Vasoactive Intestinal Polypeptide Concentrations Research Articles

Stimulatory and inhibitory actions of VIP and cyclic AMP on cytoplasmic Ca2+ signal generation in pancreatic acinar cells.

In pancreatic acinar cells the effects of vasoactive intestinal polypeptide (VIP) and dibutyryl cyclic AMP (dbcAMP) alone and during stimulation with acetylcholine (ACh) or internally applied inositol trisphosphate (InsP3) were investigated utilizing the patch-clamp whole-cell current recording configuration to assess changes in cytoplasmic Ca2+ concentration by measurement of Ca2+ dependent Cl- current. VIP (1 nM) and dbcAMP (0.5 mM) each evoked repetitive pulses of Ca(2+)-dependent Cl- current. A high VIP concentration (100 nM) acutely and reversibly inhibited the responses evoked by 1 nM VIP and also acutely inhibited ACh-evoked responses. DbcAMP (2 mM) also reversibly inhibited the ACh-evoked responses. Neither VIP nor dbcAMP were able to inhibit InsP3-evoked repetitive Ca2+ pulses. VIP in a low concentration can generate cytosolic Ca2+ oscillations via cyclic AMP, but high VIP concentrations inhibit both ACh and VIP-evoked Ca2+ signals and this effect is mediated by high intracellular cyclic AMP levels.

Retinal lesion by bright artificial light increases vasoactive intestinal polypeptide in the rat ventral tegmental area/substantia nigra

Sprague-Dawley rats were treated with bright light to induce retinal lesions and vasoactive intestinal polypeptide in the ventral tegmental area/substantia nigra was measured by radioimmunoassay. In Sprague-Dawley rats, but not in Brown Norway rats where light did not induce retinal lesions, significantly increased concentrations of vasoactive intestinal polypeptide were found 21 days after exposure with bright light. This increase declined to control values 60 days after the treatment. Our studies indicate that vasoactive intestinal polypeptide may be involved in visual neurotransmission and that the ventral tegmental area/substantia nigra may be connected to retinal input.

Age-related changes in substance P and vasoactive intestinal polypeptide immunoreactivity in the rat stomach and small intestine

Immunoreactivity for substance P (SP-LI) and vasoactive intestinal polypeptide (VIP-LI) in the stomach, duodenum, jejunum and ileum of young (3-month-old), adult (12-month-old) and old (28-month-old) male Wistar rats were determined by radioimmunoassay. SP-LI and VIP-LI did not show changes in the stomach or in the small intestine portions investigated in adult in comparison with young rats. In old rats SP-LI levels were unchanged in the stomach and in the duodenum, reduced in the jejunum and increased in the ileum. VIP-LI concentrations were unchanged in the stomach, and remarkably reduced in the duodenum, jejunum and ileum of old rats. Since the two neuropeptides investigated are localized primarily within different intrinsic gastrointestinal neurons, the present findings suggest that the various populations of gastrointestinal neurons are affected in a different manner during aging.

Glycine-extended processing intermediate of proVIP: A new form of VIP in the rat

The biosynthesis of many peptides including vasoactive intestinal polypeptide (VIP) requires enzymatic α-carboxyamidation via a glycine-extended intermediate form. In an effort to identify and quantify glycine-extended VIP in rat tissue extracts a radio-immunoassay specific for this peptide was developed. The concentrations of glycine-extended VIP ranged from 1.3 pmol/g in the brain to 83.9 pmol/g in the small intestine. The identity of the peptide was substantiated by cation-exchange HPLC. The ratio of glycine-extended VIP to amidated VIP varied considerably being highest (63%) in the small intestine. The natural occurrence of glycine-extended VIP in connection with our recent demonstration of its biological activity suggest a physiological role for this biosynthetic intermediate VIP form.

