Cholecystokinin inhibits gastrin secretion independently of paracrine somatostatin secretion in the pig

Background: Cholecystokinin inhibits the secretion of gastrin from antral G cells, an effect that is speculated to be mediated by D cells secreting somatostatin. The aim of the study was to test directly whether cholecystokinin inhibition of antral gastrin secretion is mediated by somatostatin. Methods: The effects of CCK on gastrin and somatostatin secretion were studied in isolated vascularly perfused preparations of pig antrum before and after immunoneutralization brought about by infusion of large amounts of a high affinity monoclonal antibody against somatostatin. Results: CCK infusion at 10 ^?9 M and 10 ^?8 M decreased gastrin output to 70.5%?±?7.6% (n?=?8) and 76.3%?±?3.6% (n?=?7) of basal output, respectively. CCK at 10 ^?10 M had no effect (n?=?6). Somatostatin secretion was dose‐dependently increased by CCK infusion and increased to 268?±?38.2% (n?=?7) of basal secretion during infusion of CCK at 10 ^?8 M. Immunoneutralization of somatostatin caused a doubling of the basal secretion of gastrin, but did not affect the CCK‐induced decrease in gastrin secretion. Conclusion: CCK inhibits gastrin secretion independently of paracrine somatostatin secretion.     

Cholecystokinin inhibits gastrin secretion independently of paracrine somatostatin secretion in the pig

BACKGROUND: Cholecystokinin inhibits the secretion of gastrin from antral G cells, an effect that is speculated to be mediated by D cells secreting somatostatin. The aim of the study was to test directly whether cholecystokinin inhibition of antral gastrin secretion is mediated by somatostatin. METHODS: The effects of CCK on gastrin and somatostatin secretion were studied in isolated vascularly perfused preparations of pig antrum before and after immunoneutralization brought about by infusion of large amounts of a high affinity monoclonal antibody against somatostatin. RESULTS: CCK infusion at 10(-9) M and 10(-8) M decreased gastrin output to 70.5% +/- 7.6% (n = 8) and 76.3% +/- 3.6% (n = 7) of basal output, respectively. CCK at 10(-10) M had no effect (n = 6). Somatostatin secretion was dose-dependently increased by CCK infusion and increased to 268 +/- 38.2% (n = 7) of basal secretion during infusion of CCK at 10(-8) M. Immunoneutralization of somatostatin caused a doubling of the basal secretion of gastrin, but did not affect the CCK-induced decrease in gastrin secretion. CONCLUSION: CCK inhibits gastrin secretion independently of paracrine somatostatin secretion.     

Megakaryocytes their precursors and their progeny

Although first defined nearly 40 years ago, the existence of thrombopoietin, the primary regulator of megakaryocyte and platelet production, was in doubt until only very recently. Since the initial reports of its cloning in 1994, much has been learned about the effects of the hormone on megakaryocytic proliferation and differentiation. Thrombopoietin affects all aspects of megakaryocyte development, from the commitment of hematopoietic stem cells to the megakaryocytic lineage through their maturation into large highly polyploid cells capable of fragmentation into thousands of platelets. As such, recombinant thrombopoietin will undoubtedly find use to augment platelet production in states of impaired bone marrow function. Moreover, as a number of pathologic states of platelet production are associated with abnormalities of homeostasis or thrombosis, a better comprehension of the mechanisms by which platelets are derived from marrow megakaryocytes will likely aid in our approach to a number of cardiovascular disorders. The availability of thrombopoietin ushers in a new era of understanding of the physiology of megakaryocytes, their precursors, and their progeny. © 1996, Elsevier Science Inc. (Trends Cardiovasc Med 1996;6:261–265).     

Cholecystokinin and gastrin induce cell contraction in pig ileum by interacting with different receptor subtypes.

