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W R Gower

Publications and source records attributed to W R Gower.

At least 55 records · Page 3Linked to original sources
PubMed1991

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.

Animals↗
PubMed1990

Endocrine neoplasms (non-gastrin) of the pancreas.

Although neoplasms that produce gut regulatory peptides and amines can be found throughout the gastroenteropancreatic axis (excluding carcinoids), the vast majority of these lesions are found within the pancreas. Recognition of the various clinical syndromes produced by the secretions of these tumors, the development of sensitive and specific radioimmunoassays for the elaborated peptides, and development of more effective localization techniques have contributed to earlier diagnosis and marked improvement in patient care. Treatment is directed toward medical management to correct the metabolic disturbances produced by the excessive amounts of gut regulatory peptides, followed by localization and extirpation of tumor. In the presence of unresectable tumor or metastases, palliative treatment directed at reducing peptide secretion or preventing its effects by surgery, chemotherapy, hormonal therapy, and hepatic-artery embolization can produce long-term remission of symptoms. Because the majority of these tumors are malignant, the ultimate goal in successful patient management is the early detection and surgical excision of the islet cell tumor before metastases occur.

Adenoma, Islet Cell↗
PubMed1990

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.

Culture Media↗
PubMed1990

Posttranslational gastrin processing depends on tumor morphology.

Extracellular matrices have recently been demonstrated to alter cell morphology in culture. Altered cell morphology has been associated with changes in gene transcription and translation, but it is not known whether it also affects posttranslational processing. Using tyrosine-O-sulfation as a marker of processing, we studied the effects of various substrates on biologically active gastrin (IRG) production and sulfation in gastrin-containing tumor cells (GT cells). Dispersed GT cells were plated onto different substrates and then incubated. Culture media from days 4, 7, and 28 were assayed with specific antibodies that recognize total IRG and nonsulfated IRG. Cells cultured on plastic and dried films of laminin, collagen, and Matrigel (Collaborative Research Inc., Lexington, Mass.) flattened and formed monolayers of GT cells. Cells cultured on a porous membrane and hydrated gels of collagen and Matrigel did not flatten but formed spheroids of GT cells. The monolayer cultures showed an increase in sulfation with time but a decrease in IRG production. The spheroid cultures maintained a constant level of sulfation over time and, with the exception of Matrigel (gel), also showed a decrease in IRG production. These results indicate that the level of sulfation was unchanged from that of the original tumor when cells were grown in spheroids but increased when cultured as monolayers. It appears that alteration of the cellular milieu alters colony morphology, which in turn alters gastrin processing.

Cell Survival↗
PubMed1989

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.

Animals↗
PubMed1989

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.

Animals↗
PubMed1988

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%.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1987

Effect of somatostatin analogue (SMS 201-995) on molecular species of gastrin in gastrinoma.

Somatostatin analogue (SMS 201-995) has been shown to decrease total serum gastrin in patients with gastrinoma; however, the gastrin level rarely returns to normal, despite the near-complete inhibition of acid secretion. This implies that SMS may have an inhibitory action on the biologically active molecular species of gastrin and have little effect on biologically inactive species. To test this hypothesis, we determined the effect of SMS on the molecular species of gastrin in eight patients with the Zollinger-Ellison syndrome. Serum obtained before treatment and 6 hours and 18 hours after treatment (SMS 1 microgram/kg, subcutaneously) was sampled and assayed for molecular species of gastrin by means of gel filtration chromatography and fractional quantitation of gastrin species by radioimmunoassay. There was a significant decrease in the amount of G-34 and G-17 species. BBG and G-14 decreased, a change not significant at 6 hours but significant 18 hours after SMS. The distribution of the various molecular species as a percent of total immunoreactive gastrin was analyzed before and after SMS. There was a shift in the distribution of the molecular species, so that 6 hours after SMS treatment nearly 50% of total gastrin activity was accounted for by BBG and component I. SMS seems to have a different potency to inhibit release of the various gastrin molecular species. This observation may explain the failure of total gastrin levels to return to normal after SMS treatment in patients with the Zollinger-Ellison syndrome.

