Biomedical subjects

J D Gardner

Publications and source records attributed to J D Gardner.

At least 55 records · Page 3Linked to original sources

PubMed1994

Characterization of a persistent inhibitory action of L-364,718 on cholecystokinin-stimulated enzyme secretion in pancreatic acini.

Examining the actions of L-364,718 on rat pancreatic acini, we found that L-364,718 causes persistent inhibition of cholecystokinin (CCK)-8-stimulated enzyme secretion in acini that were first incubated with L-364,718, washed repeatedly, and then reincubated with CCK-8. This inhibition is maximal after as little as 5 s of first incubation with L-364,718, is unaltered by reducing the temperature of the first incubation from 37 to 4 degrees C and is specific for CCK-8 in that carbachol-stimulated enzyme secretion is unaltered. The inhibitory potency of L-364,718 added to the first incubation followed by washing and reincubation with CCK-8 is nearly the same as when L-364,718 is added together with CCK-8 in the same incubation. The persistent inhibitory action of L-364,718 is not attributable to residual free L-364,718 in the bulk phase of the second incubation medium. In addition, L-364,718 does not cause persistent inhibition by binding irreversibly to CCK receptors because the binding reaction is completely reversible and the persistent inhibition can be surmounted with appropriate concentrations of CCK-8. When acini are first incubated with L-364,718 and washed repeatedly, approximately 0.2% of the original L-364,718 remains trapped in a microenvironment within the acini. This trapping presumably results in a sufficiently high concentration of L-364,718 to produce its persistent, albeit surmountable inhibition.

Amylases↗

PubMed1993

A newly recognized action of cholecystokinin on pancreatic acini-release of lactate dehydrogenase.

In the course of examining the actions of the cholecystokinin octapeptide (CCK-8) on pancreatic acini we found that CCK-8 can stimulate release of the large-molecular-weight cytoplasmic protein, lactate dehydrogenase (LDH) by as much as 6-fold. CCK-8-stimulated LDH release is mediated by a CCK-preferring receptor, detectable at 100 pM CCK-8, maximal at 100 nM CCK-8, constant for up to 30 min, reversible, not desensitized, and dependent on oxidative metabolism and incubation temperature but not on calcium in the extracellular medium. This action of CCK-8 is blocked by inhibitors of protein kinases, staurosporine, H-7, H-8 and H-9, but not by calmodulin antagonists, chlorpromazine, trifluoperazine or W-7. This action of CCK-8 on LDH release is not reproduced by TPA, 8Br-cAMP or A23187. Thus, it appears to be mediated by a previously uncharacterized protein kinase or an isoform of protein kinase C that is not maximally stimulated by TPA.

Alkaloids↗

PubMed1993

Occupation of low-affinity cholecystokinin (CCK) receptors by CCK activates signal transduction and stimulates amylase secretion in pancreatic acinar cells.

Based on the effects of monensin on binding of 125I-CCK-8 and its lack of effect on CCK-8-stimulated amylase secretion we previously proposed that pancreatic acinar cells possess three classes of CCK receptors: high-affinity receptors, low-affinity receptors and very low-affinity receptors [1]. In the present study we treated pancreatic acini with carbachol to induce a complete loss of high-affinity CCK receptors and then examined the action of CCK-8 on inositol trisphosphate IP3(1,4,5), cytosolic calcium and amylase secretion in an effort to confirm and extend our previous hypothesis. We found that first incubating pancreatic acini with 10 mM carbachol decreased binding of 125I-CCK-8 measured during a second incubation by causing a complete loss of high-affinity CCK receptors with no change in the low-affinity CCK receptors. Carbachol treatment of acini, however, did not alter the action of CCK-8 on IP3(1,4,5), cytosolic calcium or amylase secretion or the action of CCK-JMV-180 on amylase secretion or on the supramaximal inhibition of amylase secretion caused by CCK-8. The present findings support our previous hypothesis that pancreatic acinar cells possess three classes of CCK receptors and suggest that high-affinity CCK receptors do not mediate the action of CCK-8 on enzyme secretion, that low-affinity CCK receptors may mediate the action of CCK on cytosolic calcium that does not involve IP3(1,4,5) and produce the upstroke of the dose-response curve for CCK-8-stimulated amylase secretion and that very low-affinity CCK receptors mediate the actions of CCK on IP3(1,4,5) and cytosolic calcium and produce the downstroke of the dose-response curve for CCK-8-stimulated amylase secretion. Moreover, CCK-JMV-180 is a full agonist for stimulating amylase secretion by acting at low-affinity CCK receptors and is an antagonist at very low-affinity CCK receptors.

