Role Of Vasoactive Intestinal Polypeptide Research Articles

Vasoactive intestinal polypeptide plasma levels associated with affective symptoms and brain structure and function in healthy females

Vasoactive intestinal polypeptide (VIP) is a neuroendocrine peptide distributed throughout the human body, including the CNS, where it is particularly abundant in brain regions associated with anxiety and depression. Based on earlier studies indicating that peripheral VIP may cross through the blood–brain barrier, we hypothesized plasma VIP levels to be associated with symptoms of anxiety and depression, as well as brain volume and resting-state functional connectivity in the amygdala, hippocampus, parahippocampus, and orbitofrontal cortex. Plasma VIP concentrations and anxiety/depression symptoms were measured in 37 healthy females. Functional and structural magnetic resonance imaging were used to evaluate functional connectivity and brain volume respectively, and their associations with VIP concentrations within brain regions associated with anxiety and depression. Negative correlations were found between VIP levels and symptoms of anxiety (r = − 0.44, p = 0.002) and depression (r = − 0.50, p = 0.001). Functional connectivity demonstrated significant VIP-dependent positive associations between the amygdala seed region with both the right parahippocampus (t(33) = 3.1, pFDR = 0.02) and right lateral orbitofrontal cortex (OFC; t(33) = 2.9, pFDR = 0.02). Moreover, VIP concentrations were significantly, positively correlated with brain volume in the left amygdala (r = 0.28, p = 0.007) and left lateral OFC (r = 0.29, p = 0.004). The present findings highlight a potential role for VIP in the neurobiology of affective symptoms.

Development-Dependent Plasticity in Vasoactive Intestinal Polypeptide Neurons in the Infralimbic Cortex.

The onset of several neuropsychiatric disorders including anxiety disorders coincides with adolescence. Consistently, threat extinction, which plays a key role in the regulation of anxiety-related behaviors, is diminished during adolescence. Furthermore, this attenuated threat extinction during adolescence is associated with an altered synaptic plasticity in the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for threat extinction. However, the mechanism underlying the altered plasticity in the IL-mPFC during adolescence is unclear. Given the purported role of vasoactive intestinal polypeptide expressing interneurons (VIPINs) in disinhibition and hence their potential to affect cortical plasticity, we examined whether VIPINs exhibit an adolescence-specific plasticity in the IL-mPFC. We observed an increase in GABAergic transmission and a decrease in excitability in VIPINs during adolescence. Male mice show a significantly higher VIPIN-pyramidal neuron GABAergic transmission compared with female mice. The observed increase in GABAergic transmission and a decrease in membrane excitability in VIPINs during adolescence could play a role in the altered plasticity in the adolescent IL-mPFC. Furthermore, the suppression of VIPIN-mediated GABAergic transmission in females might be relevant to sex differences in anxiety disorders.

Chemically induced inflammation and nerve damage affect the distribution of vasoactive intestinal polypeptide-like immunoreactive (VIP-LI) nervous structures in the descending colon of the domestic pig.

The enteric nervous system (ENS), situated in the wall of the gastrointestinal tract, regulates the majority of intestinal activities in physiological conditions and during pathological processes. Enteric neurons are diversified in terms of active substance expression. One of the most important neuropeptides within the ENS is vasoactive intestinal polypeptide (VIP). It seems to be one among the important inhibitory peptides in addition to neuropeptide Y (NPY), nitric oxide (NO), and adenosine triphosphate (ATP) of the intestinal motility and secretion, however, many issues connected with distribution and roles of VIP in the large intestine, especially during pathological states, still remain unknown. Changes in the VIP-like immunoreactivity of the enteric nervous structures under experimental pathological states, including chemically induced inflammation and nerve damage was examined using the double immunofluorescence technique with commercial antibodies. Generally, both pathological factors studied caused an increase in the number of VIP-like immunoreactive (VIP-LI) neurons and nerve fibers, but the intensity of fluctuations depended on both the acting factor and the part of the ENS studied. The obtained results suggest that VIP participates in pathological processes concerning the digestive tract, and its exact functions probably depend on the type of damaging factor acting on the intestine.