The aim of this study was to determine the cholecystokinin (CCK) receptor subtype involved in the direct myogenic effect of CCK on pig ileum. Smooth muscle cells were dispersed from pig ileum circular muscle layer and incubated in the presence of various concentrations of CCK agonists and antagonists. Contraction was assessed by measuring the length of 50 cells and expressed as the percentage decrease in cell length from control. Maximal contraction varied between 19% +/- 3% (gastrin II, 10 nmol/L) and 26% +/- 3% [CCK octapeptide (CCK-8), 10 nmol/L]. EC50 for CCK tetrapeptide (CCK-4) was the same than for pentagastrin (30 pmol/L), which were more potent than CCK-8 (100 pmol/L) and unsulfated gastrin 17 (100 pmol/L), which in turn were more potent than unsulfated CCK heptapeptide (CCK-7; 300 pmol/L) and sulfated gastrin II (300 pmol/L). The maximal contraction induced by synthetic analogs of CCK was 22% +/- 1% for 1 nmol/L JMV 170 and 23% +/- 1% for 10 nmol/L JMV 180. EC50 was 10 pmol/L for JMV 170 and 800 pmol/L for JMV 180. Contraction induced by 10 nmol/L CCK was inhibited as follows: L 365,260 half maximal inhibition (IC50) = 1 nmol/L greater than L 364,718 (IC50 = 90 nmol/L) greater than proglumide (IC50 = 1 mumol/L). Contraction induced by 10 nmol/L unsulfated gastrin 17 was inhibited as follows: L 365,260 (IC50 = 1 pmol/L) greater than L 364,718 (IC50 = 60 nmol/L) greater than proglumide (IC50 = 4 mumol/L). Removal of Ca2+ from the extracellular medium did not alter the contraction induced by CCK-8 (10 nmol/L) but impaired the contraction induced by unsulfated gastrin 17 (10 nmol/L) -56% in Ca(2+)-free medium, -77% in Ca(2+)-free medium plus 2 mmol/L EGTA, and -70% in the presence of 1 mumol/L nifedipine. These results show that the CCK receptor of pig ileum smooth muscle cells is closely similar to the B receptor and is not dependent on an influx of extracellular Ca2+ to induce cell contraction. By contrast, gastrin could act through a specific receptor subtype, the "gastrin receptor," triggering a Ca2+ influx into the cell to induce cell contraction.     

Expression of gastrin,gastrin/CCK-B and gastrin/CCK-C receptors in human colorectal carcinomas

To investigate further the presence of an autocrine proliferative loop involving gastrin in colorectal carcinomas and to clarify the receptor responsible, 102 human colorectal carcinomas and 10 hepatic metastases were investigated for the expression of the genes encoding gastrin, the gastrin/CCK-B receptor and the gastrin/CCK-C receptor. Levels of RNA expression were assayed by RNase protection assay. In addition, gastrin/CCK receptors on crude membranes of tumour tissue were assayed by radioligand binding. High-affinity gastrin/CCK-B receptors were not detected in any of the carcinomas investigated, whereas in 36% low-affinity binding was observed, consistent with the expression of the gastrin/CCK-C receptor. RNase protection assay detected the RNA for the gastrin/CCK-B receptor in 11% of the carcinomas investigated, whereas the RNA for the gastrin/CCK-C receptor was demonstrated in 75% and the RNA for gastrin in 86% of the carcinomas investigated. These results confirm the recent demonstration of progastrin fragments in colorectal carcinomas. One possible explanation for progastrin expression is that such progastrin fragments may participate in an autocrine proliferative loop. The receptor involved in this loop is more likely to be the low-affinity gastrin/CCK-C receptor rather than the gastrin/CCK-B receptor, which is rarely expressed in colorectal carcinomas.     