Amylases↗

PubMed1993

Cibacron blue-induced enhancement of agonist binding to cholecystokinin (CCK) receptors in solubilized pancreatic membranes.

The pancreatic receptor for cholecystokinin (CCK) typifies many G protein-coupled receptors in that its ability to bind agonist can be reduced by GTP or the solubilization of membranes. We found, however, that a dye, cibacron blue, caused up to a 6-fold increase in binding of the CCK receptor agonist, 125I-CCK-8, to rat pancreatic membranes solubilized with digitonin. Binding optimally enhanced in this manner was comparable to binding of 125I-CCK-8 to native membranes with respect to time-course, maximal amount bound, reversibility, and sensitivity to inhibition by various CCK receptor ligands. Increases in affinity of the CCK receptor for CCK-8 accounted fully for the enhancement of binding of 125I-CCK-8. Cibacron blue did not enhance binding of 125I-CCK-8 to native membranes, and also failed to enhance binding of the CCK receptor antagonist, [3H]L-364,718, to solubilized or native membranes. The ability of cibacron blue to enhance binding of agonist but not that of antagonist suggests that this dye may mimic or perhaps stimulate the effects of G protein on CCK receptors. Such a phenomenon may provide new insights into the mechanisms by which receptors distinguish agonists from antagonists.

Animals↗

PubMed1993

Prospective study of efficacy and safety of lansoprazole in Zollinger-Ellison syndrome.

Lansoprazole, a new substituted benzimidazole H+,K(+)-ATPase inhibitor, profoundly inhibits gastric acid secretion and has potential use in the management of diseases such as Zollinger-Ellison syndrome (ZES). In the present study we evaluated the efficacy and safety of lansoprazole in controlling acid hypersecretion in 20 patients with ZES. The starting dose was 60 mg once daily. Control of acid hypersecretion was defined as the dose required to reduce acid secretion to < 10 meq/hr in the last hour before the next dose. Doses were adjusted upwards until effective control was achieved. Patients not controlled with 120 mg once daily were placed on twice daily lansoprazole. Most patients (90%) required lansoprazole once daily. During long-term follow-up (mean 18.5 months), 25% of patients required upward dose adjustments and 25% of patients required twice daily lansoprazole. Following cessation of therapy, the mean time for gastric acid output to reach half basal acid output was 39.1 hr. Lansoprazole was well-tolerated without side effects. Clinical chemistry and hematological studies were unchanged, and no gastric carcinoids developed. These results demonstrate that lansoprazole is a safe and effective inhibitor of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Because it has a long duration of action, lansoprazole can be used to control gastric acid hypersecretion in most patients with Zollinger-Ellison syndrome using a once daily dosing schedule.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1993

Effect of verapamil on the cyclic AMP-mediated pathway for amylase secretion in rat pancreatic acini.

In dispersed acini from rat pancreas, verapamil (a phenylalkylamine calcium channel blocker) potentiated amylase secretion stimulated by vasoactive intestinal peptide (VIP), secretin, peptide histidine isoleucine, helodermin, forskolin, and 8-bromocyclic AMP. The action of verapamil on VIP-stimulated amylase secretion was detectable at 10 microM verapamil and maximal at 100 microM verapamil. Verapamil did not alter binding of 125I-VIP, basal cAMP, the increase in cAMP caused by VIP, or the increase in cAMP-dependent protein kinase caused by VIP. The effects of verapamil on stimulated amylase secretion were fully reversible and could be reproduced by nicardipine (a 1,4-dihydropyridine calcium channel blocker) and diltiazem (a benzothiazepine calcium channel blocker), but not by cinnarizine (a piperazine calcium channel blocker). Although 300 microM verapamil increased outflux of 45Ca, 100 microM verapamil, the concentration that produced maximal potentiation of VIP-stimulated amylase secretion, did not alter 45Ca outflux. Our results indicate that the action of verapamil to potentiate amylase secretion stimulated by secretagogues that activate the cAMP pathway occurs at a step that is distal to the activation of cAMP-dependent protein kinase.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1993

Receptor antagonists for gastrointestinal peptides.

