Iron absorption in patients with Zollinger-Ellison syndrome treated with long-term gastric acid antisecretory therapy.

Background: Gastric acid secretion is important for absorption of dietary non-haem iron, and iron deficiency is common in gastric hyposecretory states such as after gastric resection. It is not known if prolonged, continuous treatment with potent acid suppressants such as omeprazole will lead to iron deficiency or lower body iron stores.

Aim: To assess iron stores and the occurrence of iron deficiency anaemia in patients with Zollinger-Ellison syndrome (ZES) treated long-term with gastric antisecretory drugs.

Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome.

Background And Aims: Long-term treatment with H(+)-K(+)-adenotriphosphatase (ATPase) inhibitors, such as omeprazole or lansoprazole, for severe gastroesophageal reflux disease is now widely used. Whether such treatment will result in vitamin B12 deficiency is controversial. We studied whether long-term treatment with omeprazole alters serum vitamin B12 levels in patients with Zollinger-Ellison syndrome.

Loss of bombesin-induced feeding suppression in gastrin-releasing peptide receptor-deficient mice.

The gastrin-releasing peptide receptor (GRP-R) is one of three members of the mammalian bombesin subfamily of seven-transmembrane G protein-coupled receptors that mediate diverse biological responses including secretion, neuromodulation, chemotaxis, and growth. The X chromosome-linked GRP-R gene is expressed widely during embryonic development and predominantly in gastrointestinal, neuronal, and neuroendocrine systems in the adult. Surprisingly, gene-targeted mice lacking a functional GRP-R gene develop and reproduce normally and show no gross phenotypic abnormalities.

Bone metastases in patients with gastrinomas: a prospective study of bone scanning, somatostatin receptor scanning, and magnetic resonance image in their detection, frequency, location, and effect of their detection on management.

Purpose: To determine whether bone scan, magnetic resonance imaging (MRI), or somatostatin receptor scintigraphy (SRS) is best for identifying bone metastases in patients with gastrinomas, as well as their frequency and location, whether their detection affects management, and what patient subgroups should be examined.

Materials And Methods: One hundred fifteen patients with gastrinoma were prospectively studied. Patients were examined yearly and those with liver metastases were reexamined every 3 months.

Constitutive achlorhydria in mucolipidosis type IV.

Mucolipidosis type IV is an autosomal recessive lysosomal storage disease of unknown etiology that causes severe neurological and ophthalmological abnormalities. In an attempt to obtain insight into the nature of the metabolic abnormality in this disorder, we prospectively evaluated 15 consecutive patients, aged 2 to 23 years, over a period of 22 months. The finding of iron deficiency in some of the patients led us to the discovery that all patients but one had markedly elevated blood gastrin levels.

Growth of newly diagnosed, untreated metastatic gastrinomas and predictors of growth patterns.

Purpose: The growth pattern of untreated metastatic neuroendocrine tumors is unknown. This uncertainty contributes to the disagreement regarding timing and could effect evaluation of the efficacy of antitumor treatment. The purpose of this study was to determine the growth rate of untreated hepatic metastatic gastrinoma and to identify its predictors.

Value of somatostatin receptor scintigraphy: a prospective study in gastrinoma of its effect on clinical management.

Background & Aims: Recently [111In-DTPA-D-Phe1]-octreotide was approved for somatostatin receptor scintigraphy (SRS) of gastroenteropancreatic tumors. SRS and other tumor localization methods can be time consuming, expensive, and involve patient inconvenience. The role of SRS in comparison to other tumor localization modalities remains undefined because the relative effects of these methods on management have not been studied.

Management of the Zollinger-Ellison syndrome in pregnancy.

Objective: There is almost no information on the management of patients with functional pancreatic endocrine tumors such as Zollinger-Ellison syndrome during pregnancy. The purpose of this study was to develop an approach for the management of such cases during pregnancy on the basis of experience with five recent cases.

Study Design: Five women with Zollinger-Ellison syndrome who had seven pregnancies were the subject of this study.

Distinguishing small hepatic hemangiomas from vascular liver metastases in gastrinoma: use of a somatostatin-receptor scintigraphic agent.

Purpose: To compare somatostatin-receptor scintigraphy and conventional imaging modalities in the differentiation of small hepatic hemangiomas from small liver metastases in Zollinger-Ellison syndrome.

Materials And Methods: Twenty-nine patients had hypervascular liver lesions smaller than 2 cm that could have been either metastases or hemangiomas. Fourteen patients had metastases, 14 had hemangiomas, and one had both.

Identification of CCK-A receptors on chief cells with use of a novel, highly selective ligand.

Functional studies suggest that guinea pig chief cells have both cholecystokinin-A (CCK-A) and CCK-B receptors (CCK-A-R and CCK-B-R, respectively). However, all efforts to directly characterize the specific CCK-A-R using binding have been unsuccessful. Recent studies describe specific CCK-A-R agonists such as A-71378 ([desamino-Nle28,31-(N-methyl)Asp32]CCK heptapeptide].

