Pentagastrin-stimulated Gastric Acid Output Research Articles

Glucagon-Like Peptide 2 Stimulates Glucagon Secretion, Enhances Lipid Absorption, and Inhibits Gastric Acid Secretion in Humans

The gut-derived peptide glucagon-like peptide 2 (GLP-2) has been suggested as a potential drug candidate for the treatment of various intestinal diseases. However, the acute effects of GLP-2 on gastric functions as well as on glucose and lipid homeostasis in humans are less well characterized. Fifteen healthy male volunteers were studied with the intravenous infusion of GLP-2 or placebo over 120 minutes in the fasting state, and pentagastrin-stimulated gastric acid output was assessed. Another 15 healthy male volunteers were studied with a 390 minutes infusion of GLP-2 or placebo during the ingestion of a solid test meal. Gastric emptying was determined using a 13C-sodium-octanote breath test. Plasma concentrations of glucose, insulin, C-peptide, glucagon, GLP-2, free fatty acids, free glycerol, and triglycerides were determined. GLP-2 administration led to a marked increase in glucagon concentrations both in the fasting state and during the meal study (P < .001). Postprandial plasma concentrations of triglycerides and free fatty acids were significantly higher during GLP-2 infusion compared with placebo (P < .01), while glycerol concentrations were similar (P = .07). GLP-2 administration caused an approximately 15% reduction in pentagastrin-stimulated gastric acid and chloride secretion (P < .01), whereas gastric emptying was not affected (P = .99). GLP-2 reduces gastric acid secretion but does not seem to have an influence on gastric emptying. The stimulation of glucagon secretion by GLP-2 may counteract the glucagonostatic effect of GLP-1. Changes in postprandial lipid excursions seem to reflect enhanced intestinal nutrient absorption during GLP-2 administration.

Intravenous lansoprazole: in erosive oesophagitis.

An intravenous formulation of lansoprazole, a proton pump inhibitor, is approved for use in patients with erosive oesophagitis who are temporarily unable to take oral lansoprazole. In healthy volunteers, oral and intravenous lansoprazole 30 mg/day were equivalent in suppressing basal and pentagastrin-stimulated maximum gastric acid output. Moreover, the mean 24-hour intragastric pH did not differ significantly following oral or intravenous administration of lansoprazole and was significantly higher with both formulations than with intravenous polyethylene glycol vehicle. After treatment for 7 days in patients with erosive oesophagitis, intravenous lansoprazole (30 mg/day) recipients had significantly lower median stimulated and basal gastric acid output measurements than placebo recipients. Median pentagastrin-stimulated gastric acid output levels were equivalent after 7 days treatment with intravenous or oral lansoprazole. Intravenous lansoprazole is generally well tolerated. All adverse events experienced by patients with erosive oesophagitis who received intravenous lansoprazole were mild or moderate in severity.

Gender-related differences in pentagastrin-stimulated gastric acid output in proton pump inhibitor-treated subjects

Gender-related differences in pentagastrin-stimulated gastric acid output in proton pump inhibitor-treated subjects

Gender-Related Differences in Pentagastrin-Stimulated Gastric Acid Output in Proton Pump Inhibitor-Treated Subjects

Gender-Related Differences in Pentagastrin-Stimulated Gastric Acid Output in Proton Pump Inhibitor-Treated Subjects

Increased Gastric Acid Secretion in Cholecystokinin-1 Receptor-Deficient Otsuka Long-Evans Tokushima Fatty Rats

Background: It is hypothesized that cholecystokinin stimulates acid secretion directly and indirectly by binding to CCK-2 (CCK-B/gastrin) receptors on both parietal and enterochromaffin-like cells. At the same time, however, it inhibits acid responses by stimulating the paracrine secretion of somatostatin from D cells and thereby exerts a tonic inhibition on the parietal cells. To test the validity of this hypothesis, we determined gastric acid secretion in the CCK-1 (CCK-A) receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rats. Methods: Gastric acid secretion was determined in the acute fistula OLETF and the control Long-Evans Tokushima Otsuka (LETO) rats. Plasma concentrations of gastrin, CCK, somatostatin and histamine were determined by radioimmunoassay. The levels of CCK-2 receptor mRNA in the mucosa of the glandular stomach were determined by Northern blot analysis. Results: Pentagastrin- and CCK-8-stimulated as well as basal acid outputs in OLETF rats were significantly higher than those in LETO rats. CCK-2 receptor antagonist reduced basal acid outputs and completely suppressed CCK-8-stimulated acid secretion in both strains. CCK-8 enhanced the pentagastrin-stimulated gastric acid output in OLETF rats, but not in LETO rats. In LETO rats, CCK-1 receptor antagonist increased CCK-8-stimulated gastric acid secretions to those in OLETF rats. The level of CCK-2 receptor mRNA in the stomach in OLETF rats was 2-fold higher than that in LETO rats. In OLETF rats, plasma concentrations of CCK and histamine were higher, whereas somatostatin concentrations were lower than those in LETO rats, with no change in basal plasma gastrin concentrations. Conclusions: These results in the CCK-1 receptor-deficient OLETF rats confirmed that CCK stimulates acid secretion by binding to CCK-2 receptors, but at the same time inhibits acid responses by stimulating the paracrine secretion of somatostatin from D cells in the gastric mucosa.

