Pancreatic vasoactive intestinal polypeptide-oma as a cause of secretory diarrhoea

A 42-year-old woman presented with a 4-year history of worsening diarrhoea that was watery, profuse and confirmed to be secretory in nature. She had tested positive for phenolphthalein on urinary laxative screening but continued to deny laxative usage. Her vasoactive intestinal polypeptide (VIP) level was subsequently found to be markedly elevated. Despite a normal abdominal ultrasound, a computed tomography scan revealed a 5-cm pancreatic tail mass. Octreotide scanning was used to exclude metastatic disease and she went on to have surgical removal of a localized pancreatic vasoactive intestinal polypeptide-oma which resulted in the complete resolution of her diarrhoea.     

Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus diarrhoea

BACKGROUND AND AIMS: The mechanisms underlying intestinal secretion in rotavirus diarrhoea remain to be established. We previously reported that rotavirus evokes intestinal fluid and electrolyte secretion by activation of the enteric nervous system. We now report that antagonists for the 5-hydroxytryptamine 3 receptor (5-HT(3)) and vasoactive intestinal peptide (VIP) receptor, but not antagonists for 5-hydroxytryptamine 4 receptor or the muscarinic receptor, attenuate rotavirus induced diarrhoea. METHODS: Neurotransmitter antagonists were administered to wild-type or neurokinin 1 receptor knockout mice infected with homologous (EDIM) or heterologous (RRV) rotavirus. RESULTS: While RRV infected mice had diarrhoea for 3.3 (0.2) days (95% confidence interval (CI) 3.04-3.56), the 5-HT(3) receptor antagonist (granisetron) and the VIP receptor antagonist (4Cl-D-Phe(6),Leu(17))-VIP both reduced the total number of days of RRV induced diarrhoea to 2.1 (0.3) (95% CI 1.31-2.9) (p<0.01). EDIM infected mice treated with granisetron had a significantly shorter duration of diarrhoea (5.6 (0.4) days) compared with untreated mice (8.0 (0.4) days; p<0.01). Experiments with neurokinin 1 receptor antagonists suggest that this receptor may possibly be involved in the secretory response to rotavirus. On the other hand, rotavirus diarrhoea was not attenuated in the neurokinin 1 receptor knockout mice. CONCLUSIONS: Our results suggest that the neurotransmitters serotonin and VIP are involved in rotavirus diarrhoea; observations that could imply new principles for treatment of this disease with significant global impact.     

Mechanisms of vasoactive intestinal peptide release in short-term culture of vasoactive intestinal peptide-producing tumor

Vasoactive intestinal peptide-producing tumor tissue fragments obtained at surgery were maintained in short-term culture. Functional cellular integrity of vasoactive intestinal peptide-producing tumor tissue was reflected by progressive protein synthesis and the ability of tumor tissue to release vasoactive intestinal peptide when stimulated by the intracellular second messengers cyclic adenosine monophosphate and calcium. Studies with verapamil and ethyleneglycol-bis (beta-aminoethylether)-N,N'-tetraacetic acid suggest that cyclic nucleotide- and ionophore A23187-mediated vasoactive intestinal peptide release are dependent, at least in part, upon the availability and transmembrane transport of extracellular calcium.     

血管活性肠肽对神经细胞脂褐素影响的实验研究

采用小鼠神经母细胞癌细胞无血清培养建立神经细胞老化实验研究模型。以显微荧光分光光度术测定的细胞内脂褐素自发荧光值为神经细胞老化指标，观察血管活性肠肽（ＶＩＰ）对实验性神经细胞内脂褐素荧光值的影响。结果发现：ＶＩＰ作用５ｄ可显著升高细胞内的脂褐素荧光值（Ｐ＜０．０１）．提示ＶＩＰ可加速实验性神经细胞的老化过程。     

Twenty-four-hour secretory pattern of vasoactive intestinal polypeptide in the elderly

