Intravenous Secretin Research Articles

Effect of parenteral amino acids on human pancreatic exocrine secretion.

Parenteral administration of amino acids has been utilized for the nutritional support of patients with a variety of gastrointestinal disorders including protracted pancreatitis and pancreatic fistulae. However, the effect of parenteral amino acid administration alone on human pancreatic secretion has not been studied. We have studied the short-term effect of parenteral administration of amino acids on pancreatic exocrine secretion in seven healthy men. A double-lumen tube was placed in the duodenum and polyethylene glycol was perfused into the proximal duodenum at the rate of 10 ml/min. A second double-lumen tube was placed in the stomach and bromsulfthalein was perfused into the cardia. Samples of duodenal contents were aspirated and gastric contents recovered during one hour of intravenous saline infusion followed by two hours of an amino acid mixture infusion. Hourly outputs of protein and pancreatic enzymes were determined, correcting for duodenogastric reflux based on concentrations of both markers in the samples. Despite an average increase of 72% in the plasma concentration of the infused amino acids, the outputs of protein, trypsin and amylase did not change significantly during amino acid infusion; the output of lipase decreased significantly during amino acid infusion. Two subjects were given intravenous secretin and cholecystokinin following amino acids; this resulted in increased outputs of protein, trypsin, and amylase in both. We conclude that the parenteral administration of amino acids to healthy young men does not stimulate pancreatic enzyme secretion as measured by the method using duodenal marker perfusion at the rate of 10 ml/min.

Pancreatic enzyme response to a liquid meal and to hormonal stimulation. Correlation with plasma secretin and cholecystokinin levels.

Pancreatic trypsin output and plasma secretin and cholecystokinin (CCK) levels were measured in five healthy volunteers to investigate the mechanisms involved in regulating postprandial pancreatic secretion. The pancreas was stimulated by a liquid test meal or by either intravenous secretin (1-82 pmol/kg-1 per h-1) or caerulein, a CCK analogue (2.3-37 pmol/kg-1 per h-1), or by a combination of secretin and caerulein. Pancreatic secretion was assessed by a marker perfusion technique (polyethylene glycol [PEG 4000]), plasma secretin, and CCK by specific radioimmunoassays. Increasing doses of secretin produced increasing bicarbonate output (P less than 0.01), whereas trypsin was not stimulated over basal. Graded caerulein produced a stepwise increase in trypsin and bicarbonate output (P less than 0.01). Potentiation occurred for bicarbonate secretion between secretin and caerulein, but not for trypsin output. Postprandial trypsin secretion averaged 29.1 IU/min-1 over 150 min (equal to 55% of maximal response to caerulein). The peak trypsin response amounted to 90% of maximal caerulein. Significant increases of plasma secretion (P less than 0.05) and CCK (P less than 0.01) were observed after the meal. Comparison of enzyme and CCK responses to the testmeal or to exogenous caerulein suggested that the amount of CCK released after the meal could account for the postprandial trypsin secretion. We conclude that (a) the postprandial enzyme response in man is submaximal in comparison to maximal exogenous hormone stimulation; (b) CCK is a major stimulatory mechanism of postprandial trypsin secretion, whereas secretin is not involved; and (c) Potentiation of enzyme secretion is not a regulatory mechanism of the postprandial secretory response.

Intestinal chemosensitivity.

Intestinal chemosensitivity.

An improved technique for accessory papilla cannulation in pancreas divisum

Cannulation of the accessory papilla with dorsal pancreas ductography was accomplished in 13 of 15 consecutive cases of pancreas divisum. When routine cannulation of the main pancreatic papilla fails to produce a pancreatogram or yields only a ventral pancreas, the use of intravenous secretin and a 23-gauge needle catheter is recommended to facilitate accessory duct cannulation.

Inhibition of Pancreatic Secretory and Trophic Response to Caerulein by the H<sub>2</sub>-Receptor Antagonist Ranitidine in the Rat

The effect of ranitidine (20 mg . kg-1) and cimetidine (50 mg . kg-1) on pancreatic secretory and trophic responses to caerulein (1 microgram . kg-1) was studied in the rat. Ranitidine or cimetidine were administered alone or combined with caerulein twice a day for 7 days. Saline-treated rats were used as controls. At the end of treatment animals were anesthetized and pancreatic juice was collected for 1 h after intravenous secretin plus CCK-PZ (8 U . kg-1). Afterwards rats were sacrificed and growth and composition of pancreatic tissue were determined. Compared with control (saline) values, volume of pancreatic juice and output of trypsin and amylase were increased by treatment with caerulein. Ranitidine, when given combined with caerulein, completely abolished the secretory response induced by the peptide, whereas it was totally ineffective when given alone. Cimetidine (alone or combined with caerulein) was always ineffective. Caerulein increased pancreatic weight, total pancreatic trypsin, amylase and RNA content. Here again ranitidine, combined with caerulein, abolished almost completely the trophic effect of caerulein on the pancreas, but when given alone it did not influence pancreatic growth and composition. Also in this case, cimetidine was completely inactive. These results suggest that ranitidine affects exocrine pancreas with an action independent of the H2-receptor blockade.