Neuropeptides in skin disease: increased VIP in eczema and psoriasis but not axillary hyperhidrosis

The neuropeptides vasoactive intestinal polypeptide (VIP), substance P and somatostatin were studied in skin biopsies from patients with eczema, psoriasis and axillary hyperhidrosis. VIP concentrations were elevated in skin affected by eczema and psoriasis, whereas substance P and somatostatin levels did not differ from controls. There was a higher concentration of VIP, but not of substance P or somatostatin, in normal axillary skin when compared to adjacent trunk skin, with abundant VIP-containing fibres surrounding eccrine sweat glands. The VIP concentration was unchanged in skin affected by axillary hyperhidrosis. VIP may increase local blood flow in eczema and psoriasis, but does not appear to play a role in axillary hyperhidrosis.

Hepatic metabolism of vasoactive intestinal polypeptide during liver transplantation in the pig

In order to investigate hepatic clearance of vasoactive intestinal polypeptide we measured its concentration in blood from the common carotid artery, right atrium and portal vein during orthotopic liver transplantation in six pigs. Just after laparotomy we found a significantly higher concentration of vasoactive intestinal polypeptide in portal plasma compared to that of the right atrium (p less than 0.05). This difference was soon eliminated by a fall in portal concentration, and, apart from fluctuations in portal concentration, no significant gradient between portal and atrial blood was recorded during the remaining part of the operation. When portal concentrations exceeded 30 pmol/l, the median reduction after transhepatic passage was 29% (range 16.8%-63.9%), while portal concentrations less than 30 pmol/l had a median reduction of only 6.3% (range 1.4%-16.5%) (p less than 0.05). No gradient between right atrial and systemic arterial blood was recorded. We suggest that a concentration-dependent clearance of splanchnic vasoactive intestinal polypeptide takes place in the porcine liver.

Epithelial cells purified from choroid plexus have receptors for vasoactive intestinal polypeptide

Using the choroid plexus from pig a method has been developed to purify the epithelial cells from the underlying vascularized connective tissue stroma. An epithelial cell fraction was obtained that showed a purity of at least 95%, as determined by light microscopic analysis. The epithelial cells were investigated for the presence of binding sites for the neurotransmitter peptide, vasoactive intestinal polypeptide (VIP). Suspensions of epithelial cells were found to have high affinity binding sites for 125I-labelled VIP, with maximum binding obtained after 30 min incubation at 20 °C with a concentration of 50 μg cell protein per sample. Competition experiments with displacement of [ 125I]VIP binding by increasing concentrations of unlabeled VIP indicated the presence of a single class of binding sites with aK d of 3 nM and a binding capacity of 970 pmol/g cell protein. Cross-linking of [ 125I]VIP to epithelial cells with disuccinimido dithiobis (propionate) (DSP), followed by SDS-polyacrylamide gel electrophoresis, demonstrated binding to a single 55 kD protein. The receptor was highly specific for VIP as binding was only inhibited in the presence of high concentrations of the related peptides helodermin, growth hormone-releasing factor, secretin, and peptide histidine isoleucine. This is the first demonstration of VIP-binding to choroid plexus epithelial cells.

Interactions between sialoadenectomy and capsaicin-sensitive afferent fibers on gastric acid secretion in rats

In this study we have investigated the relative influence of capsaicin-sensitive afferents and sialoadenectomy on gastric acid secretion. Sialoadenectomized (SALX) rats showed a decrease in gastric acid secretion and an increase in gastric calcitonin gene-related peptide-like immunoreactivity (CGRP-li) as compared to sham-operated animals. Capsaicin pretreatment (50+100 mg kg −1 in two days) markedly decreased gastric CGRP-li in both sham and SALX-operated rats and increased acid concentration and output only in SALX animals. In this latter case the concomitant absence of two potent endogenous antisecretory agents (CGRP and epidermal growth factor; EGF) may contribute to the observed hypersecretion. Gastric content of vasoactive intestinal polypeptide (VIP)-li was unaffected in SALX and capsaicin-treated rats. Capsaicin-sensitive afferents and EGF contained in the salivary glands may interact in the regulation of the gastric acid secretion.

