High Dose Of Secretin Research Articles

Diabetes-induced changes of nitric oxide influence on the cardiovascular action of secretin.

The modulation by condition of the lack or the excess of nitric oxide (NO) on cardiovascular action of secretin in diabetic rats was investigated. In vitro the isolated heart function and in vivo, the systolic (SBP), diastolic (DSP) blood pressure and heart rate (HR) were measured. Secretin evoked inotropic positive effect and increased coronary outflow (CO), in vivo did not increase systemic pressure and the highest dose of the peptide increased the heart rate. NO synthase inhibitor, N(G) nitro-L-arginine methyl ester (L-NAME) deeply increased the systemic pressure and in vitro decreased coronary outflow. L-arginine and sodium nitroprusside (SNP) did not influence the isolated heart function and in vivo decreased the systemic pressure. L-NAME preserved the inotropic positive effect of secretin and the increase of the coronary outflow. In vivo co-administration of L-NAME+secretin evoked hypotensive effect and abolished the increase of the heart rate after the highest dose of the peptide. L-arginine abolished inotropic positive effect of the peptide and the increase of coronary outflow. In vivo co-administration of these substances caused hypotension and attenuated the increase of the heart rate after the highest dose of secretin. Co-injection of SNP and secretin preserved the inotropic effect of secretin and abolished the increase of the coronary outflow. In vivo infusion of SNP+secretin evoked hypotension and similarly to L-arginine, SNP abolished tachycardia induced by the highest dose of secretin. Both the lack and the excess of nitric oxide changed the cardiovascular action of secretin in diabetic rats.

Secretin and pancreatic islet blood flow in anesthetized rats: increased insulin secretion with no augmentation of blood perfusion.

Secretin is a stimulator of both endocrine and exocrine secretions of the pancreas, and we aimed to evaluate its effects on splanchnic blood flow in rats with a microsphere technique. Anesthetized rats were infused with secretin (0.5 or 2.0 micrograms/kg body weight/hr) for 10 minutes. Some animals were normoglycemic, whereas other received a glucose injection 3 minutes before blood flow measurements. Secretin did not affect serum insulin concentrations in normoglycemic animals but consistently led to higher insulin concentrations in the hyperglycemic rats. Total pancreatic blood flow was increased by the highest secretin dose in normoglycemic animals, whereas no effects were seen in the hyperglycemic rats. Administration of glucose caused a pronounced increase in islet and fractional islet blood flow in saline-infused animals. Secretin affected neither islet nor fractional blood flow in normoglycemic or hyperglycemic rats. Glucose administration increased duodenal blood flow in animals infused with saline and both duodenal and colonic blood flow in rats given the lowest dose of secretin. No effects on either colonic or duodenal blood perfusion were seen in animals infused with the highest dose of secretin. Secretin mainly affects blood flow to the whole pancreas and not that of the islets. Furthermore, glucose-induced insulin release can be achieved without a simultaneous increase in islet blood flow; that is these two events may be dissociated from one another.

Effects of Epidermal Growth Factor, Cholecystokinin, and Secretin on Growth of the Alimentary Tract in the Neonatal Guinea Pig

Gut hormones and growth factors are likely to be involved in the functional changes and substantial growth of the alimentary tract that occurs during early neonatal life. The present experiments investigated the effects of continuous subcutaneous infusion of cholecystokinin (CCK), secretin, and epidermal growth factor (EGF) in neonatal guinea pigs for 4 or 15 days. At doses of 20, 100 or 500 pmol/kg/h, CCK and secretin had no effect on alimentary tract organs except for an increase in pancreatic weight at 4 days with the highest dose of CCK and an increase in stomach weight at 4 days with the highest dose of secretin. In contrast, EGF showed dose-dependent and time-dependent effects on all the alimentary tract organs when infused at 70, 210 and 630 pmol/kg/h. These results suggest that EGF, but not CCK or secretin, is likely to be an important trophic factor during the neonatal period.

Gastric emptying changes are neither necessary nor sufficient for CCK-induced satiety.

If gastric emptying plays a significant role in the satiety produced by exogenous cholecystokinin octapeptide (CCK-8) then 1) the effects on emptying and feeding should share similar kinetics and 2) peptides that inhibit emptying should also inhibit feeding. In the first experiment, CCK-8 (5.6 micrograms/kg) injected immediately before the introduction of an intragastric load (10 ml saline) or presentation of a test meal (15% sucrose) produced a rapid inhibition of both emptying and feeding. In contrast, the same dose administered 15 min before testing caused no inhibition of emptying, even though it retained the ability to reduce meal size. In experiment 2, the abilities of the peptides pentagastrin (100 micrograms/kg), bombesin (8 and 16 micrograms/kg), and secretin (2.86, 14.3, and 28.6 micrograms/kg) to reduce food intake and inhibit emptying were tested. Pentagastrin influenced neither food intake nor gastric emptying. Bombesin caused a small transient delay in emptying but a large and sustained eating suppression. However, a high dose of secretin caused no significant reduction of food intake, in spite of the fact that it inhibited emptying to the same degree as 1.4 micrograms/kg CCK-8, which does reduce intake. These results suggest that the inhibition of emptying by CCK is not sufficient to explain the satiety effect of CCK-8.

