Release of Vasoactive Intestinal Polypeptide (VIP) by Intraduodenal Stimuli

The effect of intraduodenal infusion of amino acids, glucose, fat, HCl, ethanol, or saline on plasma VIP concentration was investigated in 7 normal subjects, 5 post-vagotomy patients, and 12 anaesthetized pigs. Furthermore, the concentrations of VIP in plasma after ingestion of a mixed meal were measured in 6 normal subjects. In normal subjects the median peripheral concentration of VIP in the basal state was 4.3 pmol × 1-¹ (range 0-12.0). No significant changes occurred after amino acids, glucose, saline, or ingestion of a meal. In contrast infusion of HCl, fat, or ethanol resulted in a rise in plasma VIP concentration in all the subjects studied. The peak values (medians and ranges) after HCl, fat, or ethanol were 9.8 (5.9-12.6), 7.5 (2.4-10.2), and 12.6 (7.8-16.8) pmol × 1-¹, respectively. Truncal vagotomy did not change the response of HCl. The results from measurements in portal plasma of pigs confirmed the findings in peripheral plasma of normal subjects and showed that the levels of VIP in portal plasma are 1.6-2.9 times higher than the levels of VIP in arterial plasma. The pH threshold to release of VIP was pH 1.1-2.1, and the effect of HCl was not abolished by ganglionic blockade.     

Effectiveness of the intestinal polypeptides,IRP, GIP,VIP and motilin on insulin release in the rat

Summary Intestinal insulin releasing polypeptide (IRP) and Gastric inhibitory polypeptide (GIP) have a similar effect on intravenous glucose tolerance in the rat. Both augment the insulin response to intravenous glucose and increase the rate of glucose disappearance. VIP and motilin have no discernible effect. Plasma insulin dose-response curves to IRP and GIP are similar; both peptides stimulate insulin release in the presence of small blood glucose increments. A direct comparison of the insulin releasing potency of IRP and GIP is not possible as the former is not yet available in pure form.     

Effect of vasoactive intestinal polypeptide (VIP) antagonism on rat jejunal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins

BACKGROUND: The enteric nervous system is important in the pathophysiology of intestinal fluid secretion induced by cholera toxin (CT), Escherichia coli heat labile (LT), and heat stable (STa) toxins. The neurotransmitters involved are not fully elucidated. Vasoactive intestinal polypeptide (VIP), a potent intestinal secretagogue present in the enteric nervous system, is increased after exposure of the cat intestine to CT. Whether VIP is involved in the pathogenesis of cholera and other toxins in not known. AIM: To study in vivo the effect of VIP antagonism on jejunal fluid secretion induced by CT, LT, and STa. METHODS: CT, LT (25 microg), or 0.9% NaCl was instilled in an isolated 25 cm segment of rat jejunum, and the VIP antagonist (VIPa) [4Cl-D-Phe(6), Leu(17)]-VIP (0.2 or 2 microg/kg/min) or 0.9% NaCl was given intravenously. Two hours later, single pass in vivo jejunal perfusion was performed to assess fluid movement. In STa experiments, intravenous VIPa or 0.9% NaCl was given and 30 minutes later the jejunal segment was perfused with a solution containing STa 200 microg/l. RESULTS: VIPa had no effect on basal intestinal fluid absorption. CT induced net fluid secretion (median -68 microl/min/g dry intestinal weight (interquartile range -80 to -56)) which was dose dependently reversed by VIPa (6.2 (-16 to 34) and 29 (17 to 42); p<0.01). Similarly, LT induced secretion (-63 (-73 to -30)) was attenuated by VIPa (0.2 microg/kg/min) (-15 (-24 to -1); p<0.01) and totally reversed to normal levels by VIPa (2 microg/kg/min) (37 (28-56); p<0. 01 compared with LT and not significant compared with normal controls). STa induced secretion (-17 (-19 to -2)) was also reversed by VIPa (12 (9-23) and 14 (0-26); p<0.01). CONCLUSION: VIP plays an important role in CT, LT, and STa induced intestinal secretion and may be the final putative neurotransmitter in the pathophysiology of these toxins.     

