Eugene Straus

HYPERSECRETION OF GASTRIN ASSOCIATED WITH THE SHORT BOWEL SYNDROME

Abstract Marked hypergastrinemia characterized by high fasting levels and a prompt sharp response to a standard test meal was observed in a group of 4 patients with short bowel syndrome, but not in a patient with jejunoileal bypass. In keeping with the findings in other gastrin hypersecreters, the predominant form of circulating gastrin in the patients with short bowel syndrome was big gastrin. The possibility that hypergastrinemia might result from the absence of a factor in the distal small intestine that inhibits gastrin release is considered.

Studies on the Distribution and Degradation of Heptadecapeptide, Big, and Big Big Gastrin

Spaces of distribution and rates of degradation were determined for both unlabeled and radioiodinated gastrin peptides after pulse injection. The major forms of circulating gastrin; heptadecapeptide gastrin, big gastrin, and big big gastrin were found to have half-times for disappearance of approximately 3, 9, and 90 min, respectively. Since the plasma concentration of each component under steady state conditions is determined not only by its secretion rate, but also by its distribution into extravascular spaces and its rate of degradation, these findings put into proper perspective the previously described patterns of the relative concentrations of the three components in different clinical conditions and in response to physiologic secretagogues and suppressants.

Degradation of vasoactive intestinal polypeptide by tissue homogenates

Abstract Extracts of liver, kidney and brain contain an enzyme that is highly specific for degradation of vasoactive intestinal polypeptide (VIP). The Michaelis constants (Kms) appear to be nearly identical in all three tissues, averaging about 10−5 mol/liter. The Vmax for kidney and liver are about the same but that for cerebral cortex is about two-fold lower. Since the relative Vmax in the three organs differ for insulin and VIP, it is concluded that it is unlikely that the same enzyme is responsible for the degradation of both peptides.

Canine Zollinger-Ellison Syndrome

The unusual finding of peptic esophagitis and duodenal ulceration in a dog was associated with a malignant pancreatic islet cell tumor producing gastrin and ACTH. The finding of a gastrinoma in a non-human species introduces the potential for developing an animal model for the study of the protean genetic biochemical, physiologic and metabolic aspects of the Zollinger-Ellison syndrome.

Immunochemical studies relating to cholecystokinin in brain and gut.

Publisher Summary This chapter presents an overview of the immunochemical studies relating to cholecystokinin in the brain and gut. Cholecystokinin (CCK) is a central nervous system (CNS) peptide. It is exceptional in its high brain concentration—far exceeding the brain concentrations of other brain–gut peptides—and remarkable in its abundance and broad distribution throughout the cerebral cortex. It is further unusual in the variety of its heterogeneous molecular forms; these are distributed differently in brain and gut tissues. Both intact CCK-33 and its COOH-terminal fragments are found in the brain as well as in the gut. The chapter discusses the two discoveries that have contributed to the current surge of interest in immunochemical studies of CCK. The COOH-terminal approach is preferred for the measurement of CCK peptides in gastrin-free tissue extracts but is not applicable to the measurement of plasma CCK because of the relative abundance of gastrin peptides in plasma and their strong cross-reactivity in this assay.

Comparative reactivities of 125I-secretin and 125I-6-tyrosyl secretin with guinea pig and rabbit anti-secretin sera

Abstract Since secretin contains only an N-terminal histidyl and no tyrosyl residue, a synthetic secretin has been commercially prepared containing tyrosine in place of phenylalanine to facilitate the preparation of a radioiodine labeled tracer. We have found that although the rate of iodination of 6-Tyr-secretin is more rapid than that of secretin, the efficiency of iodination is not greatly increased and the shelf-life of the labeled product is not prolonged. The striking disadvantage of the use of 125I-6-Tyr-secretin as a tracer in radioimmunoassay is its diminished immunoreactivity with several guinea pig and rabbit antisera compared to 125I-secretin.

Ontogeny of immunoreactive CCK and VIP in pig brain and gut

The concentrations and hormonal forms of CCK and VIP have been determined in extracts of the brain and duodenum of the developing and adult pig. In methanol extracts of the brain cortex, the single hormone form, CCK8, increased from 130 +/- 20 (Mean +/- SEM) pmol/g at birth to an adult level of 300 +/- 50 pmol/g. In acid extracts of brain, the predominant immunoreactive form had N-terminal immunoreactivity and increased from 240 +/- 20 pmol/g at birth to an adult level 490 +/- 30 pmol/g; the C-terminal immunoreactivity was about 10-fold lower. The concentrations and hormonal forms of immunoreactive CCK in duodenal extracts did not appear to be age-related. C-terminal immunoreactivity in methanol extracts averaged 140 +/- 20 pmol/g and in acid extracts 240 +/- 60 pmol/g. The concentration of N-terminal immunoreactivity in acid extracts averaged 490 +/- 70 pmol/g. The VIP concentrations in acid extracts of the brain cortex was 13.5 +/- 2 pmol/g at birth and rose gradually to 30 +/- 9 pmol/g in the adult; in duodenal extracts it was 240 +/- 18 pmol/g at birth and 195 +/- 38 pmol/g in the adult. These results are in marked contrast with the ontogeny of these hormones in the rat in which brain concentrations of CCK and VIP in the neonate are less than 10% of adult levels and in which there are age-related changes in the content of these hormones in the duodenum as well.

Alkaline extraction of cholecystokinin-immunoreactivity from rat brain

Abstract Alkaline aqueous extractants remove from rat brain 2 to 4 times the CCK-immunoreactivity that is removed by acidic or neutral aqueous extractants. The distribution among the various hormonal forms appears to be independent of the extractant: about 1 10 in the larger basic forms (CCK-33 and CCK-39); about 1 4 as the C-terminal dodecapeptide (CCK-12) and the remainder as the octapeptide (CCK-8). In contrast, alkaline and acidic aqueous solutions are equally efficient in extraction of enkephalin-immunoreactivity from the same tissues. We are presently unable to account for the very different efficiencies of the various extractants in removing CCK-immunoreactivity from brain.

Cholecystokinin and Enkephalin levels following ethanol administration in rats

Using radioimmunoassay, cholecystokinin and enkephalin levels were determined in the brain and gut of rats following ethanol administration. Acute or chronic administration of ethanol did not affect the cholecystokinin or enkephalin content of rat brain cortex, hypothalamus, striatum or proximal small bowel. This contrasts with the reports of altered levels of several classical neurotransmitters following ethanol administration.

Nature of immunoreactive CCK in rat and pig brain.

Two major classes of immunoreactive cholecystokinin peptides (iCCK) have been identified in rat and pig brains: (1) large basic peptides (Big iCCK) resembling pCCK33 in size and charge; (2) small acidic peptides (Small iCCK) resembling the COOH-terminal fragments of CCK. Boiling 0.1 N HCl maximally extracts Big iCCK; boiling 0.1 N NaOH maximally extracts Small iCCK. The differences in hormonal forms removed by these extractions are not likely to be due to enzymatic conversion during the extraction procedures. Fractionation on Sephadex G50 and starch gel electrophoresis combined with radioimmunoassay using 3 antisera of different specificities: (1) directed towards the NH2-terminus of pCCK33; (2) produced by immunization with CCK8; (3) produced by immunization with CCK4; are consistent with the hypothesis that a major fraction of Big iCCK may represent intact CCK with a COOH-terminus extension as has recently been suggested for gastrin, a molecule having a COOH-terminal pentapeptide identical with that of CCK.