The Role of VIP in Social Behavior: Neural Hotspots for the Modulation of Affiliation, Aggression, and Parental Care.

Although the modulation of social behaviors by most major neurochemical systems has been explored, there are still standouts, including the study of vasoactive intestinal polypeptide (VIP). VIP is a modulator of circadian, reproductive, and seasonal rhythms and is well known for its role in reproductive behavior, as it is the main vertebrate prolactin-releasing hormone. Originally isolated as a gut peptide, VIP and its cognate receptors are present in virtually every brain area that is important for social behavior, including all nodes of the core "social behavior network" (SBN). Furthermore, VIP cells show increased transcriptional activity throughout the SBN in response to social stimuli. Using a combination of comparative and mechanistic approaches in socially diverse species of estrildid finches and emberizid sparrows, we have identified neural "hotspots" in the SBN that relate to avian affiliative behavior, as well as neural "hotspots" that may represent critical nodes underlying a trade-off between aggression and parental care. Specifically, we have found that: (1) VIP fiber densities and VIP receptor binding in specific brain sites, such as the lateral septum, medial extended amygdala, arcopallium, and medial nidopallium, correlate with species and/or seasonal differences in flocking behavior, and (2) VIP cells and fibers within the anterior hypothalamus-caudocentral septal circuit relate positively to aggression and negatively to parental care while VIP elements in the mediobasal hypothalamus relate negatively to aggression and positively to parental care. Thus, while a given behavior or social context likely activates VIP circuitry throughout the SBN and beyond, key brain sites emerge as potential "hotspots" for the modulation of affiliation, aggression, and parental care.

Nesting behavior is associated with VIP expression and VIP–Fos colocalization in a network-wide manner

Many species, including humans, engage in a series of behaviors that are preparatory to the arrival of offspring. Such “nesting behaviors” are of obvious importance, but relevant neuroendocrine mechanisms remain little studied. We here focus on the potential roles of vasoactive intestinal polypeptide (VIP) in the performance of appetitive and consummatory nesting behaviors in male and female zebra finches (Taeniopygia guttata). Using combined immunocytochemistry for Fos and in situ hybridization for VIP, we now show that many VIP cell groups show increased transcriptional activity in response to nest building in male and female zebra finches. Particularly strong data come from the preoptic area (medial preoptic area and medial preoptic nucleus), where VIP–Fos co-expression correlates positively with three different measures of nesting behavior, as does the number of VIP-expressing cells. Remarkably, we find that VIP mRNA and/or VIP–Fos co-expression is correlated with nesting behavior in virtually every brain area that we examined, including the medial amygdala (anterior and posterior), medial bed nucleus of the stria terminalis, medial preoptic area, medial preoptic nucleus, anterior hypothalamus, ventromedial hypothalamus, periaqueductal gray complex (central gray and nucleus intercollicularis), and ventral tegmental area. Near-significant effects are also obtained in the tuberoinfundibular hypothalamus. Although most correlations are positive, negative correlations are observed for the VIP cell group of the anterior hypothalamus, a population that selectively promotes aggression, and also the periaqueductal gray complex. These data demonstrate a network-wide relationship between peptide production and social behavior that is, to our knowledge, unparalleled by other peptidergic modulators.

