Effect of truncal vagotomy on pancreatic polypeptide response after intravenous glucose administration

Intravenous glucose infusion was performed in six dogs with and without truncal vagotomy, and plasma pancreatic polypeptide (PP) responses were compared before and after truncal vagotomy. Following truncal vagotomy, basal PP levels decreased significantly from 286 ± 64 pg/ml (mean ± S.E.) to 94 ± 14 pg/ml (P < 0.05). Basal plasma insulin and blood glucose levels also tended to be lower, but not significantly. During the influsion of glucose, blood glucose concentrations rose rapidly in both groups and after 15 min reached peak values which were not significantly different from each other. In the vagotomized group the plasma insulin response to intravenous glucose infusion was significantly lower than in the control group. Following intravenous glucose loading, plasma PP concentrations decreased rapidly in both groups, but the PP level in the vagotomized group was suppressed only to 77 ± 4% of the basal level whereas in the control group it decreased to 45 ± 8%, significantly lower than in the vagotomized group (P < 0.01).These results suggest that basal PP is regulated by vagal tonus and that vagus controls, at least in part, suppression by intravenous glucose administration.     

Effect of truncal vagotomy on intestinal phase of pancreatic polypeptide release in dogs

In order to elucidate the role of the vagus nerve in the intestinal phase of pancreatic polypeptide (PP) release, mongrel dogs were given a 4-min intraduodenal infusion of saline, 20% glucose, or 10% soybean oil solution (50 ml each), before and one month after truncal vagotomy including pyloroplasty (TV). The saline infusion did not change the basal PP level, while the glucose infusion elicited a monophasic transient PP release, and the soybean oil infusion elicited a monophasic prolonged PP release in the intact dogs. The PP response following glucose infusion was almost abolished after TV, while the PP response to fat was attenuated, but a significant increase was nevertheless observed after TV. These results suggest that the vagus nerve has an important role in the intestinal phase of PP release and that other factors, e.g. hormonal, might also be involved in the regulatory mechanism, especially after fat loading.     

Effect of adding albumin to solutions of cholecystokinin on pancreatic protein output and pancreatic polypeptide release

In four conscious dogs with chronic gastric and pancreatic Thomas fistulas we studied the effect of 99% pure cholecystokinin-33 (CCK-33) solutions on pancreatic secretion and PP release. CCK-33 was dissolved in 0.154 M NaCl alone or in the same solution containing 1 g per 100 ml dog albumin. The response of pancreatic protein output to increasing doses of CCK-33 (0.5, 1, 2, 4 IDU/kg per h) was significantly $\text{(P < 0.05)}$ higher when CCK was dissolved in NaCl with albumin than in NaCl alone. These results were confirmed by measuring CCK immunoreactivity in samples from tips of infusion lines by a gastrin radioimmunoassay. Release of pancreatic polypeptide (PP) following increasing doses of CCK-33 was also significantly $\text{(P < 0.05)}$ elevated when CCK was dissolved in an albumin-containing solution. There was a significant $\text{(P < 0.02)}$ correlation between plasma concentrations of PP and pancreatic protein output.This study suggests that albumin should be added to CCK-33 solutions to preserve biological activity. The biological effect of CCK-33 may be substantially underestimated if albumin is omitted.     

Effect of proglumide, a cholecystokinin receptor antagonist, on caerulein-stimulated pancreatic enzyme secretion and pancreatic polypeptide release in the dog

In five conscious dogs we studied the effect of proglumide, a cholecystokinin (CCK) antagonist, on caerulein-stimulated pancreatic secretion and release of pancreatic polypeptide (PP). Graded doses of caerulein (15-240 ng/kg per h) were infused intravenously. Experiments were repeated with a fixed infusion of proglumide (40 mg/kg per h). Release of PP following increasing doses of caerulein was significantly inhibited by proglumide (P less than 0.01). However, proglumide did not significantly affect caerulein-stimulated pancreatic protein secretion. Proglumide might be useful in defining the physiological role of CCK.     

Effect of nicotine on basal and bombesin stimulated canine plasma levels of gastrin, cholecystokinin and pancreatic polypeptide

The influence of nicotine on the basal and bombesin (BBS) stimulated plasma levels of gastrin, cholecystokinin (CCK) and pancreatic polypeptide (PP) was investigated in conscious dogs. Plasma levels of nicotine and gastrointestinal (GI) hormones were measured by employing gas liquid chromatography and specific radioimmunoassay (RIA). The basal levels of gastrin, CCK and PP were found to be in pg/ml (pmol/l) (mean +/- S.E.), 28 +/- 5 (13 +/- 3), 252 +/- 32 (66 +/- 8) and 347 +/- 136 (83 +/- 32), respectively and these values remained unchanged with nicotine. Significant increases in levels of gastrin, CCK and PP were, however, found with infusions of BBS alone or with BBS in combination with nicotine. Gastrin levels were higher whereas CCK and PP levels were lower with BBS alone than with BBS plus nicotine. The peak values for CCK and PP, but not gastrin, were less during second BBS infusion. These results indicate that nicotine, in presence of bombesin, has an inhibitory effect on the release of gastrin and a stimulatory effect on the release of PP and CCK.     

