Secretion In Conscious Dogs Research Articles

Effects of biliary and pancreatic juice diversion into the ileum on gastrointestinal motility and gut hormone secretion in conscious dogs

The aim of the present study was to investigate the effects of diversion of biliary and pancreatic juices on upper gut motility and hormone secretion. We used dogs equipped with strain gauge force transducers to measure upper gut motility. Dogs were divided into 5 groups: control, sham operation, biliary diversion (BD), pancreatic juice diversion (PJD), and biliopancreatic juice diversion (BPD). Postprandial plasma concentrations of insulin, gastric inhibitory polypeptide (GIP), and peptide YY (PYY) were also measured. Occurrence and migration velocity of the migrating motor complex in the jejunum in the interdigestive state were decreased in the BD and BPD groups compared with the other 3 groups (P<.05). In the BD and BPD groups, areas of postprandial contractile curves in the upper gut were decreased, and the duration of the postprandial contractions in the proximal jejunum, which a previous study showed to correlate with gastric emptying, were less compared with the other 3 groups (P < .05). Plasma insulin levels did not differ among the 5 groups. Plasma concentrations of GIP suppressed in the PJD and BPD groups (P < .05), whereas plasma PYY level was increased in the BD group (P < .05). Bile diversion seems to inhibit interdigestive and postprandial upper gut contractions in association with an increase of plasma PYY. Pancreatic juice was considered to play a role in the secretion of GIP.

Optimization of the in Vitro and in Vivo Properties of a Novel Series of 2,4,5-Trisubstituted Imidazoles as Potent Cholecystokinin-2 (CCK2) Antagonists

The systematic optimization of the structure of a novel 2,4,5-trisubstituted imidazole-based cholecystokinin-2 (CCK(2)) receptor antagonist afforded analogues with nanomolar receptor affinity. These compounds were now comparable in their potency to the bicyclic heteroaromatic-based compounds 5 (JB93182) and 6 (JB95008), from which the initial examples were designed using a field-point based molecular modeling approach. They were also orally active as judged by their inhibition of pentagastrin stimulated acid secretion in conscious dogs, in contrast to the bicyclic heteroaromatic-based compounds, which were ineffective because of biliary elimination. Increasing the hydrophilicity through replacement of a particular methylene group with an ether oxygen, as in 3-{[5-(adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]amino}benzoic acid (53), had little effect on the receptor affinity but significantly increased the oral potency. Comparison of the plasma pharmacokinetics and the inhibition of pentagastrin-stimulated acid output following bolus intraduodenal administration of both 53 and 6 indicated that 53 was well absorbed, had a longer half-life, and was not subject to the elimination pathways of the earlier series.

Pancreatic Response to Mild Non–Insulin-Induced Hypoglycemia Does Not Involve Extrinsic Neural Input

Mild non-insulin-induced hypoglycemia achieved by administration of a glycogen phosphorylase inhibitor results in increased glucagon and decreased insulin secretion in conscious dogs. Our aim was to determine whether the response of the endocrine pancreas to this mild hypoglycemia can occur in the absence of neural input to the pancreas. Seven dogs underwent surgical pancreatic denervation (PDN [study group]), and seven dogs underwent sham denervation (control [CON] group). Each study consisted of a 100-min equilibration period, a 40-min control period, and a 180-min test period. At the start of the test period, Bay R3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally. Arterial plasma glucose (mmol/l) fell to a similar minimum in CON (5.0 +/- 0.1) and PDN (4.9 +/- 0.3). Arterial plasma insulin also fell to similar minima in both groups (CON, 20 +/- 6 pmol/l; PDN, 14 +/- 5 pmol/l). Arterial plasma glucagon rose to a similar maximum in CON (73 +/- 8 ng/l) and PDN (72 +/- 9 ng/l). Insulin and glucagon secretion data support these plasma hormone results, and there were no significant differences in the responses in CON and PDN for any parameter. Pancreatic norepinephrine content in PDN was only 4% of that in CON, confirming successful sympathetic denervation. Pancreatic polypeptide levels tended to increase in CON and decrease in PDN in response to mild hypoglycemia, indicative of parasympathetic denervation. It thus can be concluded that the responses of alpha- and beta-cells to mild non-insulin-induced hypoglycemia can occur in the absence of extrinsic neural input.