Aged↗
PubMed1986

Characterization of the in vivo and in vitro inhibition of gastrin secretion from gastrinoma by a somatostatin analogue (SMS 201-995).

Earlier experiments characterized the effect of SMS 201-995 on gastrin secretion from gastrinoma in vivo. The results showed that the somatostatin analogue inhibits basal as well as secretin- and calcium-stimulated gastrin secretion. The current study examined the effect of SMS 201-995 on gastrin secretion from gastrinoma in vitro. Gastrinoma cells were prepared in cell culture or acute cell dispersion to study basal gastrin release. In cell culture, SMS 201-995 at 10(-9) M, 10(-8) M, and 10(-7) M significantly stimulated gastrin secretion (basal medium gastrin, 157 +/- 7.9 pg/ml; with SMS 201-995 10(-9) M, 786 +/- 62 pg/ml; with SMS 201-995 10(-8) M, 569 +/- 72 pg/ml; and with SMS 201-995 10(-7) M, 258 +/- 26 pg/ml). In contrast, in acute cell dispersion, the somatostatin analogue inhibited gastrin secretion (basal medium gastrin, 12.8 +/- 1.3 ng/ml; with SMS 201-995 10(-9) M, 9.0 +/- 0.1 ng/ml; with SMS 201-995 10(-8) M, 8.4 +/- 1.5 ng/ml; and with SMS 201-995 10(-7) M, 7.9 +/- 0.2 ng/ml). Gastrinoma cells were prepared in cell culture to study the effect of SMS 201-995 on gastrin secretion stimulated by secretin and by post-receptor increases in adenosine cyclic nucleotide. The somatostatin analogue inhibited gastrin secretion stimulated by secretin (10(-6) M) (797 +/- 48 pg/ml for secretin alone, compared with 396 +/- 9.4 pg/ml for secretin plus SMS 201-995). SMS 201-995 did not inhibit gastrin secretion stimulated by dibutyryl cyclic AMP (10(-7) M) (617 +/- 62 pg/ml for dibutyryl cyclic AMP alone, compared with 778 +/- 55 pg/ml for the two together). In vitro, SMS 201-995 inhibits basal gastrin secretion from gastrinoma prepared in acute cell dispersion, but not gastrinoma in cell culture, probably due to differences in basal secretory rates. The effect in vitro is less than that in vivo. SMS 201-995 does not inhibit postreceptor increases in adenosine nucleotide. This indirectly supports the hypothesis that SMS 201-995 acts in gastrinoma cells to inhibit gastrin secretion by inhibition of adenylate cyclase activity.

Adult↗
PubMed1986

Hyperparathyroid glands contain G-17 and G-34 gastrin.

To determine if gastrin in hyperparathyroid glands is true gastrin or artifact and to determine the frequency of gastrin in parathyroid glands, 20 parathyroid glands from 11 patients with hyperparathyroidism but without MEA were extracted and analyzed for gastrin. The parathyroid glands from 4 out of 11 patients had measurable gastrin immunoreactivity (10.7 + 6 pg/mg tissue). Column separation chromatography confirmed that this was true gastrin (40% G-34; 50% G-17). Immunohistochemistry with ABC (avidin biotin complex) immunoperoxidase confirmed the presence of gastrin in cytoplasmic vesicles in scattered parathyroid cells. True gastrin does exist in some cells in some patients with hyperparathyroidism.

APUD Cells↗
PubMed1986

Peritoneal fluid in human acute pancreatitis blocks hepatic mitochondrial respiration.

