Inhibition Of Pancreatic Protein Secretion Research Articles

"Transformation of pancreatic secretion with intraduodenal administration of trypsin and amylase with nonspecific substrates for them."

The results of the study on the effects of enter sorbents allowed us to draw a fundamental conclusion, in our view, that the inhibitory influence on the secretion of pancreatic enzymes is exerted by only the solubilized enzymes in the duodenum contents. Immobilized enzymes bound to enter sorbents lose or significantly reduce this ability to inhibit pancreatic secretion. The de-blocking effects are also induced by nutrients introduced intraduodenally. In our laboratory, it has been demonstrated (Korotko G.F., Baybekova G.D.) that starch as a substrate for amylase removes its selective inhibitory effect on the secretion of pancreatic amylase; the selective inhibition of pancreatic protein secretion is reduced by intraduodenal administration of protein, and emulsified fat eliminates inhibitory effects on pancreatic secretion of lipase. The fundamental similarity of effects between sorbents and nutrients, considering the latter as factors immobilizing enzymes, allows us to observe some external analogy between the comparable effects.

Inhibition of pancreatic protein secretion by ghrelin in the rat.

1. The role of ghrelin in the regulation of pancreatic protein secretion was investigated in vivo using anaesthetized rats with pancreatic ductal cannulas, and in isolated pancreatic acinar cells and pancreatic lobules in vitro. 2. In vivo, pancreatic protein output stimulated by CCK-8 (400 pmol kg(-1) h(-1)) was dose-dependently inhibited by continuous ghrelin infusion (1.2 and 12 nmol kg(-1) h(-1)) by 45 +/- 8 and 84 +/- 7 %, respectively. 3. In rats with acute subdiaphragmatic vagotomy, ghrelin (12 nmol kg(-1) h(-1)) significantly inhibited CCK-stimulated pancreatic protein secretion by 75 +/- 18 %. 4. Infusion of ghrelin (12 nmol kg(-1) h(-1)) abolished pancreatic protein secretion caused by the central vagal stimulant 2-deoxy-D-glucose (75 mg kg(-1)), whereas bethanechol-stimulated pancreatic protein output was inhibited by only 59 +/- 7 %. 5. In vitro, ghrelin (10(-11)-10(-7) M) produced no change in basal amylase release from dispersed, purified acinar cells. Co-incubation of ghrelin (10(-11)-10(-7) M) with CCK-8 (10(-10) M) demonstrated no inhibition of CCK-stimulated amylase release from dispersed acini. In contrast, ghrelin (10(-9)-10(-7) M) dose-dependently inhibited amylase release from pancreatic lobules exposed to 75 mM potassium. 6. Our results show that (1) ghrelin is a potent inhibitor of pancreatic exocrine secretion in anaesthetized rats in vivo and in pancreatic lobules in vitro; and (2) the actions of ghrelin are indirect and may be exerted at the level of intrapancreatic neurons.

Central CGRP inhibits pancreatic enzyme secretion by modulation of vagal parasympathetic outflow.

Calcitonin gene-related peptide (CGRP) is a potent inhibitor of pancreatic enzyme secretion in vivo. Recent studies have shown that CGRP exerts its inhibitory action at a central vagal site. The present study investigates the mechanism responsible for the central action of CGRP. Rats were fitted with lateral cerebroventricular cannulas, using stereotaxic instruments, 4 days before pancreatic secretion studies. In anesthetized rats, administration of 2-deoxy-D-glucose (2-DG) (75 mg/kg iv) or CCK-8 (40 pmol. kg-1. h-1) produced a 100 and 75% increase in protein secretion, respectively, which was completely blocked by atropine. Intracerebroventricular (ICV) administration of CGRP (0.03-0.6 nmol/h) resulted in a dose-related inhibition of pancreatic protein secretion evoked by 2-DG or CCK-8. CGRP administered by the ICV route was 10-40 times more potent than CGRP given by the intravenous route. In contrast, ICV administration of CGRP had no significant effect on pancreatic protein secretion evoked by electrical vagal stimulation or bethanechol, which directly activates the pancreatic muscarinic receptor. Chemical sympathectomy induced by pretreatment with guanethedine (20 mg/kg ip, 2 days) or alpha-adrenergic receptor blockade with phentolamine did not alter the inhibitory effects of CGRP. We recently demonstrated that CCK stimulated the enteropancreatic neural pathways to mediate pancreatic secretion in rats with a chronic vagotomy. ICV-administered CGRP did not affect CCK-stimulated pancreatic secretion in rats with a chronic vagotomy. In conclusion, CGRP in the central nervous system inhibits pancreatic enzyme secretion stimulated by 2-DG and CCK-8, which act through vagal pathways. The inhibitory action of CGRP is not mediated by the sympathetic nervous system but appears to depend on intact vagus nerves.