The effect of calcitonin gene-related peptide on pancreatic blood flow and secretion in conscious dogs

The effects of human α-calcitonin gene-related peptide (α-CGRP) and β-CGRP on pancreatic arterial (PA), superior mesenteric (SMA) and left gastric arterial (LGA) blood flows were studied by ultrasound transit-time blood flow meters in five conscious dogs. Intravenous injections of α-CGRP and β-CGRP (5–200 pmol/kg) induced a dose-related increase in PA flow and a dose-related decrease in its resistance. At lower doses, α-CGRP was more potent than β-CGRP, but their maximal responses were similar. The blood flow responses to α-CGRP (200 pmol/kg) were 153% of the basal flow in LGA, 313% in PA, and 534% in SMA, while those to VIP (100 pmol/kg) were 467% in LGA, 953% in PA and 163% in SMA. Somatostatin reduced blood flow in all arteries. α-CGRP, but not β-CGRP, at higher doses induced gastric contractions and pancreatic protein-rich secretion, which were blocked by atropine. These results suggest that CGRP in perivascular nerves in the pancreas may regulate pancreatic blood flow in dogs but its physiological function remains to be studied.

Canine pancreatic juice stimulates the release of secretin and pancreatic secretion in the dog.

A secretin-releasing factor (SRF) was found in canine pancreatic juice that increases plasma secretin and stimulates pancreatic secretion in rats, suggesting that a positive feedback mechanism may be involved in the regulation of pancreatic secretion. In the present study, we investigated to determine whether or not SRF releases endogenous secretin and stimulates exocrine pancreatic secretion in conscious dogs. Fresh pancreatic juice was collected from four dogs by intravenous administration of secretin at 0.5 microg. kg(-1). h(-1) and CCK at 0.2 microg. kg(-1). h. The juice was boiled for 10 min at 100 degrees C. Experiments were carried out in phase I of spontaneous cycle of interdigestive pancreatic secretion. The testing solutions were infused intraduodenally in separate experiments: NaHCO3 solution (0.1 M, 4.5 ml/min, 60 min), a corn oil (Lipomul, 2 ml/min, 10 min), boiled pancreatic juice (BPJ, 4.5 ml/min, 60 min), and mixture of BPJ and Lipomul. Pancreatic secretion of fluid and bicarbonate was significantly increased by either BPJ or a mixture of BPJ and Lipomul (34- and 31-fold or 41- and 38-fold, respectively). Plasma secretin level also significantly increased by 164.7 +/- 13.4% and 223.1 +/- 35.0%, respectively, from basal concentration of 1.7 +/- 0.5 pM. In contrast, neither bicarbonate solution nor Lipomul influenced the plasma secretin level or pancreatic secretion. In addition, when Lipomul was incubated with BPJ, no fatty acid was produced. Thus the increased pancreatic secretion in the dog infused with a combination of BPJ and Lipomul was caused by SRF in BPJ, which released endogenous secretin. Moreover, the increases by BPJ of both plasma secretin level and bicarbonate secretion were completely blocked by intravenous administration of an antisecretin antibody in these dogs. The observations suggest that SRF in pancreatic juice exerts a positive feedback effect on exocrine pancreatic secretion that is mediated by the release of secretin in the interdigestive state in dogs.

