vasoactive-intestinal-peptide and Pheochromocytoma

Watery diarrhea, hypokalemia and achlorhydria (WDHA) syndrome caused by vasoactive intestinal polypeptide (VIP) -producing tumor only rarely occurs in patients with nonpancreatic disease. A 49-year-old woman was referred for evaluation of a right adrenal tumor incidentally diagnosed by abdominal ultrasound during the investigation of chronic watery diarrhea. Laboratory findings showed hypokalemia and excessive production of VIP and catecholamines. After surgical resection of the tumor, diarrhea subsided and both electrolytes and affected hormone levels normalized. Immunohistochemical examination confirmed a diagnosis of pheochromocytoma, which contained VIP-positive ganglion-like cells. We herein present the clinical and histogenetic implications of this rare clinical entity, with literature review.

Topics: Achlorhydria; Adrenal Gland Neoplasms; Adrenalectomy; Catecholamines; Diarrhea; Female; Humans; Hypokalemia; Incidental Findings; Middle Aged; Pheochromocytoma; Tomography, X-Ray Computed; Treatment Outcome; Vasoactive Intestinal Peptide; Vipoma

A case of malignant pheochromocytoma, with a recurrence 15 years after adrenalectomy and with an associated watery diarrhea, hypokalemia, achlorhydria syndrome, is reported. Histological evaluation of the tumors revealed composite malignant pheochromocytoma-ganglioneuroblastoma (well differentiated type). Vasoactive intestinal polypeptide and catecholamine levels were high both in the plasma and in the tumors. Somatostatin was also rich in the metastatic tumor of the liver, but not in the plasma. Immunohistochemical studies have demonstrated that immunoreactive vasoactive intestinal polypeptide is present in the ganglioneuroblastoma component, and that immunoreactive somatostatin is present in the pheochromocytoma component. Literature on the watery diarrhea, hypokalemia, achlorhydria syndrome associated with pheochromocytoma was reviewed.

Topics: Achlorhydria; Adrenal Gland Neoplasms; Adult; Diarrhea; Ganglioneuroma; Humans; Hypokalemia; Male; Neoplasm Recurrence, Local; Pheochromocytoma; Syndrome; Vasoactive Intestinal Peptide

The aim of the present review was to compare in mammals and amphibians the data concerning the presence of neuropeptides in the chromaffin cells and the possible action of these substances on adrenocortical cell function. Major homologies are to be found concerning the coexistence in chromaffin granules of catecholamines, Met-and Leu-enkephalins, and their precursor, proenkephalin A. However, the inhibitory action that might be exerted by enkephalins in vitro on corticosteroid production in mammalian adrenal gland, does not occur in amphibia. Dynorphin has been isolated in bovine adrenal medulla extracts; the presence of this opioid peptide has not been reported yet in amphibian interrenal tissue. All chromaffin cells of the frog interrenal gland contain VIP-like immunoreactivity whereas this neuropeptide is not contained in the adrenal medulla of mammals, exept in certain pheochromocytomas. In the frog, VIP, Metenkephalin and catecholamines are co-sequestered in the same chromaffin granules. In addition, synthetic porcine or chicken VIP stimulate in vitro the secretion of corticosteroids by frog interrenal fragments. In mammals, the steroidogenic action of VIP has been observed exclusively in tumor cell lines. The existence of somatostatin has been demonstrated in the human adrenal medulla and in pheochromocytomas, but not in amphibia. Somatostatin has been found to inhibit the response of adrenocortical cells to angiotensin II in mammals. A similar effect of somatostatin was not observed in amphibia. The coexistence of VIP and catecholamines in frog chromaffin granules and the stimulatory effect exerted by VIP on corticosteroidogenesis suggest that, in these animals, VIP may be co-liberated with noradrenaline during stress conditions, and thus may act locally on adrenocortical cells to stimulate corticosteroid secretion.

Topics: Adrenal Cortex; Adrenal Cortex Hormones; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Amphibians; Angiotensin II; Animals; Anura; Catecholamines; Chromaffin Granules; Enkephalin, Leucine; Enkephalin, Methionine; Enkephalins; Histocytochemistry; Humans; Immunologic Techniques; Mammals; Nerve Tissue Proteins; Pheochromocytoma; Protein Precursors; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Histopathological and experimental observations indicate that tumors composed wholly or in part of neuroendocrine elements may arise in tissues derived from ectoderm (including neuroectoderm), mesoderm, and endoderm. These tumors frequently exhibit multidirectional differentiation as manifested by multihormonality and by the presence of morphological features indicative of divergent differentiation both in vivo and in vitro. The existence of stem cells, plasticity of differentiated cells, microenvironmental influences, and random events are factors which might all interact to determine the characteristics of any particular tumor. The production of characteristic regulatory peptide products in association with tumors of specific histological subtypes and with other neuroendocrine markers suggests mechanisms for nonrandom activation of multiple genes common to neuroendocrine-programmed cells. Future studies applying new molecular biological techniques to intact tissues and to in vitro models may help to clarify the mechanisms that regulate the expression of the neuroendocrine phenotype in normal and neoplastic states.

Topics: Adrenal Gland Neoplasms; Animals; Apudoma; Calcitonin; Carcinoid Tumor; Cricetinae; Female; Gastrins; Hormones, Ectopic; Humans; Neurotensin; Ovarian Neoplasms; Pancreatic Neoplasms; Pheochromocytoma; Rats; Somatostatin; Thyroid Neoplasms; Uterine Neoplasms; Vasoactive Intestinal Peptide

As sensitive radioimmunoassays for the detection of polypeptide hormones are developed, the exciting discovery of a diffusely distributed system of interrelated endocrine cells has begun a new era of endocrinology. This system, although anatomically disassociated, is bound together by a number of common features such as its biosynthetic mechanism, histochemical and ultrastructural features, and embryologic origin (Table I). The most prominent feature, however, is their biosynthetic pathways for hormone production, from which the acronym APUD has been derived. These are the capacity for Amine Precursor Uptake such as DOPA and then subsequent Decarboxylation, resulting in the synthesis of bioactive amines or polypeptide hormones. Hyperplasias or neoplasms of these cells are defined as apudomas. In the last ten years a great deal of research has rapidly altered the original concepts of this system, especially in terms of its embryologic origin, physiologic interrelationships, classification, as well as the addition of many new APUD cell members. These will be reviewed, and the origin, diagnosis, and treatment of each recognized apudoma will be synthesized in light of its membership within the APUD system.

Topics: Adenoma, Islet Cell; APUD Cells; Apudoma; Carcinoid Tumor; Carcinoma; Endocrine Glands; Humans; Neural Crest; Neuroblastoma; Paraganglioma; Pheochromocytoma; Pituitary Neoplasms; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Pheochromocytoma (PHEO) clinical manifestations generally mirror excessive catecholamines secretion; rarely the clinical picture may reflect secretion of other hormones. Watery diarrhea, hypokalemia and achlorhydria (WDHA) is a rare syndrome related to excessive secretion of vasoactive intestinal peptide (VIP).. A 73-year-old hypotensive man affected by adrenal PHEO presented with weight loss and watery diarrhea associated with hypokalemia, hyperchloremic metabolic acidosis (anion gap 15 mmol/l) and a negative urinary anion gap. Abdominal computed tomography scan showed a right adrenal PHEO, 8.1 cm in maximum diameter, with tracer uptake on. A rare case of WDHA syndrome caused by malignant VIP-secreting PHEO was diagnosed. High levels of circulating VIP were responsible of the rapidly evolving clinical picture with massive dehydration and weight loss along with severe hyperchloremic metabolic acidosis and hypokalemia due to the profuse untreatable diarrhea. The rescue treatment with lanreotide was unsuccessful because of the paucity of somatostatin-receptor-2A on VIP-secreting PHEO chromaffin cells.