Plasma vasoactive intestinal polypeptide concentration determination in patients with diarrhea

Determination of plasma levels of vasoactive intestinal polypeptide (VIP) has been used for screening patients with chronic diarrhea to identify potential neuroendocrine tumors. This 6-year blinded study from 1981 to 1986 examines the causes of elevated VIP levels in patients. In healthy volunteers (n = 144), VIP concentrations ranged from 14 to 76 pg/mL (mean ± SE, 28 ± 12), whereas in chronic renal failure, 4 of 34 patients or 12% [serum creatinine 4.5–9.0 mg/dL (397–795 μmol/L)] had an elevation to > 100 pg/mL. No patient with idiopathic hepatic cirrhosis (n = 12) had elevation of serum concentration of this peptide. Among 588 consecutive unselected patients undergoing evaluation for chronic diarrhea (n = 362; 62%) or possible neuroendocrine tumor (n = 214; 36%), 23 patients (3.9%) had concentrations >76 pg/mL. In this group, 5 patients had functioning (VIP, 160–5975 pg/mL) and 5 had nonfunctioning (VIP, 80–120 pg/mL) pancreatic islet cell carcinomas: all 10 patients had hepatic metastases. Other known causes of elevated levels of VIP, ranging from 80 to 340 pg/mL, included other neurogenic tumors (n = 3), small- bowel resection (n = 2), inflammatory bowel disease (n = 2), chronic renal failure (n = 1), and prolonged fasting (n = 1). Patients with diarrhea in which VIP-secreting tumors were identified had plasma vasoactive intestinal peptide concentrations >140 pg/mL. In patients with chronic diarrhea, determination of plasma vasoactive intestinal peptide levels did identify tumors secreting this peptide, but the results from this referral institution did not show identification of these tumors early in their clinical course.

Perception of breathlessness during bronchoconstriction induced by antigen, exercise, and histamine challenges.

Perception of breathlessness was studied in eight patients with mild, stable asthma after a histamine and exercise challenge performed before and 24 and 48 hours respectively after an antigen challenge. FEV1 and perception of breathlessness, evaluated by Borg's 10 point category scale, were measured after each administration of doubling antigen or histamine concentrations to achieve a greater than 20% fall in FEV1, and after six minutes of steady state exercise at 80% of maximal oxygen consumption (VO2max). The geometric mean provocative concentration of histamine causing a 20% fall in FEV1 (PC20) fell from 1.67 mg/ml before antigen challenge to 0.52 mg/ml 24 hours after the challenge. The median maximal % fall in FEV1 with exercise was 24.9% (range 10.5-40.5%) before and 30.6% (range 13.8-52.3%) 48 hours after antigen challenge. The median maximum % fall in FEV1 after antigen inhalation was 20.1% (range 13.3-35.2%) within the first hour; only two subjects had a late fall in FEV1 (23% and 58%). The median (range) of Borg scores obtained when FEV1 was reduced by 20% did not differ significantly for the three types of acute challenges: 1.25 (0.5-2.5) and 1.0 (0.5-3.0) after histamine tests, 1.0 (0.5-4.1) and 1.55 (0.5-2.0) after exercise, and 1.5 (0-3.0) after antigen challenge. In the two subjects who had a late response to antigen the Borg score was reduced for the same % fall in FEV1 as with the early response. It is concluded that the perception of breathlessness does not differ appreciably during the early response to histamine, antigen exposure, or exercise, but that it is reduced during the late asthmatic response. It was not influenced by previous antigen exposure, despite an increase in airway responsiveness.

Studies of vasoactive intestinal polypeptide expression in injured peripheral neurons using capsaicin, sympathectomy and mf mutant rats

The increased expression of vasoactive intestinal polypeptide (VIP) in injured peripheral neurons was studied. In contrast to substance P, there was a marked increase, and maintained fast axonal transport, of VIP in rat sciatic nerve after peripheral axotomy. Local capsaicin application to the nerve trunk failed to inhibit the injury-induced VIP increase, and capsaicin even increased VIP levels when applied locally to uninjured nerves. Pharmacological sympathectomy showed that some of the peripheral VIP increase may occur in post-ganglionic sympathetic fibres. The VIP increase after injury appeared unaffected in the mf mutant rat, in spite of its loss of lumbar dorsal root ganglion cells. VIP-staining fibres in the epi- and peri-neurium and perivascular plexuses of sciatic nerve showed an increase in number in parallel with the changes of the nerve VIP content. These findings suggest that sensory and sympathetic nerve fibres expressing VIP after injury play a role in the regulation of blood flow to nerves, and in the pathophysiological processes in nerve and dorsal spinal cord which follow peripheral nerve injury.