A chronobiological study was carried out in 8 elderly male subjects (74-85 years) to evaluate the 24-hour vasoactive intestinal polypeptide (VIP) secretory pattern. Eight young adult males (21-32 years) made up the control group. Blood samples were drawn from each subject every 2 h during the day and hourly during the night for a 24-hour period. Mean 24-hour VIP values in elderly (21.1 +/- 0.3 pg/ml) and young adults (19.1 +/- 0.3 pg/ml) did not differ statistically, but daytime VIP values observed in elderly subjects (21.4 +/- 0.5 pg/ml) were higher (p less than 0.05) than those recorded in young adults (17.5 +/- 0.5 pg/ml). The young adults showed significant (p less than 0.05) circadian VIP fluctuations with highest values during the nighttime, while the elderly subjects did not. An age-related decreased activity of the peripheral neuronal VIP-ergic network is hypothesized.     

Synovial expression of vasoactive intestinal peptide in polymyalgia rheumatica

OBJECTIVE: Polymyalgia rheumatica (PMR) is an inflammatory disease that typically affects elderly people. Its clinical hallmark is the severity of pain in the shoulder and pelvic girdle. Mild to moderate synovitis and/or bursitis of the joints involved has been described. Neuropeptides are involved in nociception and modulation of inflammatory reaction. To evaluate whether neuropeptides have a role in PMR pathophysiology, we studied the expression of substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) and somatostatin (SOM) in shoulder synovial tissues of PMR patients. METHODS: Synovial expression of neuropeptides was investigated by immunohistochemical analysis, in two groups of PMR patients: the first one at the onset of disease and the second one after corticosteroid treatment, and in other joint diseases, rheumatoid arthritis (RA) and osteoarthritis (OA). RESULTS: The only significant expression of VIP was found in PMR and, to a lesser extent, in RA synovial tissue. In PMR, we observed VIP immunostaining both in the lining layer and in the sublining area. In patients on corticosteroid treatment VIP lining layer expression was not significantly different while VIP positive cells in the sublining area were almost absent. CONCLUSION: Local VIP production in PMR synovial tissue might contribute to the typical musculoskeletal discomfort and it may have a role in the immunomodulation of synovial inflammation.     

Autocrine control of prolactin secretion by vasoactive intestinal peptide

The functions of vasoactive intestinal polypeptide (VIP) and the many other neuropeptides that are localized in the anterior pituitary gland remain unknown although VIP of hypothalamic origin is established to act as a PRL-releasing factor. Evidence is presented here that locally-produced VIP acts in an autocrine fashion to stimulate PRL release. VIP antibodies or a VIP antagonist profoundly but reversibly suppressed PRL secretion in primary cultures of rat pituitary cells or the GH3 cell line. This evidence was obtained with the use of a reverse hemolytic plaque assay for microscopic demonstration of PRL release from individual cells under conditions precluding cell-cell interaction. We suggest that most of the high rate of "spontaneous" PRL secretion attributed to lactotropes deprived of hypothalamic influence is due in fact to the stimulatory effects of VIP acting in an autocrine fashion.     

Cardiovascular effects of vasoactive intestinal peptide in healthy subjects

Hypotension and flushing are occasionally observed in patients with pancreatic cholera syndrome. Similar effects are produced when vasoactive intestinal polypeptide (VIP) is administered to healthy subjects. To characterize further these responses, serial measurements of heart rate, blood pressure, cardiac output and forearm blood flow were made in 6 healthy subjects during constant VIP infusion (400 pmol/kg/hr for 100 minutes). VIP infusion caused sustained vasodilatation and decreased total peripheral resistance and mean arterial pressure by 30 and 12%, respectively. Forearm resistance decreased by 65%. The effects on cardiac output and stroke volume were biphasic. During the early phase of VIP infusion (0 to 70 minutes), heart rate and cardiac output increased with only minor changes in stroke volume. Later (71 to 100 minutes) the tachycardia persisted, but cardiac output decreased toward control levels due to decreased stroke volume. Echocardiograms during the infusion demonstrated increased left ventricular contractility as defined by the relation between end-systolic wall stress and shortening fraction. These data document potent vasodilatory and inotropic actions of VIP. It is likely that intravascular volume losses from increased intestinal secretion account for the decreased stroke volume seen late in the VIP infusion period and immediately thereafter. The tachycardia appears to be an appropriate compensatory mechanism to maintain blood pressure in the presence of vasodilatation and loss of intervascular volume. These observations provide an explanation for the cardiovascular findings in patients with sudden release of VIP from tumors.     

