Pentagastrin Infusion Research Articles

Modeling the development of panic disorder with interoceptive conditioning

Panic disorder is characterized by the paroxysmal occurrence and fear of bodily symptoms. In recent years it has been proposed that patients “learn” to fear cardiorespiratory sensations through interoceptive conditioning. This study sought to model the initial stage of this process in healthy volunteers (N=44) using mild cardiac sensations. An additional aim was to explore whether anxiety sensitivity – a known risk factor for panic disorder – modulates such interoceptive learning. Infusions of pentagastrin and saline were used to manipulate the presence versus absence of cardiac sensations, respectively, and served as conditioned stimuli in a differential interoceptive conditioning paradigm. Inhalation of 35% CO2-enriched air served as the panicogenic, unconditioned stimulus (UCS). In half of the participants (“prepared” condition), cardiac sensations caused by pentagastrin were followed by inhalation of CO2-enriched air (penta CS+), whereas the absence of such sensations (saline) was followed by room air (saline CS−). The reversed combination (“unprepared” condition) was used in the other half of the participants. Conditioning effects showed up for self-reported UCS-expectancy, but not for skin conductance and anxiety ratings. Only participants from the prepared group learned to expect the UCS, and differential learning was impaired with higher scores on anxiety sensitivity. Expectancy learning was more easily established towards the presence compared to the absence of cardiac sensations, whereas the reverse effect was observed for safety learning. Modeling impaired discriminatory learning and the moderating effect of anxiety sensitivity provides new insight in the development of panic disorder.

FFA2 activation suppresses gastric acid secretion via 5‐HT 3 receptor activation in rats in vivo

The observation that exogenous 5-HT inhibits stimulated gastric acid secretion (GAS) implicates endogenous, locally released 5-HT in the regulation of GAS. We have reported that the short-chain fatty acid (SCFA) receptor FFA2 (GRP43) is expressed in duodenal 5-HT containing enterochromaffin (EC) cells. We thus hypothesized that FFA2 activation alters gastric acid secretion (GAS) via 5-HT release. We measured GAS in the perfused stomach in vivo using back-titration and flow-through pH and CO2 electrodes, with or without luminal application of the selective FFA2 agonist phenylacetamide-1 (PA1), followed by IV pentagastrin infusion. Immunostaining localized FFA2 to 5-HT-positive fundic EC cells. Luminal perfusion of PA1 reduced basal and pentagastrin-induced GAS, without changing the rate of HCO3- secretion. The PA1-associated reductions of GAS were significantly reversed by the IV injection of the 5-HT3 antagonist ondansetron, whereas atropine, the 5-HT1/5-HT2 antagonist pizotifen, or a somatostatin receptor antagonist cyclosomatostatin had no effect. These results suggest that FFA2 activation suppresses GAS via 5-HT3 activation, unmasking a previously undescribed GAS regulatory system. The presence of the SCFA receptor FFA2 in gastric EC cells implicate ingested or microbially-produced SCFA in the genesis of 5-HT3-related functional dyspepsia symptoms. Supported by VA Merit Review, NIH R01 DK54221

Gastric secretion does not affect the reliability of the13C-acetate breath test: A validation of the13C-acetate breath test by magnetic resonance imaging