Topics: Acidosis; Adrenal Gland Neoplasms; Adrenalectomy; Aged; Chromaffin Cells; Diarrhea; Humans; Hypokalemia; Male; Peptides, Cyclic; Peripheral Nervous System Neoplasms; Pheochromocytoma; Radionuclide Imaging; Receptors, Somatostatin; Somatostatin; Syndrome; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide; Weight Loss

Topics: Adrenal Gland Neoplasms; Biomarkers, Tumor; Female; Humans; Middle Aged; Pheochromocytoma; Vasoactive Intestinal Peptide

The watery diarrhea, hypokalemia and achlorhydria (WHDA) syndrome due to vasoactive intestinal polypeptide (VIP)-producing extra-pancreatic tumors is rare. We report on a 45-year-old woman who suffered from persistent secretory diarrhea for six years and who was admitted to hospital with complaints of muscular weakness and myalgia. Biochemical testing revealed pronounced rhabdomyolysis due to severe hypokalemia. Gastrointestinal evaluation of long-standing diarrhea including endoscopy of the upper and lower gastrointestinal tract and the small intestine did not show any pathologies. An abdominal computed tomography scan revealed a mass of 4 × 5 cm in the left adrenal gland demonstrating a strong uptake in the 123I-labelled metaiodobenzylguanidine scintigraphy. Plasma levels of chromogranin A, calcitonin, parathormone, basal renin and most prominently VIP were increased in line with a increased 24 hour urinary secretion of noradrenaline, dopamine, normetanephrine and vanillymandelic acid. A WDHA (watery diarrhea, hypokalaemia, achlorhydria) syndrome with hypokalemic rhabdomyolysis due to a VIP-producing adrenal tumor was diagnosed that was removed surgically. The histological evaluation demonstrated a composite pheochromocytoma. Diarrhea stopped immediately after surgery together with a normalization of laboratory parameters. In conclusion, this case report focuses on the rare clinical presentation of secretory diarrhea and electrolyte disturbances in combination with hypokalemic rhabdomyolysis which was caused by a VIP-producing composite pheochromocytoma.

Topics: Adrenal Gland Neoplasms; Biomarkers, Tumor; Female; Humans; Hypokalemia; Middle Aged; Pheochromocytoma; Rhabdomyolysis; Treatment Outcome; Vasoactive Intestinal Peptide

The watery diarrhoea, hypokalaemia and achlorhydria syndrome is a rare cause of secretory diarrhoea. In this case report, we highlight a young female with watery diarrhoea, hypokalaemia and achlorhydria syndrome as a consequence of a vasoactive intestinal peptide producing composite adrenal phaeochromocytoma-ganglioneuroma. She made a complete recovery after curative surgical resection.

Topics: Achlorhydria; Adrenal Gland Neoplasms; Diarrhea; Female; Ganglioneuroma; Humans; Hypokalemia; Pheochromocytoma; Vasoactive Intestinal Peptide; Young Adult

To report a case of a pheochromocytoma secreting vasoactive intestinal peptide (VIP).. We studied a 77-year-old woman who had suffered from persistent diarrhea and episodes of sweating and palpitations.. She had neither previous or current anamnesis of hypertension nor any known familial dispositions to endocrine diseases. Initially gastrointestinal investigations were carried out based on longstanding diarrhea with hypopotassemia, but radiological imaging revealed a unilateral adrenal mass. Biochemical testing showed increased levels of catecholamine and VIP, and (123)I-metaiodobenzylguanidine scintigraphy confirmed the adrenal origin as well as the diagnosis of a VIP-producing pheochromocytoma. The patient underwent surgical removal of the tumor which led to relief of symptoms and normalized laboratory values.. This case report focuses on the protean mode of presentation seen in pheochromocytomas as well as their capacity to produce several neuropeptides, ultimately intensifying the need for early examination for this condition despite unrelated symptoms.

Topics: Adrenal Gland Neoplasms; Aged; Catecholamines; Female; Humans; Hypertension; Pheochromocytoma; Vasoactive Intestinal Peptide

A 47-year-old woman with neurofibromatosis type 1 suffered from general muscle weakness and watery diarrhea. Laboratory findings showed elevated muscular enzymes, severe hypokalemia and excessive production of catecholamines and vasoactive intestinal polypeptide (VIP). A computed tomography scan showed a 10 cm left adrenal mass, in which [(131)I]-metaiodobenzylguanidine scintigraphy showed high uptake. After she underwent surgical removal of the tumor, all the symptoms and signs subsided. A histological study revealed that the mass consisted of pheochromocytoma and ganglioneuroma, respectively producing catecholamines and VIP. In immunohistochemical staining of neurofibromin, pheochromocytoma and ganglion cells showed positive staining, whereas the staining was negative for nerve bundles and Schwann cells. We concluded that the patient had hypokalemic rhabdomyolysis due to watery diarrhea, hypokalemia and achlorhydria (WDHA) syndrome, which was induced by a VIP-producing composite pheochromocytoma. Composite pheochromocytoma is a neuroendocrine tumor that is composed of pheochromocytoma and ganglioneuroma, both derived from the neural crest. Deficiency of neurofibromin in Schwann cells might have played an important role in the development and the growth of the composite pheochromocytoma in this patient.

Topics: 3-Iodobenzylguanidine; Achlorhydria; Adrenal Gland Neoplasms; Diarrhea; Female; Humans; Hypokalemia; Middle Aged; Neurofibromatosis 1; Pheochromocytoma; Radionuclide Imaging; Radiopharmaceuticals; Rhabdomyolysis; Syndrome; Tomography, X-Ray Computed; Vasoactive Intestinal Peptide

The syndrome of watery diarrhea associated with hypokalemia and achlorhydria was originally described in 1958. Subsequently, this syndrome was shown to be caused by a neuroendocrine tumor secreting vasoactive intestinal peptide (VIP), and such tumors are almost always pancreatic in origin. We describe the case of a 78-year-old woman with gradual onset of hypokalemia, watery diarrhea, and weight loss. After a left adrenal mass was discovered, the patient chose medical therapy over surgical intervention. Initially her condition responded, then gradually became refractory to medical therapy. She had elevated levels of VIP, pancreatic polypeptide, dopamine, and vanillylmandelic acid. Subsequently, the patient underwent surgical excision of the mass that was found to be a VIP-producing pheochromocytoma. After surgery her diarrhea subsided, and her electrolytes and affected neuroendocrine hormone levels normalized.

Topics: Adrenal Gland Neoplasms; Aged; Diarrhea; Female; Humans; Hypokalemia; Pheochromocytoma; Vasoactive Intestinal Peptide

Topics: Adrenal Gland Neoplasms; Biomarkers; Catecholamines; Ganglioneuroma; Humans; Male; Middle Aged; Neoplasms, Multiple Primary; Pheochromocytoma; Treatment Outcome; Vasoactive Intestinal Peptide; Vipoma

A patient with neurofibromatosis type 1 and watery diarrhoea syndrome due to a VIP-producing adrenal phaeochromocytoma (Case Report). J Intern Med 1999; 246: 231-234. A 43-year-old patient with neurofibromatosis type 1 suffered from watery diarrhoea syndrome induced by excessive production of vasoactive intestinal polypeptide (VIP) in an adrenal phaeochromocytoma. This case report emphasizes that patients with neurofibromatosis are prone to develop more than one disease induced by tumours originating from the neural crest. Since excessive VIP production in a phaeochromocytoma may mask the symptoms of catecholamine overproduction, and in view of the therapeutic consequences, neurofibromatosis patients with hyperVIP-aemia must be checked for the presence of a phaeochromocytoma.

Topics: Adrenal Gland Neoplasms; Adult; Diarrhea; Female; Humans; Neurofibromatosis 1; Pheochromocytoma; Syndrome; Vasoactive Intestinal Peptide

Phaeochromocytomas may produce several neuropeptides as they are considered neuroendocrine tumours. Nevertheless, studies are scarce and no clear predictive biologic value has been stablished in the case of neuropeptides expression.. We have investigated immunohistochemically the neuropeptides expression of a serie of 36 phaeochromocytomas: 25 sporadic, seven familial type MEN (multiple endocrine neoplasm) and four familial phaeochromocytomas not associated with MEN syndrome. The reactivity for neuron-specific enolase (NSE), synaptophysin, vasoactive intestinal peptide (VIP), chromogranin A, calcitonin, ACTH, somatostatin and HMB-45 was tested according to the avidin-biotin complex (ABC) method using polyclonal antibodies.. Phaeochromocytomas have a multiple synthetic activity as main neuroendocrine feature. Despite phaeochromocytoma tumour cells heterogeneity chromogranin and synaptophysin are the most common neuropeptides synthesised, as they are associated with the presence of neuroendocrine storage granules. We find a statistically significant higher synthesis of corticotrophin hormone in familial phaeochromocytomas than in sporadic forms, on the contrary the synthesis of VIP is statistically associated with sporadic forms of phaeochromocytomas. We also found a direct relation of ACTH and overexpression and malignant tumours and a positive relationship between NSE and benign forms of phaeochromocytomas.