Receptors for gastrointestinal peptides are all G protein-coupled receptors. Since the discovery that dibutyryl guanosine 3',5'-cyclic monophosphate was a cholecystokinin-receptor antagonist, a variety of receptor antagonists have been developed for a number of different gastrointestinal peptides. These antagonists have been useful in classifying receptors for gastrointestinal peptides and in elucidating complex regulation of gastrointestinal function. Some antagonists also have therapeutic potential. Based on the receptors with which they interact, gastrointestinal peptides can be grouped into families, and, in general, a given receptor antagonist is specific for a given family. This review covers the different families of gastrointestinal peptides and the major antagonists that exist for each family.

Animals↗

PubMed1992

Thapsigargin defines the roles of cellular calcium in secretagogue-stimulated enzyme secretion from pancreatic acini.

In the present study we used thapsigargin (TG), an inhibitor of microsomal calcium ATPase, to evaluate the roles of free cytoplasmic calcium and intracellular stored calcium in secretagogue-stimulated enzyme secretion from rat pancreatic acini. Using microspectrofluorimetry of fura-2-loaded pancreatic acini, we found that TG caused a sustained increase in free cytoplasmic calcium by mobilizing calcium from inositol 1,4,5-trisphosphate-sensitive intracellular stores and by increasing influx of extracellular calcium. TG also caused a small increase in basal amylase secretion, inhibited the stimulation of amylase secretion caused by secretagogues that increase inositol 1,4,5-trisphosphate, and potentiated the stimulation of amylase secretion caused by 12-O-tetradecanoylphorbol-13-acetate or secretagogues that increase cyclic adenosine 3',5'-monophosphate. Bombesin, which like TG increased free cytoplasmic calcium, also potentiated the stimulation of amylase secretion caused by secretagogues that increase cyclic adenosine 3',5'-monophosphate, but did not inhibit the stimulation of amylase secretion caused by secretagogues that increase inositol 1,4,5-trisphosphate. Finally, TG inhibited the sustained phase of cholecystokinin-stimulated amylase secretion and potentiated the time course of vasoactive intestinal peptide-stimulated amylase secretion. The present findings indicate that stimulation of amylase secretion by secretagogues that increase inositol 1,4,5-trisphosphate does not depend on increased free cytoplasmic calcium per se. In contrast, TG-induced potentiation of the stimulation of secretagogues that increase cellular cyclic adenosine 3',5'-monophosphate appears to result from increased free cytoplasmic calcium per se.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1992

Effects of curative gastrinoma resection on gastric secretory function and antisecretory drug requirement in the Zollinger-Ellison syndrome.

The chronic hypergastrinemia in diseases such as the Zollinger-Ellison syndrome has trophic effects on the gastric mucosa, causing increased parietal cell mass reflected by increased maximal acid output (MAO) and basal acid output (BAO). The time course for the development of these gastric changes in humans is unknown, and controversy exists regarding whether reversal of the hypergastrinemia results in rapid normalization of gastric secretory function. To address these uncertainties, gastric secretory function was prospectively evaluated in 20 patients with the Zollinger-Ellison syndrome undergoing successful curative resection of gastrinoma. Each patient had gastric acid measurements, imaging studies, fasting serum gastrin and secretin provocative testing preoperatively, postoperatively at 3-6 months, and yearly thereafter. Preoperative mean BAO was 39 mEq/h, MAO 56 mEq/h, BAO-MAO ratio 0.73, and fasting gastrin output 1020 pg/mL. All patients were evaluated at 6 months, 17 at 1 year, 15 at 2 years, 13 at 3 years, and 9 at 4 years. By 3-6 months, MAO decreased by 50% in men (mean, 30 mEq/h) and by 35% in women (mean, 29 mEq/h) and then remained relatively unchanged for up to 4 years. Before surgery, 14 of 20 patients (70%) had an elevated MAO, whereas 4 years after resection, none of 9 patients had elevated levels. By 3-6 months, BAO decreased by 75% and remained unchanged for up to 4 years. At 3-6 months, 56% of patients were mild hypersecretors and 67% remained hypersecretors up to 4 years. Preoperatively, the BAO-MAO ratio was elevated in 16 of 20 patients (80%); postoperatively, only 5 of 18 patients (28%) at 3-6 months, 2 of 15 (13%) at 1 year, and 2 of 10 (20%) at 4 years continued to have elevated ratios. Preoperatively, the mean ranitidine dose was 1597 mg/day, whereas after surgery the mean dose was 535 mg/day at 3-6 months and approximately 300 mg/day at 1-4 years with 8 patients requiring no antisecretory drug. These results show that the trophic effects of chronic hypergastrinemia are, in general, rapidly reversible with a 50% decrease in MAO within 3-6 months of cure. Similarly, BAO decreased by 75% within 3-6 months. Despite these decreases, careful monitoring of acid secretion is required after reversal of the chronic hypergastrinemia in diseases such as the Zollinger-Ellison syndrome, because 55% of patients at 3-6 months and up to 67% at 4 years continue to remain mild hypersecretors and require low doses of antisecretory drugs.