Hepatic bile formation in the rat

While changes in gastric, pancreatic, and intestinal secretion in response to more recently identified gastrointestinal peptides have been characterized, there has been less investigation into effects of these hormones on hepatic bile production. The isolated perfused rat liver model has been used to examine effects of vasoactive intestinal peptide (VIP), somatostatin, bombesin, and thyrotropin-releasing hormone (TRH) on bile flow and bile acid transport. No changes were seen following bolus administration of bombesin (3×10^–8–1.5×10^–6 M) or TRH (3×10^–7–3×10^–6 M), while somatostatin (6×10^–6 M) produced a small decrease in bile flow without any change in bile acid output. VIP (3×10^–7 M) caused a highly significant increase in both volume of bile flow (0.85±0.8 to 1.11±0.09 l/min/g liver,P<0.001) and bile acid output (31.6±1.5 to 43.2±1.7 nmol/min/g liver,P<0.001). Elimination of Ca²⁺ from liver perfusate did not prevent VIP-induced increases in bile flow and bile acid output, and no synergistic effect of concomitant theophylline administration was observed. While effects of VIP on bile flow appear to be due to alterations in hepatic transport of bile acids, the exact mechanism(s) producing these changes remains to be elucidated.This work was supported by National Institutes of Health grant AM-32208 and the Research Service of the Veterans Administration.     

Colocalization of NADPH-diaphorase staining and VIP immunoreactivity in neurons in opossum internal anal sphincter

Nitric oxide and vasoactive intestinal polypeptide (VIP) are important inhibitory neurotransmitters mediating relaxation of the internal anal sphincter. The location and coexistence of these two neurotransmitters in the internal anal sphincter has not been examined. We performed a double-labeling study to examine the coexistence of nitric oxide synthase and VIP in the oppossum internal anal sphincter using the NADPH-diaphorase technique which is a histochemical stain for nitric oxide synthase. In perfusion-fixed, frozen-sectioned tissue, VIP-immunoreactive neurons were labeled using immunofluorescence histochemistry. After photographing the VIP-immunoreactive neurons, nitric oxide synthase was labeled using the NADPH-diaphorase technique. Ganglia containing neuronal cell bodies were present in the myenteric plexus for the entire extent of the internal anal sphincter. VIP-immunoreactive and NADPH-diaphorase-positive neurons were present in ganglia in the myenteric as well as the submucosal plexuses. Most of the VIP-immunoreactive neurons were also NADPH-diaphorase positive. VIP and nitric oxide synthase are present and frequently coexist in neurons in the internal anal sphincter of the opossum. These neurons may be an important source of inhibitory innervation mediating the rectoanal reflex-induced relaxation of the sphincter. The demonstration of the coexistence of these two neurotransmitters will be of fundamental importance in unraveling their relationship and interaction in the internal anal sphincter as well as other systems.Supported by DK-02094 (RBL) and DK-35385 (SR) from the National Institutes of Health and an institutional grant from Thomas Jefferson University.     

胃腺癌组织中分泌血管活性肠肽的肿瘤细胞研究

目的　研究胃腺癌中是否存在分泌血管活性肠肽 (VIP)的肿瘤细胞 ,探讨VIP在胃腺癌发生发展中的作用。方法　 2 0 0 1- 12～ 2 0 0 2 - 0 5通过免疫组化的方法 ,检测华中科技大学同济医院附属协和医院 15例正常胃窦黏膜、2 0例胃腺癌组织中VIP蛋白的表达情况 ,观察样本中VIP阳性反应的细胞和神经纤维。结果　 8例 (8/2 0 )胃腺癌组织中发现VIP阳性细胞 ,其中高分化 2例 (2 / 5 )、中分化 2例 (2 / 7) ,低分化 4例 (4/ 8)。阳性细胞的检出率与胃腺癌的恶性程度无相关性 (P >0. 0 5 )。阳性细胞形态不规则 ,多数细胞核膜及核着色 ,少数胞浆着色 ,核大而不规则。 6例局限分布于肿瘤组织中 ,2例低分化胃腺癌阳性细胞散在分布于整个肿瘤组织中。胃腺癌组织中未见阳性神经纤维 ,正常胃黏膜可见阳性神经纤维 ,但未发现阳性细胞。结论　 4 0 %胃腺癌组织中含有分泌VIP的肿瘤细胞 ,VIP可能对胃腺癌的发生有重要的影响。     