Relationship between intravenous ethanol, alcohol-induced inhibition of pancreatic secretion and plasma concentration of immunoreactive pancreatic polypeptide, vasoactive intestinal peptide, and somatostatin in man

We have studied in seven men, consuming less than 50 g alcohol daily, the effect of intravenous (i.v.) ethanol on (a) hormonally (secretin + CCK PZ) submaximally stimulated pancreatic secretion and (b) blood levels of pancreatic polypeptide (PP), vasoactive intestinal peptide (VIP) and somatostatin. After intravenous ethanol (600 mg/kg), pancreatic secretion decreased in all subjects and plasma levels of PP and VIP increased significantly. Moreover, there was a significant correlation between the mean inhibition of chymotrypsin output and the mean increase in PP plasma levels during the first 45 min following ethanol infusion. Therefore i.v. infusion of alcohol elicits release of PP and VIP and PP release could explain in part at least the alcohol-induced pancreatic inhibition observed in non-alcoholic men.     

Pancreatic polypeptide response to ethanol in humans and dogs

We studied the effect of a drink of various concentrations of pure ethanol and several commonly ingested alcoholic beverages on plasma levels of immunoreactive pancreatic polypeptide in six healthy human volunteers and compared the results to a protein-rich meal. A drink of distilled water (250 ml) and of pure ethanol (250 ml or 125 ml in the case of 40% v/v ethanol) in concentrations (4, 10, 20, and 40%, v/v) normally present in beer, wine, liquor and whisky did not stimulate plasma pancreatic polypeptide levels above basal. Neither beer, red and white wine (250 ml each) nor whisky (125 ml) caused an increase in basal plasma pancreatic polypeptide levels. The 90-min integrated plasma pancreatic polypeptide response to the protein-rich meal was significantly reduced by an additional drink of 250 ml of white wine ($\text{5987 ± 1315}$ versus $\text{4126 ± 809}\text{pmol · min}{}^{\mathrm{?1}}\text{· 1}{}^{\mathrm{?1}}$). An intravenous infusion of ethanol (300 mg · kg^?1 over 30 min) did not increase plasma pancreatic polypeptide levels above basal.In six dogs with gastric and duodenal fistulas the infusion of pure ethanol into a peripheral vein, into the stomach or into the duodenum did not alter plasma pancreatic polypeptide levels. When ethanol (200 ml of either 1.8, 10 or 40%, v/v) was given as an intragastric bolus injection, only 40% ethanol caused an increase in the mean 90-min integrated plasma pancreatic polypeptide response which was only one-twelfth of the pancreatic polypeptide response to an oral mixed meat meal (35 g · kg^?1). We conclude that in man neither an intravenous infusion nor a drink of ethanol in concentrations normally present in beer, wine and whisky, release pancreatic polypeptide. Also, beer, red and white wine and whisky have no effect on plasma pancreatic polypeptide concentrations. In dogs, a large amount of intragastric ethanol was needed to produce a very small rise in plasma pancreatic polypeptide levels. These results do not favour the hypothesis that, in man and dog, pancreatic polypeptide is the hormonal mediator of the ethanol induced inhibition of exocrine pancreatic secretion.     