Adult↗

PubMed1992

Carbachol does not down-regulate substance P receptors in pancreatic acini.

In a previous study, we found that first incubating guinea pig pancreatic acini with carbachol caused desensitization of the enzyme secretory response to cholecystokinin-octapeptide (CCK-8), bombesin, and carbachol but not that to substance P. This carbachol-induced desensitization could be accounted for by carbachol-induced down-regulation of receptors for CCK-8, bombesin, and carbachol. Although carbachol did not desensitize the enzyme secretory response to substance P, an effect of carbachol on substance P receptors was not examined. In the present study, in dispersed acini from guinea pig pancreas, substance P caused a twofold increase in amylase secretion. Stimulation was half-maximal at 0.7 nM and was maximal at 10 nM. Analysis of the ability of substance P to inhibit binding of 125I-substance P to substance P receptors indicated that acini possess a single class of receptors for substance P (Kd = 0.8 +/- 0.1 nM; Bmax = 1,037 +/- 145 fmol/mg of DNA). There was a close correlation between the relative potency with which substance P stimulated amylase secretion (0.7 nM) and the potency for inhibiting binding of 125I-substance P (Kd = 0.8 nM). First incubating pancreatic acini with carbachol did not alter either substance P-stimulated enzyme secretion or binding of 125I-substance P to substance P receptors, whereas in the same experiments, carbachol reduced binding of 125I-CCK-8 to cholecystokinin receptors by 50% and decreased in CCK-8-stimulated enzyme secretion by 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Amylases↗

PubMed1992

Stereologic investigations of human gastric mucosa. II. Oxyntic mucosa from patients with Zollinger-Ellison syndrome.

Biopsy specimens from the oxyntic mucosa were obtained on 210 occasions from 76 patients with the Zollinger-Ellison syndrome (ZES) before and during omeprazole treatment. One-micrometer sections were examined by light microscopy, and in 5% linear hyperplasia of endocrine cells was observed. Morphometry was carried out in 91 of the specimens and showed a significant increase of the mean endocrine cell density in comparison with both young, healthy subjects and patients suffering from active peptic ulcer disease (PUD). No metaplasia, dysplasia, or neoplasia was detected in patients with ZES, and the mean mucosal thickness and parietal cell density remained normal. The parietal cells often displayed endosome-like structures, and occasionally there were lingulate cytoplasmic projections into the gland lumen. Electron microscopic morphometry was carried out in specimens from nine patients with ZES and did not show any significant differences in the parietal cells in comparison with healthy subjects.

Adolescent↗

PubMed1991

Down-regulation and recycling of high affinity cholecystokinin receptors on pancreatic acinar cells.

First incubating dispersed acini from rat pancreas with monensin, a cation ionophore that can inhibit recycling of receptors, inhibited binding of 125I-cholecystokinin 8 (125I-CCK-8) measured during a second incubation by as much as 50%. A maximal effect of monensin required 90 min of first incubation. Detectable inhibition of binding of 125I-CCK-8 occurred with 300 nM monensin, and inhibition increased progressively with concentrations of monensin up to 25 microM. Pancreatic acini possess two classes of receptors that bind 125I-CCK-8. One class has a high affinity (Kd = 461 pM) and a low capacity for CCK (512 fmol/mg DNA); the other class has a low affinity (Kd = 47 nM) and a high capacity for CCK (18 pmol/mg DNA). First incubating acini with monensin caused an 84% decrease in the number of high affinity CCK receptors with no change in the number of low affinity CCK receptors or the values of Kd for either class of receptors indicating that there is recycling of high affinity CCK receptors but not low affinity CCK receptors. First incubating acini with monensin did not alter CCK-stimulated amylase secretion indicating that in contrast to previous conclusions, occupation of low affinity CCK receptors mediates CCK-stimulated enzyme secretion. Moreover, the biphasic dose-response curve for CCK-stimulated enzyme secretion from monensin-treated acini suggests that pancreatic acini also possess a third, previously unrecognized class of very low affinity CCK receptors.

Animals↗

PubMed1991

Peptic ulcer perforation as the presentation of Zollinger-Ellison syndrome.

