: 1) ruminal starch hydrolysate (SH; 34.2 g/[h.site]) or abomasal water and 2) abomasal SH or ruminal water. Starch hydrolysate is raw cornstarch that has been partially digested by a heat-stable alpha-amylase. Experimental periods were 14 d with 9 to 10 d of adaptation, 4 d of pancreatic collection, and blood collection on d 14. Abomasal SH infusion tended (P < .10) to increase pancreatic fluid secretion. The pH of pancreatic juice was higher (P < .01) for ruminal SH infusion, and abomasal SH infusion tended (P < .10) to result in lower pH of pancreatic juice. alpha-Amylase concentrations (units/milliliter and units/milligram of protein) and secretion (units/hour) were less (P < .002) for abomasal SH infusion. Chymotrypsin concentration (units/liter; P < .01) and secretion (units/hour; P < .10) were less for abomasal SH infusion; however, a rumen x abomasal interaction was found (P < .05). Chloride concentration (milligrams/deciliter) and secretion (milligrams/hour) were increased (P < .01) for abomasal SH infusion. Abomasal SH infusion resulted in increased (P < .01) portal blood glucose concentrations; however, portal plasma insulin concentration was not affected (P > .10). Abomasal SH infusion altered alpha-amylase secretion in steers, but ruminal SH infusion had minimal effect on alpha-amylase secretion. These changes suggest abosamal infusion of SH may negatively impact secretion of pancreatic alpha-amylase.     

Reserpine-induced dissociation of canine pancreatic secretion

In five dogs, provided with chronic pancreatic and gastric fistulas (Thomas' cannula), the effects on exocrine pancreatic secretion of an intravenous continuous perfusion of gastrin (Eurorga, hog gastrin I-II, 6 mug./kg./hr.) and secretin (GIH, 0.5 C.U./kg.hr.) was studied before and after 48 hours of reserpine treatment (0.1 mg./kg./24 hr.). When compared with the pretreated plateau levels, reserpine induced a significant pancreatic secretion dissociation, a depressive of the alkaline and a rising of the protein component. The former phenomenon suggests a participation of a catecholamines in the secretin-elicited pancreatic electrolyte secretion. The latter, an enhanced sensitivity of intranpancreatic and/or acinar cells of the "pancreon" to gastrin stimulation.     

Feedback regulation of exocrine pancreatic secretion in dogs

Important basic physiological mechanisms of exocrine pancreas secretion were delineated in a canine model. However, dogs have been considered unsuitable for the study of the controversial feedback regulation of exocrine pancreas secretion. The present study reveals a marked modification of pancreas secretion following the intraduodenal instillation of lipase: The postprandial lipase secretion decreases from 2,421 U x 180 min-1 to 1,490 U x 180 min-1, but simultaneously determined cholecystokinin (CCK) concentrations in plasma do not increase under these circumstances. The intraduodenal application of a protease inhibitor (800 mg camostate) significantly stimulates the secretion of the exocrine pancreas in the fasting dog: After 15 min the protein release increased to 133 +/- 30 mg. Intravenous atropine blocks this increase. The plasma concentrations of CCK are not significantly influenced. These results in our canine model show that the secretory activity of the exocrine pancreas depends on the intraduodenal enzyme content. CCK is irrelevant in this context.     

Postprandial biliary and pancreatic secretion during profound inhibition of gastric secretion in humans

This study assessed the effect of profound inhibition of gastric secretion by an H2 antagonist on postprandial gastric emptying of acid and chyme, and on bile acid and pancreatic enzyme secretion under physiological conditions in humans. Six subjects were studied before and while they were given famotidine (40 mg). This study combined a continuous intestinal perfusion technique using 14C-polyethylene glycol (14C-PEG) as duodenal recovery marker, with intermittent sampling of gastric content using PEG 4000 as meal marker. During the three hour study, the area under the curve for gastric acid output decreased from mean (SEM) 88.9 (7.6) mmol for those not receiving treatment, to 21.2 (2.7) mmol for subjects receiving famotidine (p < 0.01). The corresponding values for the rate of acid delivery into the duodenum decreased from 65.2 (11.9) to 16.6 (2.9) mmol (p < 0.05), and those for the rate of gastric emptying of chyme remained unchanged for the group receiving no treatment and during famotidine (1040 (200) v 985 (160) ml respectively, NS). Duodenal bile acid and trypsin output remained unchanged (area under the curve, 457 (128) v 373 (86) umol/kg and 5022 (565) v 5058 (400) IU/kg respectively, NS) receiving no treatment and during famotidine. It is concluded that profound inhibition of postprandial gastric acid secretion by anti-secretory drugs is not accompanied by changes in biliary and pancreatic secretion, mainly because the gastric emptying of chyme is unaffected.     