Effects of Helicobacter pylori gastritis on gastric secretion in healthy human beings.

Helicobacter pylori gastritis is common, but effects on gastric secretion are not well understood. We measured basal and pentagastrin-stimulated gastric acidity, pepsin activity, and fluid output, as well as serum gastrin concentrations and H. pylori antibody levels, before and after treatment of H. pylori gastritis in 28 men and women. Subjects were studied before and 1 and 3 mo after a course of bismuth, metronidazole, and tetracycline. Elimination of H. pylori gastritis, accomplished in 14 subjects, increased basal and pentagastrin-stimulated gastric acidity (by 15 meq/l) and basal acid output significantly (by 2.1 meq/h 1 mo after therapy). Elimination of H. pylori had an opposite effect on pepsin secretion, significantly decreasing pepsin output by 30%. Elimination of H. pylori significantly reduced nonparietal fluid output by 35%, without affecting fluid output from parietal cells. Serum gastrin and H. pylori antibody levels declined significantly after elimination of H. pylori. None of these changes was observed in 14 subjects whose H. pylori gastritis was resistant to antimicrobial therapy. In summary, eradication of H. pylori infection increases gastric acidity by reducing nonparietal gastric secretion from peptic and other cells.

Safety, tolerability and effect on pentagastrin-stimulated gastric acid output (PSAO) of the new reversible proton pump inhibitor BY841: B. Simon, P. Müller, M. Hartmann∗, R. Huber∗, H. Bliesath∗, R. Lühmann∗, W. Wurst∗, H.W. Radtke∗. Clinic Schwetzingen, Salem Clinic, Heidelberg and ∗Byk Gulden Pharmaceuticals, Konstanz, Germany

Safety, tolerability and effect on pentagastrin-stimulated gastric acid output (PSAO) of the new reversible proton pump inhibitor BY841: B. Simon, P. Müller, M. Hartmann∗, R. Huber∗, H. Bliesath∗, R. Lühmann∗, W. Wurst∗, H.W. Radtke∗. Clinic Schwetzingen, Salem Clinic, Heidelberg and ∗Byk Gulden Pharmaceuticals, Konstanz, Germany

Neurotensin and oxyntomodulin-(30-37) potentiate PYY regulation of gastric acid and somatostatin secretions

The present study was designed to investigate, in cats provided with both a gastric fistula and a denervated fundic Heidenhain pouch, the effect of peptide YY (PYY) on pentagastrin-stimulated gastric acid and somatostatin secretions and to determine whether neurotensin (NT) and the COOH-terminal octapeptide of oxyntomodulin [Oxm-(30-37)] would modify these secretions. Intravenous infusion of PYY (0.1 nmol.kg-1.h-1), NT (15 nmol.kg-1.h-1), or Oxm-(30-37) (60 nmol.kg-1.h-1) did not affect basal acid secretion. However, they significantly inhibited pentagastrin-stimulated gastric acid output up to 50% (P < 0.01) in the main stomach. Furthermore, they significantly increased gastric somatostatin release by +750, +1,700, and +600% over basal level (P < 0.01) for (in nmol.kg-1.h-1) 0.1 PYY, 15 NT, and 60 Oxm-(30-37), respectively. On the other hand, the effects of 0.1 nmol.kg-1.h-1 PYY were potentiated by subthreshold doses of NT (5 nmol.kg-1.h-1) or Oxm-(30-37) (15 nmol.kg-1.h-1). These findings suggest that there could be a cooperation between the three peptides in the intestinal regulation of gastric secretions.

Hypothalamic neuropeptide Y inhibits gastric acid output in rat: role of the autonomic nervous system.