Chief cells possess somatostatin receptors regulated by secretagogues acting through the calcium or cAMP pathway.

Inhibition both in vivo and in vitro of pepsinogen secretion by somatostatin (SS) and the histological demonstration that fundic D-cells contain long cytoplasmic processes extending to chief cells suggest a possible direct effect of SS on chief cell function. The aim of the present study was to determine whether SS interacts directly with receptors on isolated gastric chief cells and, if so, how SS alters cell function. Binding of 125I-[Tyr11]SS14 to chief cells was saturable, time and temperature dependent, and was inhibited by both SS14 (Ki 1.

Binding of 125I-CCK-8 and 125I-gastrin-I to dispersed chief cells from guinea-pig stomach.

In dispersed gastric chief cells from guinea-pig stomach, binding of iodinated cholecystokinin octapeptide (125I-CCK-8) was relatively slow, temperature-dependent, to a single class of binding sites and inhibited by various gastrin- and CCK-related agonists and receptor antagonists. Binding of iodinated gastrin-I (125I-gastrin-I) was moderately rapid, temperature-dependent, to a single class of binding sites, and inhibited by various gastrin and CCK-related agonists and receptor antagonists. Gastrin-I as well as C-terminal fragments of CCK containing from eight amino acids (CCK-8) to four amino acids (CCK-4) stimulated pepsinogen secretion and inhibited binding of 125I-CCK-8 and 125I-gastrin-I.

Characterization of cholinergic receptors mediating pepsinogen secretion from chief cells.

By use of a highly enriched preparation of chief cells (greater than 90% pure) prepared from guinea pig stomach, the cholinergic receptors regulating pepsinogen secretion were studied. Each of five different muscarinic cholinergic agonists, but not the nicotinic cholinergic agonist nicotine, stimulated pepsinogen release. Carbamylcholine-stimulated pepsinogen release was inhibited by each of seven different cholinergic receptor antagonists with relative potencies of N-methylscopolamine greater than scopolamine = 4-diphenylacetoxy-N-methylpiperidine methiodide = atropine much greater than pirenzepine greater than AF-DX-116 much greater than tetraethylammonium.

CCK-JMV-180: a peptide that distinguishes high-affinity cholecystokinin receptors from low-affinity cholecystokinin receptors.

When pancreatic acini are incubated with increasing concentrations of cholecystokinin octapeptide (CCK-8) the dose-response curve for stimulation of enzyme secretion increases, reaches a maximum and then decreases. The upstroke of the dose-response curve reflects occupation of high-affinity, stimulatory CCK receptors (Kd 69 pM), whereas the downstroke of the dose-response curve reflects occupation of low-affinity inhibitory CCK receptors (Kd 10 nM). In the present study, we used dispersed acini from rat pancreas to examine the effects of CCK-JMV-180, an analogue of the C-terminal heptapeptide of CCK (CCK-7) having the structure BOC-Tyr(SO3) Ahx-Gly-Trp-Ahx-Asp2 phenylethyl ester.

Characterization of receptors for calcitonin gene-related peptide on gastric smooth muscle cells.

Rat calcitonin gene-related peptide (rat CGRP) and related peptides did not cause contraction of gastric smooth muscle cells; however, preincubation with rat CGRP or human CGRP inhibited smooth muscle contraction caused by carbachol. Rat CGRP and human CGRP were equipotent in opposing contraction with a half-maximal effect produced by 0.1 nM, but rat calcitonin-adjacent peptide (rat CAP) and human calcitonin had no effect.

Functionally distinct receptors for cholecystokinin and gastrin on dispersed chief cells from guinea pig stomach.

Caerulein, gastrin, and C-terminal fragments of cholecystokinin (CCK) varying in length from eight (CCK-8) to four (CCK-4) amino acids stimulate pepsinogen secretion from dispersed chief cells prepared from guinea pig stomach. C-terminal fragments of CCK containing fewer than four amino acids, even when tested at concentrations as high as 3 mM, do not stimulate pepsinogen secretion. The efficacies of gastrin and the various CCK-related peptides, coupled with the pattern of action of CCK receptor antagonists, indicate that chief cells from guinea pig stomach possess two functionally distinct classes of receptors, C-receptors and G-receptors.

Actions of vasoactive intestinal peptide and secretin on chief cells prepared from guinea pig stomach.

Vasoactive intestinal peptide and secretin increased cellular cAMP and pepsinogen secretion in dispersed chief cells from guinea pig gastric mucosa. With each peptide there was a close correlation between the dose-response curve for changes in cellular cAMP and that for changes in pepsinogen secretion. Vasoactive intestinal peptide-(10-28) and secretin-(5-27) had no agonist activity and antagonized the actions of vasoactive intestinal peptide and secretin on cellular cAMP and pepsinogen secretion.

Carbobenzoxy amino acids: structural requirements for cholecystokinin receptor antagonist activity.