Secretion of pyruvate and lactate in pancreatic juice induced by acetazolamide or secretin

In vivo studies using pentobarbital sodium-anesthesized dogs were performed to investigate whether a transport pathway for pyruvate and lactate is present in the exocrine pancreas. Concentrations of both acids were measured in peripheral blood and pancreatic juice before and after intravenous 15-min administration of 2.25 mmol/kg DL-lactate, superimposed on continuous intravenous infusion of 3 U X kg-1 X h-1 secretin. The concentration ratio of lactate to pyruvate in pancreatic juice was found to be approximately 1, a lower value than found in other tissues or body fluids. D-lactate, not detected in either blood or juice during basal periods, rapidly appeared in both fluids in parallel with the physiological isomer L-lactate, after the infusion of DL-lactate. Further addition of acetazolamide or a high dose of secretin caused a marked secretory response of pyruvate and lactate with no increase in juice bicarbonate levels. We conclude that these acids can be transported from blood to lumen when the transmembrane pH gradient across the duct cell membranes is augmented by stimulants via a proton pump mechanism involving a CO2-HCO3-buffer system.

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.

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.

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.

Secretin-Induced Inhibition of Acid Secretion before and after Vagal Denervation of Canine Gastric Pouches

Sjödin, L. & Miura, S. Secretin-induced inhibition of acid secretion before and after vagal denervation of canine gastric pouches. Scand. J. Gastroent. 1974, 9, 185-190.The inhibitory effect of secretin on pentugastrin-stimulated secretion was studied before and after transformation of vagally innervated futidic pouches (Pavlov type) into vagally denervated pouches (Heidenhain type). A high dose of secretin (3.0 U per kg-hr) profoundly inhibited the secretion from both types of pouch, whereas a lower dose of secretin (0.75 U per kg-hr) produced a significant inhibition only in the Heidenhain pouches. Urecholine was shown to reduce the inhibitory effect of secretin on pentagastrin-stimu-lated secretion from vagally denervated pouches. It is suggested that when the fundic mucosa is vagally innervated, endogenous secretin is of little or no importance as an inhibitor of gastric acid secretion under physiological conditions. Pepsin output evoked by combinations of pentagastrin and secretin was low compared with that produced by a single infusion of Urecholine. The physiological significance of the stimulatory effect of secretin on pepsin secretion remains to he established.

A Secretin Test with High Doses of Secretin and Correction for Incomplete Recovery of Duodenal Juice

Summary The duodenal response to about 8 units per kilogram of secretin was studied in 15 normal cases and 12 pancreatic disease cases. The total flow of duodenal juice was calculated from the dilution of radioactive vitamin B 12 , which was continuously infused into the duodenum. The dead space of the duodenum and the tube was calculated and found to be, on an average, about 30 ml. The mean duodenal secretion recovered immediately after 1 unit per kilogram of secretin was 65 ml per 15 min, or equal to the response obtained by Agren et al. in 1935 to 1937. 17 The corresponding value for the corrected secretion was, on an average, 80 ml per 15 min. The corrected secretion increased to 124 ml per 15 min after further 7.5 units per kilogram and dropped to the volume obtained after one standard dose of secretin after 60 min. The average volume in the normals during 60 min, after the high dose of secretin, was 3.15 ml per kilogram. Corrections for intestinal losses and body weight decreased the coefficient of variation from 29 to 17%. The maximal bicarbonate concentration did not rise significantly above the values reported for 1 unit per kilogram of secretin. It was 110 mEq per liter with a standard deviation of 15. Signs of exhaustion of the bicarbonate secretion, reported for animal experiments, occurred during different parts of the experiment. The mean total bicarbonate secretion calculated per 60 min amounted to 0.509 mEq per kilogram. The standard deviation was 0.107 mEq per kilogram. The total amylase production during 60 min was, on an average, equal to the amylase amount obtained with the thousand times less potent preparation from the years 1935 to 1942. The range of the total amylase outputs in 60 min was much greater than that of the bicarbonate. The coefficient of variation was 41% after correction for weight and intestinal losses. Total Cryptic activity and total amounts of lipase varied between the same limits as in an earlier material from 1935 to 1942. The correlation between amylase, lipase, and total Cryptic activity was poor. Twelve cases of pancreatitis were investigated. Six cases with malabsorption showed a marked decrease in the bicarbonate secretion and in the enzymes assayed. Of the other 6, 3 had a reduction in the maximal bicarbonate concentration and total bicarbonate output during 60 min; 2 of the latter also had a decrease in the total tryptic activity during 30 min, and 1 had a decrease of amylase.