[Comparative evaluation of the secretin-cerulein and secretin-pancreozymin tests in the study of the exocrine function of the pancreas].
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Interaction of porcine vasoactive intestinal peptide with dispersed pancreatic acinar cells from the guinea pig. Structural requirements for effects of vasoactive intestinal peptide and secretin on cellular adenosine 3':5'-monophosphate.
Secretin and vasoactive intestinal peptide (VIP), but not glucagon, stimulate accumulation of cyclic AMP in dispersed guinea pig pancreatic acinar cells. Secretin stimulated cellular accumulation of cyclic AMP by interacting with a single class of high affinity receptors. On the other hand, the dose-response curve for VIP-stimulated cellular cyclic AMP was biphasic and reflected interaction of this peptide with two classes of receptors. Results obtained with synthetic fragments of VIP and secretin indicate that the receptor having a high affinity for VIP has a low affinity for secretin, interacts with, but does not distinguish among, secretin, secretin 5-27 and [6-tyrosine] secretin or among secretin 14-27, VIP 14-28, VIP 15-28, and increases cellular cyclic AMP when occupied by VIP, but not when occupied by secretin, [6-tyrosine] secretin, or secretin 1-14. The receptor having a low affinity for VIP has a high affinity for secretin, interacts with and distinguishes among secretin, secretin 5-27, and [6-tyrosine] secretin, interacts with secretin 14-27 but not with VIP 14-28 or VIP 15-28, and increases cellular cyclic AMP when occupied by VIP, secretin, [6-tyrosine] secretin, or secretin 1-14.
Animals↗
A comparison of the pepsin stimulating effects of secretin preparations.
1. The peptic responses to Boots, GIH and synthetic secretins have been compared in fasting anaesthetized cats in which the pylorus and bile duct were occluded to prevent the release of duodenal hormones by acid and bile salts. A quantity of dilute acid introduced into the stomach at regular intervals ensured the total recovery of viscid secretions and preserved peptic activity. 2. The mean peak outputs of pepsin obtained in response to Boots secretin were significantly greater than the mean peak outputs of pepsin stimulated by equipotent doses of GIH secretin (4 Crick-Harper-Raper units of Boots secretin have been shown to stimulate a flow of juice and bicarbonate from the pancreas equal to that produced by 1 clinical unit of GIH secretin). The maximum output of pepsin stimulated by Boots secretin, 16 C.H.R. u./kg hr was 3 times the observed maximum output in response to the 4 times more potent dose of GIH secretin, 16 c.u./kg hr. The slopes of the log dose-response lines were significantly different for these two products indicating that their modes of action in stimulating pepsin may not be identical. 3. The outputs of pepsin following GIH and synthetic secretin were similar. Both these secretins stimulated the secretion of pepsin when infused in doses which stimulated the pancreas supramaximally. The less pure product Boots secretin evoked significantly higher peptic responses at doses submaximal for pancreatic stimulation, suggesting that a substance other than secretin exists in Boots preparations which contributes significantly to the overall output of pepsin in response to this product. The peptic response which was accompanied by a slight increase in acid output, but without any increase in pancreatic lipolytic activity, was not inhibited by atropine. This substance which is not present in highly purified GIH secretin does not appear to be cholic acid, gastrin, pancreozymin, glucagon or insulin. 4. The possibility that a vasodilator substance is present in Boots secretin which by expanding the splanchnic bed increases the concentration of secretin at target sites in the stomach and pancreas seems unlikely, as the flow of pancreatic juice does not increase proportionately with the vast increase in pepsin. A vasodilator substance which specifically affects the gastric vasculature remains a theoretical but unlikely explanation for our observation.
Animals↗
Effect of glucagon on secretin-stimulated bile flow.
The effect of glucagon on secretin-stimulated bile flow was evaluated in dogs with chronic biliary and gastric fistulas. Evaluation of the effects of secretin and glucagon alone on hepatic bile flow indicated that the calculated maximal response (CMR) values of the two agents were similar. Secretin increased the bicarbonate concentration in hepatic bile whereas glucagon did not, suggesting basic differences in mechanism of action. Administration of glucagon to secretin-stimulated bile flow produced an increase in bile flow while decreasing the bicarbonate concentration in secretin-stimulated bile. Since the maximal response for bile flow to glucagon and secretin was significantly greater than the maximal response to either agent alone, glucagon produced potentiation of secretin-stimulated bile. Glucagon increased the CMR value of secretin-stimulated bile from 513 mul/min for secretin alone to 692 mul/min for secretin and glucagon. This was associated with no significant change in the values of the respective D50S. These data suggest that glucagon produced a noncompetitive augmentation of secretin-stimulated bile flow and suggest that the two agents do not utilize the same receptor to stimulate bile flow.