The effect of VIP/PACAP family of peptides on pancreatic blood flow and secretion in conscious dogs

The effects of PACAP-38, PACAP-27, VIP and secretin on pancreatic blood flow were compared with those of meals in five conscious dogs using an ultrasound transit-time blood flow meter. All peptides (1–100 pmol/kg) induced dose-related increases of pancreatic blood flow, and fluid and bicarbonate secretion. Only PACAPs stimulated protein secretion. Both PACAPs at doses which did not stimulate pancreatic secretion, induced significant pancreatic vasodilatation. VIP was less potent than PACAP-38 and PACAP-27 at lower doses (1–25 pmol/kg), but was similar to PACAPs at higher doses. The maximal effects of PACAPs and VIP were comparable to those observed after meals. Secretin was a significant but weak vasodilator. When pancreatic secretion was maximally stimulated by secretin, a reduction of vascular resistance was 75% of postprandial peak levels. PACAP(6–38), a competitive antagonist of PACAP, inhibited pancreatic vascular responses to PACAPs, but not those to VIP and secretin. Its inhibitory effects on protein response to PACAPs were not significant. Atropine inhibited pancreatic protein but not the vascular effect of PACAP-27. Pancreatic vasodilatation by PACAPs appears to be mediated by both PACAP-specific and VIP/PACAP common receptors in dogs. PACAP, like VIP, is a good candidate for a mediator of atropine-resistant vasodilatation of the pancreas.

Influence of ammonia (NH4OH) and H. Pylori lipopolysaccharide (HP-LPS) on gastric secretion in conscious dogs and rats

Influence of ammonia (NH4OH) and H. Pylori lipopolysaccharide (HP-LPS) on gastric secretion in conscious dogs and rats

Central cholinergic regulation of pancreatic polypeptide secretion in conscious dogs.

The secretion of pancreatic polypeptide (PP) is regulated by fluctuations in blood glucose concentrations and food intake, in which vagal-cholinergic mechanisms play an important role, especially for the cephalic phase of PP secretion. In this study, we examined whether central cholinergic mechanisms are also important for PP secretion by relaying information in the brain to the vagus nerve and the muscarinic cholinergic receptors in the pancreas. Atropine sulfate (20-200 micrograms) was administered into the lateral cerebral ventricle and its effects on the basal secretion of PP as well as the secretions stimulated by insulin-induced hypoglycemia (Actrapid MC, 0.25 U/kg) and a mixed meal (243 kcal) were studied in seven dogs. Intralateral cerebroventricular (ILV) atropine (100 and 200 micrograms) abolished the fluctuations in basal PP secretion without appearing in the plasma. Pretreatment with 20, 100, and 200 micrograms ILV atropine significantly decreased the PP response to insulin-induced hypoglycemia, with the integrated PP response to 58, 32, and 26% of that of controls respectively. Atropine (100 micrograms ILV) significantly reduced the postprandial PP secretion in both the cephalic and the gastrointestinal phases, whereas increased insulin and glucose levels were unaffected. Centrally administered atropine was able to suppress the basal secretion of PP as well as the secretions stimulated by hypoglycemia and food intake. These findings suggest that (1) the spontaneous release of PP is governed by an oscillating, central cholinergic tone, and (2) the stimulating PP secretion is, at least in part, regulated by the central cholinergic system.

P-190 - Effects of loxiglumide (CR1505) on pancreatic exocrine secretion in conscious dogs.

P-190 - Effects of loxiglumide (CR1505) on pancreatic exocrine secretion in conscious dogs.

Colectomy suppresses pancreatic bicarbonate secretion in conscious dogs: [formula omitted], I. Sasaki, T. Tsuchiya, M. Takahashi, C. Shibata, N. Ohtani, S. Matsuno. 1st Dept. of Surgery, Tohoku University School of Medicine, Sendai, Japan

Colectomy suppresses pancreatic bicarbonate secretion in conscious dogs: [formula omitted], I. Sasaki, T. Tsuchiya, M. Takahashi, C. Shibata, N. Ohtani, S. Matsuno. 1st Dept. of Surgery, Tohoku University School of Medicine, Sendai, Japan

Antisecretory Effect of Leminoprazole on Histamine-Stimulated Gastric Acid Secretion in Dogs: Potent Local Effect