Injection of neuropeptide Y (NPY) into the hypothalamic paraventricular nucleus (PVN) inhibits gastric acid secretion in anesthetized rats. The role of the autonomic nervous system in mediation of this response was investigated. Unilateral microinjection of 200 pmol NPY into the PVN of anesthetized rats inhibited spontaneous and pentagastrin-stimulated gastric acid output. Inhibition was abolished by subdiaphragmatic vagotomy, atropine, and bethanechol but was restored by electrical stimulation of the distal cut end of the vagus in cervically vagotomized rats. Although sympathectomy, phenoxybenzamine, and yohimbine abolished the inhibition, it was not affected by prazosin treatment. Gastric blood flow was not altered by injection of NPY. These results suggest that the antisecretory effect of NPY in the PVN was sympathetically mediated via suppression of gastric vagal cholinergic tone through activation of alpha 2-adrenoceptors.

Lack of Effect of Synthetic Human Gastric Inhibitory Polypeptide and Glucagon-LikePeptide 1 [7-36 Amide] Infused at Near-Physiological Concentrations on Pentagastrin-Stimulated Gastric Acid Secretion in Normal Human Subjects

Gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 [7-36 amide] (GLP-1) are glucose-dependent insulinotropic gut hormones. Under experimental conditions, both have been shown to reduce stimulated gastric acid secretion. To study their individual and combined effects on pentagastrin-stimulated (0.1 micrograms/kg/h from -90 to 120 min) gastric volume, acid and chloride output, on separate occasions, synthetic human GIP (1 pmol/kg/min) and/or GLP-1 [7-36 amide] (0.3 pmol/kg/min) or placebo (0.9% NaCl with 1% albumin) were infused intravenously (from -30 to 120 min) in 9 healthy volunteers. At 0 min, a glucose infusion was started that mimicked the glycemic profile after an oral glucose load of 50 g/400 ml and allowed for the glucose-dependent insulinotropic action of GIP and GLP-1 [7-36 amide]. Pentagastrin stimulated acid output significantly, but neither GIP nor GLP-1 [7-36 amide] either alone or in combination, reduced pentagastrin-stimulated gastric acid secretion. The circulating concentrations of GIP and GLP-1 [7-36 amide] obtained at steady state during exogenous administration of synthetic peptides were similar to or higher than those reached after oral glucose (endogenous secretion). In conclusion, (penta)gastrin-stimulated gastric acid secretion is not inhibited by physiological circulating concentrations of GIP or GLP-1 [7-36 amide]. Therefore, the insulinotropic action of these intestinal hormones is physiologically more important than their possible role as enterogastrone.

Distinct hemodynamic and gastric effects of human CGRP I and II in man

The human calcitonin gene-related peptides I and II (or α and β) (CGRP I and II) are encoded by two different genes, but they have 34 of the 37 amino acid residues in common. Human CGRP I more potently stimulated blood flow through the skin and carotid artery ( p<0.01), and the heart rate ( p<0.05), and plasma renin activity and aldosterone secretion than human CGRP II ( p<0.02). Inhibition of pentagastrin-stimulated gastric acid output, on the other hand, was only obtained with CGRP II. The separate effects of human CGRP I and II on the cardiovascular and gastric systems are presumably mediated by different receptors or receptor pathways recognized by the two closely related neuropeptides.

Fish oil reduces ethanol‐induced damage of the duodenal mucosa in humans

Eight healthy volunteers were studied before and after 3 weeks of dietary supplementation with fish oil (10.5 g day-1, 18% (1.9 g) eicosapentaenoic acid). Duodenal mucosal lesions were induced by instillation of 40 ml ethanol (40%). Mean endoscopic lesion score was lower after fish oil treatment (1.62 +/- 0.32; mean +/- SEM) than before (3.25 +/- 0.31; P less than 0.01). Histologic lesion score fell from 22.75 +/- 1.98 before treatment to 13.50 +/- 1.51 after fish oil (P less than 0.01). Basal and pentagastrin-stimulated gastric acid output remained unaffected. Release of prostaglandin E2, 6-keto-prostaglandin F1 alpha, and thromboxane B2 from biopsy specimens of the duodenal mucosa in vitro was not significantly altered after fish oil ingestion. In the same in vitro system calcium ionophore A23187-induced release of total leukotriene C (LTC) increased from 10.6 +/- 1.5 ng g-1 mucosa 20 min before treatment to 30.4 +/- 3.2 ng after fish oil. High pressure liquid chromatography analysis showed that this increase was partly due to formation of LTC5 as after fish oil 28% of total LTC were identified as LTC5 whereas 72% were LTC4. We conclude that in humans fish oil reduces ethanol-induced damage of the duodenal mucosa without inhibiting gastric acid secretion or stimulating prostaglandin formation. It remains to be clarified if the changes in leukotriene formation are relevant for the mucosaprotective fish oil effect.

