Acid Secretion In Conscious Dogs Research Articles

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.

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.

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.

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.

Peptide YY interacts with secretin and duodenal acidification to inhibit gastric acid secretion.

Previous studies have indicated that plasma levels of peptide YY (PYY) increase significantly after a meal. The purpose of this study was to characterize the interaction of PYY and secretin in the inhibition of gastric acid secretion, and to determine whether PYY can influence acid-induced inhibition of gastric acid secretion in conscious dogs. I.v. administration of PYY at 200 pmol/kg/h inhibited pentagastrin (1 microgram/kg/h)-stimulated gastric acid output (P less than 0.05). PYY further augmented i.v. secretin-induced inhibition of pentagastrin-stimulated gastric acid output by 32 +/- 7%, and intraduodenal hydrochloric acid-induced inhibition of pentagastrin-stimulated gastric acid output by 40 +/- 12%. The mean integrated release of secretin response to duodenal acidification (3.9 +/- 1.0 ng-[0-60] min/ml) was not affected by PYY (3.3 +/- 0.9 ng-[0-60] min/ml). The present study demonstrates that PYY can interact with secretin and duodenal acidification in an additive fashion to inhibit pentagastrin-stimulated gastric acid secretion. Our results suggest that several hormones that are released postprandially can interact with each other to inhibit gastric acid secretion.

Inhibition of gastric acid secretion by brain peptides in the dog: Role of the autonomic nervous system and gastrin

We have studied the effects of 30 peptides administered intracerebroventricularly on basal and pentagastrin-stimulated (8 μg/kg s.c.) gastric acid secretion in conscious dogs. None of the peptides significantly increased basal gastric acid secretion. Twelve peptides (2 nmol/kg) significantly (p < 0.01) decreased the pentagastrin-stimulated 2-h acid output (percentage inhibition in parentheses): human calcitonin (CT) (36%), neurotensin (NT) (52%), rat corticotropin-releasing factor (CRF) (59%), human calcitonin gene-related peptide (CGRP) (59%), ovine CRF (66%), β-endorphin (β-End) (80%), urotensin-I (81%), rat CT (81%), porcine gastrin-releasing peptide (GRP) (83%), sauvagine (Svg) (85%), rat CGRP (87%), and bombesin (Bom) (95%). Blockade of the autonomic nervous system with chlorisondamine abolished the gastric inhibitory action induced by CRF, β-End, CT, and NT, but not by CGRP and Bom (1 nmol/kg each). Corticotropin-releasing factor, βEnd, CT, NT, CGRP, and Bom significantly inhibited gastric acid secretion stimulated by an intragastric 8% peptone meal for 2 h. None of these six peptides significantly altered plasma gastrin concentrations in response to the peptone meal as compared with control experiments. A rise of plasma concentrations of gastrin, CT, CRF, and CGRP could not be detected by radioimmunoassay in animals after intracerebroventricular administration of these four peptides. The results of this study indicate that CT, CGRP, NT, β-End, and peptides of the CRF and Bom families act within the brain to inhibit pentagastrinand meal-stimulated gastric acid secretion in conscious dogs. None of the 30 peptides administered intracerebroventricularly increased basal gastric acid secretion in the dog. Inhibition of gastric acid secretion induced by CRF, β-End, CT, and NT, but not by CGRP and Bom is mediated by the autonomic nervous system. Gastrin does not appear to play a role in gastric acid inhibition induced by the six brain peptides studied.