血管活性肠肽参与电针对大鼠胃粘膜损伤的保护作用

目的：探讨血管活性肠肽(VIP)参与电针对胃粘膜损伤大鼠保护作用的机制。方法：采用束缚冷应激胃粘膜损伤大鼠模型，通过放射免疫测定法和中枢迷走背核复合体(DVC)微量注射，观察电针对各组外周血、胃粘膜和脑组织的VIP含量的变化，胃粘膜血流量(GMBF)、损伤指数(LI)和跨壁电位差(PD)的影响。结果：电针模型组外周血、胃粘膜和脑组织VIP含量均增加，GMBF、PD也明显增加，LI下降；中枢DVC微量注射VIP后，外周血和胃粘膜中VIP含量增加。结论：VIP作为信号分子，通过神经内分泌免疫网络系统对胃粘膜损伤具有整体调控作用。     

Catalytic Hydrolysis of VIP in Pregnant Women with Asthma

Rationale: The neuropeptide vasoactive intestinal peptide (VIP) is one of the physiologic mediators of non-adrenergic, non-cholinergic smooth muscle relaxation of the airway and an important modulator of innate and adaptive immune responses. VIP catalytic autoantibodies are increased in asthma and serum VIP level is decreased during acute exacerbation of asthma. The effect of pregnancy on asthma is variable and depends in part on the severity of pre-existing asthma, along with other physiological and pathophysiological changes. We hypothesized that hydrolysis of VIP by circulating catalytic VIP antibodies will be increased in pregnancy in patients with asthma. Study objective: To determine the level of catalytic autoantibodies to VIP in pregnant asthmatics compared to non-pregnant asthmatics and control pregnant women without asthma. Methods: We prospectively enrolled eight pregnant asthmatics (age, 26.5 ± 2.6 years; mean ± SEM), nine pregnant women without asthma (32.0 ± 3.0 years), seven non-pregnant women with asthma (25.0 ±1.9 years), and seven non-pregnant women without asthma (34.4 ± 2 years) into the study. VIP hydrolysis was performed in all subjects. Results: Immunoglobulin G (IgG) autoantibodies that catalyze the hydrolysis of vasoactive intestinal peptide (VIP) were present at greater levels in the blood of pregnant women with asthma (7.6 ± 1.1 pM VIP/6 h) compared to pregnant women without asthma (4.0 ± 0.5; p < 0.001), non-pregnant asthmatics (4.9 ± 0.9; p < 0.05) or non-pregnant women without asthma (1.9 ± 0.7; p < 0.05). Conclusion: An increase in the VIP hydrolyzing activity of IgG is independently associated with asthma and pregnancy. The autoantibodies hold the potential of affecting the pathophysiology of the airways in pregnant asthmatics.     