The relation of vasoactive intestinal peptide and acute hypoxia

In order to observe the effect of acute hypoxia on release of vasoactive intestinal peptide (VIP), the plasma VIP content was determined in anesthetized dogs by a specific radioimmunoassay technique during acute hypoxia. Blood gases and hemodynamics were monitored simultaneously. After inhalation of 10% oxygen. the plasma VIP levels elevated along with decrease in PaO2 and increase in pulmonary artery pressure. The plasma concentration of VIP in the portal vein increased significantly from 106 +/- 21 pg/ml before hypoxia to 173 +/- 36 pg/ml 15 minutes after the onset of hypoxia (P less than 0.01). The difference of arterio-venous VIP content increased from -3 +/- 6 pg/ml before hypoxia to +9 +/- 7 pg/ml after inhalation of 10% oxygen for 30 minutes. The results suggested that VIP was released from the gastrointestinal tract as well as from the lung in case of hypoxia and pulmonary hypertension. It is considered that the release of VIP may be an adaptive and compensatory response, promoting vasodilation and perfusion in vital organs.     

A new neuroregulator: The vasoactive intestinal peptide or VIP

VIP is a neuroregulator occurring in the central and peripheral nervous system which exhibits the function of neurotransmitter in the brain, neuroendocrine substance at the pituitary level, and neuroparacrine substance in peripheral organs. The structure and the specificity of the molecule as studied by antibody and receptor, and its location in brain and peripheral organs are summarized as well as its numerous biological effects. The method used to demonstrate the involvement of VIP in a physiological regulation is described and illustrated by two examples: the effect of VIP on gut epithelium and the neuroendocrine action of VIP in inducing prolactin release from pituitary cells. The consequence of this recent progress in the knowledge of VIP release and action in human physiology and disease is indicated.     

The effect of vasoactive intestinal peptide on the rat ovary

In recent years, the localization and physiological significance of vasoactive intestinal peptide (VIP) in various organs have been studied. Investigations of the significance of VIP in the ovary have been done, but the detailed mechanism of action is still unknown. We made in vitro studies of VIP using rat ovaries. Ovarian granulosa cells were collected after treatment with estrogen in immature hypophysectomized rats. Luteal cells were collected from immature rats treated with pregnant mare serum (PMS) and human chorionic gonadotropin (hCG). These cells were cultured in a serum free medium for 48 hr in the absence or presence of various amounts of VIP. We determined the amount of steroids produced in the culture medium by specific RIA. Activities of 3 beta-HSD in the granulosa cells were determined by the amount of progesterone formed from labelled pregnenolone. Induction of LH-receptor in the granulosa cells by VIP and VIP-receptor in these cells was investigated. VIP stimulated estrogen and progesterone production dose and time dependently with an approximate ED50 value of 3 x 10(-8) M. The amount of cyclic adenosine monophosphate (c-AMP) was similarly increased. VIP enhanced 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity when incubated with the granulosa cells for 24 hours. VIP stimulated the granulosa cells in a way similar to follicle stimulating hormone (FSH), but the stimulating effect was slightly less than that of FSH. Unlike FSH, VIP did not induce LH-receptor. The binding of 125I-VIP with the granulosa cells was blocked, dose dependently, by unlabelled VIP, suggesting the presence of VIP-receptor in the granulosa cells. Another peptide, PHM-27, stimulated the granulosa cells although its potency was less than that of VIP. In contrast, gastrin, CCK and secretion did not stimulate the granulosa cells at all. According to the present study. VIP did not exert any effect on the luteal cells, and progesterone production in vitro was not stimulated by this peptide. The VIP effects seem to be at least partly c-AMP dependent and may be mediated through the VIP-receptor in the granulosa cells. The observed direct effects of VIP suggest that it may act as a local hormone to regulate the ovarian function.     

