Localization of gastrinoma using arterial secretin stimulation--worthwhile or passing fancy?
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Gastrins↗
Biomedical subjects
M M Wolfe
Publications and source records attributed to M M Wolfe.
Zollinger-Ellison syndrome.
As clinical experience with patients with ZES has grown, increasing recognition has been made of the broad spectrum of symptoms associated with gastrinomas. Diarrhea and acid-induced esophageal injury have taken their place alongside chronic peptic ulcer disease as indications for screening for gastrinoma. Diagnostic testing should begin with fasting serum gastrin levels and should include intravenous secretin infusion if fasting serum levels of gastrin are nondiagnostic and the patient is not found to be hypochlorhydric. Tumor localization is critical to aid in the identification of patients with potentially curable localized disease. Preoperative evaluation utilizing CT scanning with intravenous contrast should be done early and should be supplemented by other imaging modalities as necessary. Exploratory laparotomy, including a thorough examination of the duodenum and perhaps intraoperative ultrasound, should be performed in all patients with sporadic gastrinoma who lack evidence of extensive metastatic disease on preoperative evaluation. By utilizing this approach, it is likely that at least 20% of patients with ZES can be cured. With the availability of the highly effective H(+)-K(+)-ATPase inhibitor omeprazole, excellent control of symptoms related to gastric acid hypersecretion can be expected. Patients with unresectable gastrinoma may thus avoid potentially morbid antisecretory surgery and be managed with a fairly simple medical regimen. Further developments in the chemotherapeutic management of these patients with unresectable disease should be forthcoming in the future.
Gastric Acid↗
Somatostatin stimulates gastrin mRNA turnover in dog antral mucosa.
Previous studies have demonstrated that antral somatostatin exerts inhibitory effects on gastrin cells via paracrine pathways, accomplished by its release from somatostatin-containing cells into the immediate interstitial environment of the gastrin cell. The present studies were directed to examine the effect of somatostatin on gastrin gene transcription in the dog antrum and to determine whether somatostatin modulates gastrin mRNA turnover. In response to the immunoneutralization of endogenous antral somatostatin, basal gastrin gene transcriptional activity increased by 34 +/- 3.3% (p less than 0.01). Moreover, somatostatin significantly inhibited gene transcription that had been stimulated by dibutyryl-cAMP and carbachol. To determine the effect of somatostatin on gastrin mRNA turnover, antral mucosal fragments were incubated with antibodies to somatostatin, total RNA was extracted, and gastrin mRNA was measured at several time points. Following the immunoneutralization of antral somatostatin, maximum induction was achieved at 60 min, at which time gastrin mRNA levels had increased by 184 +/- 6.0% (p less than 0.01). At that time, a somatostatin analogue which is biologically active, but nonimmunoreactive with the antiserum, was added to the incubation medium. The analogue produced a prompt and steady de-induction of gastrin mRNA concentration, which returned to basal levels by 120 min. Regression analysis of RNA induction and de-induction profiles demonstrated a 292 +/- 40.6% increase (p less than 0.01) in gastrin mRNA turnover induced by somatostatin. In separate experiments antral mucosa was incubated with cycloheximide, both in the presence and absence of somatostatin antibodies. Incubation in the presence of cycloheximide resulted in a 52.3 +/- 8.4% (p less than 0.01) increase in gastrin mRNA levels under basal conditions, but had no effect following antral somatostatin immunoneutralization. Our results indicate that, although somatostatin inhibits gastrin gene transcription, its predominant effect on gastrin gene expression appears to occur at the posttranscriptional level by increasing the turnover of gastrin mRNA.
Animals↗
Cholecystokinin binding and degradation by isolated rat liver cells.