Animals↗
Observations of plasma secretin levels by radioimmunoassay in response to duodenal acidification and to a meat meal in humans.
The endogenous release of secretin in healthy human subjects was studied by measuring plasma secretin levels by radioimmunoassay (RIA) before, during, and following duodenal acidification and eating a meal. The sensitivity of our RIA was assessed by measuring plasma secretin levels during constant intravenous infusions of 4 graded doses of secretin. Our RIA detected significant increases (P less than 0.001) in plasma secretin with each dose, including a low dose of 0.125 U (41.3 ng)/kg hr. Intraduodenal infusion of 0.1 N HCl resulted in marked increases (P less than 0.001) in plasma secretin levels whenever pH in the second portion of the duodenum was reduced to less than 3.5. In contrast, following a meal, pH in the second portion of the duodenum remained consistently greater than 4.5 and plasma secretin levels showed no changes from basal levels. These studies confirm that endogenous release of secretin depends on an acidic pH of the duodenum, and insigificant changes in the plasma secretin level following ingestion of a meal suggest that endogenous release of secretin in the postprandial period is probably to small in quantity to be detected by the present radioimmunoassay method.
Adolescent↗
Elimination of porcine secretin in pigs.
1. The elimination of immunoreactive secretin was studied in anaesthetized pigs by using constant infusions of pure natural porcine secretin. 2. The mean metabolic clearance rate was 15.4 ml min-1 kg-1, and was independent of the level at which it was determined. The mean distribution space was 64.4 ml/kg. The half-life of secretin after termination of the infusion averaged 2.6 min. 3. During intravenous infusion of secretin in a dose of 27.8 pmol h-1 kg-1 the renal extraction was 52%. Exclusion of the kidneys increased plasma secretin concentration from 26.5 pmol/l to 47.3 pmol/l and increased the half-life to 4.4 min. 4. Exclusion of the liver during infusion of secretin in a dose of 27.8 pmol h-1 kg-1 resulted in an increment in plasma secretin concentration of 7.8 pmol/l and an increase of the half-life to 3.6 min. 5. A gradient of endogenous secretin across the liver was present but no arteriovenous difference was found across the foreleg. 6. Incubation of secretin with whole blood or serum for 20 min at 37 degrees C did not result in any degradation of secretin.
Animals↗
Effect of chronic pentagastrin, cholecystokinin, and secretin on pancreas of rats.
Pentagastrin (1.5 mg/kg), 20% pure natural cholecystokinin (CCK, 37.5 Ivy dog U/kg) or secretin (25 microgram/kg) was given in a depot carrier subcutaneously to rats 3 times daily for 15 days. The dose of CCK and secretin was submaximal for pancreatic secretion, whereas the dose of pentagastrin was supramaximal for gastric acid secretion. The pancreatic wet weight increased by 12% (P less than 0.01) in the rats treated with pentagastrin, 57% (P less than 0.001) in those treated with CCK, and 9% (P less than 0.01) in those treated with secretin. In CCK-treated rats, the maximal protein and bicarbonate outputs in response to cholecystokinin increased proportionately to the increase in pancreatic weight, but maximal bicarbonate and protein outputs in response to secretin were unaltered. The secretin-treated rats showed a lowered basal secretion of bicarbonate and a lowered sensitivity to secretin stimulation, but the maximal bicarbonate and protein outputs to secretin and CCK were unchanged. Treatment with pentagastrin produced no significant changes in pancreatic responses to secretin or CCK. We conclude that 1) the increase in pancreatic weight produced by repeated injections of cholecystokinin was accompanied by proportional increase in functional capacity as reflected by the increased maximal bicarbonate and protein outputs in response to cholecystokinin, and 2) repeated administration of secretin decreased the sensitivity of the pancreas to secretin without altering maximal bicarbonate response.