(13)C-Acetate labeled meals are widely used to determine meal emptying by means of analyzing resulting (13)CO(2) exhalation dynamics. In contrast to the underlying metabolic processes, only few (13)C breath test meal emptying studies have focused on intragastric processes that may alter (13)CO(2) exhalation. This work assessed the effect of enhanced gastric secretion on the reliability of half emptying time (t50) measurements by (13)C-acetate breath test. (13)CO(2) exhalation data were acquired in a double-blind, randomized, cross-over gastric emptying study in 12 healthy volunteers receiving either pentagastrin or placebo intravenously. The standard method proposed by Ghoos et al. was applied to calculate t50 (t50_Ghoos) from (13)CO(2) exhalation data, which were compared and tested for agreement to meal half emptying times (t50_MV) from concurrent recorded MRI (magnetic resonance imaging) volume data. In addition, the accumulated gastric secretion volumes during infusion as detected by MRI (AUC_SV(60)) were correlated with the corresponding cumulative percent (13)C doses recovered (cPDR(60)). t50_Ghoos and t50_MV showed a linear correlation with a slope of 1.1 ± 0.3 (r(2) = 0.67), however, a positive offset of 136 min for t50_Ghoos. No correlation was detected between AUC_SV(60) and cPDR(60) (r(2) = 0.11). Both, breath test and MRI, revealed a prolonged t50 under pentagastrin infusion with median differences in t50_Ghoos of 45[28-84] min (P = 0.002) and t50_MV of 39[28-52] min (P = 0.002). This study suggests that (13)CO(2) exhalation after ingestion of a (13) C-labeled liquid test meal is not affected by stimulated gastric secretion, but is rather reflecting the dynamics of meal or caloric emptying from the stomach.

The role of the lateral amygdala in the retrieval and maintenance of fear-memories formed by repeated probabilistic reinforcement.

The lateral nucleus of the amygdala (LA) is a key element in the neural circuit subserving Pavlovian fear-conditioning, an animal model of fear and anxiety. Most studies have focused on the role of the LA in fear acquisition and extinction, i.e., how neural plasticity results from changing contingencies between a neutral conditioned stimulus (CS) (e.g., a tone) and an aversive unconditioned stimulus (US) (e.g., a shock). However, outside of the lab, fear-memories are often the result of repeated and unpredictable experiences. Examples include domestic violence, child abuse or combat. To better understand the role of the LA in the expression of fear resulting from repeated and uncertain reinforcement, rats experienced a 30% partial reinforcement (PR) fear-conditioning schedule four days a week for four weeks. Rats reached asymptotic levels of conditioned-fear expression after the first week. We then manipulated LA activity with drug (or vehicle) (VEH) infusions once a week, for the next three weeks, before the training session. LA infusions of muscimol (MUSC), a GABA-A agonist that inhibits neural activity, reduced CS evoked fear-behavior to pre-conditioning levels. LA infusions of pentagastrin (PENT), a cholecystokinin-2 (CCK) agonist that increases neural excitability, resulted in CS-evoked fear-behavior that continued past the offset of the CS. This suggests that neural activity in the LA is required for the retrieval of fear memories that stem from repeated and uncertain reinforcement, and that CCK signaling in the LA plays a role in the recovery from fear after the removal of the fear-evoking stimulus.

Inhibition of dimaprit- and pentagastrin-induced gastric acid secretion in cats by the new histamine H2 antagonist, CM 57755.

The antisecretory effects of CM 57755, a new histamine-H2 receptor antagonist, have been compared with those of cimetidine on gastric acid secretion induced by intravenous infusions of dimaprit or pentagastrin into conscious cats with chronically implanted gastric fistulae. Intravenous infusion of CM 57755 induced a parallel shift to the right of the dimaprit dose-response curve. The potency of CM 57755 was comparable with that of cimetidine as shown by similar doses causing a 5-fold displacement to the right of the dimaprit dose-response curve (4.9 mumol kg-1 h-1 for CM 57755 and 4.7 mumol kg-1 h-1 for cimetidine). Unlike that with dimaprit, the acid secretion stimulated by increasing doses of pentagastrin was inhibited by CM 57755 with depression of the maximal effect, indicating non-competitive antagonism. In a second series of experiments the time course of the anti-secretory action of intragastrically administered CM 57755 was studied from the gastric acid secretion induced by constant infusion of dimaprit. At equieffective doses, CM 57755 caused more sustained inhibition than cimetidine.