Effect of opiate-active substances on pancreatic polypeptide levels in dogs

The present study examines the effect of orally and intravenously administered opiate-active substances on peripheral vein plasma pancreatic polypeptide (PP) levels in conscious dogs. The intragastric instillation of digested gluten stimulated postprandial PP levels significantly which was reduced by the specific opiate-receptor antagonist naloxone. Naloxone had no effect when added to undigested gluten. Similarly, naloxone reduced significantly the postprandial PP response to a test meal of casopeptone which contains the opiate-active β-casomorphins. The addition of synthetic β-casomorphins to a liver extract/sucrose test meal significantly augmented the rise of postprandial PP levels which was also blocked by naloxone. The intravenous infusion of morphine, leu-enkephalin, D-ala²-D-leu⁵-enkephalin, β-casomorphin-5 and β-casomorphin-4 elicited a dose-dependent and naloxone reversible effect on basal PP levels. During a background infusion of glucose and amino acids the same opiate-active substances had either none or a stimulatory effect on PP release in these dogs. The addition of naloxone abolished the stimulatory effect in response to β-casomorphin-5 and β-casomorphin-4 and resulted in an inhibition of PP levels during the infusion of morphine and leu-enkephalin. This latter inhibitory effect was no longer observed when the dose of naloxone was increased ten- and fifty-fold, respectively. The present data suggest that orally ingested opiate-active substances participate in the stimulation of postprandial PP release in dogs via specific opiate-receptor mediated mechanisms. The effect of intravenously administered opiate-active substances on PP levels depends on the metabolic state with regard to the level of circulating nutrients. It is suggested that PP release is stimulated via μ-opiate receptors and inhibited via δ-opiate receptors. An increase of circulating nutrients would “activate” μ-receptor sites which are masked in the basal state when exogenous opiates are administered. However, with regard to endogenous opiates an increase of circulating nutrients, mainly carbohydrates, activates inhibitory effects of endogenous opiates suggesting that exogenous and endogenous opiates act at different target sites.     

A microsphere study on the effects of somatostatin and secretin on regional blood flow in anesthetized dogs

The endogenous peptides somatostatin and secretin are effective in the therapy of upper gastrointestinal tract bleeding and acute pancreatitis. The clinical effects may be partly brought about by changes in the regional blood flow. To evaluate the effects of somatostatin (50 and 100 μg/min over 6–8 min) and secretin (0.1 and 0.5 U · kg^?1 · min^?1 over 3–5 min) on tissue blood flow, particularly of the gastrointestinal tract, the tracer microsphere reference sample method was used in anesthetized dogs.Infusion of somatostatin significantly diminished gastric and pancreatic blood flow whereas no changes of duodenal and ileal blood flow could be obtained. Blood flow through spleen, kidneys and adrenal glands was increased but no changes were observed in the blood flow of other tissues. Cardiac hemodynamics remained unchanged.Secretin increased the blood flow of the duodenum, the kidneys and the adrenal glands and diminished gastric blood flow without changing pancreatic, ileal, hepatic, pulmonary and muscle blood flow. Cerebral, pituitary and myocardial blood flow was increased by a higher dose of secretin. It also evoked a slight but significant positive ino- and chronotropic effect. Since secretin and somatostatin differ in their respective effects on gastrointestinal blood flow it is suggested that the previously reported beneficial effects of both peptides on upper gastrointestinal bleeding cannot solely be attributed to changes in regional blood flow.     

Meal stimulated levels of pancreatic polypeptide (PP) and vasoactive intestinal polypeptide (VIP) in gastroplasty for morbid obesity

Plasma concentrations of pancreatic polypeptide (PP) and vasoactive intestinal polypeptide (VIP) were measured after a meal consisting of 11 ml meat extract and 40 ml of 20% soya oil in 11 patients before and 3 months after gastroplasty for morbid obesity. Gastroplasty results in a small proximal pouch with a narrow stoma allowing delayed emptying into the distal pouch, and consequently postprandial distension of the proximal pouch. Postprandial plasma PP increased significantly (P less than 0.01) independent of gastroplasty. PP is therefore not involved in the early satiety after gastroplasty. Postprandial plasma VIP increased significantly from fasting levels both before and after gastroplasty (P less than 0.05). Only 10 min after a meal, the median value of VIP was significantly higher after than before gastroplasty (P less than 0.02) and may be caused by distension of the proximal pouch.     

Elevated levels of circulating pancreatic polypeptide in inflammatory and infectious disorders

Circulating levels of pancreatic polypeptide (PP) were found to be elevated when compared to healthy controls in 54% of patients with chronic inflammatory connective tissue disorders (SLE, rheumatoid arthritis, scleroderma, mixed connective tissue disease and temporal arteritis) and in 96% of patients with acute viral or bacterial infections. Significant positive correlations were obtained between the serum values of PP and those of haptoglobin or orosomucoid. Accompanying successful anti-inflammatory treatment of patients with autoimmune disorders, a reduction of PP levels was observed. The findings suggest that the magnitude of increase in PP was associated with the degree of the inflammatory activity. Raised PP levels may contribute to the alterations in carbohydrate and lipid metabolism observed during active inflammatory diseases in man.     