We examined the characteristics of patients with Zollinger-Ellison syndrome who developed a perforation prior to diagnosis to determine whether any clinical features were useful markers of the syndrome. Of 160 patients with Zollinger-Ellison syndrome, perforation occurred prior to the diagnosis being made in 11 (7%). At surgery, perforations were found in the duodenum in six cases and in the jejunum in five. In no case was tumor identified at emergency surgery, and the diagnosis of Zollinger-Ellison syndrome was made only in the postoperative period when excessive gastric secretions were noted. Neither acid output nor serum gastrin concentration were useful predictors for perforation. The patients, six men and five women, were 27-61 years old (median 48) and one had MEN-1. Three patients had no symptoms prior to the perforation. The other eight had symptoms for 1-15 years, with diarrhea occurring in 45% of the cases. Following the diagnosis of Zollinger-Ellison syndrome, patients were given medication to control gastric acid hypersecretion. Eight patients remained well, but the three patients who had had a partial gastrectomy had a complicated course despite medical therapy. Although features of perforation in Zollinger-Ellison syndrome are not specific, jejunal perforation or perforation associated with a history of diarrhea is suggestive of the diagnosis. Serum gastrin should be measured in every case and a partial gastrectomy avoided.

Adult↗

PubMed1991

Pharmacokinetics of oral and intravenous omeprazole in patients with the Zollinger-Ellison syndrome.

The pharmacokinetics and pharmacodynamics of oral and IV omeprazole after a single dose were studied in 9 patients with the Zollinger-Ellison syndrome to determine whether the increased dose required to control gastric acid hypersecretion could be explained on the basis of altered pharmacokinetics. Each patient was studied both after receiving a single IV bolus of omeprazole (40 mg) and after receiving a single oral dose of omeprazole (80 mg). Intravenous and oral omeprazole doses were administered 1 week apart. Gastric acid secretion and plasma concentrations of omeprazole after drug administration were determined in each patient. The area under the plasma concentration curve, clearance, and volume of distribution after IV omeprazole administration and the area under the plasma concentration curve, peak plasma concentration, and time required to reach the peak after oral omeprazole administration were not different from those reported previously for normal subjects and patients with peptic ulcer disease. Mean (+/- SEM) bioavailability of oral omeprazole for all patients was 68% +/- 16%, which was similar to the bioavailability reported previously for normal subjects. Three patients had a significantly lower bioavailability reported previously for normal subjects. Three patients had a significantly lower bioavailability (20% +/- 8%) than the others, and their basal acid outputs were significantly higher than those of the other 7 patients. For all patients there was an inverse correlation between bioavailability and basal acid output (r = 0.76; P less than 0.02). The mean (+/- SEM) elimination half-lives of IV and oral omeprazole were not different (2.3 +/- 0.4 vs. 2.4 +/- 0.5 hours) but were significantly longer than those reported previously for normal subjects (P less than 0.02). The duration of action correlated with the elimination half-life of the drug (r = 0.87; P less than 0.003) and area under the plasma concentration curve (r = 0.72; P less than 0.03). The mean durations of action of IV and oral omeprazole were not significantly different (34 +/- 7.2 vs. 35 +/- 6.2 hours). It was concluded that altered pharmacokinetics do not account for the increased drug requirement of omeprazole in patients with the Zollinger-Ellison syndrome. In contrast to a previous study, the oral and IV omeprazole had the same duration of action, suggesting that intermittent bolus administration of parenteral omeprazole will obviate the need for continuous infusion of histamine H2-receptor antagonists in patients requiring parenteral antisecretory drugs. Furthermore, an IV dose every 12 hours controlled acid secretion in all patients, suggesting this as the recommended dose interval in patients requiring parenteral drug therapy.

Administration, Oral↗

PubMed1991

Bombesin receptor antagonists. 2. Analogues based on substance P antagonists.

Although bombesin (BN) and substance P share only the C-terminal dipeptide amide, some substance P receptor antagonists are also weak bombesin receptor antagonists. In order to increase the selectivity of the antagonism for the BN receptor, a series of hybrid peptides were synthesized by the solid-phase methodology, and screened on 3T3 fibroblasts for binding and mitogenic activity. The analogues inhibiting BN-induced thymidine incorporation were further tested for peripheral (amylase release and urinary bladder contraction) and central activity (grooming behaviour).

3T3 Cells↗

PubMed1990

Effects of interleukin-6 on fetal hematopoietic progenitors.