Ontogenic development of vasoactive intestinal peptide receptors in rat intestinal cells and liver

Changes in the functional and biochemical characteristics of membrane receptors for vasoactive intestinal peptide (VIP) were evaluated in vitro, using epithelial intestinal cells isolated during rat development, from day 17 of gestation to adulthood. These characteristics included cell cAMP generation, adenylate cyclase and cAMP-dependent phosphodiesterase cAMP-PDE activities, [125I]VIP-binding capacity, and the molecular components of [125I]VIP-binding sites. In 19-day-old fetuses, VIP induced a significant and persistent increase in cAMP production, which lasted for 10 min in intestinal cells. This effect, measured at 37 C in the absence of cAMP-PDE inhibitor, only lasted for 3 min in 5-day-old rats and was undetectable in adult intestine. Addition of the cAMP-PDE inhibitor 3-isobutyl-1-methylxanthine with VIP caused, potentiated, and maintained elevated cAMP levels at the three stages considered. Intestinal cells were more sensitive to VIP in 17- and 19-day-old fetuses (ED50 = 5 and 17 X 10(-11) M VIP, respectively, at 15 and 37 C) than in adult rats (EC50 = 2.7 and 1.6 X 10(-9) M VIP). Adenylate cyclase activity rose 4-fold in fetal intestine and had an apparent Ka of 4 X 10(-10) M VIP. These changes in VIP receptor activity were not observed for PGE2 receptors in developing rat intestinal cells or in the VIP-sensitive adenylate cyclase system prepared from liver of fetuses and adults. They might be due to differences between the molecular components of the intestinal VIP receptor, which were identified here as autoradiographic bands of 64,800 daltons in 19-day-old rat fetuses and 74,600 daltons in adults (P less than 0.01). Alternatively, the changes in VIP receptor activity in 5-day-old rats may result from decreases in the number and affinity of the [125I]VIP-binding sites and increases in the velocity of cAMP-PDE activity. The release of VIP from intestinal nerve endings during fetal and postnatal development and the absorption of VIP from milk might, therefore, modulate the intestinal VIP receptor and its effector systems. Because specific VIP receptors were expressed before the morphological and functional differentiation of intestinal and liver cells, we conclude that their activity is an indicator of their development, and suggest that in rats, this neuropeptide may regulate the maturation and functions of intestine and liver during fetal life.     

Neonatal androgenization increases vasoactive intestinal peptide levels in rat anterior pituitary: possible involvement of vasoactive intestinal peptide in the neonatal androgenization-induced hyperprolactinemia.

Accumulating evidence suggests that vasoactive intestinal peptide (VIP) may be a physiological PRL-releasing factor. In the present study, we examined a possible involvement of VIP in the neonatal androgenization (NA)-induced hyperprolactinemia. Twenty-four hours after birth, newborn female rats were injected sc with 1,000 micrograms of testosterone (NA) or with oil vehicle only (control). Both groups were sacrificed at 8 weeks of age. Compared to controls, NA rats showed significantly higher plasma PRL levels (7.3 fold), anterior pituitary (AP) PRL content (2.1 fold) and plasma estradiol levels (2.1 fold). AP VIP content was extremely higher (61 fold) in NA rats than in controls. However, NA did not affect VIP content in the suprachiasmatic nucleus, paraventricular nucleus or median eminence. These results suggest that the NA-induced hyperprolactinemia may be mediated, at least in part, by paracrine and/or autocrine effects of the increased AP VIP on PRL secretion. However, since the potentiation by NA of the AP VIP content was extremely marked compared to those of the other parameters, the possibility was also raised that the increased AP VIP may be involved in other endocrine and/or nonendocrine events occurring in the AP.     