Leminoprazole, an acid pump inhibitor, significantly reduces basal and stimulated gastric acid secretion in rats when administered via the systemic or local route. Our aim here was to characterize the antisecretory effect of leminoprazole on gastric acid secretion in conscious dogs. Gastric acid secretion by dogs with a vagally denervated Heidenhain pouch was stimulated by intravenous histamine infusion. Leminoprazole or omeprazole (as a reference drug) was administered either intravenously or locally into the pouch before or after histamine infusion. A bolus intravenous administration of leminoprazole and omeprazole, respectively, significantly and dose-relatedly inhibited the stimulated gastric acid secretion for >26 hr. Local application of leminoprazole, but not omeprazole, significantly inhibited the acid secretion when applied for 15 to 30 min. The duration of the local antisecretory effect observed after 30 min application was around 8–10 hr. The acid-degraded products of leminoprazole had no effect when applied to the pouch. The blood concentration of leminoprazole was very low at 1 hr after local application. These results indicate that leminoprazole suppresses the secretory function of the parietal cells of dogs, via both the intravenous and local routes. It remains unknown whether or not locally applied leminoprazole produced the acid inhibition by inhibiting the acid pump.

Somatostatin inhibits secretin-induced canine pancreatic response via a cholinergic mechanism

Background: Somatostatin inhibits pancreatic exocrine secretion in intact animals but not in vitro, suggesting an indirect effect. The present study examined the influence of extrapancreatic nerves and intrapancreatic cholinergic activity on somatostatin-induced inhibition of pancreatic exocrine secretion in conscious dogs. Methods: Seven dogs underwent extrapancreatic denervation and creation of pancreatic fistulae, while a second group of 6 dogs had pancreatic fistulae created without denervation. The pancreatic responses to graded doses of secretin (16–500 ng · kg−1 · h−1), both alone and during background infusions of somatostatin-14 (400 and 800 pmol/L · kg−1 · hr−1), were determined in all dogs. The secretin dose response was then repeated with a continuous infusion of bethanechol (90 μg · kg−1 · h−1) both with and without somatatostatin-14 (800 pmol/L · kg−1 · h−1). Results: Secretin-induced bicarbonate and protein outputs were significantly inhibited by Somatostatin-14 in both the innervated and denervated animals. The inhibitory effects of Somatostatin-14 were partially reversed by bethanechol in the innervated animals and completely reversed in the denervated animals. Bethanechol alone potentiated secretin-induced bicarbonate output from both the innervated and denervated pancreas. Conclusions: The data suggest that extrapancreatic nerves do not mediate the inhibitory effects of somatostatin-14. Rather, Somatostatin-14 appears to inhibit secretin-induced pancreatic response by an intrapancreatic cholinergic mechanism.

The Inhibitory Effect of Octreotide on Exocrine Pancreatic Secretion in Conscious Dogs

The effects of somatostatin and its analogue, octreotide (SMS201-995), on pancreatic secretion and gastroduodenal motility in response to secretin and cholecystokinin octapeptide (CCK-8) were studied in five conscious dogs. Intravenous infusions of octreotide or somatostatin (1 nmol kg-1 h-1) inhibited periodic pancreatic secretion and the potentiation of fluid and bicarbonate responses to secretin at 60 ng kg-1 h-1 associated with the interdigestive gastroduodenal motility peaks (migrating motor complex). Pancreatic fluid and bicarbonate responses to secretin (125-1,000 ng kg-1 h-1) were not inhibited by octreotide or somatostatin. Pancreatic protein and enzyme responses to secretin and CCK-8 at 50 and 100, but not at 200 and 400, ng kg-1 h-1 were inhibited by octreotide and somatostatin. These inhibitory effects were similar to those of atropine (25 micrograms kg-1 h-1). The inhibition of protein responses to CCK-8 (100 ng kg-1 h-1) was dependent on octreotide dose. It is concluded that both octreotide and somatostatin, like atropine, inhibit interdigestive pancreatic secretion and the responses to small, but not large, doses of secretin and CCK-8 in conscious dogs.