Effects of interleukin-6 (IL-6) on cycling status and clonogenic maturation of human fetal (cord blood) and adult hematopoietic progenitors were compared. Adult marrow cells were incubated for various lengths of time with various concentrations of IL-6, in a serum-free system, after which tritiated thymidine suicide studies were performed. After incubation of 2 to 5 x 10(6) cells/mL for 4 hours in 5.0 ng IL-6/mL, increased thymidine suicide rates were observed for multipotent progenitors (CFU-Mix), granulocyte-macrophage progenitors (CFU-GM), and erythroid burst-forming units (BFU-E). Similar incubations of fetal cells in IL-6 resulted in similar increases in tritiated thymidine suicide rates. In other studies, IL-6 used alone did not support colony formation from adult progenitors. However, it did support colony formation from fetal CFU-Mix (P less than .05), CFU-GM (P less than .001), and BFU-E (P less than .05). In cultures of adult progenitors, IL-6 acted synergistically with IL-3 to support CFU-Mix colony formation (P less than .001), but synergistic actions on CFU-GM and BFU-E were not seen. In contrast, IL-6 acted synergistically with IL-3 and with GM-CSF to support colony formation by fetal CFU-Mix, CFU-GM, and BFU-E. Thus, IL-6 appears to have a wider spectrum of action on fetal progenitors from cord blood than on adult progenitors; including not only the induction of cycling, but also the support of clonogenic maturation of CFU-Mix, CFU-GM, and BFU-E.

Aging↗

PubMed1990

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. In addition, each of five different receptor antagonists inhibited binding of 125I-CCK-8 and 125I-gastrin-I and inhibited pepsinogen secretion stimulated by CCK-8 or gastrin-I. With each of eight different agonists and with each of five different antagonists the value of IC50 for inhibition of binding of 125I-CCK-8 was not significantly different from the value of IC50 for inhibition of binding of 125I-gastrin-I, indicating that in gastric chief cells the sites to which 125I-CCK-8 binds are the same sites to which 125I-gastrin-I binds. With the agonists as well as with the antagonists, however, there was no consistent relationship between the ability of a particular agent to inhibit binding and its ability to modify pepsinogen secretion, indicating that in gastric chief cells the sites that bind 125I-CCK-8 and 125I-gastrin-I are not the receptors that mediate stimulation of pepsinogen secretion by CCK-8 or by gastrin-I.

Amino Acid Sequence↗

PubMed1990

Multiple hormone elevations in Zollinger-Ellison syndrome. Prospective study of clinical significance and of the development of a second symptomatic pancreatic endocrine tumor syndrome.

In the present study of 45 patients with Zollinger-Ellison syndrome, the frequency and clinical importance of the release of multiple gastrointestinal peptides were assessed prospectively. During an initial evaluation, extent of gastrinoma, clinical symptoms, disease duration, and presence or absence of multiple endocrine neoplasia, type I (MEN-I) were assessed. All patients had determinations of fasting plasma gastrin, human pancreatic polypeptide, motilin, neurotensin, and somatostatin; 35 had determinations of insulin and gastrin-releasing peptide and 21 had determinations of glucagon. A plasma elevation of additional peptides besides gastrin was detected in 62%, with 44% having one, 18% having two, and 0% having three additional peptides elevated. Motilin was elevated in 29%, human pancreatic polypeptide in 27%, neurotensin in 20%, and gastrin-releasing peptide in 10%, whereas insulin, glucagon, and somatostatin were not elevated in any patient. The presence or absence of elevation of any peptide did not differ in patients with or without MEN-I, with gastrinoma size, with the presence or absence of metastatic disease, or with various clinical symptoms. Patients were assessed yearly for clinical evidence of a secondary symptomatic pancreatic endocrine tumor syndrome with a median follow-up of 146 and 84 months from onset or diagnosis, respectively. Only one patient (2% of patients) developed a second syndrome (rate, 2 patients per 100 patients observed for 10 years). These results demonstrate that the plasma elevation of multiple gastrointestinal peptides is common in patients with Zollinger-Ellison syndrome; however, the rate of developing a second symptomatic pancreatic endocrine tumor syndrome is much lower than generally believed. Furthermore, no evidence is found to support the conclusions that the detection of the plasma elevation of these peptides is clinically important in assessing MEN-I status, disease extent, or presence of metastatic disease or that elevated levels of motilin, neurotensin, gastrin-releasing peptide, or human pancreatic peptide are associated with any distinct clinical symptoms. Therefore, we recommend that plasma concentrations of these additional gastrointestinal peptides should not be assessed routinely but rather only if new symptoms develop.

Adult↗