Effects of vasoactive intestinal peptide on plasma prolactin in passerines

Vasoactive intestinal peptide (VIP) is a potent releaser of prolactin (PRL) in domestic fowl, turkey, and ring doves. However, few comparative studies have investigated this in wild species. We tested the effects of intravenously administered chicken VIP on plasma PRL concentrations in four passerine species: the white-crowned sparrow (Zonotrichia leucophrys gambelii), the dark-eyed junco (Junco hyemalis), the Florida scrub-jay (Aphelocoma coerulescens), and the western scrub-jay (A. californica). In the white-crowned sparrow, junco, and Florida scrub-jay, which were tested during the breeding season, VIP induced a rapid increase in plasma PRL. Serial plasma samples taken after VIP injection in the white-crowned sparrow show a 10-fold increase in PRL within 2 min of treatment, followed by a gradual decline. Effects of VIP, as compared to saline, remained significant for at least 20 min after treatment. Western scrub-jays did not respond to intravenous VIP with a significant rise in PRL secretion, possibly because they were tested after termination of the breeding season. This study indicates that VIP control of PRL release may be widespread among avian species, and that seasonal changes in plasma PRL may be mediated in part at the level of the pituitary. In addition, analysis of the control data revealed no increase in plasma PRL as a result of injection or restraint, suggesting that unlike in mammals, PRL is not released during acute stress in passerines.     

Interaction of vasoactive intestinal peptide with human blood mononuclear cells

The binding of vasoactive intestinal peptide (VIP) and the stimulation of adenylate cyclase were studied in mononuclear cells from human peripheral blood. The binding depended on time, temperature and pH, and was reversible, saturable and specific. Binding studies suggested the presence of 2 classes of binding site: a class with high affinity (Kd = 2.4 X 10(-10)M) and low capacity (8 fmoles/10(6) cells), and a class with low affinity (Kd = 8.0 X 10(-8)M) and high capacity (800 fmoles/10(6) cells) at 15 degrees C. Secretin displaced [125I]VIP from the cells with a 400-fold lower affinity than VIP, but glucagon, somatostatin and insulin did not show any effect. VIP was a potent and efficient stimulator of cyclic AMP production. The stimulation was observed at a concentration as low as 3 X 10(-11)M and depended on time, temperature and pH. Maximal cyclic AMP production (4-fold above basal levels) was observed with 10(-9) M at 15 degrees. Half-maximal response was obtained at 10(-10)M VIP. Secretin was an agonist of VIP but exhibited a 7000 times lower potency. Peripheral blood mononuclear cells constitute an easily accessible and suitable system for the study of VIP action in different physiological and pathophysiological conditions.     

Functional receptors for vasoactive intestinal peptide on human osteosarcoma cells

We have previously reported that vasoactive intestinal peptide (VIP) stimulates bone resorption in organ culture via a cAMP-dependent mechanism. Here we describe functional receptors for VIP on a clonal line of human osteosarcoma cells, SaOs-2. SaOs-2 cells respond to VIP with an increase in cAMP. The effect was rapid (2 min) and dose dependent from 0.15-15 nM VIP, with half-maximal stimulation at 1.4 nM. SaOs-2 cells produce prostaglandin E2 (PGE2) and respond to exogenous PGE2 with increases in cAMP approximately one third as great as those induced by VIP. However, the VIP-stimulated increases in cAMP occurred without detectable increases in PGE2 production, and increases in cAMP were unaffected by the cyclooxygenase inhibitor indomethacin. SaOs-2 cells pretreated with VIP for 24 h were significantly less responsive to a second acute challenge with VIP, but retained their ability to respond to PGE2. Similarly, pretreatment with PGE2 induced homologous desensitization to PGE2, but had no effect on the VIP-stimulated increase in cAMP. These patterns of response paralleled those previously described in whole bone in organ culture. Binding studies with [125I]VIP demonstrated specific, saturable, high affinity receptors for VIP on SaOs-2 cells. Scatchard analysis of [125I]VIP binding at 37 C resulted in a curvilinear plot. Analysis based upon the assumption of two independent binding sites gave Kd values of 0.44 and 17 nM for high and low affinity binding sites, respectively. The numbers of high and low affinity sites per cell were determined to be 8,500 and 57,000, respectively. Binding of [125I]VIP was partially inhibited by two related peptides, secretin and PHI-27, but not by PTH, calcitonin or a variety of unrelated peptides. We conclude that the action of VIP on human SaOs-2 cells is similar to that observed in intact mouse calvaria, and that these cells provide a good model for the study of the initial steps of VIP action in bone.