Peritoneal fluid may be the source of multi-system failure during the initial stages of acute pancreatitis. The toxicity of human pancreatic ascitic fluid (HPAF) collected under sterile conditions from 12 patients with acute pancreatitis was investigated with the use of an in vitro preparation of mitochondria. Hepatocyte mitochondria from Sprague-Dawley rats were prepared by standard techniques. Mitochondrial oxidative activity was determined in glutamate-malate medium, with micromodification of the YSI Model 53 (Yellow Springs, Ohio) oxygen electrode system. The oxygen uptake of 150 to 200 microliter samples of mitochondria suspension (20 to 25 mg/ml) was monitored for 3 minutes, after which 3 microliter of 0.1 M adenosine diphosphate (ADP) was added to the chamber to induce state 3 respiration. Two minutes after the oxygen trace returned to state 4 respirations, 20, 40, or 80 microliter of the HPAF sample was introduced into the reaction vessel and the oxygen measurement continued for an additional 3 minutes. After this, 3 microliter of 0.1 M ADP again was added to the reaction chamber and the oxygen measurement continued. Control runs were made with reconstituted pooled human serum used in place of the HPAF samples. A significant (p less than 0.05) increase in state 4 respiration occurred in all 12 samples of HPAF. Addition of ADP showed a significant decline (p less than 0.05) in respiratory control ratio in all specimens. A dose-response curve was observed in 8 of 12 HPAF samples tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1986

Effect of secretin on gastrin release from gastrinoma cells in vitro.

Secretin appears to have a direct effect on gastrinoma cells, which results in a paradoxic increase in the serum gastrin level in patients with the Zollinger-Ellison syndrome. To evaluate this effect, gastrinoma cells were challenged with secretin in acute cell dispersion or after 2 weeks in culture. Acutely dispersed cells were incubated for 15 minutes or 3 hours with and without secretin 10(-6) mol/L. (sec). There was no significant difference in gastrin release between control and sec groups in the two acute incubation periods. At 15 minutes the control value was 47 +/- 1 and the sec value was 54 +/- 1 ng/ml, while at 3 hours the control value was 59 +/- 1 and the sec value was 61 +/- 1 ng/ml. In the cell culture preparation, secretin stimulated gastrin release at all doses (control 463 +/- 85, SEC 10(-10) mol/L 603 +/- 37, sec 10(-8) mol/L 706 +/- 37, sec 10(-6) mol/L 798 +/- 48 pg/ml ([p less than 0.05, Student t test]). These results indicate that secretin stimulates gastrin release directly from cultured gastrinoma cells in a dose-dependent manner but does not stimulate gastrin release from acute cell dispersion. This might be attributed partly to the recovery of secretin receptors in the cultured cells.

Cells, Cultured↗
PubMed1985

Hyperplastic G cell responsiveness in vitro.

To evaluate the responsiveness of isolated, hyperplastic antral gastrin-producing G cells to a variety of secretagogues, hyperplastic hypergastrinemia was produced in Sprague-Dawley rats by fundusectomy. Mean serum immunoreactive gastrin (IRG) concentration was elevated fivefold above controls 4 days after operation and rose steadily to an eightfold increase at 66 days. Mean antral G cell density remained at control levels for as long as 7 days, increased twofold at 14 days, then remained between twofold and threefold greater than controls for as long as 66 days after operation. Antral mucosa IRG content increased from 141 +/- 38 (control) to 262 +/- 58 ng IRG/gm mucosa (4 to 6 weeks after fundusectomy). Crude fractions of dispersed antral mucosa cells enriched in G cells from fundusectomized rats contained 6.5% +/- 1.4% G cells with 0.19 +/- 0.6 pg IRG/G cell. Corresponding preparations from nonoperated rats contained 5.1% +/- 0.5% G cells with 0.07 +/- 0.02 pg IRG/G cell. Viability averaged greater than 95% for all preparations. Gastrin secretion was monitored in cell preparations further enriched in G cells (9% to 10%) by Percoll density gradient centrifugation either in the absence (basal) or presence of bombesin (1 mumol, 1 nmol/L), carbachol (1 mmol/L), leucine (10 mmol/L), and ethylamine (10 mmol/L). The basal secretory rate of hyperplastic G cell populations averaged 250% greater than normal G cell basal rates. Hyperplastic G cell preparations had an increased IRG secretory rate in the presence of bombesin (1 mumol/L, 750%; 1 nmol/L, 191%), leucine (120%), ethylamine (236%), and carbachol (183%). These conditions failed to increase the IRG secretory rate above basal in preparations from normal antra. Viable, dispersed, hyperplastic G cells have increased IRG content and basal IRG secretory rate and are functionally responsive to a variety of secretagogues.