Pharmacological evidence for histamine H3 receptor in the control of gastric acid secretion in cats

We investigated the possible involvement of H3 receptor in the control of gastric acid secretion in the conscious cat provided with a gastric fistula [main stomach (MS)] and a denervated Heidenhain pouch (HP). Intravenous infusion of the selective H3 agonist (R)-alpha-methylhistamine at 3, 10, and 30 nmol.kg-1.h-1 induced a dose-related inhibition of pentagastrin-stimulated gastric acid output. Maximal inhibition in MS (48 +/- 3%, P less than 0.01) and HP (36 +/- 5%, P less than 0.01) was obtained with 30 nmol.kg-1.h-1. This dose also significantly inhibited peptone meal-induced gastric acid output by 38 +/- 4 and 46 +/- 8% (P less than 0.01) in MS and HP, respectively. These inhibitions were completely prevented by 10 nmol.kg-1.h-1 iv of the selective H3 receptor antagonist thioperamide. On the other hand, (R)-alpha-methylhistamine was without any effect on histamine-stimulated gastric acid output, whereas thioperamide produced a slight but not significant increase of this output in contrast to the H2 receptor antagonist ranitidine, which showed a strong inhibitory effect. These findings suggest that pentagastrin- or meal-induced gastric acid secretion involves an H3 receptor pharmacologically distinct from the H2 receptor.

Telenzepine, a New M1-Receptor Antagonist, Is a More Potent Inhibitor of Pentagastrin-Stimulated Gastric Acid Output Than Pirenzepine in Dogs

In conscious dogs with a gastric fistula we compared the action of different doses of telenzepine (ranging from 1 to 243 nmol/kg/h) and pirenzepine (ranging from 4.7 to 1170 nmol/kg/h) on gastric acid output in response to pentagastrin (1 to 8 micrograms/kg/h). Pentagastrin caused a dose-dependent increase in gastric acid output. A dose of 27 nmol/kg/h and all subsequent doses of telenzepine and a dose of 130 nmol/kg/h and all higher doses of pirenzepine significantly inhibited (up to 74% of control values) the gastric acid response to pentagastrin. Doses above 27 nmol/kg/h of telenzepine and doses above 130 nmol/kg/h of pirenzepine did not further inhibit the gastric acid output. Only the highest doses of telenzepine (243 nmol/kg/h) and pirenzepine (1170 nmol/kg/h) significantly increased heart rate from 66 +/- 3.1 to 77.1 +/- 3.9 and 72.5 +/- 3.2, respectively (beats/min, chi +/- SEM, n = 6). Differences between both drugs were not found with regard to cardiovascular responses of equipotent doses. We conclude that in conscious dogs with an intact stomach, the new M1-receptor antagonist telenzepine is, on a molar basis, more than 4.7 times more potent than pirenzepine in inhibiting pentagastrin-stimulated gastric acid output. This inhibition occurs at doses that do not increase heart rate, and, therefore, probably cause few systemic effects.

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.

Neural pathways involved in intracisternal bombesin-induced inhibition of gastric secretion in rats.

Possible humoral and neural components mediating intracisternal bombesin (500 ng)-induced inhibition of gastric secretion were studied in rats. Intracisternal bombesin induced a marked rise in gastric pH from 2.0 +/- 0.5 up to 6.5 +/- 0.6 whereas gastric secretion in parabiotic saline-treated partners was not modified. Bombesin inhibited pentagastrin-stimulated gastric acid output by 88 +/- 5% in intact rats and 71 +/- 7% in vagotomized animals. Spinal cord transection at the level of the 5th or 7th cervical but not the 8th or 13th thoracic vertebrae significantly reversed the rise in pH and the decrease in acid concentration induced by bombesin and abolished the hyperglycemic effect of the peptide. These results suggest that bombesin inhibitory action on gastric secretion is not mediated through humoral factors but through neural pathways in part related to the sympathetic nervous system along the spinal cord, whereas the parasympathetic outflow from the vagus or the sacral spinal nerves does not seem to play an important role.

Dissociated effects of misoprostol on gastric acid secretion and mucosal blood flow.

