Quercetin increases bioavailability of nitric oxide in the jejunum of euglycemic and diabetic rats and induces neuronal plasticity in the myenteric plexus.

Considering the antioxidant, neuroprotective, inflammatory and nitric oxide modulatory actions of quercetin, the aim of this study was to test the effect of quercetin administration in drinking water (40 mg/day/rat) on neuronal nitric oxide synthase (nNOS), vasoactive intestinal peptide (VIP), overall population of myenteric neurons (HuC/D) and nitric oxide (NO) levels in the jejunal samples from diabetic rats. Male Wistar rats were distributed into four groups (8 rats per group): euglycemic (E), euglycemic administered with quercetin (E+Q), diabetic (D) and diabetic administered with quercetin (D+Q). Rats were induced to diabetes with streptozotocin (35mg/kg/iv) and, after 120 days, the proximal jejunum were collected and processed for immunohistochemical (VIP, nNOS and HuC/D) and chemiluminescence (quantification of tissue NO levels) techniques. Diabetes mellitus reduced the number of nNOS-IR (immunoreactive) (p <0.05) and HuC/D-IR (p <0.001) neurons, however, promoted an increased morphometric area of nNOS-IR neurons (p <0.001) and VIP-IR varicosities (p <0.05). In D+Q group, neuroplasticity effects were observed on HuC/D-IR neurons, accompanied by a reduction of cell body area of neurons nNOS- and VIP-IR varicosities (p <0.05). The NO levels were increased in the E+Q (p <0.05) and D+Q group (p <0.001) compared to the control group. In conclusion, the results showed that quercetin supplementation increased the bioavailability of NO in the jejunum in euglycemic and mitigate the effects of diabetes on nNOS-IR neurons and VIP-IR varicosities in the myenteric plexus of diabetic rats.

The Effect of Opiates on Bone Formation and Bone Healing.

PURPOSE OF REVIEW: Opioids have been shown to be associated with an increased risk of fracture. The purpose of this paper is to review recent research into the effects of opioids on bone formation and bone healing in animal models and in human studies. RECENT FINDINGS: Most opioids, such as morphine and fentanyl, negatively affected bone remodeling and bone healing in animal models. Conversely, remifentanil has been recently shown to promote in vitro osteoblast differentiation and to inhibit differentiation and maturation of osteoclasts, therefore reducing bone resorption. According to the possible negative role of opioids in bone healing, opioid antagonists have been shown to enhance bone mineralization, suggesting a possible therapeutic role in the future for osteoporosis. Other neuropeptides, such as the vasoactive intestinal peptide (VIP) and the neuropeptide Y (NPY), have been proved to promote osteogenesis. The increased risk of fractures among opioid users may be related to their central nervous system side effects or to the reduced bone density, partly due to their endocrine effects, and partly to their direct activity on bone cells. Clinical data strongly suggested a potential negative effect of opioids in bone healing. The risk of nonunion fracture is significantly increased in opioid users, and bone mass density was reduced in patients under long-term opioid treatment. The direct effects of opioids on bone remodeling appears evident from these reports. Not all opioids have the same potential for negatively impacting bone healing. Opioid antagonists may increase bone density and could represent a possible future treatment for low bone mass density pathologies. However, further trials are warranted to clarify the clinical relevance of these emerging findings from animal studies.

Comparison of the effects of pantethine and fursultiamine on plasma gastrointestinal peptide levels in healthy volunteers.

Pantethine and fursultiamine have been evaluated for their clinical usefulness in the treatment and prevention of uncomplicated postoperative adhesive intestinal obstruction. In recent years, the actions of drugs used to treat gastrointestinal diseases have been elucidated pharmacologically from the viewpoints of gastrointestinal peptide levels. We examined the effects of pantethine and fursultiamine on plasma levels of calcitonin gene-related peptide (CGRP)-, vasoactive intestinal polypeptide (VIP)-, motilin- and substance P (SP)-like immunoreactive substances (IS) in healthy subjects. An open-labeled study was conducted on five healthy volunteers. Each subject was administered a single oral dose of pantethine, fursultiamine and placebo at intervals of one month. Venous blood samples were collected before and at 20, 40, 60, 90, 120, 180 and 240 min after each administration. Plasma peptide levels were measured using a highly sensitive enzyme immunoassay. A single oral dose of pantethine resulted in significant increases of plasma CGRP- and VIP-IS levels compared to placebo. Furthermore, areas under the plasma concentration-time curves (AUC(0-240)) of CGRP- and VIP-IS were significantly higher after pantethine administration compared with placebo. On the other hand, fursultiamine had no effect on plasma levels and AUC(0-240) of CGRP-, VIP-, motilin- and SP-IS. This study demonstrated the different effects of pantethine and fursultiamine from the viewpoint of plasma gastrointestinal peptide changes. The pharmacological effects of pantethine may be closely related to the changes in plasma CGRP- and VIP-IS levels.