The present studies were directed to examine and quantify binding and degradation of radiolabelled cholecystokinin (CCK) peptides by isolated rat liver cells. After incubation with liver cells (4.5 x 10(6) cells/ml) at 14 degrees C, minimal binding (less than 5%) of labelled CCK33 was detected. When labelled nonsulfated (nsCCK8) and sulfated CCK8 (sCCK8) were incubated, 16.2 +/- 1.8% (mean +/- S.E.) and 7.2 +/- 0.1% of 125I-nsCCK8 and 125I-sCCK8, respectively, were bound to the cell fraction. However, no inhibition of binding of either labelled nsCCK8 or sCCK8 was observed when incubated in the presence of excess unlabelled peptide (10 ng-10 micrograms). Preferential binding of labelled sCCK8, the biologically active form of the octapeptide, appeared to be to the nonparenchymal liver cell, rather than the hepatocyte, fraction; when corrected for cell size and protein content, binding of sCCK8 was approximately 15-times greater by the nonparenchymal cell population. When incubated with hepatocytes at 37 degrees C for 60 min, no degradation of labelled sCCK8 was detected by high pressure liquid chromatography. In contrast, progressive degradation of sCCK8 was observed when the peptide was incubated with the nonparenchymal cells. The results of these studies confirm previous observations that CCK33 is not bound by the liver. They further demonstrate that to some degree CCK8 is preferentially bound and degraded by hepatic nonparenchymal cells; however, this binding appears to be noncompetitive and, therefore, probably not receptor-mediated.
Animals↗
Diagnosis of gastrinoma: much ado about nothing?
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Calcium↗
Effect of antibodies to the neuropeptide GRP on distention-induced gastric acid secretion in the rat.
The present study examined and compared the effects of muscarinic blockade, beta-adrenergic blockade and immunoneutralization of the neuropeptide gastrin-releasing peptide (GRP) on distention-induced gastric acid secretion and gastrin release. In response to distention of rat stomachs with 0.9% NaCl, acid output rose from 3.5 +/- 0.5 mumol H+/30 min to 15.4 +/- 2.5 mumol H+/30 min (P less than 0.01). Intravenous administration of 4 mg/kg propranolol did not affect the acid secretory response to distention, however both 2 mg/kg atropine and 6 mg/kg pirenzepine significantly decreased gastric acid secretion by 44.8 +/- 7.8% and 40.9 +/- 5.7% (P less than 0.05), respectively. When specific antibodies to GRP were infused intravenously, the acid secretory response to distention was nearly abolished, decreasing to 5.1 +/- 0.8 mumol H+/30 min (P less than 0.01). In contrast to the effects on acid secretion, GRP antiserum did not significantly alter the gastrin release observed following distention. Results of these studies indicate that, under the conditions of these experiments, the acid secretory response to gastric distention may be independent of its effect on gastrin release. Although distention-induced gastric acid secretion may be partially governed by muscarinic pathways, the acid secretory response to distention in the rat appears to involve GRP-containing neurons.
Animals↗
Inhibition of antral gastrin cells by peptide histidine isoleucine.
The present studies were directed to determine whether peptide histidine isoleucine (PHI), like its structural analogues secretin and gastric inhibitory peptide, inhibits antral gastrin. In separate experiments, the effects of PHI on medium gastrin concentrations, the incorporation of [35S]methionine into newly synthesized gastrin, and steady-state gastrin mRNA were determined. The inclusion of PHI in the incubation medium decreased medium gastrin levels at all concentrations examined, an effect that was not altered by the addition of 10(-6) M tetrodotoxin to the medium. PHI also inhibited the incorporation of [35S]methionine into newly synthesized gastrin in a concentration-dependent manner. Steady-state levels of gastrin mRNA were determined by dot-blot hybridization, using a 32P-labeled gastrin cRNA probe. PHI inhibited gastrin mRNA levels in a concentration-dependent manner; in contrast, no effect on the levels of actin and ubiquitin mRNA could be detected, indicating specificity of PHI on gastrin mRNA. The results of these studies indicate that PHI may exert a physiological inhibitory effect on antral gastrin cells and that this inhibition may occur at several steps along the biosynthetic pathway.
Animals↗
Inhibition of gastrin gene expression by somatostatin.