Mo1789 Sulforaphane Inhibits Expression of the Central Iron Regulator Hepcidin STAT3-Independently in an Inflammatory Cell Model

Glucagon-like peptide-2 (GLP-2) has potent anti-inflammatory effects in the intestinal mucosa. Vasoactive intestinal polypeptide (VIP) neurons in the enteric neuronal plexus have been shown to be important in these actions using pharmacologic blockers; but little is known about other specific subsets of neurotransmitters, such as nNOS. Aim: To investigate the role of VIP and nNOS signaling, individually and together, in mediating the antiinflammatory effects of GLP-2. Methods: With animal committee use approval, mice with selective knockouts of VIP-/-, nNOS-/-, and combined VIP-/-/ nNOS-/were used, with wild type (WT) controls; all animals were treated with trinitrobenzene sulfonic acid (TNBS) to induce colitis. Animals received (1-33) GLP-2 (50 μg/kg s.c. bid) or saline for 5 days. Mice were sacrificed and colonic tissue was taken for inflammation indices (myeloperoxidase [MPO] and histological damage scores), immunohistochemistry (BrdU:proliferation marker; Caspase-3: apoptosis marker), and mucosal cytokine levels (TNFα, IL1β, IFNγ, IL10). Results: GLP-2 treatment resulted in significant anti-inflammatory effects in VIP-/-and nNOS-/animals, but had no effects in the VIP-//nNOS-/treated animals. The response included improved weight and mucosal inflammation indices with reduced levels of proinflammatory cytokines (TNFα, IL1β, IFNγ), and reduced proliferation and apoptosis rates. In VIP-/nNOS-/animals treated with GLP-2 these cytokines and cell kinetic rates remained unchanged. (See table, n=8 per group, data: Mean±SEM, *p<0.05 by ANOVA) Conclusions: These findings suggest that the anti-inflammatory effects of GLP-2 can be mediated by either VIP or nNOS pathways, however when both pathways are abolished concomitantly, the anti-inflammatory effects of GLP-2 are lost. Further study is required to identify the enteric neuronal circuitry which mediates these potent anti-inflammatory effects

Mo1788 Vasoactive Intestinal Polypeptide and Neuronal Nitric Oxide Synthase Act via Parallel Pathways As Mediators of GLP-2 Anti-Inflammatory Activity

Glucagon-like peptide-2 (GLP-2) has potent anti-inflammatory effects in the intestinal mucosa. Vasoactive intestinal polypeptide (VIP) neurons in the enteric neuronal plexus have been shown to be important in these actions using pharmacologic blockers; but little is known about other specific subsets of neurotransmitters, such as nNOS. Aim: To investigate the role of VIP and nNOS signaling, individually and together, in mediating the antiinflammatory effects of GLP-2. Methods: With animal committee use approval, mice with selective knockouts of VIP-/-, nNOS-/-, and combined VIP-/-/ nNOS-/were used, with wild type (WT) controls; all animals were treated with trinitrobenzene sulfonic acid (TNBS) to induce colitis. Animals received (1-33) GLP-2 (50 μg/kg s.c. bid) or saline for 5 days. Mice were sacrificed and colonic tissue was taken for inflammation indices (myeloperoxidase [MPO] and histological damage scores), immunohistochemistry (BrdU:proliferation marker; Caspase-3: apoptosis marker), and mucosal cytokine levels (TNFα, IL1β, IFNγ, IL10). Results: GLP-2 treatment resulted in significant anti-inflammatory effects in VIP-/-and nNOS-/animals, but had no effects in the VIP-//nNOS-/treated animals. The response included improved weight and mucosal inflammation indices with reduced levels of proinflammatory cytokines (TNFα, IL1β, IFNγ), and reduced proliferation and apoptosis rates. In VIP-/nNOS-/animals treated with GLP-2 these cytokines and cell kinetic rates remained unchanged. (See table, n=8 per group, data: Mean±SEM, *p<0.05 by ANOVA) Conclusions: These findings suggest that the anti-inflammatory effects of GLP-2 can be mediated by either VIP or nNOS pathways, however when both pathways are abolished concomitantly, the anti-inflammatory effects of GLP-2 are lost. Further study is required to identify the enteric neuronal circuitry which mediates these potent anti-inflammatory effects

Functional role of vasoactive intestinal polypeptide in inhibitory motor innervation in the mouse internal anal sphincter