Dissimilar trophic effects of cerulein and xenopsin on the rat pancreas

Cholecystokinin (CCK), gastrin, cerulein, and other analogs are known to stimulate the growth of the rat pancreas. In the present study, we compared the trophic action of a member of this gastrin/CCK family, the amphibian peptide cerulein, with a member of the structurally unrelated neurotensin/ xenopsin group, the amphibian peptide xenopsin. For this purpose, 0.56 nmols/kg cerulein, 1.0 nmols/kg xenopsin, or normal saline were injected intraperitoneally three times a day in 28 rats for 3 d. Pancreatic weight, DNA, and incorporation of³H-thymidine into DNA were determined. In another study, pancreatic weight, DNA, and the polyamines, putrescine, spermidine, and spermine, were determined after a single dose of 2.7 nmol/kg cerulein, 4.5 nmol/kg xenopsin, or saline. The polyamines were measured by reverse-phase HPLC and post-column derivatization. Cerulein increased pancreatic weight, stimulated³H-thymidine incorporation into DNA, and raised putrescine concentrations significantly, but led to a significant reduction of pancreatic DNA concentration. Xenopsin also stimulated³H-thymidine incorporation into DNA, but did not affect pancreatic weight, DNA concentration, or the polyamines during the 4 h of the experiment. These findings suggest that cerulein, in the dose and intervals applied, initiated hyperplasia and induced hypertrophy of the pancreas, whereas xenopsin only initiated hyperplasia. These results, together with the dissimilar secretory effects of the two peptide families, may be the expression of a dissimilar mode of action. However, it cannot be excluded that, since cerulein is more potent than xenopsin, the differences also are owing to dosage. We conclude that cerulein and xenopsin, which both have trophic effects on the pancreas, may act by different mechanisms.     

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.     

The Effect of Insulin-Induced Hypoglycemia with and without Atropine on Plasma Vasoactive Intestinal Polypeptide in Man

Plasma vasoactive intestinal polypeptide (VIP) was measured in six healthy male students on 2 separate days after insulin-induced hypoglycemia with and without atropine and on a 3rd day in five of the students after atropine alone. A significant increase in peripheral plasma VIP was observed when atropine was given together with insulin, whereas insulin or atropine alone had no effect on plasma VIP. It is suggested that cholinergic nicotinic receptors may be involved in the increase of VIP after insulin-induced hypoglycemia and that the lack of VIP increase seen after insulin alone may be caused by an inhibitory effect of other gastrointestinal hormones.     

VIP immunoreactive nerves and somatostatin and serotonin containing cells in Crohn's disease

INTRODUCTION With the progress of the studies on neuroendocrine and immunology in the gastrointestinal tract, it has been recognized that the intestinal neuroendocrine system and the immune system can influence and modulate each other and a neuroendocrine immunomodulation network in the intestine has been established[1]. Neuropeptides, such as vasoactive intestinal peptide (VIP), substance P (SP), somatostatin (SS) etc. are widely distributed in the gastrointestinal tract and they play an important role in the immunomodulation of the intestinal mucosa.     

Substance P,vasoactive intestinal polypeptide,and gastrin catabolism in canine liver and kidney

No reports have described the catabolic mechanism of substance Pin vivo. We studied the effects of hepatic or renal transit on substance P, vasoactive intestinal polypeptide, and gastrin in anesthetized dogs. It was found that the liver plays a more important role in vasoactive intestinal polypeptide catabolism than the kidney and the kidney is more important in gastrin catabolism than the liver. Substance P was more rapidly degraded than the other two peptides in both organs. The transrenal substance P loss measured byC-terminal antiserum differed from that measured byN-terminal antiserum, although there was no difference in the liver. This suggested that there were different patterns of cleavage of substance P between the liver and the kidney, and that itsC terminal was degraded more strongly than itsN terminal in the kidney.     

Changes in the somatostatin,substance P and vasoactive intestinal polypeptide content of the gastrointestinal tract following streptozotocin-induced diabetes in the rat

Summary Rats with streptozotocin-induced diabetes of 10 weeks' duration showed significant changes in the total content of somatostatin, substance P and vasoactive intestinal polypeptide in the stomach and small intestine compared with control animals. An increase (p<0.05) in the concentration and total content of gastric somatostatin and a decrease (p<0.05) in the concentration and content of gastric substance P were seen in the streptozotocin-treated rats. The increase in the vasoactive intestinal polypeptide (VIP) content (54%, p<0.05) and the decrease in the substance P content (35%, p<0.05) of the gut may contribute to the impaired intestinal motility observed in animals with experimentally produced diabetes. Both the diabetogenic effect of streptozotocin and the changes in regulatory peptide concentrations were prevented by injection of nicotinamide before streptozotocin suggesting that the changes did not arise from a non-specific toxic effect of streptozotocin upon gastrointestinal neurones and/or endocrine cells.     