Stimulatory effects of human pancreatic polypeptide on rat pancreatic acini

The effect of human pancreatic polypeptide (HPP) on rat pancreatic acini has been studied. It was found that HPP stimulated amylase and lipase release from the acini. The secretory response of acini to HPP was dose-dependent in a sigmoidal fashion. Between 10(-9) M and 10(-8) M concentration of HPP there was a slow increase of enzyme release to about 40-60% over basal release. At concentrations of HPP above 10(-8) M there was a rapid increase of enzyme release, amounting to 4-6 times over basal release at 10(-6) M concentration of HPP. The potency of HPP compared to other secretagogues at 10(-7) M concentration was 45% of CCK, 60% of carbachol and 75% of secretin. HPP did not inhibit the effect of CCK, secretin and carbachol on amylase release. The amylase release stimulated by HPP was accompanied by an increase in 45Ca2+ efflux. Atropine or dibutyryl cyclic GMP did not influence the effect of HPP. It is concluded that HPP stimulates the release of enzymes from rat pancreatic acini and that Ca2+ may be a mediator for this secretion.     

Effect of endogenous gastric inhibitory polypeptide (GIP) on the removal of triacylglycerol in dogs

In order to clarify the effect of endogenous gastric inhibitory polypeptide (GIP) upon lipid metabolism, the removal of intravenously administered triacylglycerol was investigated following an oral glucose or galactose load in dogs. After an overnight fast, the triacylglycerol emulsion was infused at a constant rate of 1 ml/min for 90 min, and glucose, galactose or tap water was orally administered at 30 min. Blood glucose increased after the glucose load but it did not change following the galactose load or water ingestion. Plasma insulin increased after the glucose load but did not change after galactose or tap water ingestion. Plasma glucagon did not show any discernible change in the three experimental groups. Plasma GIP increased following the glucose or galactose load to 4360 or 1653 pg/ml, respectively. Plasma triacylglycerol increased to the same levels at 30 min in the three experimental groups. The peak levels of plasma triacylglycerol and integrated plasma triacylglycerol for 150 min did not differ in the three groups. Moreover, there was no difference in the removal rate of plasma triacylglycerol following the withdrawal of the fat emulsion. It is concluded from the present study that endogenously released GIP does not elicit any effect upon triacylglycerol removal.     

The effect of somatostatin and 16,16-dimethyl-prostaglandin E2 on bombesin-stimulated canine gastric acid, plasma gastrin and pancreatic polypeptide secretion

We studied the effect of the intravenous infusion of 16,16-dimethylprostaglandin E2 methyl ester (di-M-PGE2) and somatostatin on bombesin-stimulated gastric acid secretion, plasma gastrin and plasma pancreatic polypeptide in four chronic gastric fistula dogs. Bombesin-stimulated gastric acid secretion was significantly inhibited by somatostatin and virtually abolished by di-M-PGE2. Both agents caused significant, but indistinguishable inhibition of gastrin release (P less than 0.05). Bombesin-stimulated pancreatic polypeptide release was also significantly inhibited by both somatostatin and di-M-PGE2; the inhibitory effect of somatostatin was significantly greater than that of di-M-PGE2 (P less than 0.05). This study provides further evidence in support of the complex interrelationships between agents responsible for the modulation of gastrointestinal physiology.     

Linkage between genes for coat colour and for blood plasma esterase in dogs

A study on linkage in dogs has been made on the basis of comparable studies in other mammal species. In a breeding experiment one dog was mated to 14 bitches. The dog was heterozygous for the plasma esterase locus (Es-1) and the extension locus (E) for coat colour. The 14 bitches, homozygous for both loci, produced a total of 96 offspring. The recombination distance between the loci is calculated to be 34.4 +/- 4.8 cM. The basis for homology between species for the two loci has been discussed.     

Comparison of enkephalin and atropine in the inhibition of vagally stimulated gastric and pancreatic secretion and gastrin and pancreatic polypeptide release in dogs

Enkephalins have been detected in vagal nerves and myenteric plexus neurons but no study has been performed to determine their action on vagally stimulated gastric and pancreatic secretion. In this study we infused IV methionine-enkephalin (Met-enk) alone, naloxone (a pure opiate antagonist) alone, or their combination before, during and after vagal stimulation in 4 dogs with esophageal, gastric and pancreatic fistulas. For the comparison, atropine was given before, during and after vagal stimulation in the same animals. Vagal stimulation was obtained by 15 min sham-feeding, which produced an increase in gastric H⁺ output to a peak of about 75% of the maximal response to pentagastrin and pancreatic protein secretion amounting to about 71% of the maximal response to caerulein. It was accompanied by a significant rise in serum gastrin and pancreatic polypeptide (PP) levels. Met-enk inhibited significantly both gastric H⁺ and pancreatic protein secretion and reduced plasma PP but not gastrin levels. Similar effects were obtained after the administration of atropine. The effects of Met-enk were partly reversed by the addition of naloxone. We conclude that (1) enkephalin suppresses vagally stimulated gastric and pancreatic secretion and plasma PP release; (2) these secretory effects of enkephalin seem to be mediated by opiate receptors and could be explained by its inhibitory action on acetylcholine release (“anticholinergic” action) in the stomach and the pancreas.     