Animals↗
Uneven and transient secretin release after a liquid test meal.
In order to test the hypothesis that secretin may be released intermittently after feeding, the plasma secretin concentration was measured at short intervals, and the duodenal pH continuously recorded, after a liquid test meal in 10 human subjects. Secretin was measured with a radioimmunoassay in which the entire molecule is specifically recognized and the immunoreactivities of human secretin and of the porcine peptide used as standard are similar. In the total group, no significant variation of the mean plasma secretin concentration above basal was observed within 45 min after feeding. Analysis of the individual patterns revealed that secretin was released transiently in 5 of the 10 subjects, namely those showing variations of the duodenal pH down to or below 4.0 at some time after the meal. The mean peak delta secretin in these subjects was 7.2 pg ml-1 of plasma. In 7 additional subjects, bolus intravenous injections of 0.005 and 0.01 clinical units kg-1 of porcine secretin resulted in peak delta secretin concentrations of 5.5 and 10.5 pg ml-1, respectively, and were followed by a significant increase of bicarbonate output in the duodenal aspirate. These results indicate that secretin is released unevenly and intermittently in the early period after a liquid meal in man, in amounts that seem sufficient for the initiation of a significant bicarbonate response.
Adult↗
The effect of fat on secretin release.
The effect of graded doses of intravenously infused secretin and intestinally perfused sodium oleate and HCl on pancreatic exocrine secretion and plasma secretin was determined in cats and dogs prepared with pancreatic fistulas. The pancreatic dose--response curves for bicarbonate following duodenal perfusion of oleate and HCl in cats were almost identical and paralleled the response to exogenous secretin. Although the bicarbonate response to oleate in dogs was less pronounced than the response to HCl or secretin, the bicarbonate output was observed to increase relative to protein output with increasing doses of the intestinally perfused fat. These observations suggested that secretin or a substance with secretin-like activity may be released from the intestine on contact with fat. The inability to detect changes in secretin immunoreactivity in both cats and dogs with increasing doses of oleate suggests that if secretin is released, it is in amounts undetectable by our radioimmunoassay or that some other unknown substance with secretin-like activity may be released.
Animals↗
Immunoreactive secretin in gastrointestinal mucosa of several mammalian species.
Immunoreactive secretin in hydrochloric acid extracts is relatively constant in the duodenum and proximal jejunum of pig and dog (3 microgram per g), but peaks in the distal duodenum of guinea pig (1 microgram per g), no secretin being detectable in the ileum of these species. Secretin is relatively constant throughout the small intestine of the rat and rabbit (0.4 to 0.1 microgram per g). Sephadex gel filtration patterns of all species and throughout the gastrointestinal mucosa revealed primarily a single peak with elution characteristics identical with that of purified or synthetic porcine secretin. The "big" secretin prominent in Boots secretin may be an alteration product perhaps attributable to chemicals used to stabilize the preparation. The "intermediate secretin" described by others has not been detected. It is concluded that in a variety of mammalian species most of the immunoreactive secretin extractable from the intestinal tract lies distal to the proximal duodenum and is not distinguishable from duodenal secretin in terms of molecular size.
Animals↗
Effect of secretin on basal- and glucose-stimulated insulin secretion in man.
Plasma immunoreactive secretin and insulin concentrations were measured in fasting normal humans after intraduodenal infusions of hydrochloric acid, isotonic or hypertonic glucose. The effect of intraduodenal acidification or intravenous bolus injections of secretin on plasma insulin concentrations during infusions of glucose was also examined. The intraduodenal glucose load did not cause an increase in plasma secretin concentrations. Secretin concentrations rose after acid both in the fasting state and during infusions of glucose. A concomitant rise in insulin levels was however only observed during infusions of glucose. Intravenous injection of secretin in a dose which mimicked the response to intraduodenal acidification was without effect on the glucose-stimulated insulin release, while a 30 times higher dose caused a highly significant augmentation of the insulin release. The insulin response pattern to this high dose of secretin differed completely from that observed after intraduodenal infusion of acid. It is concluded and confirmed that the stimulating effect of secretin on insulin secretion is pharmacological and that secretin plays no significant role in the entero-insular axis.
