Fundusectomy-induced hypergastrinemia is not due to acid inhibition alone.

Hypergastrinemia is often attributed to loss of acid inhibition in the gastric antrum. Prior studies suggest, however, that hypergastrinemia after fundusectomy occurs earlier and to a greater degree than hypergastrinemia after total acid inhibition with high dose (8 mg/kg/day) famotidine. To explain the very early (0 to 21-day) gastrin response, 45 male Sprague-Dawley rats (250 to 350 gm) were equally allocated to fundusectomy alone, famotidine alone, and fundusectomy plus famotidine groups. Vena cava blood samples and antral tissue were harvested at 0, 4, 7, 9, 14, and 21 days. Fundusectomy produced dramatic, sustained hypergastrinemia as early as 4 days after the procedure. Minimal, transient hypergastrinemia was seen with famotidine treatment, but this returned to baseline in spite of total acid inhibition. Antral gastrin was comparable in all three groups at the intervals assessed. Furthermore, fundusectomy plus famotidine did not demonstrate a significant difference from fundusectomy alone. Thus it appears that fundusectomy produces early and sustained hypergastrinemia by a mechanism other than acid inhibition.

Control of gastrin release in cultured gastrinoma-derived G cells.

Functional gastrin-containing tumor cells (GT cells) have been maintained in short-term culture on microporous membranes, and their response to selected agents has been determined. After dispersion of gastrinoma by collagenase-DNAase digestion coupled with mechanical disruption, dispersed cells were depleted in stromal material by selective attachment to a plastic substrate, then cultured for 72 hours on porous cellulose membranes. Cultures contained 68 +/- 5% GT cells with a viability of 92 +/- 2%. Secretin stimulated the rate of gastrin release from cultured GT cells in both a time- and a dose-dependent fashion. To examine the possible involvement of adenylate cyclase- and protein kinase C-mediated mechanisms in regulating gastrin release from the neoplastic GT cells, we evaluated the effects of 8-bromoadenosine 3':5'-cyclic monophosphate (8-BrcAMP; 10(-4) - 10(-2) mol/L), the diterpene forskolin (10(-5) mol/L), 12-0-tetradencanoylphorobol 13-acetate (TPA; 10(-8) - 10(-6) mol/L), and 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD; 10(-8) - 10(-6) mol/L) on gastrin release. Among all compounds tested, 8-BrcAMP (10(-2) mol/L) was the most potent, stimulating the rate of gastrin release 263% above basal. Both 8-BrcAMP and TPA stimulated gastrin release in a dose-dependent fashion. The biologically inactive phorbol ester, 4 alpha PDD, was without effect at all concentrations. Somatostatin (10(-8) - 10(-6) mol/L) inhibited 8-BrcAMP-stimulated gastrin release in a dose-dependent fashion to a maximum of 75%.

Atrial natriuretic factor: a possible new gastrointestinal regulatory peptide.

Although associated primarily with the cardiovascular system, atrial natriuretic factor (ANF) has been found to increase the magnitude of duodenal contractions and may play a role in salt and water absorption across gastrointestinal epithelium. Because secretory diarrhea and increased peristalsis are commonly associated with conditions related to hypergastrinemia, we examined an animal model of hypergastrinemia (fundusectomy) to evaluate a possible role for ANF. Sprague-Dawley rats underwent either fundusectomy or sham operation. Circulating levels of gastrin (1085 +/- 105 vs 59 +/- 5 pg/ml), ANF (209 +/- 50 vs 59 +/- 10 pg/ml), and pro-ANF 1-98 (786 +/- 80 vs 599 +/- 49 pg/ml) were elevated significantly 3 months after fundusectomy versus control animals. The increased levels of ANF and pro-ANF 1-98 correlated with the increased gastrin levels (p less than 0.05). Tissue content of ANF and pro-ANF 1-98 were determined at sequential sites in the stomach and small intestine. In normal rats ANF concentrations were greatest in the small intestine; pro-ANF 1-98 content was similar in all tissues except ileum (increased). In rats that underwent fundusectomy, ANF and pro-ANF 1-98 were markedly increased in duodenum compared with all other tissues. Only duodenum showed a difference in peptide levels between normal rats and rats that underwent fundusectomy, (ANF, 1.5 +/- 0.5 vs 16.7 +/- 2.3 ng/gm; pro-ANF 1-98, 0.6 +/- 0.3 vs 51.2 +/- 36.1 ng/gm). Circulating ANF and pro-ANF 1-98 are increased in rats that have undergone fundusectomy. Our results suggest that duodenum may be the source of these increased levels.