Topics: Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Antigens, Neoplasm; Calcitonin; Chromogranin A; Chromogranins; Humans; Immunohistochemistry; Melanoma-Specific Antigens; Multiple Endocrine Neoplasia; Neoplasm Proteins; Neuropeptides; Pheochromocytoma; Phosphopyruvate Hydratase; Somatostatin; Synaptophysin; Vasoactive Intestinal Peptide

Glia cell line-derived neurotrophic factor (GDNF), a recently cloned member of the transforming growth factor-beta (TGF-beta) superfamily, has been implicated in the survival, morphological and functional differentiation of midbrain dopaminergic neurons and motoneurons in vitro and in vivo. The factor may thus have utility in the treatment of various human neurodegenerative disorders. Mechanisms regulating expression of GDNF in normal and diseased brain as a possible means to increase the local availability of GDNF are only beginning to be explored. We have established and employed a competitive reverse transcriptase-polymerase chain reaction (RT-PCR) to study and compare levels of expression of GDNF mRNA in several cell types and to investigate its regulation. GDNF expression was clearly evident in primary cultured astrocytes, the glioma B49 and C6 cell, but less pronounced in the Schwannoma RN22 cell lines. Little or no signal could be observed in neuroblastoma cell lines (IMR32, LAN-1) or the pheochromocytoma cell line PC12, emphasizing the glial character of this factor. Using the C6 cell line we found that fibroblast growth factor-2 (FGF-2; bFGF) can increase GDNF mRNA levels, whereas FGF-1, platelet-derived growth factor (PDGF), and vasoactive intestinal polypeptide (VIP) are apparently ineffective. Several other factors (forskolin, kainic acid, triiodothyronine dexamethasone, GDNF, TGF-beta 1, and interleukin-6) appear to have slightly negative effects on GDNF mRNA levels at the concentrations tested. To further explore the relationship between FGF-2 and GDNF, we also addressed the question whether GDNF, like FGF-2, may have an effect on C6 cell proliferation. We conclude that (1) glial and glial tumor cells, rather than neuronal cell lines, express GDNF, (2) that FGF-2 has a prominent inductive effect on GDNF expression and (3) that GDNF stimulates C6 cell proliferation. Finally, these data suggest that neurotrophic actions of FGF-2 in mixed glial-neuronal cell cultures might be mediated in part by GDNF.

Topics: Animals; Astrocytes; Brain Neoplasms; Cell Division; Colforsin; Dexamethasone; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Gene Expression Regulation, Neoplastic; Glial Cell Line-Derived Neurotrophic Factor; Glioma; Humans; Interleukin-6; Kainic Acid; Neoplasm Proteins; Nerve Growth Factors; Nerve Tissue Proteins; Neuroblastoma; Neurons; Organ Specificity; Pheochromocytoma; Platelet-Derived Growth Factor; Polymerase Chain Reaction; Rats; Recombinant Proteins; RNA, Messenger; RNA, Neoplasm; Triiodothyronine; Tumor Cells, Cultured; Vasoactive Intestinal Peptide

The ability of PACAP-38 to stimulate morphological development was studied using rat pheochromocytoma PC12 cells. PACAP-38 produced concentration-dependent increases in percentage of cells exhibiting neurite extension. Similar increases were produced by forskolin (28 +/- 2% at 96 h) and 8-bromo cAMP (30 +/- 2%). Vasoactive intestinal peptide and alpha-calcitonin gene-related peptide were without effect. PACAP-38 produced significant increases in PC12 cell cAMP content and inositol phosphate turnover. Intracellular [Ca2+] increased from 169 +/- 14 nM to 560 +/- 58 nM in response to 1 microM PACAP-38. PACAP-stimulated neurite outgrowth was abolished by RpcAMPS, an inhibitor of cAMP-dependent kinases but was unaffected by the protein kinase C antagonist H7.

Topics: Adrenal Gland Neoplasms; Analysis of Variance; Animals; Calcitonin Gene-Related Peptide; Calcium; Cyclic AMP; Dose-Response Relationship, Drug; Kinetics; Neurites; Neuropeptides; Neurotransmitter Agents; PC12 Cells; Pheochromocytoma; Phosphatidylinositols; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Time Factors; Vasoactive Intestinal Peptide

The potent protein kinase inhibitor staurosporine enhances cAMP-mediated responses in human neuroblastoma cells as represented by neurite extension and induction of tyrosine hydroxylase. To explore how staurosporine regulates cAMP signaling pathway, we examined transcriptional activity of the human vasoactive intestinal polypeptide (VIP) gene promoter carrying a cAMP-responsive element. In PC12 cells stably transfected with a reporter plasmid, staurosporine alone had little effect; however, in combination with forskolin or dibutyryl cAMP, staurosporine dose-dependently (1-50 nM) enhanced cAMP-mediated transcription from the VIP gene promoter, which was comparable to that maximally induced by cAMP plus 12-O-tetradecanoylphorbol-13-acetate. This is the first report of potentiation of cAMP-mediated promoter activity by staurosporine in neuroendocrine cells.

Topics: Adrenal Gland Neoplasms; Alkaloids; Animals; beta-Galactosidase; Colforsin; Cyclic AMP; Enzyme Inhibitors; Humans; Kinetics; Neurites; Neuroblastoma; PC12 Cells; Pheochromocytoma; Promoter Regions, Genetic; Protein Kinase C; Rats; Recombinant Proteins; Staurosporine; Transfection; Tumor Cells, Cultured; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

Exposure of PC12-VG cells to an extremely low frequency magnetic field (ELFMF) enhanced the beta-galactosidase gene expression stimulated by treatment of the cells with forskolin. The enhancing effect of the ELFMF was inhibited by treatment of the cells with a specific inhibitor of PKC, calphostin C, as well as with the Ca2+ entry blockers nifedipin and dantrolen. Enhancement appeared within the first hour of a 4h forskolin treatment when the ELFMF was given at different times during culture. We speculate that exposure of PC12-VG cells to an ELFMF during the early response to forskolin treatment affects cell signal transduction, resulting in enhanced gene expression.

Topics: Adrenal Gland Neoplasms; Animals; beta-Galactosidase; Colforsin; Dantrolene; Escherichia coli; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Kinetics; Magnetics; Naphthalenes; Nifedipine; PC12 Cells; Pheochromocytoma; Promoter Regions, Genetic; Protein Kinase C; Rats; Recombinant Proteins; Tetradecanoylphorbol Acetate; Transfection; Vasoactive Intestinal Peptide

Pituitary adenylate cyclase activating polypeptide (PACAP) is a newly discovered neuropeptide which exists in two biologically active forms: PACAP-38 consisting of 38 amino acids and PACAP-27, a peptide corresponding to the N-terminal 27 amino acids of PACAP-38. Both PACAPs are derived from a 176 amino acid precursor (preproPACAP) which in addition gives rise to a 29 amino acid peptide, designated PACAP-related peptide (PRP). The presence of the three preproPACAP-derived peptides (PACAP-38, PACAP-27 and PRP) in tumour tissue from nine patients with VIP-producing tumours (pancreatic carcinoma, neuroblastoma, ganglioneuroma and pheochromocytoma) and eleven patients with non-VIP-secreting tumours (gastrinoma, glucagonoma, somatostatinoma, neuroblastoma) was examined by specific radioimmunoassays. In seven out of the nine VIP-secreting tumours elevated concentrations of all the three preproPACAP-derived peptides were found compared with normal tissue, while the concentrations in the non-VIP-secreting tumours were within the normal range. PACAP-38 was in all cases the dominating peptide, the concentration ranging from 41 to 3606 pmol/g. When tumour extracts were fractionated on Sephadex G50 column, tricine gel electrophoresis or reverse-phase HPLC immunoreactive components corresponding to synthetic PACAP-38, PACAP-27 and human PRP were identified, suggesting that preproPACAP was fully processed. Immunocytochemical examination showed PACAP-immunoreactive cells in the tumour tissue which also stained for VIP. This co-localization of PACAP and VIP was confirmed by double-staining experiments on the same sections, demonstrating PHM/VIP mRNA and PACAP-immunostaining in the same cells.