Previous studies performed in this laboratory have demonstrated somatostatin-containing cells in close proximity to gastrin cells in antral mucosa and have shown that somatostatin exerts a local regulatory effect on gastrin release. The present studies were directed to determine whether the effects of somatostatin on the antral gastrin cell involve pretranslational events. The effects of somatostatin on gastrin mRNA were determined by dot blot hybridization using a gastrin antisense RNA probe derived from human gastrin cDNA. Inclusion of somatostatin in the incubation medium caused a dose-dependent inhibition of steady-state gastrin mRNA. Conversely, when antral somatostatin was neutralized by the addition of specific somatostatin antibodies to the incubation medium, gastrin mRNA levels increased by 116 +/- 31% over control values (P less than 0.01). Northern blot hybridization of total antral RNA demonstrated a single major band with a molecular size of approximately 620 nucleotides, closely matching the predicted size of gastrin mRNA. The effect of somatostatin on the rate of gastrin gene transcription was examined using nuclear run-off transcription assays. Inclusion of antibodies to somatostatin in the incubation medium resulted in a 33.8 +/- 3.3% increase in gastrin gene transcriptional activity (P less than 0.01). These studies indicate that, in addition to its established effect on peptide release, somatostatin exerts inhibitory effects on antral gastrin cells at the pretranslational level. Although this inhibition appears to occur in part at the gene transcriptional level, the results also indicate that somatostatin may affect posttranscriptional processing of gastrin mRNA.
Animals↗
The physiology of gastric acid secretion.
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Animals↗
Considerations for selection of parenteral histamine (H2)-receptor antagonists.
Parenteral histamine (H2)-receptor antagonists are safe and effective therapy for the prophylaxis of stress-related erosive syndrome. Of the three agents available, parenteral cimetidine is the most widely studied; parenteral formulations of ranitidine and famotidine have not been investigated as extensively. Parenteral cimetidine appears to be effective in reducing incidence and complications associated with gastrointestinal hemorrhage caused by stress-related erosive syndrome, although its effects on bleeding that has already begun are not clear. Antacids are also effective in decreasing the incidence of stress-related gastrointestinal hemorrhage, but they are inconvenient and expensive to administer. Primed continuous of stress-related erosive syndrome in critically ill patients; the evidence available on the efficacy of continuous infusions of ranitidine is inconsistent, and very few data are available on the value of famotidine. Direct comparative clinical trials are needed to assess definitively the efficacy of primed continuous infusions of cimetidine or other H2-receptor antagonists versus that of antacid therapy.
Gastrointestinal Hemorrhage↗
Zollinger-Ellison syndrome. Current concepts in diagnosis and management.
The Zollinger-Ellison syndrome, although uncommon, is not rare, and most patients with the disorder present with clinical manifestations similar to those of patients with common peptic ulcer. Early studies emphasized death due to complications of massive gastric acid hypersecretion. However, with the availability of potent antisecretory agents to control acid secretion, death is now more frequently associated with the metastatic potential of slowly growing but malignant gastrinomas. Therefore, physicians should maintain a high degree of suspicion of the Zollinger-Ellison syndrome in assessing patients with either chronic peptic ulcer or unexplained secretory diarrhea. An evaluation aimed at early diagnosis of the Zollinger-Ellison syndrome should be instituted in such patients and should begin with a determination of the fasting serum gastrin level. At least 50 percent of patients with gastrinoma will have nondiagnostic serum gastrin concentrations and will therefore require provocative testing to establish the correct diagnosis. After the presence of the syndrome is established, patients should be treated with a potent antisecretory agent in doses sufficient to reduce basal acid output to less than 10 mmol in the hour preceding administration of the next dose. Although some patients may be maintained satisfactorily in this manner for extended periods, an approach aimed at tumor localization and extirpation is recommended in most patients. Preoperative evaluation should begin with CT scanning with intravenous contrast material. Selective angiography, and occasionally, portal venous sampling for gastrin, should be performed if the location and extent of tumor remain in question. If metastatic disease is demonstrated, or if MEN-I is present, surgery aimed at tumor resection, although it is occasionally effective, will probably be unsuccessful. Because of the considerable morbidity and mortality associated with pancreatoduodenectomy, it should not be performed for unresectable tumor in the head of the pancreas. In other patients with the Zollinger-Ellison syndrome, exploratory surgery should be performed; this should include a careful search for, and resection of, all pancreatic and extrapancreatic gastrinomas. With this approach, it is likely that at least 20 percent of all patients with the Zollinger-Ellison syndrome can be cured.