Animals↗
PubMed1983

Prostacyclin in experimental septic acute respiratory failure.

Manipulation of prostaglandins (PG) in animal models of sepsis and acute respiratory failure (ARF) is promising. Prostacyclin (PGI2), a short-acting vasodilator, was evaluated in a porcine model of ARF produced by continuous infusion of live Pseudomonas aeruginosa (Ps.). Cardiopulmonary parameters were monitored in three groups of spontaneously breathing animals that received 0.1 micrograms PGI2/kg/min begun 20 min after baseline (Group I); 2 X 10(8) Ps./20 kg/min (Group II); identical Ps. infusion and then PGI2 begun at 20 min (Group III). The decrease in mean arterial blood pressure and cardiac index with Ps. infusion was improved by PGI2 treatment. In Groups II and III, mean pulmonary artery pressure (PAP) doubled (P less than 0.005) and pulmonary vascular resistance (PVR) tripled (P less than 0.01) by 15 min. Both PAP and PVR were decreased significantly with PGI2 treatment. In both Ps. groups, significant hypoxemia occurred. PGI2 improves cardiac output and acts as a pulmonary vasodilator, but does not improve oxygenation in this porcine model of severe ARF.

Acute Disease↗
PubMed1983

Hypogastrinemia in streptozotocin diabetes with islet transplantation--reconstitution.

Gastrin is present in normal mammalian pancreatic islets, as well as in the antrum and duodenum. Serum gastrin levels are responsive to many physiologic and pharmacologic factors including hyperglycemia, somatostatin, and glucagon. To evaluate the effects of streptozotocin diabetes and islet transplantation on gastrin homeostasis, young, adult, male Lewis rats underwent streptozotocin diabetes alone (N = 14), diabetes plus intraperitoneal islet isografts (N = 22), or sham operation alone (N = 18). Streptozotocin reduced fasting gastrin immunoreactivity (107 pg/ml +/- 26 mean +/- SEM) compared to controls (256 pg/ml +/- 31) (P less than 0.001). Islet isotransplantation resulted in restoration of fasting gastrin immunoreactivity (230 pg/ml +/- 19) to levels significantly greater than diabetics (P less than 0.001) and comparable to control animals (P = NS). Normalization of serum gastrin levels occurred within one month of transplantation and persisted for up to 14 months. In addition, media from cultures of 4/7 dispersed neonatal rat pancreas cultures contained gastrin immunoreactivity. Streptozotocin diabetes produces hypogastrinemia; intraperitoneal islet isotransplantation normalizes fasting gastrin immunoreactivity. Rat islet culture medium contains gastrin-like immunoreactivity. Pancreatic islets would appear to produce or control a portion of circulating gastrin immunoreactivity.

Animals↗
PubMed1983

Experimental pancreatitis does not produce pulmonary hypertension.

The onset of experimental hemorrhagic pancreatitis in dogs was rapidly followed by a deterioration of CO, blood pressure, LVSW and RVSW, along with significant elevations of Hct, SVR and PVR. These alterations could all be reversed by the administration of Ringer's lactate. These findings support the concept that the major physiopathologic characteristic of severe acute pancreatitis is a loss of effective plasma and extracellular fluid volumes and that the replacement of fluid losses corrects the hemodynamic alterations. In neither of the experimental groups did pulmonary hypertension develop. We found no evidence in this model of hemorrhagic pancreatitis for a circulating pulmonary vasoactive substance.

Acute Disease↗
PubMed1982

What's new with G-17?

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Chromatography, Ion Exchange↗