Topics: Adrenal Gland Neoplasms; Ganglioneuroma; Humans; Neoplasms; Neuroblastoma; Neuropeptides; Neurotransmitter Agents; Pancreatic Neoplasms; Pheochromocytoma; Pituitary Adenylate Cyclase-Activating Polypeptide; Protein Precursors; Vasoactive Intestinal Peptide

A canine phaeochromocytoma was diagnosed by (1) argyrophil methods, (2) immunoreactivity to chromogranin and to vasoactive intestinal peptide (VIP), and (3) the demonstration of typical electron-dense granules by transmission electron microscopy. This is the first report of immunoreactivity to general neuroendocrine markers such as chromogranin, and to VIP, in a phaeochromocytoma in domestic animals. The use of these markers for the differential diagnosis of phaeochromocytoma, and the role of VIP in the severe chronic diarrhoea shown by the dog in this study are discussed.

Topics: Adrenal Gland Neoplasms; Animals; Chromogranins; Dog Diseases; Dogs; Female; Immunohistochemistry; Microscopy, Electron; Pheochromocytoma; Vasoactive Intestinal Peptide

A 61-year-old woman with café-au-lait pigmentation and severe cutaneous neurofibromatosis type I was noted to have persistent hypertension after coronary artery bypass grafts. Clinical investigation revealed bilateral adrenal medullary tumors. The patient did not have a duodenal lesion or gastrointestinal symptoms. Histologic examination showed both tumors to be composed of typical pheochromocytoma with large areas of ganglioneuroma (compound or composite pheochromocytomas). The neuromatous foci contained areas of cystic degeneration and thick-walled vessels. The ganglion cells and neuromatous areas were negative for chromogranin, glial fibrillary acidic protein, synaptophysin and vasoactive intestinal peptide. The typical pheochromocytomatous areas were strongly immunopositive for chromogranin and synaptophysin. Bilateral classic pheochromocytomas are rare in type 1 neurofibromatosis, and we believe that bilateral composite pheochromocytomas are an extension of this association.

Topics: Adrenal Gland Neoplasms; Chromogranins; Female; Ganglioneuroma; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; Microscopy, Electron; Middle Aged; Neurofibromatosis 1; Pheochromocytoma; Synaptophysin; Vasoactive Intestinal Peptide

By means of immunohistochemistry we analysed the distribution of chromogranin A, secretogranin II and vasoactive intestinal peptide (VIP) in 16 phaeochromocytomas, two cases of combined phaeochromocytoma-ganglioneuroma and four adrenal ganglioneuromas. Chromogranin A was found in the majority of phaeochromocytes and in mixed phaeochromocytomas-ganglioneuromas. Secretogranin II was present to a lesser degree in phaeochromocytes, but strong immunostaining was found in most ganglion cells of phaeochromocytomas, in the ganglioneuroma component of combined tumours and in adrenal ganglioneuromas. Vasoactive intestinal peptide was present in some ganglion cells of phaeochromocytomas, in the ganglioneuroma component of mixed tumours and in three of four adrenal ganglioneuromas. On semi-adjacent sections a co-localization of VIP and secretogranin II was demonstrated. These results indicate that neuronal differentiation is accompanied by an increased immunohistochemical expression of secretogranin II. Therefore, secretogranin II may be a useful marker for ganglion cell differentiation.

Topics: Adrenal Gland Neoplasms; Adrenal Medulla; Biomarkers, Tumor; Chromogranin A; Chromogranins; Ganglioneuroma; Humans; Immunohistochemistry; Pheochromocytoma; Proteins; Vasoactive Intestinal Peptide

An unusual pheochromocytoma was incidentally discovered in a 48-year-old woman. The patient had a 3-year history of myasthenia gravis. At the time of examination in our hospital, the right adrenal tumor was incidentally discovered by ultrasonography of the abdomen. She had no history of headache, perspiration, palpitation or hypertension. Although blood catecholamine levels were within the normal limits, urinary secretion of catecholamine was elevated. Histologically, the tumor was diagnosed to be mixed ganglioneuroma/pheochromocytoma and histochemically confirmed to produce vasoactive intestinal polypeptide. Such a tumor is quite rare.

Topics: Adrenal Gland Neoplasms; Catecholamines; Female; Ganglioneuroma; Humans; Middle Aged; Myasthenia Gravis; Pheochromocytoma; Vasoactive Intestinal Peptide

An increase in the cellular concentration of cAMP leads to the inhibition of platelet aggregation. We have been investigating endogenous peptides which inhibit platelet function, using an assay which detects increase in platelet cAMP. Compared with the human adrenal medulla, a pheochromocytoma (PC) contained abundant peptides that elevate platelet cAMP. About 90% of the activity was found in the SP-III fraction which contained strongly basic peptides. From the SP-III fraction, peptides P-1, P-2 and P-3 were purified to homogeneity as endogenous peptides which elevated platelet cAMP. A gas phase sequencer was used to identify these peptides as follows: P-1 = vasoactive intestinal peptide (VIP); P-2 = calcitonin gene related peptide-I (CGRP-I); P-3 = CGRP-II. It is well known these peptides are potent vasorelaxants. VIP and CGRP-I significantly increased platelet cAMP levels 15- and 6-fold, respectively. These results suggest that VIP and CGRP-I and -II act upon platelets as well as upon vascular tissue.

Topics: Adrenal Gland Neoplasms; Amino Acid Sequence; Animals; Blood Platelets; Calcitonin Gene-Related Peptide; Cyclic AMP; Dose-Response Relationship, Drug; Molecular Sequence Data; Peptides; Pheochromocytoma; Radioimmunoassay; Rats; Vasoactive Intestinal Peptide

The concentrations of immunoreactive (IR) corticotropin-releasing hormone (CRH) in 218 neuroendocrine tumors were determined by CRH radioimmunoassay. The tumors examined were 86 pancreatic endocrine tumors (PET), 22 neuroblastic tumors (NBT), 26 carcinoid tumors (CA), 24 pheochromocytomas (PHEO), 40 small cell lung carcinomas (SCLC) and 20 medullary thyroid carcinomas (MTC). IR-CRH was detectable in 21 neuroendocrine tumors (10 PET, four NBT, three CA, two PHEO and two SCLC) at levels of 10-2,700 ng/g wet weight (9.6%). The 21 patients with these CRH-producing tumors showed no clinical symptoms suggestive of Cushing's syndrome. The levels of plasma IR-CRH extracted by immunoaffinity chromatography were < 7.5 pg/ml in five normal subjects and a patient with a neuroblastic tumor containing 55 ng/g wet weight IR-CRH, but in a patient with a thymic carcinoid tumor containing 1,000 ng/g wet weight IR-CRH, the plasma level was elevated to 180 pg/ml. This patient did not have Cushing's syndrome nor an elevated plasma adrenocorticotropic hormone (ACTH) level. The concentrations of nine peptides (growth hormone-releasing hormone, somatostatin, ACTH, calcitonin, gastrin-releasing peptide, glucagon, vasoactive intestinal peptide, neuropeptide tyrosine and pancreatic polypeptide) were determined in extracts of the 21 IR-CRH-producing tumors. Some of these peptides were frequently found to be produced concomitantly with CRH. The results indicate IR-CRH to be produced by various neuroendocrine tumors, but Cushing's syndrome, due to the CRH, to be very rare. The results also show that CRH-producing tumors produce multiple hormones.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Bombesin; Calcitonin; Carcinoid Tumor; Carcinoma, Small Cell; Chromatography, Gel; Corticotropin-Releasing Hormone; Gastrin-Releasing Peptide; Gastrins; Humans; Hypothalamus; Lung Neoplasms; Neoplasms; Neuroblastoma; Pancreatic Neoplasms; Peptides; Pheochromocytoma; Somatostatin; Thyroid Neoplasms; Vasoactive Intestinal Peptide

Pheochromocytomas may produce several vasoactive peptides. We studied a 39-year-old man who presented with paroxysmal flushing and abdominal pain with normal blood pressure. Laboratory and radiologic studies established the diagnosis of right adrenal pheochromocytoma, and histologic and ultrastructural examination showed the tumor to be a typical pheochromocytoma. Tissue culture yielded large quantities of norepinephrine and epinephrine. However, immunohistochemical studies, tissue assays, and in vitro cultures documented production of several peptides, including calcitonin gene-related peptide and vasoactive intestinal polypeptide in tumor cells. The patient has been asymptomatic after tumor resection. Production of multiple peptides by this tumor may account for the flushing and lack of hypertension, despite elevated catecholamine levels in this patient.