Misoprostol, a synthetic prostaglandin analog, has been reported to inhibit gastric acid secretion and to protect the gastric mucosa from the effects of aspirin and aspirin plus hemorrhagic shock. This study examined the effect of misoprostol on basal gastric corpus mucosal blood flow (MBF), and on pentagastrin-stimulated gastric acid output and MBF. Gastric corpus MBF in ml/min/100 g was measured by hydrogen gas clearance in fasted, anesthetized rats. Acid output in mueq/min was determined by a continuous gastric perfusion technique. For the basal study, vehicle or misoprostol in doses of 50 and 1000 micrograms/kg was administered intragastrically in separate groups of rats. For the pentagastrin-stimulation study, vehicle or misoprostol, 1000 micrograms/kg, was infused intravenously after gastric acid output was stimulated to plateau by intravenous pentagastrin, 20 micrograms/kg/hr. The results showed that misoprostol had no effect on basal gastric corpus MBF. During pentagastrin stimulation, misoprostol decreased acid secretion but did not decrease gastric corpus MBF. We speculate that this dissociated effect of misoprostol on stimulated gastric acid secretion and corpus MBF may be of therapeutic importance if it can be confirmed in human studies.

Oxyntomodulin (glucagon-37) and its C-terminal octapeptide inhibit gastric acid secretion

Oxyntomodulin (OXM) is a peptide isolated from porcine intestine which consists of the whole glucagon sequence with a basic octapeptide (KA 8) at its C-terminal end. In this study, the effect of OXM and KA 8 on pentagastrin-stimulated gastric acid secretion has been studied in conscious rats and cats. In rats, OXM (25–450 pmol·kg −1) as well as KA 8 (7.5–60 nmol·kg −1) inhibited pentagastrin-stimulated gastric acid output in a dose-dependent manner; KA 8 was about 100-times less potent than OXM. In cats, KA 8 (90 nmol·kg −1) was also an inhibitor of acid secretion. We conclude that OXM, or a closely related peptide, could be a physiological modulator of gastric acid secretion, and that the C-terminal octapeptide of OXM is implicated in this effect.

Dissociated effects of somatostatin on gastric acid secretion and mucosal blood flow.

Somatostatin has been reported to control upper gastrointestinal hemorrhage, prevent restraint stress-induced gastric ulcerations, and inhibit gastric acid secretion. In this study we examined the effect of somatostatin on basal and pentagastrin-stimulated gastric acid output and mucosal blood flow. Antral and corpus mucosal blood flows were measured by hydrogen gas clearance in fasted, anesthetized rats. Acid output was determined by a continuous gastric perfusion technique. In the basal study somatostatin in doses of 8, 16, and 32 micrograms . kg-1 . h-1 was infused intravenously in separate groups of animals. In the pentagastrin stimulation study somatostatin (16 micrograms . kg-1 . h-1) was infused after gastric acid output was stimulated to plateau by intravenous pentagastrin (19.8 micrograms . kg-1 . h-1). The results showed that somatostatin had no effect on basal corpus or antral mucosal blood flow. During pentagastrin stimulation somatostatin decreased acid secretion but increased corpus mucosal blood flow. We speculate that this increase in blood flow may not be a direct effect as basal corpus or antral mucosal blood flow was unaffected by somatostatin.

Age behaviour of gastric acid secretion in males and females with a normal antral and body mucosa.

In males with a normal gastric mucosa the acid secretion expressed in terms of fat-free body weight (FFB) shows a random distribution with age, whereas in females there is a significant increase. To explain this sex-related discrepancy, we examined maximal pentagastrin-stimulated gastric acid output (AO) and the parietal cell density (P) and thickness (T) in 50 males and 50 females with a normal antral and body mucosa randomly collected from a representative Finnish population sample. Two alternatives were considered: 1) the parietal cell reactivity remains constant, and the age variation in females is due to an increase in the total parietal cell mass, 2) the age variation in females is due to an increase in the reactivity of parietal cells, the total parietal cell mass (P X T X body area (A)) remaining constant. Starting from the first alternative, P and T were measured and showed no correlation with age in males and a decrease in females. The variable A is, according to the formula, expressed by the ratio AO/P X T, and this ratio shows an expected significant correlation with AO in both males and females. However, the variable A showed a significant increase with age in females but not in males. In view of the results of Cox that A should not vary with age, the present results suggest that the ratio AO/P X T in females must include, in addition to body area, other variables, such as the reactivity of parietal cells.(ABSTRACT TRUNCATED AT 250 WORDS)