Adaptation of the Secretion of Gastric Acid and Gastric Inhibitory Peptide in Response to Propylthiouracil

The purpose of this study was designed to investigate the effects of the intravenous (IV) infusion of propylthiouracil (PTU) on basal and pentagastrin-stimulated gastric acid secretion (GAS), as well as plasma concentrations of gastric inhibitory polypeptide (GIP), and calcium (Ca(superscript 2+)). The polyethylene (PE) tubes were inserted into the esophagus, pylorus, right femoral and jugular veins as luminal and vascular exits respectively in adult male rats. Basal GAS was collected for 45 min before IV infusion of alkaline saline (2 ml/h, control group) or PTU (20 mg/ml/ 300 g BW, experimental group) for 45 min. Infusion of pentagastrin (8 μg/ml/300 g BW) was added for 90 min following infusion of alkaline saline or PTU for an additional 45 min. IV infusion of PTU increased the concentrations of plasma thyroid-stimulating hormone (TSH) and GIP but decreased the level of plasma Ca(superscript 2+) in male rats. Neither the basal nor the pentagastrin-evoked levels of gastric acid secretion were altered by the IV infusion of PTU. These results suggested that the unchanged gastric acid secretion in male rats after IV administration of PTU was at least in part due to an adaption of gastric acid secretion to PTU caused by increased release of GIP and decreased level of plasma calcium.

Stimulatory effect of pentagastrin on growth hormone and prolactin secretion in normal subjects.

Gastrin-like immunoreactive substances have been reported as occurring in both digestive tract tissues and nervous system, including the hypothalamus and the anterior and posterior pituitary. The carboxyterminal tetrapeptide shared by gastrin and cholecystokinin, which represents the bioactive site of both hormones, has been shown to be a secretagogue for insulin and glucagon and it might have a neurotrasmitter function. As small gastrin-like peptides may also play a role in the regulation of anterior pituitary hormones, the present study deals with the in vivo effect of pentagastrin on the release of growth hormone (GH) and prolactin (PRL). Six healthy volunteer males and six healthy volunteer females were studied. All females subjects were in the early follicular phase of the normal menstrual cycle and all subjects were not taking or had been taking any drug known to affect GH or PRL secretion. A continuous intravenous infusion of pentagastrin (1.5 micrograms/kg/h) was administered to all the subjects for a time of 3 hours. In males pentagastrin infusion resulted in a significant increase in GH concentration from basal values (P less than 0.01 at 60 min). In females pentagastrin infusion did not affect GH levels. PRL levels were not affected at all by intravenous pentagastrin infusion both in males and females. The exact understanding of pentagastrin action on GH release awaits further investigation. The different pattern between male and female subjects suggests a sexual hormone influence on the hypothalamic-pituitary sites of action of pentagastrin in vivo. Our data did not confirm a stimulatory effect of pentagastrin on PRL secretion in normal subjects.

The effect of gastric secretion on gastric physiology and emptying in the fasted and fed state assessed by magnetic resonance imaging

Conventional measurement of gastric secretion is invasive and cannot assess the intra-gastric distribution of gastric contents or the effects of secretion on gastric function. This study assessed the effect of gastric secretion on gastric volume responses and emptying (GE) using a validated fast T(1) mapping magnetic resonance imaging (MRI) technique. Twelve healthy participants were studied in the fasted state and after 200 kcal Gadolinium-DOTA labelled glucose meal during intravenous infusion of pentagastrin or placebo in double-blind, randomized order. Total gastric volume (TGV) and gastric content volume (GCV) was assessed by MRI volume scans and secretion by fast T(1) mapping. Data was described by the kappa-coefficient (volume change after meal ingestion), by GE half time (T(50)) and maximal GE rate (GER(max)) derived all from a GE model. Pentagastrin increased GCV and TGV compared to placebo [kappa(GCV):1.6 +/- 0.1 vs 0.6 +/- 0.1; kappa(TGV): 1.6 +/- 0.1 vs 0.7 +/- 0.1; P < 0.001]. T(1) maps revealed a secretion layer above the meal, the volume of which was associated with kappa (R(2) = 83%, P < 0.001). TGV and GCV change were similar in both conditions (kappa; P = ns). T(50) was higher for pentagastrin than for placebo (84 +/- 7 vs 56 +/- 4min, P < 0.001); however, GER(max) was similar (5.9 +/- 0.6 vs 4.9 +/- 0.4 mL min(-1), P = ns). This study shows volume and distribution of gastric secretion can be quantified in-vivo by non-invasive MRI T(1) mapping. Increased GCV drove TGV accommodation without evidence of a direct effect of pentagastrin or excess acid on gastric function. Secretion increases GCV thus prolongs GE as assessed by T(50); however, GE rate is unchanged.