Vasoactive intestinal polypeptide levels in sigmoid colon in idiopathic constipation and diverticular disease

The distribution in the bowel wall of vasoactive intestinal polypeptide-, neuropeptide Y-, and substance P-containing nerve cell bodies and nerve fibers has been described in human sigmoid colon by immunohistochemical examination. In patients with chronic idiopathic constipation, diverticular disease, and in controls (of tissue taken from patients with carcinoma, from a site distant from the tumor that appeared macroscopically normal), the concentrations of vasoactive intestinal polypeptide, neuropeptide Y, and substance P have been measured by immunoassay in the following preparations of sigmoid colon: mucosa, whole colonic wall with mucosa dissected away, circular muscle, and taenia coli. In idiopathic constipation, the vasoactive intestinal polypeptide content of the whole wall minus mucosa was reduced when compared with controls (P < 0.05) but was unaltered in the mucosa, circular muscle, and taenia coli. In diverticular disease, the vasoactive intestinal polypeptide content of the mucosa and whole wall minus the mucosal layer was increased when compared with control tissue (P < 0.05 and P < 0.02, respectively) but was unaltered in the circular muscle and taenia coli. Substance P and neuropeptide Y levels in all layers of colonic wall were unaltered in these two diseases. The disturbances in the normal neural content of vasoactive intestinal polypeptide in the bowel wall in idiopathic constipation and diverticular disease may initiate or contribute to the functional changes seen in these disorders.

Neuropeptide immunoreactivity and choline acetyltransferase activity in the mouse urinary bladder following inoculation with Semliki Forest Virus

The effect of Semliki Forest Virus, a known central demyelinating agent and a proposed model for multiple sclerosis, on the innervation of the mouse urinary bladder has been examined 3, 6, 9 and 12 weeks after inoculation. Three weeks after Semliki Forest Virus inoculation, vasoactive intestinal polypeptide content of the bladder was reduced and the density of vasoactive intestinal polypeptide-immunoreactive nerves was decreased in the smooth muscle, but not in the mucosa. Choline acetyltransferase activity and neuropeptide Y and substance P content was normal, as was the pattern of innervation by acetylcholinesterase-containing and neuropeptide Y- and substance P-immunoreactive nerve fibres. Six weeks after Semliki Forest Virus inoculation, the choline acetyltransferase activity was significantly reduced. Between 6 and 9 weeks the level of vasoactive intestinal polypeptide in the bladder of Semliki Forest Virus-infected mice significantly increased, so that at 9 weeks it was higher than the control value. However, by 12 weeks both choline acetyltransferase activity and vasoactive intestinal polypeptide content were normal. At this time, the substantial age-related increase in substance P content of the bladder was more pronounced in the Semliki Forest Virus-treated animals. Thus there are transitory changes in the innervation of the mouse bladder by vasoactive intestinal polypeptide-containing and cholinergic nerve fibres after exposure to a central demyelinating agent which may reflect changes in bladder dysfunction seen in multiple sclerosis patients.

Effects of substance P and vasoactive intestinal polypeptide on contractile activity and epithelial transport in the ferret jejunum