Topics: Adrenal Gland Neoplasms; Adult; Blood Pressure; Calcitonin Gene-Related Peptide; Catecholamines; Hormones, Ectopic; Humans; Immunohistochemistry; Male; Pheochromocytoma; Vasoactive Intestinal Peptide

Topics: Adrenal Gland Neoplasms; Ganglioneuroma; Humans; Male; Middle Aged; Pheochromocytoma; Vasoactive Intestinal Peptide

Two subclones of the rat pheochromocytoma cell line, PC12, were used to compare the effects of ethanol on adenylate cyclase activity in isolated membranes with its effects on cyclic AMP accumulation in intact cells. Consistent with previous reports, ethanol increased basal and 2-chloroadenosine-stimulated adenylate cyclase activity in isolated membrane preparations from both subclones. However, ethanol had opposite effects on agonist-stimulated cyclic AMP accumulation in intact cells of the two subclones, enhancing accumulation in one subclone, and inhibiting it in the other. The inhibition of cyclic AMP accumulation did not result from stimulation of phosphodiesterase activity, activation of the inhibitory guanyl nucleotide regulatory protein, Gi, or stimulation of protein kinase C. The results indicate that extrapolation of the effects of ethanol from one cell type to another, or from in vitro to in vivo systems, may be complicated by the interaction of ethanol with regulatory processes that influence second messenger systems, and can differ in various types of intact cells.

Topics: 2-Chloroadenosine; Adenylate Cyclase Toxin; Adenylyl Cyclases; Adrenal Gland Neoplasms; Animals; Cell Membrane; Colforsin; Cyclic AMP; Ethanol; GTP-Binding Proteins; Guanylyl Imidodiphosphate; Pheochromocytoma; Phorbol 12,13-Dibutyrate; Protein Kinase C; Rats; Tumor Cells, Cultured; Vasoactive Intestinal Peptide; Virulence Factors, Bordetella

An adrenal pheochromocytoma cell line, PC12h, was found to respond to a novel hypothalamic neuropeptide, Pituitary Adenylate Cyclase Activating Polypeptide (PACAP). The cells elevated both intracellular and extracellular cAMP levels on stimulation by PACAP, whereas they showed little response to VIP which is structurally related to PACAP. Using [125I]PACAP27 (a shorter form of the peptide) and [125I]VIP, we found large amounts of specific binding sites for PACAP but few binding sites for VIP in PC12h cells. These results indicate that PC12h cells respond to PACAP via a specific PACAP receptor.

Topics: Adrenal Gland Neoplasms; Animals; Binding Sites; Cell Line; Cyclic AMP; Kinetics; Neuropeptides; Pheochromocytoma; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Vasoactive Intestinal Peptide

Tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, is subject to regulation by the cAMP as well as the calcium and cGMP second messenger systems. Treatment of intact rat PC12 cells with neuropeptides including secretin and vasoactive intestinal polypeptide (VIP) stimulated tyrosine hydroxylase activity 2 to 3-fold in vitro. Secretin (EC50 = 10 nM) was about 3 orders of magnitude more potent than VIP (EC50 = 3 microM). A combination of several protease inhibitors failed to enhance the potency of either peptide. Other members of the secretin family including glucagon and peptide histidine isoleucine (PHI) stimulated tyrosine hydroxylase activity to a lesser extent. Somatostatin, which is not homologous to secretin, was ineffective. The maximal response of tyrosine hydroxylase activation to 1 microM secretin occurred within 6-15 sec. Secretin, VIP, and forskolin also enhanced tyrosine hydroxylase activity (3,4-dihydroxyphenylalanine production) in intact cells, as determined by high performance liquid chromatography and electrochemical detection. Secretin, VIP, PHI, and glucagon increased the levels of cAMP in PC12 cells more than 10-fold, as determined by radioimmunoassay. We also demonstrated that cAMP is released from the cells into the incubation medium following secretin treatment. Secretin and VIP treatment also enhanced the activity of cAMP-dependent protein kinase in a concentration-dependent fashion, as measured subsequently in vitro. Based on the greater potency of secretin in comparison with VIP, PHI, and glucagon, we suggest that the PC12 cells contain a secretin-preferring receptor that increases cAMP levels and brings about an activation of tyrosine hydroxylase activity through the stimulation of cAMP-dependent protein kinase.

Topics: Adrenal Gland Neoplasms; Animals; Calcium; Colforsin; Cyclic AMP; Dihydroxyphenylalanine; Enzyme Activation; Pheochromocytoma; Rats; Secretin; Theophylline; Tumor Cells, Cultured; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

Our patient had a left suprarenal mass. His blood pressure was normal, but his urinary catecholamines (CA), vanillylmandelic acid (VMA), total metanephrines (TMn) and 5-hydroxyindolacetic acid (5HIAA) were elevated. In addition, he had elevated, nonsuppressible urinary 17-ketosteroids (17KS) and androsterone, but his urinary 17-hydroxycorticoids (17OHCS) and free cortisol were normal, as were his plasma cortisol and ACTH. After resection of the suprarenal mass, the patient's urinary hormone values reverted to normal. The mass contained a pheochromocytoma and an adrenocortical adenoma. The pheochromocytoma was unusual in that it contained very little norepinephrine (NE) and dopamine (DA) and an abundance of epinephrine (E) despite normal enzyme concentrations. Electron micrographs showed primarily E granules with few of the NE-type. The immunoperoxidase histochemical stains for vasoactive intestinal peptide (VIP) and serotonin (S) were strongly positive. The patient's blood pressure may have been normal because his pheochromocytoma secreted E, VIP, or S. The associated adrenocortical adenoma produced no symptoms and was probably coincidental.

Topics: Adenoma; Adrenal Cortex Neoplasms; Androgens; Catecholamines; Gas Chromatography-Mass Spectrometry; Histocytochemistry; Humans; Immunoenzyme Techniques; Male; Microscopy, Electron; Middle Aged; Multiple Endocrine Neoplasia; Pheochromocytoma; Serotonin; Vasoactive Intestinal Peptide

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Calcitonin; Catecholamines; Child; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pheochromocytoma; Phosphopyruvate Hydratase; Prognosis; Vasoactive Intestinal Peptide

A 40 year old woman presented with a 10 year history of watery diarrhoea and an acute quadriparesis. On clinical examination there was severe muscle weakness and a nodule was palpable in the thyroid gland. Biochemical testing revealed a hypokalaemia at 1.6 mmol/l. Plasma levels of VIP were raised at 202 pmol/l. CT scanning demonstrated a mass in the area of the left adrenal gland, and isotope scanning of the thyroid gland showed a 'cold' nodule. The plasma catecholamines and calcitonin were elevated. The patient also presented with psychiatric symptoms, and the relevance of these to her condition has been discussed. At operation a left adrenal tumour was removed. Post-operatively the patient's symptoms disappeared and the plasma hormone levels returned to normal values. Histological examination of the tumour revealed a well differentiated phaeochromocytoma which contained VIP and calcitonin. The thyroid nodule was excised and showed histological features of autoimmune thyroid disease. It is suggested that in all cases of the WDHA syndrome where the tumour is in an extra-pancreatic site patients should be screened for phaeochromocytoma.