PERIPHERAL DOPAMINE D2‐LIKE RECEPTORS HAVE A REGULATORY EFFECT ON CARBACHOL‐, HISTAMINE‐ AND PENTAGASTRIN‐STIMULATED GASTRIC ACID SECRETION

It has been documented that dopamine, an important regulator of gastric function in the brain-gut axis, has an inhibitory effect on the gastric acid secretion. It has also been suggested that dopamine D1, D2 and D5 receptor proteins are present in the gastrointestinal tract from the stomach through to the distal colon. Therefore, we hypothesized that peripheral D2 receptors may be involved in the control of stimulated gastric acid secretion. To address this question, we examined the effect of quinpirole, a selective D2 receptor-like agonist, and domperidone, a peripheral D2 receptor antagonist, on rat gastric acid secretion. Quinpirole (0.0001-0.5 mg/kg, i.p.) was administered simultaneously with intravenous infusions of histamine, pentagastrin, and carbachol. In some experiments, domperidone (3 and 7 mg/kg) was administered 30 min before quinpirole injection. We found that intraperitoneal injection of quinpirole (0.0001-0.5 mg/kg) suppressed stimulated gastric acid secretion induced by histamine (0.08 mg/100 g per h), pentagastrin (1 microg/100 g per h) and carbachol (4 microg/100 g per h) in a dose-dependent manner. This inhibitory effect of quinpirole persisted until the end of the experiments (90-120 min) and was completely suppressed by domperidone (7 mg/kg). In conclusion, the results of the present study suggest that peripheral D2-like receptors have an inhibitory effect on histaminergic-, pentagastrin- and cholinergic-stimulated gastric acid secretion. This inhibitory effect may be mediated by enteric dopaminergic neurons and/or non-neuronal membranes.

Effects of Perceived Control and Cognitive Coping on Endocrine Stress Responses to Pharmacological Activation

The hypothalamic-pituitary-adrenal (HPA) axis may mediate negative health effects of stress. It is sensitive to cognitive/emotional factors like novelty, perceived control, and coping. Psychological intervention that reduces novelty and enhances cognitive coping and sense of control can reduce cortisol responses to pentagastrin, a pharmacological HPA activator. This study attempted to identify the core factors that modulate HPA axis activity in this model. Varying instructions were administered prior to drug exposure in a two-visit (placebo first) pentagastrin infusion paradigm. Healthy subjects (n = 40) were randomly assigned to one of four instruction groups: 1) standard instruction (SI); 2) full cognitive intervention (CI); 3) the CI control component alone; or 4) the CI novelty reduction/coping components alone. Blood samples were obtained via intravenous catheter before and after pentagastrin. Subjects receiving an intervention had smaller cortisol responses than subjects receiving standard instructions. Coping alone had as strong an impact as the more complex intervention that combined coping and control. Control alone also reduced cortisol but its HPA impact appeared less robust. Brief psychological manipulation can significantly reduce HPA activation in challenge paradigms. Cognitive preparation that focused on side effects, reduced potential surprise, and enhanced cognitive coping modulated HPA axis activity as effectively as a previously tested intervention that combined coping and control manipulations. A sense of control alone also reduced cortisol release. The results support development of control or coping techniques to combat negative health effects of stress that are mediated by HPA axis activation.

