James E. McGuigan

IMMUNOCHEMICAL STUDIES WITH SYNTHETIC HUMAN GASTRIN

Summary Antibodies to the gastrin molecule were evoked in rabbits by immunization with synthetic human gastrin I (2–17) conjugated to bovine serum albumin. The antibodies produced were of the γG-immunoglobulin class. A radioimmunoassay system for gastrin is described utilizing the precipitation of antibody-bound radioiodinated synthetic human gastrin I (2–17). The sensitivity of the immunoassay method is 5 μμg, a level of sensitivity anticipated to be sufficient to measure physiological levels of gastrin in human serum.

Immunochemical Measurement of Elevated Levels of Gastrin in the Serum of Patients with Pancreatic Tumors of the Zollinger-Ellison Variety

Abstract A radioiodine-immunoassay technic was used to measure fasting serum gastrin levels in four patients with the Zollinger-Ellison syndrome and 24 patients without gastrointestinal diseases. Serum gastrin levels in all the patients with the Zollinger-Ellison syndrome exceeded by approximately tenfold or greater the mean serum gastrin level of 425 μμg per milliliter in the control population. Gastrin was identified immunochemically in an extract derived from a pancreatic islet-cell tumor from one of the patients with the Zollinger-Ellison syndrome.

The carcinoid flush. Provocation by pentagastrin and inhibition by somatostatin.

THE carcinoid syndrome is characterized by episodes of flushing that appear to be secondary to the secretion of one or more substances by a tumor of enterochromaffin-cell origin.1 2 3 Flushing can ...

Serum Gastrin Concentrations in Pernicious Anemia

Abstract Fasting and postprandial (two hour) venous gastrin concentrations were measured in serums from a population of 29 patients with pernicious anemia and compared with a control population of patients. Mean fasting and postprandial gastrin concentrations for the patients with pernicious anemia were 997 (± 182 S.E.) and 1007 (± 303 S.E.) pg per milliliter respectively, whereas fasting and postprandial serum gastrin levels for the control patients were 165 (± 28 S.E.) and 209 (± 55 S.E.) pg per milliliter. The differences are significant (p less than 0.025). Among the patients with pernicious anemia nine of 29 (31 per cent) had serum gastrin levels sufficiently elevated to be considered in the hypergastrinemic range characteristic of the Zollinger — Ellison syndrome.

Effects of Calcium on Serum Gastrin Levels in the Zollinger–Ellison Syndrome

Abstract Serum gastrin levels were repeatedly measured in a patient with a total gastrectomy and hypergastrinemia associated with the Zollinger—Ellison syndrome. Fasting serum concentrations determined on consecutive days, and also at four-hour intervals during a 24-hour period, revealed persistent hypergastrinemia that varied within a relatively narrow range. Serum gastrin levels were found to relate directly to plasma calcium concentrations, falling by a factor of 20 with the development of hypocalcemia after parathyroidectomy for hypercalcemic hyperparathyroidism. Marked increases in serum gastrin concentration were induced by calcium infusion (12 and 20 mg per kilogram of body weight) but not by infusion of parathormone. The previously demonstrated effects of calcium in the control and stimulation of gastric acid secretion may be mediated by the polypeptide hormone gastrin.

Relations between Serum Gastrin Levels and Rates of Gastric Hydrochloric Acid Secretion

Abstract Fasting venous serum gastrin concentrations and both unstimulated and maximum-stimulated gastric hydrochloric acid secretory rates were determined in 168 subjects. The patients included 55 with duodenal peptic-ulcer disease, nine with gastric ulcers and 69 with assorted gastrointestinal abnormalities, and 35 control subjects without recognized gastrointestinal diseases. Fasting serum gastrin concentrations were measured by radioimmunoassay and compared for groups of patients with differing rates of basal and stimulated gastric acid secretion. There was, in general, an inverse relation between fasting serum gastrin concentrations and rates of gastric hydrochloric acid secretion. Fasting serum gastrin concentrations in patients with duodenal-ulcer disease were not found to be significantly greater than those of the control subjects. However, mean serum gastrin concentrations in the patients with gastric-ulcer disease were found to be significantly greater than those of both the control subjects and...

Studies with Antibodies to Gastrin: Radioimmunoassay in human serum and physiological studies