There is evidence that vasoactive intestinal polypeptide (VIP) participates in inhibitory neuromuscular transmission (NMT) in the internal anal sphincter (IAS). However, specific details concerning VIP-ergic NMT are limited, largely because of difficulties in selectively blocking other inhibitory neural pathways. The present study used the selective P2Y1 receptor antagonist MRS2500 (1 μm) and the nitric oxide synthase inhibitor N(G)-nitro-l-arginine (l-NNA; 100 μm) to block purinergic and nitrergic NMT to characterize non-purinergic, non-nitrergic (NNNP) inhibitory NMT and the role of VIP in this response. Nerves were stimulated with electrical field stimulation (0.1-20 Hz, 4-60 s) and the associated changes in contractile and electrical activity measured in non-adrenergic, non-cholinergic conditions in the IAS of wild-type and VIP(-/-) mice. Electrical field stimulation gave rise to frequency-dependent relaxation and hyperpolarization that was blocked by tetrodotoxin. Responses during brief trains of stimuli (4 s) were mediated by purinergic and nitrergic NMT. During longer stimulus trains, an NNNP relaxation and hyperpolarization developed slowly and persisted for several minutes beyond the end of the stimulus train. The NNNP NMT was abolished by VIP6-28 (30 μm), absent in the VIP(-/-) mouse and mimicked by exogenous VIP (1-100 nm). Immunoreactivity for VIP was co-localized with neuronal nitric oxide synthase in varicose intramuscular fibres but was not detected in the VIP(-/-) mouse IAS. In conclusion, this study identified an ultraslow component of inhibitory NMT in the IAS mediated by VIP. In vivo, this pathway may be activated with larger rectal distensions, leading to a more prolonged period of anal relaxation.

2-Methoxy-5-Amino-N-Hydroxybenzamide Sensitizes Colon Cancer (CC) Cells to TRAIL-Mediated Apoptosis Through Modulation of Death Receptor (DR)5 and Survivin

Background and Aims: IBS is a complex disease with recurring clusters of symptoms. Genetic mutations and single nucleotide polymorphisms do not fit these traits.We reported previously that neonatal inflammatory insult enhances smooth muscle reactivity to ACh in adulthood, which enhances colonic motor function to induce diarrhea-like conditions. In this study, we tested the hypothesis that adverse early life events reprogram the expression of genes encoding vasoactive intestinal polypeptide (VIP) and pore-forming α1C-subunit of the Cav1.2b channels (Canca1c) by epigenetic mechanisms in colonic muscularis externa to induce colonic motility dysfunction in adulthood.Methods: Ten-day old rat neonates received intraluminal 130 mg/kg TNBS in the colon; control pups received saline. Colonic muscularis externae (ME) were obtained 6 to 8-week later. Results: qRT-PCR and western blotting showed significant increases in the mRNA and protein expressions of VIP and α1C-subunit in the ME of about 50% of adult rats that received neonatal inflammatory insult (IBS-rats). Chromatin immunoprecipitation assays showed marked increase in acetylation of histone H3 lysine 9 (H3K9Ac, a marker of transcriptional activation) (0.8±0.1 vs. 0.45±0.06 Ctr., p<0.05) and attenuation in trimethylation of histone H3 lysine 9 (H3K9me3, a marker of transcriptional repression) (0.8±0.07 vs.1.2±0.03 Ctr., p<0.05) in the core promoter region of Cacna1c in IBS-rats. As a result, the RNA polymerase II (RNAP II) association with the Cacna1c promoter significantly increased, indicating enhanced Cacna1c gene transcription. We investigated the role of VIP in the epigenetic modification of Cacna1c by incubating ME from naive rats with 100 ng/ml VIP for 24 hours. VIP-treatment markedly increased H3K9Ac and decreased H3K9me3 at the upstream CREB-binding site (-2062/-2055) and around the transcription start site (+21 ~ +168), and hence enhanced RNAP II interaction with this promoter region suggesting that VIP modulates epigenetic components at the Cacna1c promoter to stimulate Cacna1c gene transcription. VIP antagonist, (p-Chloro-D-Phe6,Leu17)VIP, abrogated VIP-mediated RNAP II binding, H3K9 acetylation and trimethylation at the Cacna1c promoter. Intraperitoneal administration of 100 mM sodium butyrate, a histone deacetylase inhibitor, significantly elevated Cacna1cmRNA inME of naive adult rats (1.5±0.06 vs. 1±.01 Ctr., p<0.05), indicating that histone hyperacetylation is necessary for α1C gene transcription. Conclusions: Our findings reveal the epigenetic mechanisms by which adverse early life events alter the gene expression of specific cell signaling proteins to cause colonic motor dysfunction in adulthood. The intensities of epigenetic modifications are modifiable by environmental influences, such as stress, which explains relapses and remissions of symptoms in IBS patients.