Pentagastrin‐induced nitric oxide‐dependent protein secretion from the parotid gland of the anaesthetized rat

Infusion of pentagastrin (20 microg kg(-1) h(-1), i.v.) for 10 min evokes protein output but no overt fluid secretion from the parotid gland of the rat, as revealed by increased protein concentration in a subsequent wash-out flow of saliva in response to a bolus injection of methacholine (5 microg kg(-1), i.v.) 10 min later. Using this experimental set-up, the contribution of nitric oxide (NO) generation to the protein and amylase response evoked by pentagastrin was investigated. Neither the neuronal type NO synthase inhibitor N(omega)-propyl-L-arginine (N-PLA; 30 mg kg(-1), i.v.) nor the non-selective NO synthase inhibitor L-NAME (30 mg kg(-1), i.v.) as such affected the methacholine-evoked volume response or the outputs of protein and amylase. However, when preceeded by the pentagastrin infusion, the expected increases in concentrations of protein (145%) and amylase activity (127%) of the methacholine-evoked response (compared to a pre-infusion methacholine response) were reduced to 68 and 74%, respectively, in the presence of N-PLA, and to 70 and 63%, respectively, in the presence of L-NAME. Thus, NO generation resulting from the activity of the neuronal type NO synthase, most probably of parenchymal origin, plays an important role in the pentagastrin-induced protein and amylase secretion of the rat parotid gland.

Heterophilic antibodies causing falsely high serum calcitonin values

Heterophilic antibodies (HA) may interfere in some immunoassays, causing falsely high hormone values, of which practitioners should be aware when measuring calcitonin (CT) used as tumor marker for medullary thyroid carcinoma (MTC). We studied four patients with thyroid nodules, three of whom underwent surgical neck exploration, after an erroneous diagnosis of MTC because of falsely high serum CT eventually proved to be due to HA. One patient had a lingual thyroid, two autoimmune thyroiditis and the fourth a colloid goiter. The minimal incremental CT response to calcium infusion raised our suspicion of possible false high CT values due to HA. There was no linearity of the CT values obtained by testing serial dilutions of the sera in the CT assay, which employs two monoclonal mouse anti-CT antibodies. Addition of normal mouse gamma globulin eliminated the interference by HA in the sera of two patients. Serum assayed in a polyclonal radioimmunoassay using goat anti-CT antibodies gave normal CT values. Finally, incubation of the sera in Heterophilic Blocking Tubes (HBT) eliminated the false CT immunoreactivity. A spontaneous change of the CT serum concentrations was noticed in three patients over several months, apparently due to changing titles of HA. We suggest that, in patients a) whose CT response to calcium or pentagastrin infusion is minimal despite high basal CT values, b) with autoimmune thyroiditis and c) in whom an unexpected change in serum CT concentrations occurs, the possibility of spuriously high CT values because of circulating HA should be considered.

Pentagastrin-induced protein synthesis in the parotid gland of the anaesthetized rat, and its dependence on CCK-A and -B receptors and nitric oxide generation

In parotid glands of pentobarbitone-anaesthetized rats, the incorporation of [3H]leucine into trichloroacetic acid-insoluble materials, reflecting protein synthesis, increased by 17% (compared to saline-treated rats) in response to infusion of pentagastrin (20 microg kg(-1), i.v. for 1 h) under muscarinic and alpha- and beta-adrenoceptor blockade. Both the CCK-A receptor antagonist lorglumide (48 mg kg(-1), i.v.) and the CCK-B receptor antagonist itriglumide (5.5 mg kg(-1), i.v.), given separately, prevented the expected increase in pentagastrin and, in addition, reduced the glandular protein synthesis by 16 and 12%, respectively, below the level of saline-treated rats. In rats treated with saline only, the glandular protein synthesis was reduced by 22% by the CCK-A receptor antagonist and by 17% by the CCK-B receptor antagonist; combined, the two antagonists caused no further reduction (20%). There was no increase in the glandular protein synthesis of pentagastrin-treated rats compared to that of the saline-treated rats when both groups of rats were exposed to a combination of the two types of CCK receptor antagonists. In pentagastrin-treated rats, the protein synthesis in the parotid glands was 23% less in the presence of the non-selective nitric oxide (NO) synthase inhibitor L-NAME (30 mg kg(-1), i.v.) than in its absence; the result was the same (23%) when the neuronal NO synthase inhibitor Nomega-propyl-L-arginine (N-PLA; 30 mg kg(-1), i.v.) replaced L-NAME. The protein synthesis in rats treated with saline only was not reduced by L-NAME; nor was the protein synthesis of saline-treated rats different from that of pentagastrin- and L-NAME-treated rats. Thus, under 'basal' conditions, a portion of the glandular protein synthesis, as well as the whole increase in synthesis in response to administration of pentagastrin, engaged both types of CCK receptors. Furthermore, NO generation, owing to neuronal NO synthase activity, was required for the increase to occur in response to pentagastrin, whereas a non-NO-dependent pathway was responsible for the protein synthesis under 'basal' conditions.

