Doses Of Secretin Research Articles

Secretin, VIP, and PHI stimulate rat proximal duodenal surface epithelial bicarbonate secretion in vivo

The surface epithelial cells of the stomach and duodenum secrete bicarbonate at rest and in reponse to a number of agonists including the gastrointestinal hormones, glucagon, and GIP. Since those hormones with structural homology may have similar effects, the purpose of the present study was to examine the effect of graded doses (6, 24, and 96 nmol/kg) of pure porcine secretin, VIP, and PHI on bicarbonate secretion by the proximal duodenum containing Brunner's glands. Experiments were performed in vivo on unanesthetized Sprague-Dawley rats with chronic Thiry-Vella type loops of the proximal 2 cm of duodenum. The order of testing was random and only one hormone was tested on a single day. Compared to the saline control, each dose of VIP produced a significant increase in duodenal bicarbonate secretion in a dose-response manner. The two higher doses of secretin and only the 96 nmol/kg dose of PHI significantly increased bicarbonate output. The responses to 96 nmol/kg dose of secretin and VIP were similar, and each was significantly greater than observed with PHI. It is concluded that secretin and VIP stimulate proximal duodenal bicarbonate secretion and are more potent than PHI.

Plasma secretin and pancreatic response to various stimulants including a meal.

In dogs with gastric and duodenal Thomas cannulas, we investigated the threshold dose range of exogenous secretin and intraduodenal HCl for pancreatic bicarbonate secretion and, with a recently developed radioimmunoassay, measured the increase in plasma secretin concentrations. Synthetic secretin (2.5, 7.5, and 22.5 ng X kg-1 X h-1) was dissolved in saline or 0.1% dog albumin and given with or without a background infusion of 30 ng X kg-1 X h-1 of caerulein. The minimal dose of secretin that elicited a significant pancreatic bicarbonate response as well as an increase in plasma secretin concentration was 7.5 ng X kg-1 X h-1 when administered with albumin and 22.5 ng X kg-1 X h-1 without albumin. The threshold dose for duodenal HCl was 2 mmol X h-1. The threshold secretin dose for bicarbonate secretion and for an increase in plasma secretin levels was unchanged with a background caerulein infusion. Furthermore, postprandial secretin concentrations were measured. After a meat meal plasma secretin release appeared to occur in spikes up to 10 pmol X l-1 corresponding to secretin levels seen during infusion of 7.5 ng X kg-1 X h-1 of secretin and intraduodenal acid perfusion at a dose of 2 mmol X h-1.

Potentiating effect of secretin on cholecystokinin-stimulated pancreatic secretion in dogs

A possible potentiating effect of cholecystokinin octapeptide (CCK-OP) on the action of secretin on exocrine pancreatic secretion was studied in five dogs with gastric fistulas and modified Herrera pancreatic fistulas. Secretin in a dose, 2.45 pmol (0.03 clinical units) X kg-1 X h-1, that mimics the plasma secretin level in the postprandial state increased pancreatic bicarbonate secretion, but the increase was not statistically significant. CCK-OP in graded doses, 26.2, 52.5, 109, and 219 pmol (0.03, 0.06, 0.125, and 0.25 microgram) X kg-1 X h-1, given intravenously produced a significant increase in both bicarbonate and protein secretion, and the increase was dose related. The plasma concentrations of immunoreactive CCK during intravenous infusion of CCK-OP in doses of 26.2 and 52.5 pmol X kg-1 X h-1 were found to mimic the postprandial plasma concentrations of immunoreactive CCK in eight dogs. When CCK-OP in four graded doses was added to intravenous infusion of secretin, 2.45 pmol X kg-1 X h-1, the actual bicarbonate output at each dose level of CCK-OP was greater than the sum of the bicarbonate outputs produced by secretin alone and CCK-OP alone in a corresponding dose. Thus, we conclude that the action of secretin in a physiological dose that mimics the plasma level of secretin after a meal is potentiated by CCK-OP in a dose range that produces a plasma CCK-OP level comparable with that in the postprandial state and vice versa. The study indicates that, like secretin, CCK-OP is another necessary agent for pancreatic secretion of bicarbonate during digestion.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of theophylline on glucagon and secretin stimulated bile flow.