Inhibition of gastric acid secretion by brain peptides in the dog

We have studied the effects of 30 peptides administered intracerebroventricularly on basal and pentagastrin-stimulated (8 pg/kg s.c.) gastric acid secretion in conscious dogs. None of the peptides significantly increased basal gastric acid secretion. Twelve peptides (2 nmollkg] significantly (p < 0.01) decreased the pentagastrin-stimulated 2-h acid output (percentage inhibition in parentheses): human calcitonin [CT) (36%], neurotensin (NT) (52%), rat corticotropin-releasing factor (CRF) (59%j, human calcitonin gene-related peptide (CGRP) (59%), ovine CRF (66%J, P-endorphin (P-End] (SO%], urotensin-I (81%), rat CT [81%), porcine gastrin-releasing peptide (GRP) (83%), sauvagine [Svg) (85%), rat CGRP (87%), and bombesin [Born) (95%). Blockade of the autonomic nervous system with chlorisondamine abolished the gastric inhibitory action induced by CRF, @End, CT, and NT, but not by CGRP and Born (1 nmollkg each). Corticotropin-releasing factor, pEnd, CT, NT, CGRP, and Born significantly inhibited gastric acid secretion stimulated by an intragastric 8% peptone meal for 2 h. None of these six peptides significantly altered plasma gastrin concentrations in response to the peptone meal as compared with

CNS actions of calcitonin gene-related peptide on gastric acid secretion in conscious dogs

To determine the mechanisms of action of calcitonin gene-related peptide (CGRP) in inhibiting gastric acid secretion, we studied awake male beagle dogs fitted with a chronic intracerebroventricular cannula and a gastric fistula. Synthetic rat CGRP (10 pmol/kg to 10 nmol/kg) given intracerebroventricularly or intravenously significantly inhibited pentagastrin-stimulated gastric acid secretion. CGRP (1 nmol/kg) given intracerebroventricularly decreased acid secretion stimulated by 2-deoxy-D-glucose but not by histamine. CGRP-(1-14), [Tyr23]CGRP-(23-37), and [acetamidomethyl-Cys2,7]CGRP, the linear peptide molecule devoid of the disulfide bridge, did not affect gastric secretion. Ganglionic blockade with chlorisondamine, a vasopressin antagonist, naloxone, and truncal vagotomy did not abolish the gastric inhibitory action of CGRP given intracerebroventricularly. CGRP administered intracerebroventricularly and intravenously decreased gastric acid secretion, but not plasma gastrin concentrations stimulated by an 8% peptone meal. It is concluded that CGRP given intracerebroventricularly or intravenously inhibits gastric acid secretion in conscious dogs; the intact molecule appears to be necessary for biological activity; and inhibition of gastric acid secretion by CGRP in the dog is not mediated by the autonomic nervous system or vasopressin-, opiate-, or gastrin-dependent pathways.

Corticotropin-releasing factor. Mechanisms to inhibit gastric acid secretion in conscious dogs.

Immunoreactivity similar to that of corticotropin-releasing factor (CRF) is found in regions of the central nervous system that modulate autonomic responses, including gastrointestinal functions. We examined the central nervous system effects of ovine CRF on gastric acid secretion in conscious dogs. Male beagle dogs (11-13 kg) were fitted with chronic intracerebroventricular cannulae and gastric fistulae. Gastric acid secretion in response to intravenously administered gastric secretory stimuli was measured by in vitro titration of gastric juice to pH 7.0 and in response to an intragastric meal by in vivo intragastric titration at pH 5.0. Plasma gastrin was determined by radioimmunoassay. CRF microinjected into the third cerebral ventricle decreased pentagastrin-stimulated gastric acid secretion for 3 h (P less than 0.01) dose-dependently (0.2-6.0 nmol X kg-1). CRF did not inhibit histamine-stimulated gastric secretion but significantly (P less than 0.01) decreased the secretory response after 2-deoxy-D-glucose for 3 h. The gastric inhibitory action of intracerebroventricularly administered CRF on pentagastrin-stimulated gastric acid secretion was completely abolished by ganglionic blockade with chlorisondamine. The opioid antagonist, naloxone, and the vasopressin antagonist, [1-deaminopenicillamine,2-(O-methyl) tyrosine,8-arginine]-vasopressin, significantly suppressed the inhibitory effect of CRF on gastric acid secretion stimulated by pentagastrin. In contrast, truncal vagotomy did not prevent the inhibition of gastric acid secretion induced by CRF. CRF (0.2-2.0 nmol X kg-1) administered intracerebroventricularly decreased gastric acid secretion stimulated by 200-ml liquid meals containing 8% peptone. CRF did not affect plasma gastrin concentrations. These results indicate that CRF microinjected into the third cerebral ventricle inhibits gastric acid secretion in conscious dogs. CRF-induced inhibition of gastric acid secretion appears to be mediated by the sympathetic nervous system and, in part, by opiate and vasopressin-dependent mechanisms.