Cholecystokinin- and gastrin-induced protein and amylase secretion from the parotid gland of the anaesthetized rat

I.V. infusion of pentagastrin (20 μg/kg/h) or cholecystokinin (CCK)-8 (1 μg/kg/h) for 10 min caused secretion of salivary proteins from the parotid gland in the anaesthetized rat without any accompanying overt fluid secretion. This “occult” response was revealed by a subsequent wash-out injection of methacholine (5 μg/kg, I.V.) 10 min after the end of the infusion period (aiming at avoiding synergistic interactions). While the fluid response to methacholine was unaffected by the preceding infusion of pentagastrin and CCK-8, the output of protein increased by 147% (pentagastrin) and 74% (CCK-8) and that of amylase by 45% (CCK-8) compared to the responses to methacholine upon saline infusion. Those increases were abolished by the CCK-A receptor blocker (lorglumide), but not by the CCK-B receptor blocker (itriglumide). Evisceration, combined sympathetic and parasympathetic denervation of the glands and assay under adrenoceptor blockade excluded contribution from the gastro-intestinal tract, central or ganglionic mechanisms and circulating catecholamines to the increase in protein/amylase. Furthermore, Western blot demonstrated CCK receptors for both A and B subtypes in normal and chronically denervated glands. In the submandibular gland, both pentagastrin and CCK-8 evoked a trace secretion of saliva but, under the present experimental set-up, no statistically significant increase in protein output. Thus, in addition to the autonomic nervous system, gastrointestinal hormones may, in some types of glands, be involved in the secretion of salivary gland proteins.

Inhibition of Pentagastrin-Stimulated Gastric Acid Secretion by Pantoprazole and Omeprazole in Healthy Adults

Our objective was to compare the onset and duration of a single dose of pantoprazole or omeprazole on maximally stimulated gastric acid secretion. This double-blind, randomized, placebo-controlled study involved 36 healthy adults and utilized continuous pentagastrin infusion to stimulate acid secretion after administration of pantoprazole, 40 mg, omeprazole, 20 mg, or placebo. Gastric aspirates were collected over 24 hr and analyzed for volume, pH, and hydrogen ion concentration, and gastric acid outputs (GAO) were calculated. Comparison between GAO and intragastric pH was performed. Pantoprazole resulted in significantly greater inhibition of GAO than omeprazole. Mean cumulative 24-hr GAO was 164 +/- 130 mEq for pantoprazole versus 283 +/- 159 mEq for omeprazole (P = 0.031). Pantoprazole patients reached and maintained GAO levels below the 10-mEq/hr threshold at 5.7 hr, whereas omeprazole patients never reached this threshold. We conclude that pantoprazole significantly suppressed gastric acid secretion compared to omeprazole. Comparisons between pH and GAO showed that GAO was a more appropriate measure of gastric acid secretion than intragastric pH.