Somatostatin inhibits pancreatic enzyme secretion at a central vagal site.

The mechanisms and site of action of somatostatin-induced inhibition of pancreatic enzyme secretion were investigated using different stimulants of pancreatic secretion acting on different sites in anesthetized rats. Administration of graded doses of somatostatin-14 resulted in a dose-related inhibition of pancreatic protein secretion evoked by 2-deoxy-D-glucose, a central vagal stimulant that acts by stimulating the dorsal vagal nuclei. The lowest effective dose of somatostatin-14 was 1.0 microgram.kg-1 x h-1; maximal effective dose was 25 micrograms.kg-1 x h-1, which resulted in complete inhibition of protein output. Similarly, somatostatin-14 at a dose of 25 micrograms.kg-1 x h-1 also completely inhibited pancreatic protein secretion in response to a physiological concentration of cholecystokinin octapeptide (CCK-8), which acts via a vagal afferent pathway. In contrast, pancreatic protein outputs evoked by bethanechol, which directly stimulates pancreatic muscarinic receptors, or electrical stimulation of the vagal trunk, which activates the vagal efferent pathway, were unaffected by somatostatin-14. In separate studies, we demonstrated that perivagal treatment with the sensory neurotoxin capsaicin impaired pancreatic responses to CCK-8 but had no effect on the inhibitory action of somatostatin-14 on pancreatic secretion evoked by 2-deoxy-D-glucose, ruling out an effect of somatostatin on the vagal afferent pathway. Similarly we also demonstrated that perineural capsaicin treatment of the celiac-superior mesenteric ganglia did not affect the inhibitory action of somatostatin. These findings indicate that somatostatin inhibits 2-deoxy-D-glucose- and CCK-8-evoked pancreatic enzyme secretion via a vagal pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Vagal afferent pathway mediates physiological action of cholecystokinin on pancreatic enzyme secretion.

To establish the mechanism(s) and site(s) of action of cholecystokinin (CCK) on pancreatic secretion under physiological conditions, we used an in vivo model using anesthetized rats with pancreaticobiliary cannulas. Infusion of CCK-8 (10-160 pmol/kg per h) produced a dose-dependent increase in plasma CCK levels. CCK-8 infusion at 40 pmol/kg per h produced a plasma CCK level of 7.9 +/- 1.5 pM and an 80% increase in pancreatic protein output over basal. This level was closely approximated by a postprandial peak plasma CCK level by 6.2 +/- 1.1 pM. Pretreatment with atropine or hexamethonium completely abolished pancreatic protein response to low doses of CCK-8 (10-40 pmol/kg per h) but had only partial effect on doses > 40 pmol/kg per h. Bilateral vagotomy also abolished the pancreatic responses to low doses of CCK-8. Similarly perivagal treatment with a sensory neurotoxin, capsaicin, caused a complete inhibition of pancreatic protein secretion in response to CCK-8 infusion. In contrast, pancreatic protein responses to bethanechol were similar in control and capsaicin-treated rats. In separate studies we demonstrated that gastroduodenal but not jejunal application of capsaicin for 30 min abolished pancreatic protein secretion in response to physiological doses of CCK-8. In conclusion, CCK at physiological levels stimulates pancreatic enzyme secretion via a capsaicin-sensitive afferent vagal pathway originating from the gastroduodenal mucosa.

Peptide YY inhibits pancreatic secretion by inhibiting cholecystokinin release in the dog

Peptide YY inhibits the pancreatic exocrine secretion (bicarbonate, water, and protein) that is stimulated by cholecystokinin, secretin, or neurotensin in the dog, but whether peptide YY inhibits the release of gut peptides that stimulate pancreatic exocrine secretion is not known. Six dogs were prepared with gastric, pancreatic, and cecal cannulas. On separate days, a single dose of sodium oleate (3, 6, 7.5, 9, 12, 15, or 18 mmol/h) was given intraduodenally for 90 min, either alone (control) or in combination with peptide YY (25, 50, 100, 200, or 400 pmol/kg · h, i.v.). We measured plasma levels of cholecystokinin-33/39, secretin, neurotensin, and peptide YY by radioimmunoassay. During infusion of peptide YY, the integrated release of cholecystokinin (3.3 ± 0.5 ng-[0–90] min/ml) was decreased significantly (p < 0.05) when compared with control values (5.6 ± 0.6). Release of secretin and neurotensin was not affected. A positive correlation (p < 0.05) was found between the release of cholecystokinin and pancreatic protein output in both control (r = 0.68) and peptide YY-treated (r = 0.67) groups. Release of peptide YY was significant after intraduodenal or intracolonic administration of sodium oleate. These studies demonstrate that inhibition of pancreatic protein secretion by peptide YY in dogs is mediated, at least in part, by an inhibition of the release of cholecystokinin.

Effect of atropine on rat basal pancreatic secretion during return or diversion of bile-pancreatic juice.