Topics: Adrenal Gland Neoplasms; Adult; Calcitonin; Diarrhea; Epinephrine; Female; Humans; Norepinephrine; Pheochromocytoma; Thyroiditis, Autoimmune; Vasoactive Intestinal Peptide

Three adrenal medullary tumors that showed admixtures of pheochromocytomatous elements with ganglioneuroma or ganglioneuroblastoma were studied to determine the distribution of immunoreactive chromogranins, S-100 protein, and vasoactive intestinal peptide (VIP). Two tumors consisted of typical pheochromocytoma cells admixed with mature-appearing ganglioneuroma. The third consisted of pheochromocytoma admixed with ganglioneuroblastoma and contained many immature and cytologically atypical cells. In all cases, chromogranin staining was absent or weak in neuronal perikarya and moderate to intense in varicosities of neuronal processes, a finding consistent with the presumed distribution of secretory granules in neurons. Chromogranin staining was also intense in chromaffin cells. Glial cells that stained for S-100 were randomly scattered among chromaffin cells but accumulated in areas with neuronal processes. Weak staining for VIP was present in neuronal cells in one of the two tumors with ganglioneuromatous features. Intense staining for VIP occurred in the third tumor in both neuronal and apparently nonneuronal cells. We conclude that granule distribution and cell-cell interactions for specific cell types in compound tumors tend to mimic those in normal adrenal medulla and sympathetic ganglia. Although immunoreactive VIP was localized exclusively to neurons in one tumor, as in normal tissues, patterns of staining for VIP across tumors are less predictable.

Topics: Adrenal Gland Neoplasms; Adrenal Medulla; Adult; Chromogranins; Ganglioneuroma; Humans; Male; Middle Aged; Nerve Tissue Proteins; Pheochromocytoma; S100 Proteins; Vasoactive Intestinal Peptide

The primary structure and biological activity of a novel prepro-vasoactive intestinal peptide (prepro-VIP)-derived peptide has been determined from an adrenal pheochromocytoma. The peptide was purified sufficiently for characterization by fast atom bombardment mapping after cation-exchange and reverse-phase fast protein liquid chromatography. The sequence of this novel peptide corresponds exactly to prepro-VIP-81-122 and has been designated peptide histidine valine 42 (PHV-42). Synthetic PHV-42 reduced both the force and frequency of spontaneous contractions of isolated rat uterus and was at least 12 times more potent than peptide histidine methionine (prepro-VIP-81-107), and over a hundred times more potent than noradrenaline. PHV-42 was also more potent than peptide histidine methionine in relaxing smooth muscle preparations of rat stomach and guinea pig trachea, but was approximately 4-fold less potent in reducing blood pressure than VIP. PHV-42 thus forms a separate subsystem in the VIP family of peptides and may be the most biologically active product of prepro-VIP in certain tissues such as the uterus and trachea.

Topics: Adrenal Gland Neoplasms; Aged; Aged, 80 and over; Amino Acid Sequence; Amino Acids; Animals; Chromatography, High Pressure Liquid; Female; Humans; In Vitro Techniques; Mass Spectrometry; Peptide Fragments; Pheochromocytoma; Protein Precursors; Rats; Uterine Contraction; Vasoactive Intestinal Peptide

Topics: Adrenal Gland Neoplasms; Aged; Female; Gastrointestinal Hormones; Humans; Male; Middle Aged; Motilin; Neoplasm Metastasis; Pheochromocytoma; Somatostatin; Substance P; Vasoactive Intestinal Peptide

The production and secretion of immunoreactive growth hormone-releasing factor (IR-GRF) by pheochromocytomas were examined immunohistochemically and immunochemically. GRF-immunoreactive (GRF-IR) cells were found, although sparsely, in 2 of 13 tumors (Cases 1 and 2), while somatostatin (SRIF)-IR cells and vasoactive intestinal peptide (VIP)-IR cells were found in nine and five tumors, respectively. Concentrations of tissue IR-GRF of 29.8 and 17.2 ng/g wet weight tissue, respectively, were found in two (Cases 1 and 2) of three tumors examined. These three tumors also contained IR-SRIF at 19.5-105.5 ng/g wet weight tissue and IR-VIP at 13.6-24.8 ng/g wet weight tissue. An increased plasma IR-GRF concentration (30.0 pg/ml) was found in a blood sample taken from the inferior vena cava near the adrenal tumor in Case 1. This is the first report that some pheochromocytomas produce GRF and secrete it into the blood circulation.

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Aged; Catecholamines; Chromatography, Gel; Female; Growth Hormone-Releasing Hormone; Histocytochemistry; Humans; Immunoenzyme Techniques; Male; Middle Aged; Paraneoplastic Endocrine Syndromes; Pheochromocytoma; Radioimmunoassay; Somatostatin; Vasoactive Intestinal Peptide; Venae Cavae

The association of neurofibromatosis and pheochromocytoma is well recognized; more recently, attention has been drawn to links between neurofibromatosis, pheochromocytoma, and ampullary somatostatin-rich carcinoid. Because of this association, the duodenum was explored during a recent laparotomy for resection of bilateral pheochromocytoma in a patient with von Recklinghausen's disease. A clinically unsuspected ampullary tumor was discovered; this proved to be in part a ganglioneuroma and in part a somatostatin-rich carcinoid. This paper presents full details of this carefully investigated and documented case and reviews the recent advances in this field. These studies lead us to conclude that: the clinical association of neurofibromatosis, pheochromocytoma, and D cell carcinoids ("somatostatinomas") of the ampullary region is confirmed; this association may be more common than has been previously thought, and the duodenum should be carefully examined in any patient with neurofibromatosis who undergoes laparotomy for pheochromocytoma.

Topics: Adrenal Gland Neoplasms; Carcinoid Tumor; Catecholamines; Duodenal Neoplasms; Female; Histocytochemistry; Humans; Middle Aged; Neoplasms, Multiple Primary; Neurofibromatosis 1; Pheochromocytoma; Somatostatin; Vasoactive Intestinal Peptide

Topics: Aged; Diarrhea; Female; Ganglioneuroma; Humans; Neoplasms, Multiple Primary; Pheochromocytoma; Vasoactive Intestinal Peptide

A 30-year-old man presenting with watery diarrhea, hypokalemia, and hypochlorhydria (Verner-Morrison syndrome, WDHH syndrome) had raised plasma levels of vasoactive intestinal polypeptide (VIP), somatostatin (SRIF), calcitonin, and gastrin, as well as high urinary excretion of vanillylmandelic acid. A right adrenal pheochromocytoma was found and excised. The neoplastic cell population was immunohistochemically shown to contain VIP, SRIF, and calcitonin. Gross, histologic, and immunohistochemical evaluation of the pancreas revealed no abnormalities, whereas a marked hyperplasia of the gastrin-producing cells of the gastric antral mucosa was demonstrated. Postoperatively, the patient recovered from his symptoms and the plasma hormone levels returned to normal values. The clinical and histogenetic implications of this most unusual tumor of neural crest derivatives are discussed.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Adult; Calcitonin; Gastrins; Histocytochemistry; Hormones, Ectopic; Humans; Immunoenzyme Techniques; Male; Pheochromocytoma; Somatostatin; Vasoactive Intestinal Peptide; Vipoma

Amelioration or cure of hypertension, hypercortisolism, diarrhea with steatorrhea, and massive proteinuria resulted from excision of a pheochromocytoma that contained immunoreactive ACTH, VIP, and somatostatin. Ectopic ACTH production by the tumor was clearly the cause of the hypercortisolism, and the possible involvement of VIP and somatostatin in the diarrhea and steatorrhea was considered. The response to tumor removal suggested that the mesangioproliferative glomerulonephritis shown on renal biopsy was also a paraneoplastic phenomenon.

Topics: Adrenal Gland Neoplasms; Adrenocortical Hyperfunction; Adrenocorticotropic Hormone; Celiac Disease; Diarrhea; Humans; Hydrocortisone; Hypertension; Male; Middle Aged; Pheochromocytoma; Proteinuria; Somatostatin; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) acutely increases tyrosine hydroxylase (TH) activity in cultures of dispersed normal adult rat chromaffin cells and of PC12 rat pheochromocytoma cells. High concentrations of VIP (10 microM) produce about 3-fold increases in TH activity in both cell types. VIP also increases the content of cyclic adenosine 3':5'-monophosphate (cAMP) in PC12 cells. VIP may increase TH activity by promoting the cAMP-dependent phosphorylation of the enzyme. Nerve fibers containing VIP-like immunoreactive material have been reported in the adrenal medulla and in other catecholamine (CA)- storing tissues. This VIPergic innervation may regulate CA synthesis and other cAMP-dependent processes in these tissues.