Developmental Origins of Irritable Bowel Syndrome (IBS)-Like Symptoms: Epigenetic Dysregulation

Background and Aims: IBS is a complex disease with recurring clusters of symptoms. Genetic mutations and single nucleotide polymorphisms do not fit these traits.We reported previously that neonatal inflammatory insult enhances smooth muscle reactivity to ACh in adulthood, which enhances colonic motor function to induce diarrhea-like conditions. In this study, we tested the hypothesis that adverse early life events reprogram the expression of genes encoding vasoactive intestinal polypeptide (VIP) and pore-forming α1C-subunit of the Cav1.2b channels (Canca1c) by epigenetic mechanisms in colonic muscularis externa to induce colonic motility dysfunction in adulthood.Methods: Ten-day old rat neonates received intraluminal 130 mg/kg TNBS in the colon; control pups received saline. Colonic muscularis externae (ME) were obtained 6 to 8-week later. Results: qRT-PCR and western blotting showed significant increases in the mRNA and protein expressions of VIP and α1C-subunit in the ME of about 50% of adult rats that received neonatal inflammatory insult (IBS-rats). Chromatin immunoprecipitation assays showed marked increase in acetylation of histone H3 lysine 9 (H3K9Ac, a marker of transcriptional activation) (0.8±0.1 vs. 0.45±0.06 Ctr., p<0.05) and attenuation in trimethylation of histone H3 lysine 9 (H3K9me3, a marker of transcriptional repression) (0.8±0.07 vs.1.2±0.03 Ctr., p<0.05) in the core promoter region of Cacna1c in IBS-rats. As a result, the RNA polymerase II (RNAP II) association with the Cacna1c promoter significantly increased, indicating enhanced Cacna1c gene transcription. We investigated the role of VIP in the epigenetic modification of Cacna1c by incubating ME from naive rats with 100 ng/ml VIP for 24 hours. VIP-treatment markedly increased H3K9Ac and decreased H3K9me3 at the upstream CREB-binding site (-2062/-2055) and around the transcription start site (+21 ~ +168), and hence enhanced RNAP II interaction with this promoter region suggesting that VIP modulates epigenetic components at the Cacna1c promoter to stimulate Cacna1c gene transcription. VIP antagonist, (p-Chloro-D-Phe6,Leu17)VIP, abrogated VIP-mediated RNAP II binding, H3K9 acetylation and trimethylation at the Cacna1c promoter. Intraperitoneal administration of 100 mM sodium butyrate, a histone deacetylase inhibitor, significantly elevated Cacna1cmRNA inME of naive adult rats (1.5±0.06 vs. 1±.01 Ctr., p<0.05), indicating that histone hyperacetylation is necessary for α1C gene transcription. Conclusions: Our findings reveal the epigenetic mechanisms by which adverse early life events alter the gene expression of specific cell signaling proteins to cause colonic motor dysfunction in adulthood. The intensities of epigenetic modifications are modifiable by environmental influences, such as stress, which explains relapses and remissions of symptoms in IBS patients.