The effect of atropine on basal pancreatic exocrine secretion in conscious rats was determined with and without return of bile-pancreatic juice (BPJ) to the intestine. Rats were prepared with cannulas draining bile and pancreatic juice separately and with duodenal cannulas for return of secretions. Experiments were begun 3 days postoperatively. During continuous return of bile-pancreatic secretions, intravenous atropine (100 micrograms/kg-hr) caused a sustained 80-90% inhibition of pancreatic protein secretion, with a much smaller suppressive effect on pancreatic juice volume. Diversion of bile-pancreatic juice from the intestine markedly increased pancreatic protein and fluid secretion in control and atropine-infused rats, but the response was significantly inhibited by atropine (volume 31% inhibition, protein output 41% inhibition). The results indicate that basal pancreatic protein secretion during return of BPJ is largely maintained by cholinergic influence, possibly due to an enteropancreatic reflex, and that the inhibition of the pancreatic response to acute diversion of BPJ by atropine is probably secondary to inhibition of gastric secretion.

Inhibition of pancreatic protein secretion by fatty acids in rats. Partial isolation and purification of an anticholecystokinin-peptide (ACP)

Recently, Laugier and Sarles (J.Physiol. 1977,=,81) showed that in conscious rats intraileal infusion of oleic acid induced an inhibition of pancreatic protein secretion which was transmitted by cross-circulation. Our aim was 1/ to study in conscious rats the mechanism of release of this inhibitory factor, 2/ to purify it from the pig ileum. RESULTS : 1/ An intraduodenal infusion of oleic acid or of ISO-Osmolar Oleate sodium soap stimulated both volume and Protein output during infusion. At the end of infusion, v01~1~1e returned slowly to basal values while protein concentration and output decreased progressively below basal values (inhibition of respectively -65% and -60% two hours after the end of the infusion). When pancreatic juice and bile were returned into the duodenum during the infusion, OleiC acid and olive oil induced also a delayed inhibition Of protein Output. This delayed inhibition was still found with carrylate (CE), but no more with butyrate (C4). 1so-osmolar (5%). hyperosmolar (30%) glucose and casein + pancreatic ]uice did not inhibit protein secretion. 2/ Crude Extracts have been obtained from the pig ileum by the techniques described by MUTT. After chromatography on SG25 (Fine) and on Bio-Gel P6 (100-200 Mesh), the active material has been purified by carboxymethyl cellulose. The active fraction was eluted in these conditions after V.I.P. and was free of enteroglucaqon and somatostatin. This fraction inhibited volume and protein output Of basal secretion of conscious rats. This inhibition was proportiol!al to the dose ; the calculated 050 of inhibition was 18.75 q kg-l. 25 g/kg inhibited also strongly protein output stimulated by CCK-PZ and secretine. AS the name of snticholecystokinln had been proposed for the f,ictor which inhibits gallbladder contraction in the dog and which is released 1 hour after a fatty meal, (Sarles E+ al., Nutr. et Dieta, 2, 223, 1960), the name of antlch(.lecystoklnin peptldc (ACP) is proposed.

Effect of bombesin and related peptides on the release and action of intestinal hormones on pancreatic secretion.

1. Pancreatic volume flow as well as bicarbonate and protein secretion from pancreatic fistulas have been measured in response to i.v. infusion of graded doses of bombesin and related peptides containing the COOH-terminal fragment of the bombesin molecule in conscious dogs with intact antrum and in anaesthetized animals with antrectomy, or antrectomy and enterectomy. 2. Bombesin and related peptides given to conscious dogs produced a potent and dose-dependent increase in pancreatic protein output reaching a maximum equal to that induced by the octapeptide of cholecystokinin (OP-CCK) as well as a small rise in bicarbonate output attaining a peak amounting to about 10% of that evoked by secretin. The serum gastrin level rose progressively during the infusion of bombesin to reach a peak with the highest dose of peptide. 3. Bombesin infused i.v. in anaesthetized animals with resected antrum also evoked a marked increase in pancreatic protein secretion without significant changes in the serum gastrin level. Following the removal of the antrum and small intestine, bombesin failed to show any stimulation of the pancreatic secretion or any change in the serum gastrin level. It is concluded that the strong stimulatory action of bombesin and related peptides on pancreatic secretion cannot be entirely ascribed to the release of gastrin but might be attributed at least in part to the release of intestinal hormones, particularly CCK. 4. Atropine and the growth hormone-release inhibiting hormone (GH-RIH), which were shown to inhibit the release of CCK induced by duodenal perfusion of an amino acid mixture, also caused the inhibition of pancreatic protein secretion by bombesin but failed to affect the pancreatic response to OP-CCK. The results indicate that bombesin releases, in addition to gastrin, CCK from the gut by a mechanism largely dependent upon cholingeric innervation.