Appetite suppressive effects of yeast hydrolysate on nitric oxide synthase (NOS) expression and vasoactive intestinal peptide (VIP) immunoreactivity in hypothalamus.

To investigate the effects of yeast hydrolysate on appetite regulation mechanisms in the central nervous system, nitric oxide synthase (NOS) expression and vasoactive intestinal peptide (VIP) immunoreactivity in the paraventricular nucleus (PVN) and ventromedial hypothalamic nucleus (VMH) of the hypothalamus were examined. Male Sprague-Dawley (SD) rats were assigned to five groups: control (normal diet), BY-1 and BY-2 (normal diet with oral administration of 0.1 g and 1.0 g of yeast hydrolysate <10 kDa/kg body weight, respectively), AY-1 and AY-2 (normal diet with oral administration of 0.1 g and 1.0 g of yeast hydrolysate 10-30 kDa/kg body weight, respectively). The body weight gain in the BY groups was less than that in the control. In particular, the weight gain of the BY-2 group (133.0 +/- 5.1 g) was significantly lower (p < 0.05) than that of the control group (150.1 +/- 3.7 g). Among the test groups, the BY-2 group was shown to have significantly lower triacylglycerol (TG) levels (p < 0.05) than the other groups. The staining intensities and optical densities of NOS neurons in the PVN of the AY group were significantly higher (p < 0.05) than in the control and BY groups. The staining intensities and optical densities of VIP immunoreactivity in the PVN and VMH of the BY groups were higher than those of the AY groups and the control. In conclusion, these results indicated that yeast hydrolysate of <10 kDa reduced the body weight gain and body fat in normal diet-fed rats and increased the lipid energy metabolism by altering the expression of NOS and VIP in neurons.

Inflammation and inflammatory agents activate protein kinase C epsilon translocation and excite guinea-pig submucosal neurons.

BACKGROUND & AIMS: Properties of enteric neurons are transformed by inflammation and protein kinase C (PKC) isoforms are involved both in long-term changes in enteric neurons, and in transducing the effects of substances released during inflammation. We investigated roles of PKCepsilon in submucosal neurons by studying translocation in response to inflammatory mediators, effects on neuron excitability, and the changes in PKCepsilon distribution in a trinitrobenzene sulphonate model of ileitis. METHODS: Immunohistochemical detection and analysis of association with membrane and cytosolic fractions, and Western blot analysis of cytosolic and particulate fractions were used to quantify translocation. Electrophysiology methods were used to measure effects on neuron excitability. RESULTS: All submucosal neurons were immunoreactive for the novel PKC, PKCepsilon, and direct PKC activators, phorbol 12,13-dibutyrate, ingenol 3,20-dibenzoate, and the PKCepsilon-specific activator, transactivator of transduction-Psiepsilon receptor for activated C kinase, all caused PKCepsilon translocation from cytoplasm to surfaces of the neurons. Electrophysiologic studies showed that the stimulant of novel PKCs, ingenol (1 micromol/L), increased excitability of all neurons. Stimulation of protease-activated receptors caused PKCepsilon translocation selectively in vasoactive intestinal peptide secretomotor neurons, whereas a neurokinin 3 tachykinin receptor agonist caused translocation in neuropeptide Y and calretinin neurons. In all cases translocation was reduced significantly by a PKCepsilon-specific translocation inhibitor peptide. Increased PKCepsilon at the plasma membrane occurred in all neurons 6-7 days after an inflammatory stimulus. CONCLUSIONS: Major targets for PKCepsilon include ion channels near the plasma membrane. PKCepsilon is likely to have a significant role in controlling the excitability of submucosal neurons and is probably an intermediate in causing hyperexcitability after inflammation.