This experiment was performed to determine the effect of theophylline on glucagon and secretin stimulated bile flow. We intended to determine the effect of theophylline, a proposed stimulant of canalicular bile flow, on the bile flow response produced by well-recognized stimulants of canalicular (glucagon) and ductular (secretin) bile flow. Dogs with chronic bile fistulas were used. Dose-response curves for glucagon and secretin were produced by administration of a wide range of glucagon and secretin doses. The effect of 20 mg/kg/hr theophylline on the dose-response curves was determined. Theophylline significantly increased the bile flow and bile electrolyte changes produced by glucagon at low doses but not at maximal doses of glucagon for stimulation of bile flow. Theophylline significantly increased bile volume and bile electrolyte changes at all doses of secretin, including maximal doses. These results suggest that theophylline and glucagon, both purported to be stimulants of canalicular bile flow in dogs, utilize the same receptor mechanism to stimulate bile flow. The effects of secretin, a proposed ductular stimulant, are potentiated by theophylline. On a functional basis, it is possible that there are separate canalicular and ductular loci of hormone action in stimulation of bile secretion.

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.

Role of endogenous secretin in acid-induced inhibition of human gastric function.

The role of secretin in the inhibition of gastric acid secretion that occurs during acidification of the gastric lumen was studied in nine healthy men. Gastric acid secretion was stimulated by 500-ml meals of 8% peptone solution, and the pH of the stomach was maintained at 5.5, 2.5, or 2.0 by intragastric titration. The increase in plasma secretin was measured, after extraction, by a new secretin radioimmunoassay. After determining the intravenous dose of secretin required to reproduce plasma secretin concentrations achieved during pH 2.5 and 2.0 meals, similar doses were given during administration of a pH 5.5 peptone meal. The doses of secretin led to plasma secretin concentrations that averaged 3.4 pM, not different from the 3.2 and 3.9 pM concentrations achieved during acidified meals. However, exogenous secretin infusion failed to inhibit acid secretion or gastrin response to peptone, although significant inhibitions occurred in both during peptone meals given at pH 2.5 or 2.0. When secretin infusions were given at fivefold higher rates, plasma gastrin responses again failed to demonstrate significant inhibition. Gastric emptying was inhibited significantly by both acidified peptone meals but only slightly (P = 0.053) during exogenous infusion of physiologic secretin doses. The decrease in acid secretion could be explained by decreased gastrin release, but neither of these findings could be explained by circulating secretin concentrations. These results cast strong doubt on a physiological role of secretin in inhibition of acid secretion in man.

Interaction between stimulants of exocrine pancreatic secretion in dogs.

We measured bicarbonate and protein secretory responses to graded doses of intravenous caerulein and bethanechol and intraduodenal L-phenylalanine alone or with background secretin; graded doses of secretin alone or with background caerulein or L-phenylalanine; and background secretin plus graded doses of caerulein or L-phenylalanine plus background atropine sulfate. Potentiation (more-than-additive response) occurred for bicarbonate secretion between secretin and caerulein, between secretin and L-phenylalanine, but not between secretin and bethanechol. The only potentiating interaction for protein secretion was between secretin and low doses of caerulein. Atropine abolished the potentiated bicarbonate response to secretin plus L-phenylalanine but had no effect on the response to secretin plus caerulein. Potentiation between secretin and cholinergic mechanisms and cholecystokinin for pancreatic bicarbonate secretion may be an important regulatory mechanism, while potentiation of protein secretion with these stimulants does not appear to be important in dogs. A cholinergic mechanism mediates much of the bicarbonate potentiation between secretin and intestinal L-phenylalanine.