Nicotinic cholinergic influences in pancreatic secretion induced by intraduodenal alkaline and acid solutions in the rabbit

1. The effect of hexamethonium on the exocrine pancreatic response to intraduodenal acidification and alkalinization, and the secretin and VIP release after these stimuli, was studied. 2. The hydroelectrolyte secretion after hydrochloric acid and sodium carbonate perfusion was reduced by hexamethonium treated (322 +/- 44% of maximum response in flow rate to sodium carbonate perfusion in untreated animals vs 140 +/- 12% in pretreated animals, and 252 +/- 19% of maximum response in flow rate to HCl in untreated animals vs 166 +/- 11% in pretreated animals). 3. However, hexamethonium has no effect on secretin plasma levels after either intraduodenal acidification or alkalinization. 4. On the contrary, the ganglion blocker significantly (P < 0.01) reduced plasma VIP levels in response to intraduodenal HCl (maximum response 320 +/- 74% in untreated vs 184 +/- 44% in hexamethonium-treated animals). 5. Plasma VIP levels showed a similar increase in both untreated (maximum response: 151 +/- 12%) and ganglion blocked animals (170 +/- 26%) in response to sodium carbonate. 6. These data suggest the existence of complex neural mechanisms in the exocrine pancreatic response to intraduodenal stimuli, these mechanisms being different depending on the intraduodenal stimulus.     

Blocking effect of tripelennamine on histamine--induced positive chronotropic and inotropic responses of the dog atrium

The effects of histamine on inotropic and chronotropic activity were investigated in isolated canine atrium preparations which were suspended in a bath and perfused with arterial blood from a carotid artery of heparinized support dog. Histamine administered into the cannulated sinus node artery in a dose range of 0.3-100 mug produced dose-related positive chronotropic and inotropic effects. The positive responses to histamine were not suppressed by treatment with propranolol in doses which blocked responses to norepinephrine, but these were significantly suppressed by a histamine H1 receptor blocking agent, tripelennamine. On the other hand, these histamine-induced effects were not modified by a histamine H2 receptor blocking agent, burimamide. From these results, it is assumed that positive chronotropic and inotropic effect of histamine may be mediated by histamine H1 receptors in the dog heart.     

Comparison of the kinetics of pancreatic secretion and gut regulatory peptides in the plasma of preruminant calves fed milk or soybean protein

Exocrine secretion from the pancreas and concentrations of cholecystokinin, gastrin, secretin, and somatostatin in plasma were measured in relation to feeding in 70- to 120-d-old preruminant calves fed either a milk diet or a soybean diet. Pancreatic fluid was continuously collected, measured, and reintroduced in catheterized calves. Blood samples were withdrawn for measurements of gut regulatory peptide concentrations in plasma. A slight increase in outflow of pancreatic fluid was observed 30 min before the milk diet was introduced but not before the soybean diet was fed. In contrast, concentrations and outflows of protein and trypsin immediately after feeding were higher when calves were fed the soybean diet. Overall, during the first 5 h postfeeding, the outflow of pancreatic fluid was 40% higher when the milk diet was fed than when the soybean diet was fed. No difference in outflow of protein was observed, but that of trypsin was 82% higher when the soybean diet was fed. This enhanced enzyme secretion could have been related to the increased plasma concentrations of gastrin and cholecystokinin after the soybean diet was fed. Secretin release was less in calves fed the milk diet that in calves fed the soybean diet during the first 2 h postfeeding, suggesting that this gut peptide along with gastrin and cholecystokinin, contributed to the stimulation of enzyme secretion. Plasma gut regulatory peptides could be influenced by the soybean diet, which does not coagulate in the stomach, inducing faster gastric emptying of protein and fat, and by the chemical form of protein from the soybean diet and the lower susceptibility of these proteins to protease compared with casein. However, the resulting enhancement of pancreatic trypsin secretion and activity seemed to be insufficient to increase the digestibility of soybean protein up to a level similar to that of milk.     

Intravenous infusion of glucose and insulin in relation to milk secretion in the sow

1. A comparison was made of the composition of milk from front and rear tetas in four sows. There were small and not significant differences in fat, protein and lactose contents, and in the fatty-acid composition of the milk fat with the exception of the 18:3 acid where the difference was also small but significant. 2. The effects of intravenous infusions of glucose and insulin in lactating sows on milk secretion and blood composition were investigated in two sows. 3. Intravenous infusion of glucose had no effect on blood plasma glucose concentration but increased the yields of lactose, protein and water. 4. Intravenous infusion of insulin depressed plasma glucose concentration and the yields of lactose and water. The yield of protein was unaffected. 5. It is concluded that differences between the non-ruminant (the sow) and the ruminant in the responses in milk secretion to glucose infusion may be related to differences in the sensitivity to insulin of mammary tissue.     

Mullerian-inhibiting substance secretion is delayed in XX sex-reversed dog embryos

A mathematical multiple dosing model was designed so that human plasma concentration-versus-time curves of beta-lactams are reproduced in mouse plasma. The pharmacokinetic parameters of FK037, a new injective cephalosporin, in volunteers and in the mice model were 6,966 and 6,894 ml, respectively, for Vc, 2.592 and 2.698/h for alpha, 0.2875 and 0.3027/h for beta, and 0.9079 and 1.0506 for K21. Therefore, real pharmacokinetics of humans were reproduced in mice by this method. The 8-hour therapeutic efficacy (the decrease of the viable counts in the lung) against pneumonia with Staphylococcus aureus and Pseudomonas aeruginosa in mice was well correlated with the time above MIC value, but not with AUC, Cmax or AUC above MIC. These results indicate that this model was valuable to evaluate the beta-lactam antibiotics for predicting their clinical efficacy and that the time above MIC is an important factor in selecting beta-lactam agents and determining dosage in pulmonary infection.