We used dispersed acini prepared from guinea pig pancreas to examine 28 carbobenzoxy (CBZ) amino acids for their abilities to function as cholecystokinin receptor antagonists. All amino acid derivatives tested, except for CBZ-alanine, CBZ-glycine, and N alpha-CBZ-lysine, were able to inhibit the stimulation of amylase secretion caused by the C-terminal octapeptide of cholecystokinin. In general, there was a good correlation between the ability of a carbobenzoxy amino acid to inhibit stimulated amylase secretion and the ability of the amino acid derivative to inhibit binding of 125I-cholecystokinin.

N-terminal fragments of CCK-(26-33) as cholecystokinin receptor antagonists in guinea pig pancreatic acini.

In the present study we synthesized different N-terminal fragments and analogues of the C-terminal octapeptide of cholecystokinin [CCK-(26-33)] and examined their actions on dispersed acini prepared from guinea pig pancreas. None of the N-terminal fragments or analogues altered basal amylase release. Analogues of CCK-(26-32), CCK-(26-31), and CCK-(26-30) inhibited CCK-(26-33)-stimulated amylase, and there was a close correlation between the ability of an analogue to inhibit stimulated amylase and the analogue's ability to inhibit binding of 125I-cholecystokinin.

Pepsinogen secretion from dispersed chief cells from guinea pig stomach.

In the present study we examined the actions of various secretagogues on pepsinogen secretion from freshly dispersed chief cells prepared from guinea pig stomach. Chief cells were obtained by preparing dispersed gastric glands, subjecting the glands to mechanical disruption in the presence of EGTA, and fractionating the resulting mucosal cells on a Percoll density gradient. Chief cells constituted 90% of the final cell suspension and cell viability was 99%.

Derivatives of CCK-(26-32) as cholecystokinin receptor antagonists in guinea pig pancreatic acini.

In the present study we synthesized cholecystokinin-(26-32)-amide [CCK-(26-32)-NH2], N-acetyl-cholecystokinin-(26-32) [Ac-CCK-(26-32)], and N-acetyl-cholecystokinin-(26-32)-amide [Ac-CCK-(26-32)-NH2]. None of these peptides altered amylase secretion from dispersed acini prepared from guinea pig pancreas, but each peptide inhibited the stimulation of amylase secretion caused by the C-terminal octapeptide of cholecystokinin [CCK-(26-33)]. Half-maximal inhibition of CCK-(26-33)-stimulated amylase secretion occurred with 10 microM CCK-(26-32)-NH2, with 25 microM Ac-CCK-(26-32)-NH2, and with 100 microM Ac-CCK-(26-32).

Action of natural glucagon on pancreatic acini: due to contamination by previously undescribed secretagogues.

In dispersed acini from guinea pig pancreas, natural glucagon caused a two- to threefold increase in amylase secretion, and this natural glucagon-induced increase was augmented by theophylline. Natural glucagon also caused a sixfold increase in cellular cAMP but did not alter cellular cGMP or outflux of 45Ca. Natural glucagon caused detectable changes in cAMP and amylase secretion at a concentration of 1 microM, half-maximal stimulation at 10 microM, and maximal stimulation at 100 microM.

Effects of inhibitors of cyclic nucleotide phosphodiesterase on actions of cholecystokinin, bombesin, and carbachol on pancreatic acini.

In dispersed acini from guinea pig pancreas two inhibitors of cyclic nucleotide phosphodiesterase, Ro 20-1724 and 3-isobutyl-1-methylxanthine (IBMX), augmented the increase in amylase secretion caused by supramaximal concentrations of cholecystokinin but did not alter the stimulation of enzyme secretion caused by bombesin. The augmentations of the action of cholecystokinin caused by Ro 20-1724 or IBMX could be reproduced by 8-bromo-cAMP. When tested alone or with theophylline, cholecystokinin did not alter cAMP in pancreatic acini; however, with Ro 20-1724 or IBMX, concentrations of cholecystokinin that were supramaximal for stimulating amylase secretion caused a significant increase in cellular cAMP.

Effects of inhibitors of cyclic nucleotide phosphodiesterase on the actions of vasoactive intestinal peptide and secretin on pancreatic acini.

Theophylline, 3-isobutyl-1-methylxanthine (IBMX), and Ro 20-1724 each augmented the increase in cAMP and the stimulation of amylase secretion caused by vasoactive intestinal peptide (VIP) or secretin. With IBMX the dose-response curve for the stimulation of amylase secretion caused by VIP or secretin spanned a range of lower concentrations than did that obtained with Ro 20-1724, which in turn spanned a range of lower concentrations than did that obtained with theophylline. The configuration of the dose-response curve for the action of VIP on cAMP differed with each phosphodiesterase inhibitor tested.

Actions of Gila monster venom on dispersed acini from guinea pig pancreas.

Venom from Gila monster (family Helodermatidae) contains a pancreatic secretagogue. In dispersed acini from guinea pig pancreas, the venom increased enzyme secretion to the same extent as did vasoactive intestinal peptide, secretin, or PHI. The abilities of vasoactive intestinal peptide and Gila monster venom to stimulate enzyme secretion were not altered by boiling but were abolished by incubation with trypsin or chymotrypsin.