The Effect of Graded Doses of Secretin on Serum Trypsin, Serum Pancreatic Amylase, Serum Insulin, Plasma Somatostatin, and Plasma Pancreatic Polypeptide in Man

Six healthy men were studied with intravenous infusions of 0.3, 1.0, and 3.0 CU/kg-h of pure porcine secretin on separate days. The secretin elimination followed a first-order kinetics. Low pharmacological doses of secretin had no significant effects on blood levels of trypsin, pancreatic amylase, insulin, somatostatin, or pancreatic polypeptide (PP), whereas high pharmacological doses significantly elevated the blood levels of trypsin, pancreatic amylase, insulin, and somatostatin but were without effect on PP.

Presence and possible site of action of secretin in the rat pituitary and hypothalamus

Secretin-like immunoreactivity was detected in extracts of several rat brain structures by radioimmunoassay, most notably in the pituitary, hypothalamus, pineal and septum. Its localization to these structures suggested that it might play a role in neuroendocrine events similar to its structural homolog vasoactive intestinal peptide. Dose-related stimulations (MED, 10 −7M) of prolactin (PRL) release were observed after incubation of synthetic secretin with dispersed, cultured pituitary cells from male and ovariectomized (OVX) female rats. In OVX females, i.v. infusion of a high dose of secretin (10 ug) resulted in a significant elevation of PRL levels. Doses of secretin as low as 0.1 ug when administered into the third cerebroventricle were capable of significantly inhibiting PRL release in both males and OVX females, suggesting an ultrashort-loop, negative feedback of secretin. Secretin can now be added to the growing list of putative PRL-releasing agents.

The effect of secretin on canine gastric mucosal HCO 3− production

Recent studies suggest that HCO 3 − production by surface epithelium may protect gastric mucosa against H + back diffusion. Agents shown to increase gastric HCO 3 − include prostaglandins, carbachol, dibutyryl c-GMP, ethanol, Ca 2+, and cimetidine. This study was initiated to evaluate the effect of secretin on gastric mucosal HCO 3 − production. Six dogs with Heidenhain pouches were fasted 24 hr. Each study consisted of nine 15-min periods: three control periods of iv saline infusion; three test periods which followed an iv bolus of 0.15 clin units/kg secretin; and three test periods which followed an iv bolus of 0.30 clin units/kg secretin. The intragastric test solution consisted of 100 m M NaCl, 20 m M mannitol, and 50 m M EPPS buffer; pH was adjusted to 8.0–8.2 using 19 M NaOH. Fifty milliliters test solution was instilled in the pouch and a zero-time sample was taken; after 15 min a final sample was taken, the pouch was rinsed, and the next period begun. HCO 3 −, Na +, K +, and Cl − concentrations were measured as well as transmucosal electrical potential difference (PD) changes and changes in volume, pH, and osmolality. [ 14C]PEG was utilized to measure residual volume. In the first 15-min period following each secretin bolus, significant ( P < 0.05) increases in intraluminal gastric HCO 3 − occurred. However, doubling the secretin dose did not significantly increase the measured HCO 3 − when compared to the lower dose. Also undetectable were changes in ionic fluxes accompanying the increases in intraluminal HCO 3 − which might have suggested a mechanism of the HCO 3 − production. In addition to its previously described properties of acid inhibition and gastric mucus stimulation, this study demonstrates that secretin also induces production of gastric HCO 3 −. The clinical significance of these modest increases remains to be determined but they may contribute to gastric mucosal barrier defense.

The effect of secretin on pancreatic blood flow in the awake and anesthetized dog.

The canine pancreatic blood flow was studied after iv secretin (resulting in a plasma level commensurate with the postcibal state), and also after larger iv doses and after duodenal acidification. We found that blood flow was unaffected by "physiological" doses of secretin, or by perfusion of duodenum at a pH as low as 2.0, but increased by bolus doses (0.5 CU/kg and above), and by acidification to pH 1.4. Anesthesia does not affect the blood flow response although the bicarbonate response appeared to be blunted under anesthesia. We conclude that increase in pancreatic blood flow is not a physiological effect of secretin.