Stimulatory effect of endogenous orexin A on gastric emptying and acid secretion independent of gastrin

Orexin A (OXA) increases food intake and inhibits fasting small bowel motility in rats. The aim of this study was to examine the effect of exogenous OXA and endogenous OXA on gastric emptying, acid secretion, glucose metabolism and distribution of orexin immunoreactivity in the stomach. Rats equipped with a gastric fistula were subjected to intravenous (IV) infusion of OXA or the selective orexin-1 receptor (OX1R) antagonist SB-334867-A during saline or pentagastrin infusion. Gastric emptying was studied with a liquid non-nutrient or nutrient, using 51Cr as radioactive marker. Gastric retention was measured after a 20-min infusion of OXA or SB-334867-A. Plasma concentrations of OXA, insulin, glucagon, glucose and gastrin were studied. Immunohistochemistry against OXA, OX1R and gastrin in gastric tissue was performed. OXA alone had no effect on either acid secretion or gastric emptying. SB-334867-A inhibited both basal and pentagastrin-induced gastric acid secretion and increased gastric retention of the liquid nutrient, but not PEG 4000. Plasma gastrin levels were unchanged by IV OXA or SB-334867-A. Plasma OXA levels decreased after intake of the nutrient meal and infusion of the OX1R antagonist. Only weak effects were seen on plasma glucose and insulin by OXA. Immunoreactivity to OXA and OX1R were found in the mucosa, myenteric cells bodies and varicose nerve fibers in ganglia and circular muscle of the stomach. In conclusion, endogenous OXA influences gastric emptying of a nutrient liquid and gastric acid secretion independent of gastrin. This indicates a role for endogenous OXA, not only in metabolic homeostasis, but also in the pre-absorptive processing of nutrients in the gut.

Effect of peripherally administered ghrelin on gastric emptying and acid secretion in the rat

Ghrelin is a gut peptide that is secreted from the stomach and stimulates food intake. There are ghrelin receptors throughout the gut and intracerebroventricular ghrelin has been shown to increase gastric acid secretion. The aim of the present study was to examine the effects of peripherally administered ghrelin on gastric emptying of a non-nutrient and nutrient liquid, as well as, basal and pentagastrin-stimulated gastric acid secretion in awake rats. In addition, gastric contractility was studied in vitro. Rats equipped with a gastric fistula were subjected to an intravenous infusion of ghrelin (10–500 pmol kg − 1 min − 1 ) during saline or pentagastrin (90 pmol kg − 1 min − 1 ) infusion. After administration of polyethylene glycol (PEG) 4000 with 51Cr as radioactive marker, or a liquid nutrient with 51Cr, gastric retention was measured after a 20-min infusion of ghrelin (500 pmol kg − 1 min − 1 ). In vitro isometric contractions of segments of rat gastric fundus were studied (10 − 9 to 10 − 6 M). Ghrelin had no effect on basal acid secretion, but at 500 pmol kg − 1 min − 1 ghrelin significantly decreased pentagastrin-stimulated acid secretion. Ghrelin had no effect on gastric emptying of the nutrient liquid, but significantly increased gastric emptying of the non-nutrient liquid. Ghrelin contracted fundus muscle strips dose-dependently (pD 2 of 6.93 ± 0.7). Ghrelin IV decreased plasma orexin A concentrations and increased plasma somatostatin concentrations. Plasma gastrin concentrations were unchanged during ghrelin infusion. Thus, ghrelin seems to not only effect food intake but also gastric motor and secretory function indicating a multifunctional role for ghrelin in energy homeostasis.