Botulinum toxin therapy in the ovalbumin-sensitized rat.

OBJECTIVE: The aim of this study was to determine whether intranasal administration of botulinum toxin type A (BTX-A) could relieve the typical symptoms of allergic rhinitis (AR) and alter substance P (SP)- and vasoactive intestinal peptide (VIP)-immunoreactive (IR) expression in nasal mucosa of AR animals sensitized with ovalbumin (OVA). METHODS: AR was induced by intraperitoneal injection of OVA followed by its repeated intranasal instillation in female Wistar rats. Some AR animals were intranasally treated with a cotton strip containing BTX-A (10 U per nostril) for 1 h. After BTX-A treatment, OVA was repeatedly instilled in AR and AR + BTX-A groups every 2 days for 10 days. Subsequently, nasal symptoms were evaluated, and nasal secretions collected. Finally, the nasal mucosae of all animals were prepared for histological and immunohistochemical assessment. RESULTS: BTX-A administration alleviated typical AR symptoms including rhinorrhea, nasal itching and sneezing, and subsequent intranasal repeated challenge with OVA did not trigger AR symptoms. After BTX-A treatment, inflammatory histological characteristics within the nasal mucosa of AR animals were absent, but atrophy of serous glands was observed. BTX-A decreased dense SP-IR and VIP-IR cells and fibers within and beneath the epithelium, around blood vessels and close to serous glands in AR animals. CONCLUSION: Local BTX-A treatment is an effective method to reduce AR symptoms. BTX-A decreased the excessive SP-IR and VIP-IR expression induced by OVA. Therefore, BTX-A may affect the nasal mucosa via the suppression of neuropeptides, playing a major role in autonomous mucosal innervation in the pathophysiology of AR.

A novel role of VIP in colonic motility function: induction of excitation-transcription coupling in smooth muscle cells.

BACKGROUND & AIMS: 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. METHODS: The experiments were performed on primary cultures of human colonic circular smooth muscle cells and freshly obtained human and rat colonic circular muscle strips. RESULTS: 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. CONCLUSIONS: 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.

Effect of aminoguanidine treatment on diabetes-induced changes in the myenteric plexus of rat ileum.

The aim of this study was to investigate the ability of aminoguanidine (AG) to prevent diabetes-induced changes in nitric oxide synthase- (nNOS), vasoactive intestinal polypeptide- (VIP) and noradrenaline- (NA) containing nerves of the rat ileum using immunohistochemical and biochemical techniques. Diabetes was induced in adult male Wistar rats by a single intraperitoneal injection of streptozotocin (65 mg/kg). AG was administered in the drinking water to control (1.8 g/l) and diabetic (0.9 g/l) rats over a period of 8 weeks. Diabetes caused a significant increase in the thickness of nNOS-containing nerve fibres (p<0.001) in the circular muscle, in nNOS activity (p<0.05) and in the size distribution of nNOS-containing myenteric neurons (p<0.001). The thickness of VIP-containing nerve fibres was significantly greater (p<0.01) and there was a significant increase in varicosity size (p<0.01) and proportion of VIP-positive myenteric neurons (p<0.01) in diabetes. NA levels were significantly reduced (p<0.01) and the size of varicosities containing tyrosine hydroxylase (TH) was significantly increased (p<0.001) in diabetes. AG treatment completely or partially prevented the diabetes-induced increase in nNOS activity, in VIP-containing varicosity size, and in fibre width of both VIP- and nNOS-containing fibres in the circular muscle but had no effect on the diabetes-induced increase in nNOS-containing neuronal size or proportion of VIP-containing myenteric neurons. In contrast to VIP, AG treatment had no effect on the increase in TH-containing varicosity size in diabetes and also failed to prevent the decrease in NA levels induced by diabetes. These results indicate that AG treatment for neuropathy is not equally effective for all autonomic nerves supplying the ileum and that diabetes-induced changes in NA-containing nerves are particularly difficult to treat.

Evidence for a role of inducible nitric oxide synthase in gastric relaxation of mdx mice.