Previous studies in the ferret demonstrated that vagal nerve stimulation induced an atropine-resistant water secretion. Substance P and vasoactive intestinal polypeptide are possible mediators of this secretory response. The objectives of this study were to investigate the in vivo effects of substance P and vasoactive intestinal polypeptide on the jejunal musculature and epithelium. Substance P caused an increase in jejunal motility, water secretion, and transmural potential difference. Cholinergic blockade did not affect the substance P-induced contractions, but did reduce the increase in transmural potential difference, suggesting an inhibition of water secretion. Vasoactive intestinal polypeptide abolished motor activity; however, it induced an increase in transmural potential difference that was atropine and tetrodotoxin resistant. By immunohistochemical methods, immunoreactive vasoactive intestinal polypeptide and immunoreactive substance P were localized to both nerve cell bodies and nerve fibers in the ferret intestine. Determination of intestinal concentrations of vasoactive intestinal polypeptide and substance P in the ferret showed concentrations of these two neuropeptides that were similar to those in human intestine and demonstrated much higher concentrations of these substances in the muscular layer than in the epithelial layer. Our data demonstrate that in the ferret substance P excites and vasoactive intestinal polypeptide inhibits jejunal motor activity. However, both peptides increase water secretion. Our results suggest that in response to vagal stimulation, neuronally released substance P or vasoactive intestinal polypeptide may participate in the atropine-resistant water secretion.

Effects of high in vivo levels of vasoactive intestinal polypeptide on function of circulating lymphocytes in humans

To examine the possible in vivo significance of the immunomodulatory effects of vasoactive intestinal polypeptide described in vitro, several parameters of peripheral blood lymphocyte function were studied in a patient with a pancreatic endocrine tumor and high circulating levels of vasoactive intestinal polypeptide. There was no imbalance of the circulating lymphocyte subpopulations, and the in vitro responses of the patient's lymphocytes to mitogens were normal. However, there was an increased number (32%) of peripheral lymphocytes expressing interleukin 2 receptor. Serum immunoglobulin M levels were higher than in controls, and the patient's lymphocytes exhibited a spontaneous in vitro immunoglobulin M production higher than normal. Comparable increases in both interleukin 2 receptor expression and immunoglobulin M production were induced in vitro in normal peripheral lymphocyte cultures by the addition of vasoactive intestinal polypeptide concentrations similar to that detected in the patient's plasma. These findings indicate that a modulatory effect of vasoactive intestinal polypeptide on lymphocyte activation and immunoglobulin synthesis may be operating in vivo. They also suggest that vasoactive intestinal polypeptide does not mediate major defects in peripheral blood lymphocyte function in vivo.

Decreased VIP Content in Peripheral Nerve From Streptozocin-Induced Diabetic Rats

After induction of diabetes with streptozocin (STZ-D) in rats, we measured vasoactive intestinal polypeptide (VIP) content in sciatic nerve and spinal cord obtained from nondiabetic, untreated STZ-D, and insulin-treated STZ-D rats. Eight weeks after the onset of diabetes, caudal nerve conduction velocity (NCV) in the untreated STZ-D rats (n = 13) was slower than in the controls (n = 11; mean +/- SE 30.9 +/- 0.6 vs. 41.4 +/- 1.8 m/s, P less than 0.001). The decrease in NCV was less marked in the insulin-treated STZ-D rats (n = 11; 36.3 +/- 0.9 m/s, P less than 0.05 vs. control). VIP content in sciatic nerve decreased in the untreated STZ-D rats (1.33 +/- 0.23 ng/g wet wt) compared with the other groups (control, 3.10 +/- 0.44, P less than 0.01; insulin-treated STZ-D, 2.44 +/- 0.55, P less than 0.05). However, in spinal cord, VIP content was not significantly different among the three groups. The VIP levels in sciatic nerve showed a positive correlation with NCV (r = 0.430, P less than 0.01). In addition, an inverse correlation between VIP levels and blood glucose levels was observed (r = -0.5624, P less than 0.001). NCV was also inversely correlated with blood glucose levels (r = -0.7662, P less than 0.001). Together with a previous morphological study, these findings suggest a possible causal relationship between reduced VIP content and diabetic neuropathy.