Histamine H3 receptor-mediated inhibition of gastric acid secretion in conscious dogs

The effect of (R)alpha-methylhistamine (MH) and thioperamide (selective agonist and antagonist respectively of histamine H3 receptors) was examined in conscious gastric fistula dogs to investigate the role of histamine H3 receptors in the control of basal and stimulated gastric acid secretion. Intravenous infusion of MH at 0.3 and 0.6 mumol/kg/h caused a significant reduction of the 2-deoxy-D-glucose (2-DG)-stimulated acid output, maximal inhibition being 60%. The inhibitory effect of MH was counteracted by thioperamide (0.1 mumol/kg/h), which, by itself, did not modify the 2-DG-induced acid secretion. The increase in plasma gastrin levels induced by 2-DG was not significantly affected either by MH or by thioperamide. Under basal conditions MH (0.3 mumol/kg/h) did not induce any significant change in acid secretion and in plasma gastrin levels; by contrast, thioperamide (0.1 mumol/kg/h) produced a significant increase both in acid output and in plasma gastrin. These results suggest that activation of H3 receptors can exert a negative control in stimulated acid secretion in conscious dogs, when cholinergic pathways to acid secretion are activated by 2-DG; moreover, the slight, but significant, stimulatory effect of thioperamide on basal acid output and basal plasma gastrin may be suggestive for a tonic inhibitory role of H3 receptors in the regulation of basal acid secretion, however, a nonspecific effect of this drug cannot be excluded.

Gastrin-Releasing Peptide and Cholecystokinin in the Regulation of Exocrine Pancreatic Secretion in Dogs

Exocrine pancreatic secretion in conscious dogs is significantly stimulated by the intravenous application of small doses of gastrin-releasing peptide (GRP; 30 pmol x kg-1 x h-1). There is no increase of the GRP concentrations in peripheral blood which is also the case under physiological postprandial conditions. There is also no increase in the peripheral cholecystokinin (CCK) concentrations, in contrast to previous reports. Nevertheless other CCK-related mechanisms may play an important role, since the administration of the highly specific CCK receptor antagonist MK-329 causes a marked reduction of the GRP-induced exocrine pancreatic secretion.

Gastrin releasing peptide, but not pentagastrin, stimulates ACTH and cortisol secretion in conscious dogs

Gastrin releasing peptide (GRP) is the mammalian equivalent of bombesin. Bombesin has been shown to stimulate canine ACTH and cortisol secretion in a dose-related manner. In the present study, following a 30–40 min saline infusion, a progressively-increasing, stepwise infusion of GRP (60, 600, 1200 pmol/kg per h) or pentagastrin (PG) (2, 4, 8 μg/kg per h) was administered. Each drug dose was infused for 40–45 min and blood samples were drawn at 20–22.5 min intervals. GRP caused significant, dose-dependent increases in plasma ACTH ( 145 ± 6%, 242 ± 49%, 270 ± 78% of control) and cortisol ( 158 ± 16%, 218 ± 26%, 250 ± 62% of control). The dose of GRP required for a half-maximal cortisol response was 120 pmol/kg per h, while that for ACTH was 140 pmol/kg per h. PG had no effect on either ACTH or cortisol. While PG is apparently not involved in GRP/bombesin release of ACTH or cortisol, similar mechanisms of action for GRP and bombesin are suggested by their equimolar potencies.

Intracolonic Infusion of Bile Salt Stimulates Release of Peptide YY and Inhibits Cholecystokinin-Stimulated Pancreatic Exocrine Secretion in Conscious Dogs