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.

Potentiation Effect of Cholecystokinin-Octapeptide on Pancreatic Bicarbonate Secretion Stimulated by a Physiologic Dose of Secretin in Humans

We studied the potentiation effect of cholecystokinin-octapeptide and secretin on pancreatic secretion of bicarbonate and trypsin in humans. The pancreatic bicarbonate and trypsin outputs were determined by using a triple-lumen duodenal tube and indicator dilution technique while gastric juice was completely aspirated. When cholecystokinin-octapeptide in varied doses, 2.6, 5.3, 10.9, 26.3, 52.6, and 109.4 pmol . kg-1 . h-1, was added to i.v. infusion of secretin in a physiologic dose, 0.03 clinical units (CU) . kg-1 . h-1, the bicarbonate outputs were significantly greater than those achieved by secretin or cholecystokinin-octapeptide alone or the sum of the bicarbonate outputs produced by each hormone. The potentiation effect of cholecystokinin-octapeptide occurred at the dose of 10.9 pmol . kg-1 . h-1. No further further augmentation on the bicarbonate output occurred when the dose of cholecystokinin-octapeptide was increased in the dose range greater than 10.9 pmol . mg-1 . h-1. No potentiation on pancreatic secretion of trypsin was apparent when the two hormones were given simultaneously. Thus, cholecystokinin-octapeptide in a relatively small dose range potentiated the pancreatic bicarbonate secretion stimulated by a physiologic dose of secretin. The pancreatic enzyme secretion does not appear to be potentiated by two hormones.

Plasma gonadotropin, prolactin levels and hypothalamic tyrosine hydroxylase activity following intraventricular bombesin and secretin in ovariectomized conscious rats

Plasma gonadotropins, prolactin and hypothalamic tyrosine hydroxylase (TH) activity were evaluated at 15 and 30 min after third ventricular injection of bombesin at doses of 100 or 1000 ng and secretin at dotes of 1000 or 5000 ng in ovariectomized (OVX) unanesthetized rats. Bombesin had no effect on plasma gonadotropin levels. Intraventricular injection of either 100 or 1000 ng dose of bombesin significantly suppressed prolactin levels with parallel elevation in hypothalamic TH activity and there appears to be no dose response relationship. Secretin at 1000 ng dote, significantly lowered plasma LH and PRL levels and elevated hypothalamic TH activity whereas a 5000 ng dose increased PRL concentrations but had no effect on gonadotropin levels and hypothalamic TH activity. Bombesin appears to be a potent inhibitor of PRL release in OVX, conscious rats and this effect may be mediated via hypothalamic dopamine. Lower dose of secretin appears to inhibit PRL release by possibly activating the hypothalamic dopaminergic system, while at higher dose peripheral activation results in enhanced prolactin release.

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.

Mechanism of hepatic bicarbonate secretion and bile acid independent bile secretion.

To examine hepatic bicarbonate transport and bile acid independent bile secretion, bile was sampled via a T-tube inserted into the common bile duct of anaesthetized pigs. Secretin was infused intravenously at a rate of 2.7 C.U./kg body weight h-1 (large dose) or 0.45 C.U./kg body weight h-1 (small dose). Hepatic water and electrolyte secretion were studied during systemic acid-base disturbances while secretin was continuously administered. Systemic acidosis reduced the rate of NaHCO3 secretion which fell in proportion to changes in plasma pH, by 9% and 2% per 0.1 pH unit for the large and small dose of secretin, respectively. Plasma pCO2 and bicarbonate concentration had little influence on NaHCO3 secretion. Consequently, plasma pH appeared to be the main determinant of hepatic NaHCO3 secretion during acid-base changes. Secretion of 1 mol NaHCO3 was accompanied by an isotonic solution containing water and 0.25 mol NaCl. After secretin infusion, 14C-erythritol clearance increased in proportion to bile flow. Bicarbonate secretion is determined by a gradient limited H+-pump at the contraluminal cell. During secretin stimulation bile acid independent bile secretion is osmotically driven by bile NaHCO3 flux.