Differences between peptic ulcer and control patients on the basis of the response to secretin.

The secretin injection test is considered a useful adjunct to the diagnosis of gastrinoma, although it may lack specificity. This study determined whether the release of gastrin in response to secretin was different in duodenal ulcer and control patients. Tests were performed on 10 duodenal ulcer patients, 10 normal control subjects, 20 patients asymptomatic after ulcer surgery, of whom 13 had a vagotomy and drainage, 4 a highly selective vagotomy and 3 a vagotomy and antrectomy. The secretin test was also performed in 49 patients with endoscopically proven recurrent ulcers. The surgery performed in this latter had consisted of a vagotomy and drainage in 36, a highly selective vagotomy in 7 and a vagotomy and antrectomy in 6 patients. The basal plasma gastrin level was similar in normal controls, duodenal ulcer patients and patients with vagotomy and antrectomy, both with and without recurrent ulcers. The level was elevated in all the other groups of patients with vagotomy both with and without recurrent ulcer. The plasma gastrin did not change significantly after secretin injection in the normal control or asymptomatic ulcer surgery patients, but rose in the duodenal ulcer patients and all the groups of patients with recurrent ulcer. Most of these increases were validated statistically as were the differences in response between the ulcer and control patients. These results indicate that there are differences in the plasma gastrin response to intravenous secretin between active duodenal ulcer and control patients. This findings may aid our understanding of the pathophysiology of peptic ulcer disease and explains the lack of specificity of the secretin test.

Objective evaluation of ampullary stenosis with ultrasonography and pancreatic stimulation

Ultrasonography can detect changes in pancreatic and bile duct sizes after pancreatic stimulation by secretin or morphine and prostigmine. The effects of the two pharmacologic regimens on pancreatic duct dilatation were comparable and correlated with papillary stenosis determined at surgery, but the morphine and prostigmine combination produced more false-positive responses than did secretin. After administration of intravenous secretin (1 unit/kg), the pancreatic duct dilated in 83 percent of 12 symptomatic patients found at surgery to have a stenotic sphincter of Oddi and in 72 percent of 17 symptomatic patients found to have a stenotic accessory papilla associated with the pancreas divisum anomaly. Comparable dilatation occurred in 14 percent of 14 control subjects without suspected ampullary disease and in none of 10 patients with surgically disproved stenosis (p less than 0.001). The morphine and prostigmine combination produced more false-positive results in both the pancreatic duct and bile duct. Concomitant elevation of the serum amylase level and reproduction of pain were found to be of no discriminatory value. In patients whose pancreatic duct dilated preoperatively during secretin stimulation, dilatation did not occur after surgical sphincteroplasty. A positive test result was associated with a 90 percent success rate in preventing recurrent pancreatitis and ameliorating pain. A negative test result was associated with a 29 percent success rate. Ultrasonography of the pancreatic duct with secretin stimulation may provide objective criteria to supplement clinical judgment in selecting patients for sphincteroplasty to treat stenosis of either the sphincter of Oddi or the accessory papilla in pancreas divisum.

Pancreatic polypeptide release: Role of stimulants of exocrine pancreatic secretion in dogs

There are apparent similarities in the mechanisms of the intestinal phase of exocrine and pancreatic polypeptide (PP) secretion by the pancreas. To characterize this relationship, we measured incremental responses of protein, bicarbonate, and PP to graded doses of intravenous secretin, caerulein, CCK8, CCK33, bethanechol, and intraduodenally perfused HCl, sodium oleate, and l-phenylalanine in dogs with gastric and pancreatic fistulas and compared them with average postprandial values. Secretin did not release PP at any dose studied, whereas intraduodenal HCl increased PP levels slightly at a load maximal for pancreatic secretion. Caerulein produced dose-related increases in PP secretion (maximal, 106% of meal response) but CCK8 and CCK33 had much less effect at doses equivalent for protein secretion. Bethanechol was a weak stimulant for PP only at the largest tolerable dose. l-Phenylalanine and sodium oleate markedly increased protein secretion, but only oleate clearly stimulated PP. Our results suggest a greater quantitative importance of the intestinal phase for exocrine than endocrine (PP) pancreatic secretion.