Small pheochromocytomas: significance, diagnosis, and outcome

To address the unique challenges in the diagnosis and management of small pheochromocytomas, the authors performed a retrospective study of 24 patients with small pheochromocytomas (≤ 3 cm) treated between 1995 and 2011, using 51 patients with larger pheochromocytomas (> 3 cm) as controls. Patient demographics were similar between the two groups. Small pheochromocytomas presented mainly as adrenal mass and hypertension and their major complication was hypertensive crisis during unrelated procedures in 4 patients (17%). Hypertension was improved in a quarter of the patients after pheochromocytoma resection. The biochemical marker levels in patients with small pheochromocytomas were generally lower than those with larger tumors and half of the patients exhibited modestly elevated or normal levels. The authors conclude that small pheochromocytomas are frequent and may not contribute to baseline hypertension, but can cause hypertensive crisis during unrelated medical procedures. Small pheochromocytomas should be removed to prevent hypertensive crisis and future complications of pheochromocytoma.     

Morphological evaluation of monocytes and their precursors

The monocyte is still the most difficult cell to identify with confidence in the peripheral blood or in the bone marrow in healthy individuals as well as in patients with infections, and in those with leukemic proliferations. The goal of this study was to establish morphological definitions so that monocytes, including immature monocytes, could be separated from the spectrum of monocyte precursors. Cells from peripheral blood or bone marrow were selected to provide a large panel of normal and leukemic cells at different maturational stages and were submitted to 5 experts, who had previously reached a consensus, on the basis of microscopy, in defining 4 subtypes: monoblast, promonocyte, immature monocyte, mature, monocyte. They achieved a good concordance rate of 76.6% and a high κ rate confirming that the criteria for defining the 4 subtypes could be applied consistently. It has now to be established whether these monocyte subtypes correlate with immunological or molecular markers and are clinically relevant.     

Laparoscopic adrenalectomy in pheochromocytomas

BACKGROUND: The aim of this study was to evaluate 17 patients undergoing laparoscopic adrenalectomy for the treatment of pheochromocytoma by transperitoneal anterior approach. METHODS: Seventeen patients underwent laparoscopic adrenalectomy for pheochromocytoma between January 1994 and May 2002. Ten females (58.8%) and 7 males (41.2%) were operated on; 14 patients (82.3%) had sporadic pheochromocytoma and 3 (17.7%) were familiar cases. Mean age was 42 yr (range 25-72 yr). All patients were treated pre-operatively with alpha-blockers. Seven patients (41.2%) underwent right adrenalectomy; 9 (52.9%) underwent left adrenalectomy and 1 (5.9%) bilateral adrenalectomy. RESULTS: No conversion to open surgery occurred and no mortality was observed. The right-side adrenalectomy required a mean operative time of 86 min (range 45-120), the left-side procedure a mean operative time of 116 min (range 80-140) and the bilateral one 219 min. In two patients (11.8%), a laparoscopic cholecystectomy and ovariectomy, respectively, were performed without changing the position of the patient on the operating table. Only 1 patient (5.9%) presented significant intraoperative hypertension, and arrhythmia resolved by medical therapy. No other intraoperative and post-operative complications were reported. Mean hospital stay was 3 days (range 2-8 days). At mean follow-up of 48 months (range 6-96 months), regression of symptoms and control of blood pressure were obtained without additional treatment in all patients. No recurrences were reported. CONCLUSION: In our experience, adrenal pheochromocytoma can be treated safely and effectively by laparoscopic transperitoneal anterior approach.     

Anxiety in patients with pheochromocytomas

Anxiety has been considered an important clinical feature of patients with pheochromocytomas. We studied 17 patients with active pheochromocytoma to determine whether they experienced anxiety that met criteria of the Diagnostic and Statistical Manual of Mental Disorders, third edition, for either panic disorder or generalized anxiety disorder. Fifty-two patients with primary anxiety disorders were used as a comparison group. Six patients with pheochromocytomas had norepinephrine-secreting tumors and 11 had mixed-secretion tumors, with elevated levels of both epinephrine and norepinephrine. None of the 17 patients described the severe apprehension or fear characteristic of panic attacks and none described agoraphobia. One patient received a diagnosis of possible panic disorder, two met criteria for generalized anxiety disorder, and two met criteria for major depressive episode. Thus, the elevated levels of catecholamines secreted by pheochromocytomas are not sufficient to elicit an anxiety disorder.     