Vasoactive intestinal polypeptide appears to be one of the mediators in misoprostol-enhanced small intestinal transit in rats

BACKGROUND AND AIMS: Prostaglandin analogs have the pharmacologic effect of speeding up small intestinal transit (SIT). It remains unknown whether some gut peptides also mediate this enhancement. We studied the effect of misoprostol on rat SIT and looked at the role of vasoactive intestinal polypeptide (VIP) release during its action. METHODS: A group of rats initially received oral misoprostol treatment of 1, 10, 50 and 100 microg/kg, respectively. By using orally fed charcoal as a motility marker, the SIT was assessed at 30 min following oral misoprostol treatment. Another group of rats received misoprostol as an intraperitoneal injection in similar doses to the group above. The small intestinal transit was computed for this group at 30 min following misoprostol injection via an instilled radiochromium motility marker that went through a previously placed intraduodenal catheter. The plasma VIP level was measured by using a radioimmunoassay kit. RESULTS: Neither charcoal evaluated transit nor the plasma VIP level was influenced by the lower doses of oral misoprostol treatment (1 and 10 microg/kg), whereas other doses enhanced SIT and diminished the plasma VIP level (P< 0.01).The similar effects on radiochromium computed SIT (P< 0.01) and plasma VIP levels were obtained in tubed rats following misoprostol intraperitoneal treatment. The SIT results correlated negatively with plasma VIP levels. CONCLUSIONS: Enhanced SIT and diminished VIP levels are found in rats following misoprostol treatment. It appears that inhibited VIP release is one of the mechanisms in misoprostol-enhanced SIT.     

The influence of somatostatin on glucagon and pancreatic polypeptide secretion in the isolated perfused human pancreas

Summary The current study was undertaken to determine whether intraislet somatostatin regulates glucagon or pancreatic polypeptide (PP) secretion in the human pancreas. A high-affinity, high-specificity monoclonal somatostatin antibody (CURE.S6) was used to immunoneutralize somatostatin in the isolated, perfused human pancreas. Single-pass perfusion was performed in pancreata obtained from cadaveric organ donors using a modified Krebs media with either 3.9 or 12.9 mM glucose. Sequential test periods separated by basal periods were performed with infusion of either exogenous somatostatin-14 (SS-14), CURE.S6, or a combined infusion. Infusion of SS-14 did not significantly alter glucagon or PP secretion during low-glucose or high-glucose perfusion. Immunoneutralization of intraislet somatostatin with CURE.S6 resulted in a significant increase of glucagon secretion under low-glucose conditions (ΔX=15±3 pM) (p<0.05), but did not significantly effect glucagon secretion under high-glucose conditions (ΔX=−2±3 pM) (p=NS). PP secretion remained unchanged during CURE.S6 infusion. Combined infusion of SS-14 and CURE.S6 did not significantly alter glucagon or PP secretion. The data suggest that intraislet somatostatin may have an inhibitory role in the regulation of glucagon secretion during low-glucose conditions and that intraislet somatostatin does not regulate PP secretion in the isolated, perfused human pancreas.     

Effects of a transplantable insulinoma upon regulatory peptide concentrations in the gastrointestinal tract of the rat