The purpose of this study was to examine the effect of transanal (intracolonic) infusion of bile acid on release of peptide YY (PYY) and cholecystokinin (CCK)-stimulated pancreatic exocrine secretion in seven conscious dogs. CCK-8 (50 ng/kg/h) was given intravenously for 120 min and either taurocholic acid (TA, 1 or 2 mmol/h) or saline was infused transanally (150 ml/h) during the 0-60-min period of CCK infusion. Transanal infusion of TA (1 or 2 mmol/h) significantly inhibited output of CCK-8-stimulated pancreatic protein, compared to transanal infusion of saline during the first 60 min. On the average, the magnitude of inhibition was approximately 45%. Plasma concentrations of PYY increased significantly in response to intracolonic infusion of TA or saline. Transanal infusion of TA (1 or 2 mmol/h) significantly increased plasma levels of PYY when compared with transanal infusion of saline during the first 60 min. The magnitude of the increase of plasma PYY levels was approximately 50 pg/ml (p less than 0.05). Plasma levels of pancreatic polypeptide were not altered significantly by transanal infusion of TA. Our results suggest that release of endogenous PYY by TA in the colon plays a role in the inhibition of CCK-stimulated pancreatic exocrine secretion. Bile salts in the hindgut may participate in the physiologic regulation of pancreatic exocrine secretion by stimulation of release of ilealcolonic PYY.

Intra-Arterial versus Intravenous Administration of Gastric Secretory Inhibitors in Conscious Dogs

The purpose of the present study was to evaluate the effects of both intra-arterial and intravenous infusions of somatostatin, serotonin (5-hydroxytryptamine) and isoprenaline beta 1- + beta 2-adrenoceptor agonist) on gastric acid and pepsin secretion in conscious dogs with a gastric fistula. The drugs mentioned have been examined earlier for effects on gastric secretion in vivo during intravenous infusions and these effects could be hampered by the possible indirect mechanism of action as well as the different kinetics of metabolism. A catheter (vascular access port) allowed repeatedly gastric intra-arterial infusions. Somatostatin and serotonin possessed inhibitory effects on gastric acid and pepsin secretion and were without significant differences between the analyzed ways of administration. Intra-arterial infusion, isoprenaline possessed less potent inhibitory effects on gastric secretion: the effects were significant for pepsin secretion but were nonsignificant for acid secretion. The results suggest the mechanism of action of isoprenaline, somatostatin and sertonin to diverge, and for somatostatin and serotonin it was independent of the route of administration.

Stimulatory effect of pancreastatin on gastric acid secretion in conscious dogs

Pancreastatin, a new 49-amino acid peptide, has recently been isolated and characterized from extracts of the porcine pancreas. The objective of the present study was to examine the effect of various doses of pancreastatin on gastric acid secretion in conscious dogs that were prepared with chronic gastric cannulas. Pancreastatin, administered IV at 400 pmol · kg−1 · h−1, enhanced peptone meal [peptone (5%), phenylalanine (90 mmol/L), glucose (12 g/dL)]-stimulated gastric acid secretion by 50%; pancreastatin at 800 pmol · kg−1 · h−1 enhanced peptone meal secretion by 165% (P < 0.05). Intravenous administration of pancreastatin did not affect basal or peptone-stimulated release of gastrin. In addition, IV pancreastatin (400 pmol · kg−1 · h−1) failed to influence basal gastric acid secretion. Pancreastatin did not affect acid secretion stimulated by 2-deoxyglucose, histamine, or pentagastrin. The present study shows that pancreastatin can selectively enhance gastric acid secretion by a mechanism independent of cholinergic, histaminergic, or gastrin input.

Diurnal variations of cephalic exocrine pancreatic response in dogs.

The purpose of this study was to determine effects of oral stimulation of sucrose on the diurnal output of pancreatic secretion in conscious dogs. Male beagle dogs weighing 9-11 kg were prepared with gastric and duodenal fistulae. Once a day at 14:00 the animals were trained to eat a sufficient amount of a commercial stock diet to maintain their body weight. Gustatory receptors were stimulated at 9:00, 13:00, 15:00, and 18:00 for 5 min with 100 ml of 0.5% agar solutions containing 0.3 M sucrose. Pancreatic juice was collected every 5 min before and after stimulation, and volume flow and protein output were measured. As a result, we demonstrated daily fluctuations timed by feeding not only in the pancreatic basal secretions but also in pancreatic responses to the gustatory stimulation. These results suggest the significant role of taste stimuli in the nutrition of, at least digestion in, animals.