The role of nicotinic receptors in dog pancreatic exocrine secretion.

1 The effects of pentamethonium, an autonomic ganglion blocker, were studied on the exocrine pancreatic secretion of six conscious dogs given intravenous infusions of urecholine, caerulein or pentagastrin on a background of submaximal doses of secretin. 2 Urecholine-induced protein secretion was not affected but both caerulein- and to a smaller extent, pentagastrin-induced protein secretions were depressed by pentamethonium. 3 These results indicate that intravenous caerulein and pentagastrin, but not urecholine, act at least partially via nicotinic receptors. 4 Volume and bicarbonate output were depressed by pentamethonium when stimulated by intravenous caerulein with a background of secretin, but not when stimulated by pentagastrin on a background of secretin. 5 From these data it is suggested that caerulein and pentagastrin may potentiate secretin-stimulated hydrelatic secretion by different mechanisms.

Interaction of neurotensin, cholecystokinin, and secretin in the stimulation of the exocrine pancreas in the dog

The effects of exogenous neurotensin, secretin, and cholecystokinin-33 alone and in combination on pancreatic secretion were investigated in dogs prepared with pancreatic fistulae. Neurotensin infused intravenously caused a dose-dependent stimulation of exocrine pancreatic secretion. Increasing doses of neurotensin combined with a constant small dose of secretin potentiated pancreatic output of protein and had a tendency to reduce secretion of the bicarbonate. Increasing doses of neurotensin combined with a constant small dose of cholecystokinin-33 potentiated pancreatic output of bicarbonate and lead to a reduction (insignificant) of pancreatic protein secretion. These observations suggest an interaction of neurotensin with pancreatic receptors for secretin and cholecystokinin.

Pharmacologic Effect of Somatostatin on Bile Formation in the Dog

A study was carried out to define the effect of somatostatin on bile secretion using a chronic bile fistula dog preparation. Bile flow, erythritol clearance, and biliary electrolyte and lipid composition were measured under steady-state conditions during four randomized treatments: placebo, somatostatin, cimetidine, and cimetidine + somatostatin. In addition, the effect of three increasing doses of secretin was defined during each treatment. A constant cholyltaurine infusion was used to compensate for the interrupted enterohepatic circulation of bile acids. Somatostatin caused a consistent reduction in total bile flow and biliary bicarbonate output, but its effect on canalicular bile flow, as assessed by erythritol clearance, was variable. Outputs of bile acids, lecithin, and cholesterol remained unchanged during the somatostatin infusion. Because the bile/plasma ratio of erythritol concentration increased greatly during somatostatin infusion, the reduction in bile flow was attributed to enhanced ductular reabsorption (or alternatively, decreased ductular secretion) of a fluid whose calculated electrolyte composition was identical to that induced by secretin infusion in the control group. Secretin and somatostatin antagonized each other's effects: at a low dose of secretin, somatostatin caused decreased bile volume, whereas the highest dose of secretin effectively antagonized the effect of somatostatin. The anticholeretic effect of somatostatin was not due to the inhibition of endogenous secretin, since cimetidine treatment did not influence the effect of somatostatin on bile flow or bicarbonate secretion. Further, the anticholeretic effect of somatostatin was not vagally mediated, since the infusion of an anticholinergic agent did not alter the effects of somatostatin. It was concluded that, in the dog, the major effect of a pharmacologic dose of somatostatin on bile flow is an anticholeresis caused by either an enhanced ductular reabsorption or inhibition of a ductular secretion of a bicarbonate-rich electrolyte fraction of bile, and that this effect is likely to be mediated by a local effect of somatostatin on the biliary ductule. Thus, in the dog, somatostatin and secretin both evoke ductular modification of bile; however, the effects of the two hormones are exactly opposite to each other.