Gastric Juice↗
Hepatic clearance of somatostatin and gastrin-releasing peptide.
In order to examine hepatic clearance of gastrointestinal regulatory peptides, rat livers were perfused in situ, and radiolabelled somatostatin (S-14, S-28), gastrin-releasing peptide (GRP-14, GRP-27), and vasoactive intestinal peptide (VIP) were injected into the portal vein and hepatic venous effluent was collected. S-14 and S-28 were not affected significantly by hepatic transit: 91.6 +/- 2.8% (SEM) of S-14 and 95.9 +/- 2.2% of S-28 were recovered, and neither peptide was degraded by hepatic transit, as determined by immunoprecipitation and gel chromatography. GRP-14 and GRP-27 were also not affected by hepatic transit: 91.5 +/- 1.6% of GRP-14 and 94.4 +/- 2.4% of GRP-27 were recovered intact. In contrast, when radiolabelled VIP was infused into the portal vein, 56.7 +/- 7.4% of injected labelled VIP appeared in the hepatic venous effluent, of which only 33.5 +/- 1.2% was intact peptide. Results of these studies indicate that enteric VIP released into the splanchnic/portal circulation is cleared by hepatic transit. However, somatostatin and GRP peptides appear to traverse the liver intact and could potentially produce systemic biological effects.
Animals↗
Lack of interaction of ranitidine with amitriptyline.
The possibility of an interaction of ranitidine with amitriptyline was assessed by means of amitriptyline and nortriptyline plasma concentration measurements, blood pressure and pulse rate, digit symbol substitution, and visual analogue scales. Ranitidine had no effect on amitriptyline or nortriptyline concentrations. Responses recorded by the digit symbol substitution and visual analogue scale tests correlated with changes in concentrations of amitriptyline and nortriptyline in plasma. No effects on blood pressure or pulse rate were observed. We concluded that there was no effect of ranitidine on amitriptyline kinetics or response in the conditions of our study.
Adult↗
Beta-adrenergic stimulation of gastrin release mediated by gastrin-releasing peptide in rat antral mucosa.
The present studies were directed to examine the effects of beta-adrenergic and cholinergic stimulation on gastrin release and to assess the potential role of gastrin-releasing peptide in exerting these effects, utilizing incubated rat antral mucosa. Rat antral mucosa was incubated at 37 degrees C in Krebs-Henseleit bicarbonate buffer, pH 7.4, continuously gassed with 95% O2-5% CO2. After 1 h media were sampled for radioimmunoassay measurement of gastrin content. Inclusion of carbachol (2.5 X 10(-6) M) in culture medium increased medium gastrin concentration by 106 +/- 28% (P less than 0.01); addition of specific antibodies to gastrin-releasing peptide to the culture medium did not affect carbachol-stimulated gastrin release. Inclusion of isoproterenol (10(-9) M) in culture medium did not affect somatostatin release into the medium, but increased medium gastrin by 234 +/- 24% (P less than 0.001). However, in contrast to carbachol, addition of antibodies to gastrin-releasing peptide to culture medium decreased isoproterenol-stimulated gastrin release by 67 +/- 9% (P less than 0.001). Results of these studies indicate that, under the conditions of these experiments, beta-adrenergic, but not muscarinic, stimulation of gastrin release may be mediated, at least in part, through gastrin-releasing peptide.
Animals↗
Localization and resection of gastrinomas in Zollinger-Ellison syndrome.