The Role of Vasoactive Intestinal Polypeptide and Pituitary Adenylate Cyclase-Activating Polypeptide in the Neural Pathways Controlling the Lower Urinary Tract

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are expressed in the neural pathways regulating the lower urinary tract. VIP-immunoreactivity (IR) is present in afferent and autonomic efferent neurons innervating the bladder and urethra, whereas PACAP-IR is present primarily in afferent neurons. Exogenously applied VIP relaxes bladder and urethral smooth muscle and excites parasympathetic neurons in bladder ganglia. PACAP relaxes bladder and urethral smooth muscle in some species (pig) but excites the smooth muscle in other species (mouse). Intrathecal administration of VIP in cats with an intact spinal cord suppresses reflex bladder activity, but intrathecal administration of VIP or PACAP in rats enhances bladder activity and suppresses urethral sphincter activity. PACAP has presynaptic facilitatory effects and direct excitatory effects on lumbosacral parasympathetic preganglionic neurons. Chronic spinal cord transection produces an expansion of VIP-IR (cats) and PACAP-IR (rats) in primary afferent axons in the lumbosacral spinal cord and unmasks spinal excitatory effects of VIP on bladder reflexes in cats. Intrathecal administration of PACAP6-38, a PAC1 receptor antagonist, reduces bladder hyperactivity in chronic spinal-cord-injured rats. These observations raise the possibility that VIP or PACAP have a role in the control of normal or abnormal voiding.

Role of VIP and Substance P in NANC Innervation in the Longitudinal Smooth Muscle of the Rat Jejunum—Influence of Extrinsic Denervation

This study was designed to determine changes in nonadrenergic, noncholinergic (NANC) neurotransmission mediated by Vasoactive Intestinal Polypeptide (VIP) and Substance P after small bowel transplantation (SBT). Six groups of rats (n > or = 6 per group) were studied: naïve controls (NC); 1 wk after anesthesia/sham celiotomy (SC-1); 1 or 8 wk after jejunal and ileal transection/reanastomosis (TA-1, TA-8), or syngeneic, orthotopic SBT (SBT-1, SBT-8). Jejunal longitudinal muscle strips were studied under NANC-conditions for spontaneous contractile activity, response to exogenous VIP and Substance P, and electrical field stimulation (EFS). Spontaneous activity did not differ between the six groups. VIP inhibited contractile activity in all groups 1 wk postoperatively (P < 0.05), which was prevented by the NO synthase inhibitor L-N(G)-nitro arginine (L-NNA). In contrast, VIP had no effect in the other groups. Precontraction with Substance P exposed an inhibitory effect of VIP in all groups (P < 0.05 each). Substance P increased contractile activity in all groups, but to a lesser extent in SBT-8 compared with NC, TA-8, and SBT-1 (P < 0.05). The inhibitory effect of EFS at 6 Hz was prevented by L-NNA in NC and TA-8; addition of the VIP antagonist ([D-p-Cl-Phe(6), Leu(17)]-VIP) increased contractile activity in NC, but not in TA-8 and SBT-8. The Substance P antagonist ([D-Pro(2), D-Trp(7,9)]-Substance P) decreased contractile activity during EFS at 50 Hz in NC and SBT-8. SBT decreased response to exogenous Substance P, although release of endogenous Substance P (EFS) is preserved. Changes in VIP signaling are acute and reversible and not caused by effects of SBT.

A Novel Role of VIP in Colonic Motility Function: Induction of Excitation–Transcription Coupling in Smooth Muscle Cells