Decrease in alkaline secretion during duodenal ulceration induced by mepirizole in rats

The mechanisms by which the potent antiinflammatory agent, mepirizole, causes duodenal ulceration were investigated in the rat. After subcutaneous administration of 200 mg/kg of mepirizole, basal gastric acid secretion remained unchanged for 5 h but duodenal alkaline output, reliably measured, decreased significantly (p < 0.05) within 2 h. The decrease was maximal (−45%) at 3 h and persisted for a total of 6 h. The duodenal alkaline secretion returned to near normal by 24 h. A dose-response study showed that the threshold ulcerogenic dose of mepirizole (30 mg/kg) did not significantly reduce alkaline secretion, whereas higher doses did. Plasma levels of immunoreactivity of gastrin, pancreatic polypeptide, vasoactive intestinal polypeptide, and secretin were not changed at either 6 or 24 h after oral mepirizole. Vasoactive intestinal peptide levels in the duodenal mucosa were increased by 158% at 24 h after administration. Secretin levels in the duodenal mucosa were decreased by >60% at both 6 and 24 h after drug treatment. Intravenous secretin (1 CU/kg · h) had no effect on duodenal alkaline secretion in either saline- (154 mM NaCl) or mepirizole-treated animals. Exogenous 16,16-dimethyl prostaglandin E2 (10 μg/kg · h, i.v.) reversed the action of mepirizole on duodenal alkaline secretion. These findings suggest that mepirizole causes a reduction in duodenal alkaline secretion that can be reversed by administration of an exogenous prostaglandin.

Further experience with Pseudo-Zollinger-Ellison syndrome: its place in the management of neuroendocrine duodenal ulceration.

AbstractThe diagnostic and therapeutic criteria that allow differentiation of the Pseudo‐Zollinger Ellison syndrome (PsZES) from other ulcerogenic states including neurogenic duodenal ulcer disease, the retained, excluded antrum syndrome (REAS), and the Zollinger‐Ellison syndrome (ZES) are documented. Ten additional patients having clinical and diagnostic features of Ps‐ZES demonstrated hypergastrinemia of an antral source. Three of the patients had had failed complete vagotomy and drainage procedures and another had a retained excluded antrum after partial gastrectomy. Postoperatively, normal serum gastrin concentrations were attained in the 9 patients who had a definitive antrectomy, with and without concomitant vagotomy. Provocative tests demonstrate that patients with Ps‐ZES have an exaggerated serum gastrin response to a meal but not to intravenous secretin. Antral G‐cell hyperplasia (AGCH) was observed histochemically in all but one surgically treated patient who is presumed to have G‐cell hyperfunction due to pyloric obstruction. One patient with REAS exhibited no appreciable response to a meal or to secretin stimulation; the G cells of the excluded antrum were hyperplastic. None of the patients had historical or endocrine features of multiple endocrine adenopathy, type I (MEA I).Provocative testing and histochemical determination of the antral G‐cell population permits a selective approach to the surgical treatment of patients with persistent or recurrent ulceration due to hyperchlorhydria. Patients with neurogenic duodenal ulcer without hypergastrinemia may reasonably be treated by surgical vagotomy with pyloroplasty or parietal cell vagotomy. Patients proven to have an antral source (without tumor) for their hypergastrinemia (Ps‐ZES) should have antrectomy, with or without vagotomy. Patients with gastrinoma (ZES) require excision of tumor(s) with or without total gastrectomy.

Pancreatic polypeptide inhibits exocrine pancreatic responses to six stimulants.

We determined the effects of three different doses of pancreatic polypeptide (50, 200, and 800 pmol X kg-1 X h-1) on pancreatic responses to graded doses of intravenous secretin, caerulein, and bethanechol and intraduodenal HCl, L-phenylalanine, and sodium oleate in dogs. The two lowest doses of pancreatic polypeptide (PP), which produced blood levels lower than measured after a meal, significantly inhibited the pancreatic responses to secretin, caerulein, HCl, and L-phenylalanine; the highest dose of PP inhibited the responses to bethanechol and sodium oleate. There was no difference in the degree of inhibition of bicarbonate or protein secretion caused by pancreatic polypeptide. With secretin, caerulein, bethanechol, and sodium oleate, inhibition was most pronounced against lower doses and was surmountable with higher doses of these stimulants. Inhibition of responses to HCl and L-phenylalanine was observed at all doses of these stimulants. Inhibition of the exocrine pancreatic secretory responses to six different stimulants by PP suggests that this hormone may play an important role in regulation of postprandial pancreatic secretion.