Inhibition of gastric acid secretion in the conscious dog by the mast-cell stabilizing agent, FPL 52694.

The effects of the mast-cell stabilizing agent, FPL 52694, on gastric acid secretion in conscious dogs with gastric fistulae have been studied. FPL 52694 (5 or 10 mg kg-1 h-1) given intravenously during a plateau response to pentagastrin stimulation (2 micrograms kg-1 h-1) caused a maximum inhibition of acid output of about 50% but had no significant effect on volume output so that the [H+] in the juice was markedly reduced. The ratio of mucosal blood flow/acid output (Ra) was increased in the presence of FPL 52694. There was no maintained reduction of [H+] when inhibition was due to cimetidine (4 mumol kg-1, i.v.). Instillation of FPL 52694 (4.35 mg ml-1) directly into the stomach via the fistula for 30 min also resulted in an inhibition of acid output and reduction of [H+] during both pentagastrin-(2 micrograms kg-1 h-1) and histamine-stimulated (30 micrograms kg-1 h-1) secretion. Inhibition of pentagastrin-stimulated acid output by intragastric administration of FPL 52694 was much greater than the maximum effect seen following intravenous infusion. The results are discussed in relation to the possible mode of action of FPL 52694. It is concluded that FPL 52694 is active orally and has a novel action on acid secretion which may include stimulation of gastric bicarbonate secretion.

Comparison of Amino Acids Bathing the Oxyntic Gland Area in the Stimulation of Gastric Secretion

This study was undertaken to compare the ability of L- and D-isomers of amino acids bathing the oxyntic gland area to stimulate acid secretion in conscious dogs with Heidenhain pouch (HP), gastric fistula (GF) and pancreatic fistula (PF). Acid outputs from HP were determined by an intragastric titration method when amino acid solutions were perfused into HP at various concentrations, pH values, and distention pressures. Only L-isomers of all natural amino acids were found to stimulate acid secretion, whereas D-isomers of amino acids tested were completely inert in this respect. The comparison of the secretagogue activity of amino acids shows that L-histidine among essential amino acids and glycine among nonessential amino acids exhibited the strongest stimulation of acid outputs, reaching, respectively, 52 and 40% of the maximal response to histamine. Decreasing the pH of L-histidine solution perfused into HP in sequential order from 5.0 to 1.0 resulted in a stepwise reduction of acid output, falling at pH 1.0 to about 40% of the peak response achieved at pH 5.0. Local irrigation of HP by 2% xylocaine and intravenous infusion of atropine (100 mug per kg per hr) or metiamide (2.9 mg per kg per hr) reduced but did not abolish HP response to chemical stimulation and the pH dependency of this response. We conclude that only L- and not D-isomers of amino acids bathing the oxyntic gland area stimulate acid secretion by a local, gastrin-independent mechanism sensitive to distention pressure and pH.

Gastric mucosal blood flow and acid secretion in conscious animals measured by heat clearance.

The heat-clearance technic has been used to assess the effect of histamine, gastrin pentapeptide, antihistamine, and vasopressin on gastric mucosal blood flow and acid secretion in conscious dogs before and after vagotomy. The results suggest that: 1. Mucosal flow is increased with an increase in acid output, but the two processes do not always increase in parallel. At submaximal stimulation secretion can increase without a further rise in mucosal flow. 2. An increase in flow does not necessarily cause an increase in acid output. 3. If flow is decreased sufficiently then basal or stimulated acid secretion cannot continue. 4. Vagotomy has no long-term effect on the ability of the gastric mucosal vasculature to respond to vasoactive agents.