Vasoactive intestinal polypeptide (VIP) relaxes smooth muscle by generation of cAMP and activation of protein kinase A (PKA). However, PKA activation also phosphorylates the transcription factor CREB. The aim of this study was to investigate whether the phosphorylation of CREB induces gene expression of the pore-forming alpha(1C) subunit of Ca(v)1.2 channels (L-type calcium channels), whose promoter has 2 binding sites for CREB. The experiments were performed on primary cultures of human colonic circular smooth muscle cells and freshly obtained human and rat colonic circular muscle strips. The incubation of human colonic circular smooth muscle cells or muscle strips with VIP for 24 hours enhanced the expression of alpha(1C) protein and mRNA as well as the contractile response to acetylcholine and KCl. On the contrary, incubation of the muscle strips with VIP antagonist for 24 hours suppressed cell contractility. The incubation of the cells with VIP caused sustained generation of cAMP for 24 hours, but PKA activation and CREB phosphorylation were transient. The inhibition of PKA by H-89 or silencing of CREB gene with targeted RNAi blocked the transcription of alpha(1C). Progressive 5' deletions of halpha(1C)1b promoter and site-directed mutations of the 2 CREB binding cis-elements indicated that most of alpha(1C) transcription was mediated by the 5' cAMP response element. The excitation-transcription coupling stimulated by VIP induces expression of the Ca(v)1.2 channels. The influx of calcium through these channels is a critical step in excitation-contraction coupling in smooth muscle cells.

Vasoactive intestinal polypeptide inhibits the established allergic contact dermatitis in humans.

There is increasing evidence indicating that the nervous system influences the immune response. In the present study the potential immunomodulatory role of vasoactive intestinal polypeptide (VIP) in established allergic contact dermatitis in humans was investigated. Positive patch-test reactions were elicited by application of nickel sulphate for 48 h. VIP was applied under patch-test conditions after another 24-h period. The test areas were measured before and 24 h after application of VIP and biopsy specimens were taken for immunohistochemistry. After application of VIP at 10(-5) mol/L, there was a significant reduction in the diameter of the test reaction. In addition, there was a reduction in the number of Leu 3a+ cells. The influence of VIP on the proliferative response of peripheral blood mononuclear cells from nickel-allergic subjects to nickel sulphate was also tested. The cells were cultured for 6 days and VIP was added after 3 days. There was no effect on the proliferative response. However, when VIP was added at 10(-6) and 10(-5) mol/L, a higher level of interferon gamma was found in the nickel-treated cell cultures compared to the controls. In conclusion, VIP may have an inhibitory effect on established allergic contact dermatitis. This inhibitory effect is possibly mediated through an increased production of interferon gamma by peripheral blood mononuclear cells.

VIP receptors control excitability of suprachiasmatic nuclei neurones

The role of vasoactive intestinal polypeptide (VIP) receptors on excitable properties of neurones in slices acutely prepared from the suprachiasmatic nuclei (SCN) of wild-type (WT) and VPAC(2)-receptor-deficient (Vipr2 ( -/- )) mice was studied under voltage clamp with the use of patch-clamp recording in the whole-cell configuration. The resting membrane potential in Vipr2 ( -/- ) neurones was significantly hyperpolarised as compared to WT cells (-60+/-7 vs -72+/-6 mV, p<0.01). Bath application of 100 nM VIP or the VPAC(2) receptor agonist RO 25-1553 triggered a slow inward current in a subpopulation of WT SCN neurones; the VIP-induced current was not affected by slice incubation with 25 microM of bicuculline but disappeared completely when the cells were dialysed with CsCl-containing/K(+)-free solution. Application of VIP or RO 25-1553 to neurones from Vipr2 ( -/- ) mice did not induce currents in all cells tested. Incubation of WT slices with 100 nM VIP or RO 25-1553 resulted in inhibition of fast tetrodotoxin-sensitive sodium currents and delayed rectifier K(+) currents in most of the cells tested. This effect was completely absent in cells from Vipr2 ( -/- ) mice. We postulate that VIP receptors control excitability of SCN neurones at the postsynaptic level by direct modulation of membrane potential via inhibition of K(+) channels and by tonic inhibition of sodium and potassium voltage-gated currents.

The roles of vasoactive intestinal polypeptide in the mammalian circadian clock.