Dual action of prostaglandin E2 on gastric acid secretion through different EP-receptor subtypes in the rat

We examined the role of prostaglandin E (EP) receptor subtypes in the regulation of gastric acid secretion in the rat. Under urethane anesthesia, the stomach was superfused with saline, and the acid secretion was determined at pH 7.0 by adding 50 mM NaOH. The acid secretion was stimulated by intravenous infusion of histamine or pentagastrin. Various EP agonists were administered intravenously, whereas EP antagonists were given subcutaneously 30 min or intravenously 10 min before EP agonists. PGE(2) suppressed the acid secretion stimulated by either histamine or pentagastrin in a dose-dependent manner. The acid inhibitory effect of PGE(2) was mimicked by sulprostone (EP(1)/EP(3) agonist) but not butaprost (EP(2) agonist) or AE1-329 (EP(4) agonist). The inhibitory effect of sulprostone, which was not affected by ONO-8711 (EP(1) antagonist), was more potent against pentagastrin- (50% inhibition dose: 3.6 mug/kg) than histamine-stimulated acid secretion (50% inhibition dose: 18.0 mug/kg). Pentagastrin increased the luminal release of histamine, and this response was also inhibited by sulprostone. On the other hand, AE1-329 (EP(4) agonist) stimulated the acid secretion in vagotomized animals with a significant increase in luminal histamine. This effect of AE1-329 was totally abolished by cimetidine as well as AE3-208 (EP(4) antagonist). These results suggest that PGE(2) has a dual effect on acid secretion: inhibition mediated by EP(3) receptors and stimulation through EP(4) receptors. The former effect may be brought about by suppression at both parietal and enterochromaffin-like cells, whereas the latter effect may be mediated by histamine released from enterochromaffin-like cells.

Effect of Dietary Corn Oil Supplementation on Equine Gastric Fluid Acid, Sodium, and Prostaglandin E2Content before and during Pentagastrin Infusion

The effect of corn oil (approximately 60% [wt/vol] linoleic acid) dietary supplementation on various components of equine gastric secretion was studied by use of a repeated‐measures experimental design. Four healthy adult ponies were surgically fitted with gastric cannulas. The ponies were then fed a free‐choice hay diet for 5 weeks, which was followed by 5 weeks of the same diet supplemented with 45 mL of corn oil daily. Gastric contents were analyzed under basal and pentagastrin‐stimulated conditions once weekly during the latter 2 weeks on each diet. Gastric contents were collected at 30‐minute intervals, and volume, hydrogen ion concentration, sodium content, and prostaglandin E2(PGE2) content were measured. Data were analyzed by a linear fixed‐effect modeling procedure. During the diet supplemented with corn oil, the ponies had, under basal and pentagastrin‐stimulated conditions, significantly decreased acid output and significantly increased PGE2and sodium outputs compared to those measured before corn oil supplementation. We conclude that corn oil supplementation may be an effective and inexpensive way to increase the protective properties of equine glandular gastric mucosa. This could be particularly helpful in reducing the chances of ulceration associated with nonsteroidal anti‐inflammatory drug (NSAID) administration.

Regulation of expression of the receptors controlling gastric acidity

Gastric acid secretion is regulated by the stimulatory effects of gastrin, histamine and acetylcholine and the inhibitory actions of somatostatin on their respective receptors. We proposed that the expression of these receptors could be regulated at the transcription level by agonists and antagonists known to effect acid secretion. A quantitative “real-time” PCR method was used to determine changes in mRNA expression for these receptors. The agonists, pentagastrin and histamine, and the H 2 antagonist, ranitidine, were infused over a 6 h period to conscious sheep. Blood, antral and fundic tissue samples were taken for analysis. Both pentagastrin and histamine resulted in elevated plasma somatostatin concentrations during the treatment. Ranitidine stimulated a fourfold increase in plasma gastrin while histamine caused a transient decrease. Except for an increase in antral gastrin following ranitidine infusion, there was no significant change in gastric gastrin and somatostatin concentration. Histamine (H 2) receptor mRNA expression in the antrum was significantly increased by pentagastrin and decreased by ranitidine. Pentagastrin also stimulated a significant increase in the level of muscarinic (M 3) receptor mRNA in the antrum. Antral somatostatin II receptor mRNA was significantly decreased by histamine. In the fundus, pentagastrin infusion resulted in a significant increase in histamine receptor mRNA and a decrease in the muscarinic receptor mRNA. This work demonstrates that the receptors involved in the regulation of acid secretion can be regulated by local events.