Adult↗
Plasma secretin concentrations in fasting and postprandial state in man.
Plasma immunoreactive secretin concentrations were determined in both healthy subjects and patients with duodenal ulcer. The modified radioimmunoassay method could detect significant increases in the plasma secretin concentrations when 0.05 N HCl was infused intraduodenally at a rate of 1.1 and 2.2 ml/min. The mean fasting plasma secretin concentration of 13 normal healthy subjects was 4.4 +/- 0.38 pg/ml which was significantly less (P less than 0.01) than that of 13 duodenal ulcer patients, 6.9 +/- 0.64 pg/ml. In both groups ingestion of a meat-containing meal resulted in significant increase in the plasma secretin concentrations. Recording of pH from proximal duodenum indicated that pH fell periodically below 4.5 during the postprandial period, indicating that only a short segment of proximal duodenum was exposed to acid after meal. The postprandial rise in plasma secretin levels was abolished when antral pH was raised 5.5 by intragastric infusion of 0.3 N NaHCO3 solution. These observations indicate that although fasting plasma secretin levels are low, the plasma secretin levels increase significantly after ingestion of a meal. This increase appears to be attributable to an increased amount of acid delivered to the proximal duodenum, and patients with duodenal ulcer were found to release more secretin during the postprandial period than normal subjects.
Adult↗
Secretion pattern of secretin in man: regulation by gastric acid.
Median concentration of plasma secretin in the fasting state in 11 achlorhydria patients, 17 normal subjects, eight duodenal ulcer patients, and 11 Zollinger-Ellison patients was 0.3, 1.2, 2.5, and 5.9 pmol x 1(-1), respectively. Aspiration of gastric acid normal subjects and duodenal ulcer patients was followed by a significant lowering of the plasma secretin concentration. In normal subjects insulin-induced hypoglycaemia resulted in increased secretin levels when gastric acid was allowed to enter the duodenum, whereas no changes were observed when gastric acid was aspirated. Simultaneous measurements of intraduodenal pH and plasma secretin concentration in the fasting state and in response to a meal showed that rapid falls in intraduodenal pH were followed by short-lived increments in plasma secretin concentration. These changes in pH and in secretin levels were diminished after cimetidine. It is concluded that gastric acid in man does trigger release of secretin and that secretin is secreted intermittently both in the fasting state and in response to a meal when boluses of acid enter the duodenum.
Adult↗
Pancreatic bicarbonate, serum gastrin, and secretin responses to meals varying in pH.
The role of secretin in the postprandial bicarbonate response by the pancreas is not clear. This study reports secretin and bicarbonate secretion after exogenous and endogenous acidification of meal. In dogs with gastric and pancreatic fistulas, a liver extract meal at various pH levels was introduced into the stomach and kept at the preselected pH by intragastric titration. Gastric acid, pancreatic bicarbonate, serum gastrin, and plasma secretin were measured. The meal at pH 7 produced an increase of gastrin levels of 230% above basal and a gastric acid output from a basal of 0.8-16.9 meq/30 min. Acidification of the meal evoked a pH-dependent reduction of gastrin and gastric acid secretion, a pH-dependent elevation of pancreatic bicarbonate, and significant elevation of secretin at pH 3 (43% above basal) and at pH 2 (80% above basal). Postprandial endogenous acidification of a meal, without intragastric titration, also provoked significant release of secretin. Maximal pancreatic bicarbonate secretion in response to exogenous secretin was augmented 30% by the addition of a liver extract meal at pH7. It is concluded that in dogs with pancreatic fistulas, a meal exogenously or endogenously (postprandial) acidified is capable of the release of secretin in immunoassayable amounts. The normal pancreatic bicarbonate response to food may depend partially upon potentiation of the secretin effect by other neurohumoral stimuli.
Animals↗
Effect of CCK-octapeptide and secretin on amylase secretion in isolated rat pancreatic acinar cells.