Changes in adrenal neuropeptides content [peptide 7B2, neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP)] induced by pharmacological and hormonal manipulations

A novel pituitary peptide, designated 7B2, was shown to be present in the adrenal gland. 7B2-like immunoreactivity was mainly localized in the adrenal medulla, similarly to NPY and VIP. In order to elucidate the neural and humoral regulation of adrenal 7B2, NPY and VIP content, Wister rats were treated with reserpine (RES), ranitidine (RANT) or chlorpheniramine maleate (CPhM) for 7-10 days. The thyroid hormone excess and deficient states were experimentally produced with thyroxine (T4) treatment for 2 weeks, methylmercaptoimidazole (MMI) for 4 weeks, or a thyroidectomized state (Tx) for 4 weeks. Orchiectomy or neonatal monosodium glutamate (MSG) treatment was also done. 7B2, NPY and VIP contents were measured by specific radioimmunoassays. RES and RANT treatments caused significant 7B2 reduction (p less than 0.01) and adrenal NPY was significantly decreased by RES (p less than 0.05), while CPhM induced a VIP decreased (p less than 0.05). Orchiectomy did not affect the peptides concentrations, though MSG treatment did cause a reverse change in VIP and NPY. Although T4 administration did not cause any significant change, MMI treatment and Tx induced significant increase (p less than 0.05 or p less than 0.01) in these peptides. Gel or high performance liquid chromatographic analysis revealed the majority of each immunoreactivity coeluted with each standard. These results suggested that adrenal NPY seemed to be coregulated with catecholamine, while VIP was mainly affected by histaminergic control. Furthermore 7B2 might be modulated by both catecholaminergic and histaminergic nervous control. Thyroid hormone deficiency may also affect the amount of these peptides.

Content and distribution of vasoactive intestinal polypeptide (VIP) in cavernous tissue of human penis

Penile erection is controlled by a valvular structure in the helicine artery in humans. The opening and closing of this valve are believed to be regulated by the autonomic nervous system, especially through the release of vasoactive intestinal polypeptide (VIP). We determined the content of VIP in cavernous tissue in 18 impotent patients and in 5 normal controls by radioimmunoassay, and we examined the distribution of VIP-ergic nerve fibers in cavernous tissue by an immunohistochemical method. As a result, it was found that the lower penile VIP content was more frequent among patients with organic impotence than among the controls. Furthermore, VIP-ergic nerve fibers were seen to be diffusely and loosely distributed in a large number of organic impotence patients. These findings suggest that organic impotence in some patients may be due to decreases in the VIP content and in VIP-ergic nerve fibers.

The effect of oral glucose, protein, fat and water loading on blood pressure and the gastrointestinal peptides VIP and somatostatin in hypertensive elderly subjects

In elderly subjects blood pressure (BP) may fall after a meal. It can be reproduced by oral glucose, but the effect of fat and protein ingestion on postprandial BP has not been reported. Furthermore, we hypothesized that vasoactive gastrointestinal peptides are involved in this phenomenon. We studied 10 hypertensive elderly subjects (mean age 74 +/- 3 years) for the effects of oral glucose, fat, protein and water loading on BP in relation to plasma concentrations of vasoactive intestinal polypeptide (VIP), somatostatin and insulin. Glucose loading resulted in a decrease of mean arterial pressure by 14 +/- 2 mmHg (P less than or equal to 0.001). In contrast, the ingestion of fat, protein or water had no significant effect on BP. Somatostatin increased after fat and protein loading, whereas VIP increased only after fat loading. These data indicate that postprandial BP reduction in the elderly is related to glucose-related factors. The gut peptide VIP does not seem to play a role in this phenomenon.

The effects of secretin on prolactin, estradiol, vasoactive intestinal polypeptide, and somatostatin levels in women

The effect of graded doses of intravenous secretin (0.5, 1.0, and 2.0 CU.kg-1.h-1) on serum prolactin and estradiol levels, as well as plasma vasoactive intestinal polypeptide and somatostatin levels was studied in 6 normally cycling and healthy women, and compared with the hormone levels obtained by a control infusion with physiologic saline (0.15 mol/l). A significant decrease in serum prolactin concentrations was found with increasing doses of secretin at steady-state levels of plasma secretin (+30 to +60 min). A significant negative correlation (p less than 0.007, r = -0.2764) existed between serum prolactin and plasma secretin concentrations at steady-state conditions. No effect of graded doses of secretin was observed on serum estradiol levels and plasma concentrations of vasoactive intestinal polypeptide and somatostatin. The results suggest a dose-related inhibitory effect of secretin on prolactin release in women.