Pancreatic polypeptide secretion

Pancreatic polypeptide, a 36-amino peptide, is released from the pancreas by a variety of stimuli, including intravenous Boots secretin. Studies in a generalized destructive and inflammatory process such as chronic pancreatitis have revealed a markedly diminished response to stimulation. To assess whether pancreatic polypeptide release in response to Boots secretin provides a useful measure of pancreatic destruction in cystic fibrosis, 41 patients with proven cystic fibrosis, aged 14 months-23 years, and seven control subjects, aged 18-24 years were studied. Serum pancreatic polypeptide, measured by radioimmunoassay, rose from a basal of 18.5 +/- 2.7 pmol/liter to a peak of 35.6 +/- 4.3 pmol/liter at 5 min in cystic fibrosis, and from a basal of 10.8 +/- 2.8 pmol/liter to a 5-min peak of 109 +/- 27.7 pmol/liter in control subjects. The basal levels of both groups were similar but the cystic fibrosis patients had a significantly lower peak response than controls (P less than 0.05). The peak over basal pancreatic polypeptide ratio was calculated and was less than five in 93% of cystic fibrosis patients, whereas all control subjects had a ratio greater than five. Pancreatic polypeptide measurements in response to secretin may be a convenient and useful means of following the course of pancreatic disease in a chronic illness such as cystic fibrosis.

Role of sodium, bicarbonate, and plasma osmolality in biliary secretion.

To examine the effect of changes in biliary sodium and bicarbonate secretion on bile formation, experiments were performed on fasted, pentobarbital-anesthetized pigs. During continuous intravenous secretin infusion (2.7 CU X kg body wt-1 X h-1) sodium secretion was altered by increasing or reducing plasma sodium concentration. Bicarbonate secretion was altered by varying arterial plasma pH. At increased biliary sodium secretion, bile formation was depressed, but changes in bicarbonate secretion were accompanied by parallel alterations in bile formation. Bile acid secretion was increased during elevated plasma sodium concentration, whereas reduced plasma sodium concentration depressed bile acid secretion. To distinguish between the effect of changes in plasma osmolality and sodium concentration, bile formation was also studied during intravenous sucrose infusion at normal plasma sodium concentration. About 50% of the effect on bile formation of changing plasma sodium concentration is solely caused by the changes in plasma osmolality. During secretin stimulation bile formation is mainly determined by bicarbonate. Changes in plasma osmolality affect bile secretion through alterations in the net osmotic force across the hepatocellular membrane. Sodium has an impact on the bile-acid-dependent fraction, whereas bicarbonate is the mediator of the bile-acid-independent fraction of bile secretion.

Improvement of pancreatic ultrasound imaging after secretin administration

The pancreas is usually well recognized by ultrasound, but in some cases it is obscured by the presence of gas in the stomach and duodenum. Water and other orally administered fluids produced poor results. In this study we stimulated pancreatic juice secretion by a standard dose of intravenous secretin in 24 normal subjects, and continuously monitored the pancreatic region for a period of 20 min. Four to five minutes after hormone administration pancreatic juice outflow into the duodenum generated a fluid-filled echofree area around the head of the pancreas, allowing excellent visualization of its boundaries and other channel structures (distal common bile duct, pancreatic duct and gastroduodenal artery). This method should be utilized in selected patients whenever a pathological condition of the pancreatic head region is suspected.

Protective effects of exogenous secretin on ceruletide-induced acute pancreatitis in the rat.

Unconscious rats given intravenous ceruletide (diethylamine salt of the decapeptide caerulein) in large pharmacologic doses consistently developed moderate acute pancreatitis by 3 h and florid pancreatitis by 6 h. Biochemical serum markers of acute pancreatitis tended to parallel the severity of the pancreatic damage. In 50% of the rats, mesenteric fat necrosis was present, free peritoneal fluid containing massive elevations of trypsinogen and amylase were noted in most animals. Intravenous secretion at a low dose given simultaneously with ceruletide exerted a variable protective effect on the pathological process. A high dose of secretin produced a striking macroscopic, microscopic, and biochemical protective effect on ceruletide-induced pancreatitis. High resolution light microscopy and electron microscopy showed a marked cellular disorganization in the acini of animals treated with ceruletide alone. By contrast, there was a striking apical redirection of zymogen granules in acini of the animals treated with secretin. The results of this study suggest that high dose intravenous secretin may exert a beneficial effect on acute pancreatitis.