Biological oscillations with an endogenous period of near 24 h (circadian rhythms) are generated by the master circadian pacemaker or clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus. This clock is synchronised to recurring environmental signals conveyed by selective neural pathways. One of the main chemical constituents of SCN neurones is vasoactive intestinal polypeptide (VIP). Such neurones are retinorecipient and activated by light. Exogenous application of VIP resets the SCN circadian clock in a light-like manner, both in vivo and in vitro. These resetting actions appear to be mediated through the VPAC2 receptor (a type of receptor for VIP). Unexpectedly, genetically ablating expression of the VPAC2 receptor renders the circadian clock arrhythmic at the molecular, neurophysiological and behavioural levels. These findings indicate that this intrinsic neuropeptide acting through the VPAC2 receptor participates in both resetting to light and maintenance of ongoing rhythmicity of the SCN.

Vasoactive intestinal polypeptide (VIP) phase-shifts the rat suprachiasmatic nucleus clock in vitro.

In mammals, the principal circadian pacemaker is housed in the hypothalamic suprachiasmatic nuclei (SCN). The SCN exhibit high levels of vasoactive intestinal polypeptide (VIP) immunoreactivity and two of the three VIP receptors, VPAC(2) and PAC(1), are found in the rat SCN. However, the role of VIP in the SCN remains unclear. In this study, we examined the phase-resetting actions of VIP and selective VIP receptor agonists on the electrical activity rhythm of rat SCN neurons in vitro. Application of VIP during the subjective day did not shift the peak in the firing rate rhythm. However, VIP treatment during the early or late subjective night evoked a small phase delay or a large phase advance, respectively. The phase-advancing effect of VIP was reproduced by the novel VPAC(2) receptor agonist RO 25-1553, but not by pituitary adenylate cyclase-activating peptide (a potent PAC(1) receptor agonist), or by [K15,R16,L27]VIP(1-7)/GRF(8-27), a novel, selective VPAC(1) receptor agonist. These data show that VIP phase-dependently phase-resets the rodent SCN pacemaker in vitro, presumably via the VPAC(2) receptor. As the pattern of phase-shifting evoked by VIP and RO 25-1553 resembles the phase-resetting actions of light on rodent behavioural rhythms, these data support a role for VIP and the VPAC(2) receptor in photic entrainment of the rodent circadian pacemaker.

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.

Role of vasoactive intestinal polypeptide in burn-induced oedema formation

Vasoactive intestinal polypeptide has been demonstrated to lack inherent effects on capillary permeability, but also to potentiate the oedema promoting actions of other inflammatory mediators or even to strongly reduce organ damage and subsequent oedema in ischemic models of the lung and heart. This study investigated the role of VIP on oedema in partial- and full-thickness skin burns of anaesthetised rats in vivo by spectrophotometrical quantification of Evans blue albumin. Results show that systemic VIP elicited a significant drop in mean arterial blood pressure versus saline ( p<0.001) and VIP antiserum ( p<0.001) both in burned and non-burned animals. VIP also decreased heart rate versus saline ( p<0.05) and anti-VIP ( p<0.01) in non-burned and burned animals. EB-albumin in normal skin was significantly inhibited by VIP as compared to saline ( p<0.05), but did not differ significantly from VIP-antiserum. A significant inhibition of EB-albumin extravasation versus saline was also seen following administration of VIP-antiserum ( p<0.01). Similarly, VIP significantly reduced EB-albumin extravasation versus saline treatment in partial-thickness ( p<0.01) and full-thickness burns ( p<0.001), while VIP-antiserum had no significant effect on skin perfusion in any of the burned groups as compared to saline treatment. The present results show that systemic VIP is a potent inhibitor of burn oedema. This effect could be secondary to constriction of skin vessels as a result of VIP-induced systemic hypotension or be mediated by the interaction of VIP with other oedema promoting mediators released following a thermal trauma to the skin.

The role of vasoactive intestinal polypeptide and nitric oxide in abdominal surgery induced relaxations of the rat gastric fungus

The role of vasoactive intestinal polypeptide and nitric oxide in abdominal surgery induced relaxations of the rat gastric fungus