Simple calculation of the unpaired t test.

Statistical evaluation of published research data is frequently difficult. A simple calculating equation, amenable to a pocket calculator, is presented, which allows statistical comparison of two groups of data when mean and standard error of the mean are known for each group. This equation is valid in all circumstances in which a t test can be applied, even if sample sizes or variances are unequal. Comparison with the standard published equations demonstrated identical results in all instances. This equation provides a simple method of calculating statistical significance when reading papers or attending meetings.

Is there a fundic factor which regulates G cells in the antrum?

Both surgical fundusectomy and pharmacologic acid inhibition have been shown to produce antral G cell hyperplasia in rats. Fundusectomy has also been shown to be a reliable, reproducible means to produce hypergastrinemia. In contrast, treatment of animals with famotidine, a histamine H2 receptor antagonist, or omeprazole, a H+-K+-ATPase enzyme inhibitor, failed to produce hypergastrinemia. This suggests that elimination of acid inhibition may not be the sole mechanism of hypergastrinemia after fundusectomy. We hypothesized that removal of the gastric fundus may remove a factor which controls G cell activity.

Hepatic function after porto-systemic shunt.

Advanced hepatic injury can be identified by the appearance of jaundice, coagulopathy, or encephalopathy but these conditions are late, irreversible findings and represent the end stage of a long insidious process. Currently available methods for assessing "liver function" (SGOT, SGPT, GGT, LDH, etc.) do not actually measure liver function. In this study we prospectively evaluated "true" liver function in patients undergoing porto-systemic shunt. Effective hepatic blood flow [low dose galactose clearance (EHBF)], hepatocyte transport (theophylline levels at 24 hr), and hepatic conjugation ability [acetaminophen metabolism to its glucuronide and sulfate conjugates ( (S + G)/A) and acetaminophen remaining at 24 hr (A24)] were measured in normal males (NL) and in patients pre- and post-8-mm H-graft portacaval shunt (PCS). All data are means +/- SEM, analyzed by Student's t test, and significance was accepted if P less than 0.05. There were no significant differences in EHBF even after PCS. Hepatocyte transport was decreased in pre-op (1.43 +/- 0.16 vs 0.74 +/- 0.08) and post-op (1.79 +/- 0.34) PCS patients. Hepatic conjugating ability was also decreased in pre-op PCS patients [A24 was increased (0.24 +/- 0.11 vs 0.01 +/- 0.01) while the ratio of conjugation products to acetaminophen remained the same]. The ability of the liver to conjugate substrate was severely compromised postoperatively [A24 - 1.27 +/- 0.67, (S + G)/A - 1.19 +/- 0.34]. We believe that changes in liver function can be accurately measured using these noninvasive methods, and in using these methods we have identified altered hepatocyte transport and conjugating ability in patients undergoing porto-systemic shunt surgery.

Gastrinoma in vitro: morphological and physiological studies of primary cell cultures.

Functional gastrin-containing tumor cells were maintained for up to 8 wk without fibroblastoid cell overgrowth. Short-term cultures consisted mainly of colonies composed of small polygonal cells, 70%-90% of which stained positive for immunoreactive gastrin. Cultures exhibited limited growth but viability remained high for 2-3 wk. Culture medium contained component I, and gastrin 34, 17, and 14. With time the major C-terminal gastrin species in medium changed from gastrin 17 at 3 days to gastrin 34 at 5 wk. Extracts of cultured cells contained gastrin 34, 17, and 14; gastrin 17 was the major form detected at all times. Ultrastructurally, cultured tumor cells retained morphological integrity for several weeks; however, with time changes in the appearance of the secretory granules accompanied by evidence of cellular retrodifferentiation were gradually observed. Secretin, gastrin-releasing peptide, 8-bromoadenosine 3':5'-cyclic monophosphate, and phorbol, 12-myristate, 13-acetate stimulated the release of gastrin from cultured cells in a time-dependent fashion. Secretin, bombesin, gastrin-releasing peptide, L-tryptophan, and ethylamine stimulated gastrin release in a dose-dependent fashion. Somatostatin 14 inhibited secretin, bombesin, and gastrin-releasing peptide stimulated gastrin release but did not alter basal release. Cultured cells demonstrated de novo gastrin synthesis, evidenced by their ability to incorporate radiolabeled amino acids into immunoadsorbable gastrinlike material. Primary cultures of gastrin-containing tumor cells free from stromal contamination offer unique advantages for studies of factors that regulate the synthesis and secretion of gastrin and may prove of potential value for studies on cell differentiation and growth.