From 1971-1986, 24 patients were diagnosed as having Zollinger-Ellison syndrome (ZES) and 22 patients had laparotomy. Of this group, gross tumor was identified in 15 of 22 patients. Ten of 15 patients had resection of their gastrinomas with the specific aim of curing the disease. This group had responded favorably to either cimetidine or ranitidine before operation. Preoperative transhepatic portal venous sampling (PVS) with gastrin determinations was performed in six patients; three patients had this procedure twice. The tumor was correctly localized by PVS in five of six patients. In four of six patients, the tumor was easily found at surgery. In two of six patients (33%) PVS was vital to intraoperative decisions. Criteria for biochemical cure are normal periodic fasting gastrin and secretin infusion tests. Of the 10 patients who had resection for potential cure, two patients failed within 48 hours of surgery on the basis of an elevated fasting serum gastrin level in one patient and a positive secretin infusion test in the other patient. Eight patients were considered cured with follow-up from 6 months through 15 years. Of the eight cured patients, the tumors were located as follows: four were extraintestinal and extrapancreatic, four were in the duodenal wall, one patient had a tumor located in the uncinate process of the pancreas, and one tumor was located in a lymph node along the lesser curve of the stomach. Two patients had mobilization of the pancreas and duodenum for a "blind" pancreatoduodenectomy based on preoperative PVS (2 procedures each patient). In one patient a 3-mm gastrinoma was enucleated from the posterior uncinate process. The second patient had pancreatoduodenectomy with findings of two duodenal wall gastrinomas. Both patients remained cured of ZES beyond 2 years. It is concluded that PVS does indeed locate some tumors before operation, even those not easily found at surgery. ZES can be cured by an aggressive approach combining preoperative tumor localization and tumor resection. Of the eight patients biochemically and perhaps biologically cured, follow-up was greater than four years in five patients, greater than two years in two patients, and beyond six months in one patient.
Duodenal Neoplasms↗
Peptide characterization of secretin preparations.
The present study was designed to examine and compare the peptide composition and relative immunochemical purity of GIH and Boots secretin preparations. Gastrointestinal peptides were measured by radioimmunoassay using antibodies to secretin, gastrin, immunoreactive cholecystokinin, vasoactive intestinal peptide, gastric inhibitory peptide, and somatostatin. Boots secretin was found to contain substantial quantities of gastrin, immunoreactive cholecystokinin, vasoactive intestinal peptide, gastric inhibitory peptide, and somatostatin. In contrast, GIH secretin contained only a very small amount of vasoactive intestinal peptide. GIH also contained approximately three to four times more secretin per unit as did Boots secretin. Intravenous infusion of Boots, but not GIH, secretin in seven healthy volunteers produced significant increases in venous plasma of all peptides. Results of these studies indicate that Boots secretin contains large and variable quantities of gastrointestinal peptides other than secretin and that the contents of both secretin and the other peptides vary among different lots. Because the quantity of these peptides is sufficient to increase significantly their blood levels and consequent biological effects, it is concluded that GIH is preferable to Boots secretin in the clinical evaluation of patients with suspected chronic pancreatitis or gastrinoma.
Adult↗
Inhibition of gastrin release by gastric inhibitory peptide mediated by somatostatin.
The present studies were directed to examine the effect of gastric inhibitory peptide (GIP) on gastrin release and to determine the potential role of somatostatin in mediating this effect, utilizing rat antral mucosa in short-term tissue culture. Antral mucosa was incubated at 37 degrees C in Krebs-Henseleit buffer (pH 7.4) continuously gassed with 95% O2-5% CO2. Inclusion of carbachol (2.5 X 10(-6) M) in the culture medium increased media gastrin concentrations from 3.29 +/- 0.76 (SE) (control) to 6.77 +/- 0.76 ng/mg tissue prot (P less than 0.02). Rat antral mucosa was then incubated in the presence of GIP (10(-10) to 10(-7) M) to determine its effect on carbachol-stimulated gastrin release. GIP significantly inhibited carbachol-stimulated gastrin release into the culture media at all concentrations examined. To determine whether inhibition of carbachol-stimulated gastrin release by GIP was mediated by somatostatin, antral mucosa was incubated in the presence of carbachol, GIP (10(-10) to 10(-7) M), and specific antibodies to somatostatin in excess. Inclusion of antibodies to somatostatin in the culture medium abolished the capacity of GIP (10(9) to 10(-7) M) to inhibit carbachol-stimulated gastrin release. Results of these studies indicate 1) that GIP inhibits carbachol-stimulated gastrin release and 2) that, under the conditions of these experiments, GIP inhibition of gastrin release may be mediated locally through release of antral somatostatin.
Animals↗
Pharmacology of combined antidepressant/H2-blocking drug therapy.
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Amitriptyline↗