Topics: Adrenal Gland Neoplasms; Adrenal Medulla; Animals; Cell Line; Cells, Cultured; Cyclic AMP; Dihydroxyphenylalanine; Enzyme Activation; Male; Nerve Growth Factors; Pheochromocytoma; Rats; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

A 55-year-old woman presented with several protracted episodes of diarrhea; it was found to be secretory in origin. In the course of evaluating the diarrhea, an ultrasound of the abdomen was performed which disclosed a large right adrenal mass. Endocrinologic studies revealed elevated serum levels of gastrin, vasoactive intestinal polypeptide (VIP), catecholamines, and its metabolites. Surgery was performed successfully without any intraoperative complications, and postoperatively the patient was asymptomatic without further episodes of diarrhea. Histologically the tumor was a pheochromocytoma with neuroendocrine granules of vasoactive intestinal polypeptide and norepinephrine. To our knowledge, there have been six previously reported cases of pheochromocytoma secreting vasoactive intestinal polypeptide. In a patient with secretory diarrhea of unknown etiology, the adrenal glands as well as the pancreas should be examined by ultrasound and/or computerized tomography for the presence of a mass. Should an adrenal mass be discovered, it is necessary to evaluate the tumor for catecholamine production, despite the absence of clinical symptoms of a pheochromocytoma.

Topics: Adrenal Gland Neoplasms; Angiography; Diarrhea; Female; Humans; Microscopy, Electron; Middle Aged; Paraneoplastic Endocrine Syndromes; Pheochromocytoma; Tomography, X-Ray Computed; Ultrasonography; Vasoactive Intestinal Peptide

Hypersecretion of catecholamine primarily affecting adrenaline levels arose in a patient given a jejunoileal bypass for severe obesity. Apart from organic factors, including a hetero and/or orthotopic pheochromocytoma and the therapeutic effect of beta-blocking drugs, it is suggested that the pathogenesis of the patient's condition is based on a hypersecretion of VIP, as sometimes occurs in patients with short intestine/syndrome.

Topics: Adult; Catecholamines; Epinephrine; Humans; Hypertension; Jejunoileal Bypass; Male; Norepinephrine; Obesity; Pheochromocytoma; Starvation; Vasoactive Intestinal Peptide

Vasoactive intestinal peptide-like immunoreactivity (VIPLI) is not detectable in normal adult human chromaffin cells in vivo, but was demonstrated in cultured chromaffin cells from two normal adults after 22 days in vitro. Cellular content of VIPLI was markedly increased in the presence of nerve growth factor, which also stimulated neurite outgrowth. Catecholamine content decreased in the same cultures, and was not regulated in parallel with VIPLI. The amounts of VIPLI in normal human chromaffin cells in culture are comparable to those previously reported in human pheochromocytoma cell cultures. Theoretical models have attributed production of ectopic peptides by pheochromocytomas and other tumors to "immaturity" of tumor cells. Our findings, however, indicate that neither neoplasia nor cellular immaturity is a prerequisite for ectopic peptide production. Ectopic neuropeptides produced by normal chromaffin cells which undergo neuronal differentiation are of potential clinical importance in patients receiving autologous chromaffin cell transplants for Parkinsons' disease.

Topics: Adrenal Medulla; Aged; Catecholamines; Cell Differentiation; Cells, Cultured; Hormones, Ectopic; Humans; Male; Middle Aged; Pheochromocytoma; Time Factors; Vasoactive Intestinal Peptide

Immunohistochemical investigations were carried out on 16 pheochromocytomas for a study of their immunoreactivity to methionine-enkephalin, vasoactive intestinal peptide, somatostatin, corticotropin, beta-endorphin, and calcitonin on serial semithin araldite sections. All antiserums except anti-beta-endorphin, selectively stained a variable number of distinct tumor cells. Methionine-enkephalin-immunoreactive cells were the most frequent. The neuropeptide content of pheochromocytomas appears highly diverse and unpredictable. These findings are supportive of the concept of multisecretory APUD cells of neural crest origin and rule out any of these neuropeptides as reliable immunohistochemical markers for tumor chromaffin cells.

Topics: Adolescent; Adrenal Gland Neoplasms; Adrenocorticotropic Hormone; Adult; beta-Endorphin; Calcitonin; Endorphins; Enkephalin, Methionine; Female; Histocytochemistry; Humans; Immunoenzyme Techniques; Male; Middle Aged; Pheochromocytoma; Somatostatin; Vasoactive Intestinal Peptide

Neoplastic chromaffin cells from human pheochromocytomas can exhibit extensive spontaneous and nerve growth factor (NGF)-induced outgrowth of neurite-like processes in vitro, despite the absence of such processes in vivo. To determine whether acquisition of neuron-like features by human pheochromocytoma cells in culture is accompanied by functional alterations, process outgrowth, vasoactive intestinal peptide-like immunoreactivity ( VIPLI ), neurotensin-like immunoreactivity (NTLI), and catecholamine content were studied in freshly dissociated cells and in 21-day-old cultures from six human pheochromocytomas. All of the cultures produced VIPLI and exhibited spontaneous process outgrowth. NGF stimulated process outgrowth and enhanced production of VIPLI . Dexamethasone inhibited process outgrowth and tended to decrease production of VIPLI . NTLI was detected in cells from only one of the tumors, and its production appeared to be regulated comparably to that of VIPLI . Catecholamine content decreased markedly in all of the cultures and was not regulated in parallel with either VIPLI or NTLI. The findings suggest that human pheochromocytoma cultures may help to elucidate cellular and molecular mechanisms regulating ectopic and normal VIP production.

Topics: Adrenal Gland Neoplasms; Cells, Cultured; Dexamethasone; Humans; Nerve Growth Factors; Neurotensin; Pheochromocytoma; Radioimmunoassay; Vasoactive Intestinal Peptide

An adrenal pheochromocytoma producing somatostatin (SRIF) and vasoactive intestinal polypeptide (VIP) in a 17-year-old boy is presented. High concentrations of immunoreactive (IR)-SRIF were found in plasma taken from the antecubital vein (31.0-33.0 pg/ml) and the inferior caval vein near the tumor (54.6 pg/ml), but after removal of the tumor the values became normal (11.0-15.2 pg/ml). In two portions of the resected tumor, considerable but different amounts of IR-SRIF (151.7 and 12.1 ng/g wet wt) and IR-VIP (13.0 and 5.5 ng/g wet wt) were demonstrated with size heterogeneities. Immunohistochemically, many IR-SRIF cells and a few IR-VIP cells were observed, but no cell reacting with both anti-SRIF and anti-VIP sera was found. Electronmicroscopically, many tumor cells had catecholamine-like granules (250-350 nm in diameter) while some others had VIP-like granules (110-140 nm in diameter). However, no granules resembling the SRIF granules seen in the pancreatic D cells were found. This seems to be the first report of an adrenal pheochromocytoma that produces SRIF and VIP simultaneously. It provides information on the histogenesis of hormone-producing neurogenic tumors.

Topics: Adolescent; Adrenal Gland Neoplasms; Chromatography, Gel; Gastrointestinal Hormones; Histocytochemistry; Humans; Male; Pheochromocytoma; Radioimmunoassay; Somatostatin; Vasoactive Intestinal Peptide

Hybridomas secreting monoclonal anti-vasoactive intestinal polypeptide (VIP) antibodies were constructed from spleen cells sensitized to VIP in vitro. The secreted antibodies were characterized by binding to VIP in indirect radioimmunoassays and enzyme-linked immunosorbent assays. Two monoclonal antibodies, characterized for their binding activities with synthetic fragments of VIP, were found to bind different sites on the VIP molecule. These monoclonal antibodies may recognize tertiary structures of the VIP. A search was conducted for antigens recognized by the monoclonal antibodies in brain: brain proteins separated on polyacrylamide gels were electroblotted onto nitrocellulose filters and were reacted first with the mouse antibody and then with goat anti-mouse immunoglobulin coupled to horseradish peroxidase as a means of detection. The monoclonal antibodies were found to react with a protein of molecular weight 60,000, which was also recognized by polyclonal antibodies, although the latter reacted with a number of additional proteins. The relationship of the protein of molecular weight 60,000 to VIP is discussed.