Summary The rapid growth (0.8±0.3 g/day) of a transplantable insulinoma, which also contained substance P (2.9±2.3 pmol/g) and gastrin-releasing peptide (3.2± 2.1 pmoll/g), resulted in the development of hyperphagia, hyperinsulinaeinia and hypoglycaemia in rats (n=8). After a 14-day growth period, the insulinoma-bearing rats showed an increase (49%; p<0.01) in the weight of the small intestine but no significant change in stomach weight compared with control animals. The content (pmol/organ) of somatostatin, substance P, neurokinin A and vasoactive intestinal peptide in the stomachs of the tumour rats was unchanged. A depletion in the content (53% p<0.01) and concentration (57%; p<0.01) of gastrin-releasing peptide, however, suggested either hypersecretion, possibly mediated through hypoglycaemia-induced vagal stimulation, or inhibition of synthesis. The concentration and content of glucagon-like immunoreactivity (enteroglucagon) in the small intestine of the insulinoma rats increased markedly (47%; p<0.01 and 120%; p<0.01). This increase is consistent with a proposed role of this peptide as a factor trophic to the intestinal mucosa. No significant changes in the concentrations of somatostatin, substance P, neurokinin A, vasoactive intestinal peptide and gastrin-releasing peptide in the small intestine were observed. However, the increase in gut weight resulted in a greater content of vasoactive intestinal peptide (40%; p<0.01) and substance P (37%; p<0.05) in the insulinoma rats.     

Distal stomach appears essential in the regulation of gastrointestinal transit

Stomach and small bowel both influence gastrointestinal motility. We studied which portion of the stomach was essential for the regulation of gastrointestinal movement and determined the role of vasoactive intestinal polypeptide in this regulation. The study subjects consisted of 45 controls, 46 patients after subtotal gastrectomy, and 13 patients after total gastrectomy for stomach cancer. Orocecal transit time was measured, using the hydrogen breath test, to represent gastrointestinal movement, while plasma vasoactive intestinal polypeptide level was simultaneously assessed. The orocecal transit times in the study groups were (means ± SD) 91.1 ± 45.0, 57.1 ± 34.3, and 60.8 ± 34.8 min, respectively (P < 0.01). In the subtotal gastrectomy patients, age showed a negative correlation with orocecal transit time (r = −0.388; P < 0.01). In the total gastrectomy patients, no particular demographic factor influenced orocecal transit. Plasma vasoactive intestinal polypeptide levels in the three groups were 20.7 ± 10.8, 22.7 ± 10.9, and 20.6 ± 9.1 pg/ml, respectively (NS). We conclude that both types of gastrectomies enhanced gastrointestinal movement, showing a similar effect, and that the distal stomach plus pylorus are most likely to exert an important inhibitory mechanism in the regulation of this movement. Vasoactive intestinal polypeptide is not a major peptide mediating this regulation. Received: August 9, 1999 / Accepted: November 26, 1999     

Immuno-localization of sulphonylurea receptor 1 in rat pancreas

Aims/hypothesis. A sulphonylurea receptor, SUR1, and an inward rectifier potassium channel, Kir6.2, reconstitute the ATP-sensitive K⁺ channel that mediates glucose-induced insulin secretion in pancreatic beta cells. We reported previously that Kir6.2 were localized at insulin-, glucagon-, and somatostatin-producing cells. In this new study we aimed to determine the distribution of SUR1 in rat pancreatic islets and to suggest the location of the ATP-sensitive K⁺ channels in the islet. Methods. Western blot analysis was carried out using two anti-SUR1 antibodies, which had been raised against different portions of rat SUR1. SUR1, Kir 6.2, and islet hormones were then localized by indirect immunofluorescence staining of the cryosections of rat pancreas. Results. In Western blot analysis, each of the anti-SUR1 antibodies detected a band at 140 kDa, which is close to the predicted molecular weight of SUR1, in the homogenate of isolated pancreatic islets. Double immunofluorescence staining of cryosections showed that SUR1 occurred all over the islets, and that SUR1 colocalized with insulin, glucagon, somatostatin, and pancreatic polypeptide. Kir6.2 was also shown to be present in pancreatic polypeptide cells. Conclusion/interpretation. Together with our previously reported data, the above findings indicate that K_ATP channels comprising SUR1 and Kir6.2 occur not only in beta cells but also in the alpha, delta, and pancreatic polypeptide cells of the pancreatic islets, suggesting that therapeutic sulphonylureas could act on these cells directly. [Diabetologia (1999) 42: 1204–1211] Received: 21 January 1999 and in final revised form: 21 May 1999