Effects on plasma pepsinogen, gastrin and pancreatic polypeptide of Ostertagia spp. transferred directly into the abomasum of sheep

Ostertagia spp. obtained at slaughter from the abomasa. of previously infected sheep and transferred via cannulae into the abomasa of previously worm-free sheep produced severe effects. This was shown with populations of mainly adult parasites given to three sheep and also when mixed populations of 4th stage larvae and adults were given to three other sheep. Although more severe effects were produced when both larval and adult worms were transferred, there were clearly effects when isolates composed predominantly of adults were transferred. Sheep of each group had reductions in food intake and elevations in plasma pepsinogen and gastrin within 24 h of transfer of the parasites. Further increase in plasma pepsinogen and gastrin occurred when abomasal pH rose 5–7 days after infection. Plasma pancreatic polypeptide varied but showed a general tendency to be markedly lower after infection. Ostertagia spp. eggs were detected in the faeces of infected sheep 48 h after transfer. The proportions of adults and inhibited larvae recovered from the abomasa were similar to those in the donor sheep, showing that inhibition, or arrested development of larvae, continued after their transfer to worm free sheep.     

Effect of bombesin upon plasma somatostatin-like immunoreactivity, insulin and glucagon in normal and chemically sympathectomized dogs

The present study was designed to determine the effects of intravenously infused bombesin (10 ng/kg/min) upon basal and postprandial plasma somatostatin-like immunoreactivity (SLI), glucagon, insulin and triglyceride levels in normal (n = 12) and chemically sympathectomized (n = 11) dogs. Basal plasma SLI, glucagon and insulin levels rose significantly during the infusion of bombesin in the normal dogs, and this was not altered by chemical sympathectomy. Bombesin infusion enhanced the postprandial SLI response, while attenuating the postprandial glucagon response by 50% and the insulin response in the early postprandial phase of the meal. Sympathectomy did not significantly alter the basal levels of these polypeptides, but augmented the postprandial plasma SLI response during the first 90 min, and reduced the postprandial glucagon response during the infusion of bombesin. The postprandial insulin response was not affected by sympathectomy. In both normal and chemically sympathectomized dogs the rise in postprandial triglyceride levels was attenuated by bombesin infusion.     

Effect of medium-chain triglycerides and long-chain triglycerides on plasma pancreatic polypeptide secretion in man

Since it has been shown that stimulation of pancreatic enzyme secretion by triglycerides is dependent on the chain length of the fatty acids, we have studied whether the secretion of pancreatic polypeptide (PP) in response to triglycerides is also related to the chain length of the fatty acids. Therefore, the effect of equimolar amounts (60 mmol) of medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) on plasma PP was studied in 6 normal subjects. In the control study the subjects ingested 60 ml of 0.15 mol/l saline. Ingestion of LCT resulted in significant increases in plasma PP from 33 +/- 7 to 55 +/- 7 pmol/l (P less than 0.01), whereas both MCT and saline did not significantly increase plasma PP concentrations. Similarly, the integrated plasma PP secretion after LCT (1022 +/- 392 pmol/l per 90 min) was significantly greater than that after MCT (-690 +/- 358 pmol/l per 90 min; P less than 0.001) and that after saline (-462 +/- 205 pmol/l per 90 min; P less than 0.01). It is concluded that the secretion of PP in response to triglycerides is dependent on the chain length of the fatty acids.     

Effect of synthetic porcine gastrin-releasing peptide on plasma levels of immunoreactive cholecystokinin pancreatic polypeptide and gastrin in dogs

This study was conducted to determine if synthetic porcine gastrin-releasing peptide (GRP) stimulates the release of immunoreactive cholecystokinin (CCK), pancreatic polypeptide (PP) and gastrin in dogs. Three doses (0.01, 0.1 and 0.5 μg/kg-hr) of synthetic porcine GRP were administered intravenously to six conscious dogs. Synthetic procine GRP stimulated the release of each hormone in a dose-related manner. The effect of GRP on the response of gastrin was greater than its effect on CCK and PP responses. This study indicates that the biological action of synthetic porcine GRP is similar to the bombesin, an amphibian peptide shown previously to stimulate the release of gastrointestinal peptides.