Genetics of pheochromocytomas and paragangliomas

Pheochromocytoma and paraganglioma are tumors of the sympathetic or parasympathetic paraganglia. Pheochromocytoma is the tumor of the main sympathetic paraganglia, which is?the adrenal medulla. The sympathetic paraganglioma secretes?catecholamine while the parasympathetic do not. Both of them originate from neural crest cells and share similar mechanisms of tumor development. The same genetic alteration may predispose to the development of sympathetic and parasympathetic paraganglioma. The best known hereditary forms of pheochromocytoma and paraganglioma are the von Hippel-Lindau disease, in which pheochromocytoma may be associated with CNS hemangioblastoma, retinal angioma, pancreatic endocrine tumor/cysts and renal clear cell carcinoma/cysts; the multiple endocrine neoplasia type 2, in which pheochromocytoma is associated with medullary thyroid carcinoma and primary hyperparathyroidism, Type 1 neurofibromatosis, the most frequent hereditary cancer syndrome. Finally, it has been characterized the paraganglioma syndrome in which sympathetic and parasympathetic paraganglioma are variously associated. The list of predisposing gene is quite long and comprises VHL, RET, NF1, SDHB, SDHC, SDHD, SDHAF2. More rarely, two other genes may predispose to pheochromocytoma/paraganglioma development: KIF1Bbeta and PHD2. A mechanism conducing to a defective apoptosis is the common pathways of those genes. Finally, there is also good evidence of the role of other genes, not yet completely identified.     

Effect of aging on gastric acid secretion,serum gastrin,and antral gastrin content in rats

The purpose of this study was to characterize the effects of aging on gastric acid secretion and on serum and antral concentrations of gastrin in rats. Young and old Fischer 344 rats were prepared with gastric fistulas. Twenty-four hours after surgery, graded doses of human synthetic gastrin-17 (SHG-17) (2, 5, 10, 20, and 40 g/kg) were given intravenously in random order. Gastric secretions were collected for gastric acid measurement before and at 15-min intervals after each dose of gastrin. In a separate study, blood was collected and the stomachs were removed for antral gastrin extraction from fed young and old rats. Serum and antral gastrin was measured by radioimmunoassay. The basal and gastrin-stimulated acid secretions were significantly decreased in aged rats compared to the young rats. The basal acid output was 0.4±0.2 eq/15 min in the aged rats and 1.5±0.5 eq/15 min in the young. The maximal acid output stimulated by gastrin was 11.1±1.8 eq/15 min in the aged rats and 24.2±2.8 eq/15 min in the young. Both serum and antral concentrations of gastrin were significantly decreased in aged rats. Serum gastrin concentration was 114.8±7.4 pg/ml in the aged rats and 192.0±14.4 pg/ml in the young. Antral gastrin concentration was 3.9±0.5 g/g tissue in the aged rats, which was significantly less than the concentration in the young (6.5±0.4 g/g tissue). Antral gastrin content did not change with aging. Gastric acid secretion in aged rats is significantly decreased compared to the young in both the basal condition and in response to fixed doses of exogenous gastrin. Diminished concentrations of circulating gastrin may well be responsible, at least in part, for the diminished acid secretion in the aged rats.Part of this work was presented at the special session on aging during the Digestive Disease Week held by the American Gastroenterology Association (AGA) in New York, May 14, 1985, and has been published in abstract form (Gastroenterology 88:1445, 1985).Supported by grants from the National Institutes of Health (RO1 DK 15241, PO1 DK 35608, RCDA CA 00854, CA 38651) and a grant from the American Cancer Society (PDT-220).