A double antibody radioimmunoassay technique for measuring gastrin in human serum is described. The results of these studies indicate the requirement for inclusion of ethylenediaminetetraacetate in the immune incubation mixtures. In addition, heat inactivation of the serum prior to radioimmunoassay was required for authentic measurement of serum gastrin levels in human serum. Results of these studies indicate that the proteinase and peptidase inhibitor, Trasylol, which is required in the radioimmunoassay of glucagon, is not required for inclusion in this radioimmunoassay method for measurement of gastrin. Since heparin produced no systematic effects on immunoassayability of gastrin, gastrin levels were measured in serum rather than plasma. Under the conditions of elevated temperature utilized in these studies immunoreactivity of gastrin was found to be thermostable. Fasting serum gastrin levels in 14 normal young adult male volunteers were found to range from immeasurably low to 162 pg per ml with a mean value of 48 pg per ml (sd = 42 pg per ml). Increased levels of serum gastrin were detected and measured in response to stimulation of gastrin release using normal adult male volunteers by feeding a steak-containing meal, as well as following in gestion of glycine and sodium bicarbonate solutions. Elevations in serum gastrin levels in response to stimulation were observed in some, but not all, members of each experimental group. When peak elevations of serum gastrin were detected they occurred from 30 to 45 min following application of the stimulus. Peak responses to stimulation range from 100 to 600 pg of gastrin per ml. Appropriately diluted sera from a patient with hypergastrinemia associated with the Zollinger-Ellison syndrome and hypergastrinemia in a normal adult male volunteer following ingestion of a steak-containing meal yielded radioimmunoassay calibration plots indistinguishable from radioimmunoassay plots derived using dilutions of authentic human gastrin I in fasting normal human serum.

Cellular Localization of Gastrin in the Human Pancreas

Cryostat-cut sections of unfixed and formalin-fixed human pancreata obtained at autopsy were stained by the direct method with fluoresceinated antibodies to human gastrin I. The cytoplasm of a small population of cells in the islets of Langerhans exhibited a bright yellow-green fluorescence. Specificity of the inimunochemical reaction was indicated by a decrease in intensity of stain after preincubation of the fluoresceinated antibody with gastrin and after pretreating the section with nonfluoresceinated antibody-preparation. Immunological cross reactivity with cholecystokinin-pancreozymin was excluded by use of highly specific fluoresceinlabelled antibodies to human gastrin I which exhibit no binding of cholecystokinin-pancreozymin. The presence of immunoreactive gastrin in the human pancreas was also demonstrated by radioimmunoassay measurements of pancreatic tissue extracts. The gastrin-containing cells were selectively stained by the Hellerstrom-Hellman method, indicating that the gastrin cell of the pancreatic islet is the classical delta cell of Bloom (or A1 cell of Hellerstrom and Hellman).

Calcitonin Gene-Related Peptide Modulates Acid-Mediated Regulation of Somatostatin and Gastrin Release From Rat Antrum

BACKGROUND & AIMS Acid has been shown to stimulate calcitonin gene-related peptide (CGRP) release from peripheral sensory afferent nerve endings in the stomach. The aim of this study was to determine whether endogenous CGRP was involved, by a neurocrine mechanism, in acid-mediated stimulation of somatostatin and inhibition of gastrin release. METHODS A two-compartment sleeve of antral mucosal/submucosal tissue was perfused to determine sensory nerve and endocrine cell responses to luminal acid. CGRP receptor antagonist, CGRP8-37, was used to inhibit the actions of endogenously released CGRP. RESULTS Perfusion of the antral sleeve lumen with media of increasing hydrogen ion concentration caused pH-dependent increases in CGRP and somatostatin release and decrease in gastrin release. CGRP8-37 inhibited significantly basal somatostatin (-36%) and stimulated basal gastrin (+65%) release (P < 0.02). Furthermore, CGRP8-37 administration prevented luminal acid-mediated inhibition of gastrin release and stimulation of somatostatin release. These results indicate that CGRP8-37 prevented acid-mediated feedback inhibition of gastrin release and acid-induced feedforward somatostatin release. CONCLUSION These results suggest that CGRP plays an important role in the response of antral D and G cells to luminal acid and that local effector action of endogenous CGRP participates in regulation of antral regulatory peptide secretion.

The human pancreatic islet cells and their tumors. II. Ulcerogenic and diarrheogenic tumors

A comparative histologic examination of hematoxylin‐eosin stained sections of 34 ulcerogenic tumors of the pancreas (UTP), 5 diarrheogenic tumors of die pancreas (DTP), 13 beta cell tumors, and 4 alpha cell tumors revealed two correlative features: all tumors characterized by a gyriform pattern of growth throughout the lesion were either of alpha or beta cell origin, and all but 1 of the tumors containing glandular formations were of either UTP or DTP type. No differential morphological features were found between the tumors which gave rise to metastases and those which did not. A combination of histochemical, ultrastructural, and biochemical studies easily differentiated UTP‐DTP from alpha‐beta cell tumors in most instances. Histochemical stains of 18 UTP and 4 DTP revealed that except for 1 DTP the tumors did not stain with reagents that differentiated normal islet cells. One of the 4 UTP tested gave a positive reaction with a direct immunofluorescent technique using fluoresceinated antibodies to gastrin. Ultrastructurally, all 22 tumors contained secretory granules; in most tumor cells these granules had a diameter range of 150–200 nm, but in others they were pleomorphic and larger (150–360 nm). In this study no morphological, histochemical, or ultrastructural differences were observed between UTP and DTP neoplasms.