Topics: Adrenal Gland Neoplasms; Animals; Antibodies, Monoclonal; Antigen-Antibody Complex; Brain Chemistry; Cross Reactions; Enzyme-Linked Immunosorbent Assay; Gastrointestinal Hormones; Hybridomas; Liver; Lymphocytes; Mice; Pancreas; Pheochromocytoma; Structure-Activity Relationship; Vasoactive Intestinal Peptide

Chromaffin granules, the catecholamine storage granules of pheochromocytoma were isolated from five human pheochromocytoma tumors. Vasoactive intestinal polypeptide (VIP) immunoreactivity was detected in all chromaffin granule preparations, paralleling the synthetic VIP antibody binding curve over a range of serial dilutions. In addition, gel filtration revealed an immunoreactive peptide peak coeluting with VIP. However, high molecular weight immunoreactive material was also detected on the column. This high molecular weight material was further characterized by sodium dodecyl sulfate gel electrophoresis, followed by electroblotting onto nitrocellulose paper and detection by anti-VIP antibodies with a secondary antibody conjugated to horseradish peroxidase. A 70 000 dalton immunoreactive band was identified, in which reactivity with anti-VIP antibody was inhibited by VIP; this band did not cross react with non-related antibodies. This 70 000 dalton protein may be an intermediate molecule in the biosynthesis and processing of VIP.

Topics: Adrenal Gland Neoplasms; Cell Fractionation; Chromaffin Granules; Chromaffin System; Gastrointestinal Hormones; Humans; Molecular Weight; Peptide Fragments; Pheochromocytoma; Protein Precursors; Vasoactive Intestinal Peptide

A man with watery diarrhoea was found to have adrenal tumour. Pre-operative examinations located the tumour in the right adrenal gland and revealed that it secreted an excess of vasoactive intestinal peptide (VIP). All symptoms disappeared after excision of the phaeochromocytoma; they have not recurred after a 3 years' follow-up period. Histological examination of the tumour confirmed that it was the site of a triple hormonal secretion (VIP somatostatin and catecholamines).

Topics: Adrenal Gland Neoplasms; Adult; Follow-Up Studies; Gastrointestinal Hormones; Humans; Male; Pheochromocytoma; Somatostatin; Vasoactive Intestinal Peptide; Vipoma

Topics: Adrenal Gland Neoplasms; Adrenal Medulla; Animals; Cattle; Cells, Cultured; Chromaffin System; Enkephalins; Gastrointestinal Hormones; In Vitro Techniques; Nicotine; Pheochromocytoma; RNA; Subcellular Fractions; Vasoactive Intestinal Peptide

Cyclic AMP accumulation in human colon adenocarcinoma cells in culture (HT-29) is known to be particularly sensitive to the stimulating action of vasoactive intestinal peptide (VIP). This property was exploited as a means of investigating the possible role of VIP as a humoral mediator in the watery diarrhoea syndrome. Our results showed that plasma from two patients with watery diarrhoea syndrome associated with ganglioneuroblastoma and pheochromocytoma strongly stimulated cyclic AMP accumulation in HT-29 cells, whereas plasma from normal subjects and patients with other diarrhoeal disorders had no effect. The stimulation induced by serial dilutions of plasma from patients paralleled the VIP-induced response. Preincubation of these plasmas with specific anti-VIP antibody prevented their stimulatory effects. Plasma sampled after the arrest of diarrhoea (spontaneous or after surgical resection of tumours) elicited AMP rise in HT-29 cells. Tumour extract stimulated cyclic AMP accumulation in HT-29 cells with a dose-response curve which was superimposable on the one obtained with standard VIP. The results lend support to the hypothesis that VIP is a humoral mediator in WDS and suggest that the diarrhoea is mediated through a VIP-induced accumulation of cyclic AMP in intestinal epithelial cells.

Topics: Adrenal Gland Neoplasms; Adult; Biological Assay; Child, Preschool; Diarrhea; Female; Ganglioneuroma; Gastrointestinal Hormones; Humans; Male; Pheochromocytoma; Vasoactive Intestinal Peptide

Immunohistochemical studies have demonstrated that immunoreactive vasoactive intestinal peptide is present in, and restricted to, the differentiating and mature ganglion cells in a variety of normal and neoplastic neural tissues. In a composite pheochromocytoma-ganglioneuroma (associated with the syndrome of watery diarrhea, hypokalemia, and hypochlorhydria), five ganglioneuroblastomas, five ganglioneuromas (two of which were associated with diarrheal syndromes), an unusual mixed neuroblastoma-ganglioneuroma, and four normal sympathetic ganglia, vasoactive intestinal peptide was present in differentiating and mature ganglion cells. The peptide was also demonstrated in isolated ganglion cells in two pheochromocytomas but was not present in pheochromocytes, Schwann cells, or undifferentiated neuroblastic cells in the neuroblastomas and ganglioneuroblastomas. These studies indicate that the presence and presumably the production of vasoactive intestinal peptide thus reflect a particular line of neuroblastic differentiation and are not merely a reflection of common derivation of these tissues. Our identification of vasoactive intestinal peptide in neurogenic tumors associated with diarrhea supports the contention that the peptide might be an important diarrheogenic factor in these tumors.

Topics: Adrenal Gland Neoplasms; Cell Differentiation; Ganglia, Autonomic; Ganglioneuroma; Gastrointestinal Hormones; Humans; Neoplasms, Nerve Tissue; Neuroblastoma; Pheochromocytoma; Vasoactive Intestinal Peptide

Two unusual cases of the watery diarrhea syndrome are presented. In one patient an adrenal medullary tumor, a pheochromocytoma that produced vasoactive intestinal polypeptide (VIP) was excised with total relief of symptoms. The second patient a 65-year-old man with abrupt onset of massive watery diarrhea that led to acidosis and coma was symptomatically controlled for one year on 10 mg/day of prednisone. Elevated levels of VIP returned to normal after prednisone therapy was started. A benign islet cell tumor not localized by angiography was removed by distal pancreatic resection. Tissue levels of VIP were markedly elevated. VIP is a humoral mediator of the water diarrhea syndrome. Both benign and malignant pancreatic and extrapancreatic tumors may cause the watery diarrhea syndrome. Steroids may cause symptomatic relief of the diarrhea by lowering peptide levels to normal. The term watery diarrhea syndrome may be more accurate than the pancreatic cholera syndrome.

Topics: Adenoma, Islet Cell; Adrenal Gland Neoplasms; Aged; Diarrhea; Female; Gastrointestinal Hormones; Humans; Male; Middle Aged; Pancreatic Neoplasms; Pheochromocytoma; Prednisone; Vasoactive Intestinal Peptide

Topics: Achlorhydria; Adrenal Gland Neoplasms; Adult; Angiography; Diarrhea; Female; Gastrointestinal Hormones; Humans; Hypokalemia; Pheochromocytoma; Syndrome; Vasoactive Intestinal Peptide

A case of adult ganglioneuroma-pheochromocytoma with an associated watery diarrhea syndrome is reported. High levels of vasoactive intestinal peptide (VIP) were found in preoperative serum and in tumor tissue. The serum VIP levels fell to normal, and the watery diarrhae syndrome completely ceased following removal of the tumor. In addition to containing VIP, the tumor was rich in catecholamines, and calcitonin. Peptide hormone-containing extracts and catecholamine extracts from the tumor both activated the adenyl cyclase system and increased lipolytic activity in a preparation of isolated rat fat cells. The findings in this patient further link VIP with neural crest tissues, and suggest the importance of determining catecholamine levels in patients with the watery diarrhea syndrome.

Topics: Acidosis; Adenylyl Cyclases; Adipose Tissue; Adult; Calcitonin; Catecholamines; Diarrhea; Female; Ganglioneuroma; Gastrointestinal Hormones; Humans; Hypokalemia; In Vitro Techniques; Pheochromocytoma; Retroperitoneal Neoplasms; Syndrome; Vasoactive Intestinal Peptide

Topics: Catecholamines; Humans; Hypertension; Neuroblastoma; Paraganglioma, Extra-Adrenal; Pheochromocytoma; Prostaglandins; Vasoactive Intestinal Peptide