Regionally perfused fatty acids augment acid-induced canine pancreatic secretion.

To study interactions between hydrochloric acid and fatty acids on pancreatic secretion, six dogs with chronic gastric, pancreatic, and small intestinal cannulas received various combinations of the following intestinal perfusates: 20, 40, and 80 mM hydrochloric acid, oleate, dodecanoate, or 0.15 M saline. Regional intestinal perfusion (a proximal segment measuring 45 cm from the pancreatic duct versus the remaining small bowel) was utilized to separate the aqueous acid and lipid solutions. Both oleate and dodecanoate augmented the bicarbonate output induced by intraluminal acidification. In other experiments, intraluminal oleate, when combined with exogeneous intravenous secretin (12.5-900 ng . kg-1 . h-1), potentiated the secretin-induced bicarbonate output at low secretin doses. Dodecanoate also increased secretin-induced bicarbonate output. In all of these studies, protein outputs were increased by intestinal fatty acids. It is concluded that intestinal fatty acids can enhanced acid-induced canine pancreatic secretion.

Use of secretin in the roentgenologic and biochemical diagnosis of duodenal gastrinoma

The use of secretin in the biochemical and roentgenologic diagnoses of a duodenal gastrinoma has been described. Preoperatively, the secretin test indicated that a gastrinoma and not a retained antrum was the cause of hypergastrinemia in a patient who had previously undergone Billroth II gastrectomy. Intravenous infusion of secretin during selective angiography resulted in greatly enhanced visualization of the tumor which allowed it to be localized to the duodenal stump. Several months postoperatively, the secretin test result had become negative, which presumably suggested that the tumor had been excised completely. Our experience has revealed that intravenous secretin might improve the diagnostic usefulness of selective angiography.

Effects of atropine on the action and release of secretin in humans.

Using two groups of volunteers, we investigated the effects of atropine on pancreatic secretion of bicarbonate, protein, and trypsin stimulated by secretin. Secretin given intravenously in graded doses of 0.03, 0.06, and 0.125 clinical units.kg-1.h-1 produced significant increases in pancreatic secretion of bicarbonate in a dose-related manner. Pancreatic secretion of bicarbonate and protein was significantly suppressed by intravenous atropine, despite the dose of secretin infused. Intrajejunal perfusion of HCl at a rate of 3.3 mM/h, producing plasma secretin concentration comparable with that of the postprandial state, resulted in significant increases in the pancreatic secretion of bicarbonate. The increase in the pancreatic secretion of bicarbonate and trypsin was significantly suppressed by atropine. However, atropine did not affect the increase in the plasma secretin concentration produced by jejunal acidification or intravenous secretin. These studies indicate that atropine inhibits the pancreatic effect but not the intestinal release of secretin.

Effect of sodium oleate on plasma secretin concentration and pancreatic secretion in dog

The effects of sodium oleate and triglyceride infused into the duodenum of dogs with chronic pancreatic fistulas on pancreatic secretion and plasma immunoreactive secretin were investigated. The responses were compared with those following intravenous secretin infusions. Oleate markedly increased pancreatic water and bicarbonate secretion in a dose-related fashion, and these increases were accompanied by a small, but significant rise in the level of circulating immunoreactive secretin. No change in pancreatic secretion or in plasma secretin level was observed by the administration of triglyceride. Comparison of the bicarbonate response after oleate infusion with that after secretin administration suggests that the pancreatic stimulatory effect of intraduodenal sodium oleate is mediated to a major extent by the release of endogenous secretin.

Secretin stimulated pancreatic polypeptide: a test for chronic pancreatitis.

The level of serum pancreatic polypeptide (PP) in response to intravenous Boots secretin has been measured by radioimmunoassay in 50 patients with documented chronic pancreatitis and 33 controls with no evidence of pancreatitis. Both groups showed significant increases in serum PP but patients with chronic pancreatitis had a significantly smaller response than controls. An abnormal PP response to Boots secretin has been defined as a peak/basal ratio of less than five. Using this criterion. 90% of patients with chronic pancreatitis had a ratio of less than 5, whereas 91% of controls had a ratio of 5 or greater. There was a 92% correlation between a normal or abnormal pancreatic bicarbonate concentration and a normal or abnormal peak/basal PP ratio in response to Boots secretin. These results suggest that the serum PP response to Boots secretin may provide a simple, inexpensive and noninvasive method of accurately diagnosing chronic pancreatitis.