Isolated acinar cells from rat pancreas responded well to hormonal treatment. Both secretin (synthetic and highly purified from porcine origin) and CCK-octapeptide stimulated amylase secretion in these cells. The response in both cases was very rapid. A maximal output of enzyme was reached within 5-10 min after the addition of hormones. The concentration producing maximal output for synthetic secretin (Schwarz/Mann) was 5 x 10(-8) M, synthetic secretin (Squibb), 10(-5) M, for purified porcine secretin, 10(-5) M, and for CCK-octapeptide was 5 x 10(-10) M. Secretin (2-fold at optimal concentration) was found to be less efficient compared to CCK-octapeptide (5-fold at optimal concentration) in stimulating amylase release. A combination of secretin and CCK-octapeptide had a synergistic action in stimulating enzyme release by the acinar cells. In addition, pretreatment of acinar cells with secretin potentiated the secretory response of the treated cells to CCK-octapeptide. To a lesser extent pretreatment with CCK-octapeptide also increased the effect of secretin in stimulating enzyme secretion.
Amylases↗
Effect of secretin on plasma insulin and glucagon in man.
To investigate the effect of physiological doses of secretin on pancreatic A and B cell functions, secretin was infused at a rate of 0.5, 1.0 and 2.0 clinical unit per kg body weight per hr into eight normal men for 30 min or 60 min after an over-night fast, and changes in plasma immunoreactive insulin (IRI) and glucagon immunoreactivity (GI) were measured while monitoring circulating secretin levels by a radioimmunoassay. During the infusion of secretin, the plasma immunoreactive secretin (IRS) levels rose to 140-390 pg/ml which was within a range of the physiological fluctuation in plasma secretin levels reported hitherto. No significant alteration of plasma IRI and GI levels could be demonstrated during these simulated physiologic infusions of secretin. These data suggest that, in humans, the physiological dose of secretin does not influence insulin and glucagon secretion from the pancreas in the basal state.
Adult↗
The effect of duodenal acidification on plasma secretin and gastrin and pancreatic bicarbonate secretion in man.
Plasma secretin, plasma gastrin and pancreatic bicarbonate output were measured in three healthy youths before and after a 10 min period of duodenal infusion of 50, 75 and 100 ml 100 mmol/1 HCl. Plasma secretin rose to a shortlived peak within 10 min, whereas plasma gastrin fell gradually to values significantly below the basal level 60 min after the start of duodenal acidification. Pancreatic bicarbonate output showed a more sustained increase following duodenal acidification. Significant positive correlations were obtained between plasma secretin and infused dose of HCl, between pancreatic bicarbonate output and infused dose of HCl and between plasma secretin and pancreatic bicarbonate output. The calculated maximal pancreatic bicarbonate output (Vmax) of 30.6 mEq/h and the calculated dose of secretin to elicit half maximal pancreatic bicarbonate output (S50) of 0.2 CU/kg-h following duodenal acidification were comparable to that seen after intravenous infusion of secretin. No significant correlation was found between plasma secretin and plasma gastrin. It is suggested that the pancreatic stimulation subsequent to duodenal acidification is mainly effected by release of secretin, and that the fall in plasma gastrin may be caused by a HCl-induced inhibition of gastrin release from the duodenum.
Adult↗
Radioimmunoassay of secretin in acidified plasma.
Antibody was readily produced in a rabbit against synthetic porcine secretin coupled to BSA. The final dilution of the antiserum to bind 50% of 1 fmol 125I-labeled secretin was 1 : 150,000. The effective equilibrium constant (Keff) according to Scatchard was 3.4 X 10(11) l/mol, the average equilibrium constant (Ko) according to Sips 3.5 X 10(11) l/mol, and the index of heterogeneity (alpha) according to Sips 1,00. No cross reactivity was found for gastrin, glucagon and insulin. 125I-labeled synthetic porcine secretin was prepared by the Chloramine-T-method, and the label purified on a Sephadex G-15 column followed by a SP Sephadex C-25 column had a specific radioactivity of 1.150 muCi/nmol. The radioimmunoassay method described has a detection limit of 1.6 pmol/l with 95% confidence limit, a within assay precision of 9,6%, and a between assay precision of 12.8%. It allows detection of fasting plasma secretin in the low pmol/l range, and the rather sharp rise and fall in plasma secretin subsequent to a brief period of duodenal acidification. The problem involved in measuring plasma secretin have been overcome by acidification of the plasma, and by subtracting the "apparent" secretin concentration in corresponding secretin-free plasma prepared by incubation at 37 degrees C for 96 h for each subject.
Animals↗