Alterations of gastric mechanical activity have been reported in mdx mouse, animal model for Duchenne muscular dystrophy. This study examined if alterations in the vasoactive intestinal polypeptide (VIP) system are present in mdx stomach. Gastric mechanical activity was recorded in vitro as changes of endoluminal pressure and neurally or pharmacologically evoked relaxations were analysed in mdxvs normal stomach. Reverse-transcription polymerase chain reaction was used to detect inducible nitric oxide synthase (iNOS) expression. Relaxations to sodium nitroprusside in mdx stomach showed no difference in comparison with normal preparations. In normal stomach, VIP produced relaxation, which was reduced by VIP6-28, antagonist of VIP receptors, but was not modified by Nomega-nitro-L-arginine methyl ester (L-NAME), 1-H-oxodiazol-[1,2,4]-[4,3-a]quinoxaline-1-one (ODQ) or by N-(3-(aminomethyl)-benzyl)acetamidine (1400W) and aminoguanidine, inhibitors of iNOS. In contrast, in mdx stomach VIP responses were antagonized not only by VIP6-28, but also by L-NAME, ODQ, 1400W or aminoguanidine. In normal stomach, the slow relaxation evoked by stimulation at high frequency was reduced by VIP6-28, but it was unaffected by 1400W or aminoguanidine. In mdx stomach, it was reduced by VIP6-28 or 1400W, which did not show additive effects. iNOS mRNA was expressed only in mdx stomach. The results suggest that in mdx gastric preparations, iNOS is functionally expressed, being involved in the slow relaxation induced by VIP.

Clinical-biochemical correlates of migraine attacks in rizatriptan responders and non-responders.

The present study was aimed at verifying the clinical characteristics of a typical attack in 20 migraine patients, 10 responders and 10 non-responders to rizatriptan, and at investigating any differences in the levels of neuropeptides of the trigeminovascular or parasympathetic systems [calcitonin gene-related peptide (CGRP), neurokinin A (NKA) and vasoactive intestinal peptide (VIP) measured by radioimmunoassay methods in external jugular blood] between responders and non-responders. In all responders to rizatriptan, pain was unilateral, severe, and pulsating, and in five of them at least one sign suggestive of parasympathetic system activation was recorded. Five patients who were non-responders to rizatriptan referred bilateral and non-pulsating pain, even though severe in most of them. CGRP and NKA levels measured before rizatriptan administration were significantly higher in responders than in non-responders (P < 0.0001 and P < 0.002, respectively). In the five patients with autonomic signs among rizatriptan responders, detectable VIP levels were found at baseline. One hour after rizatriptan administration, a decrease in CGRP and NKA levels was evident in the external jugular venous blood of rizatriptan responders, and this corresponded to a significant pain relief and alleviation of accompanying symptoms. VIP levels were also significantly reduced at the same time in the five patients with autonomic signs. After rizatriptan administration, CGRP and NKA levels in non-responder patients showed less significant variations at all time points after rizatriptan administration compared with rizatriptan responders. The present study, although carried out on a limited number of patients, supports recent clinical evidence of increased trigeminal activation associated with a better triptan response in migraine patients accompanied by parasympathetic activation in a subgroup of patients with autonomic signs. In contrast, the poor response seems to be correlated with a lesser degree of trigeminal activation, lower variations of trigeminal neuropeptides after triptan administration, and no evidence of parasympathetic activation at baseline.

Effects of ascorbic acid on the vasoactive intestinal peptide synthesis in the ileum submucous plexus of normal rats.

BACKGROUND: The aging process is a deteriorating process that attacks the gastrointestinal tract, causing changes in the number and size of neurons from the enteric nervous system. The activity of free radicals on enteric neurons is helped by the significant reduction of antioxidants. AIM: Evaluate the effect of the ascorbic acid supplementation on the neurons that produce the vasoactive intestinal peptide (VIP) in the submucous plexus of the ileum of normal rats for a period of 120 days. METHODS: Fifteen rats were divided in three groups: untreated control with 90 days, untreated control with 210 days and ascorbic acid-treated rats with 210 days. Ascorbic acid was given for 16 weeks from the 90th day of age by adding it to drinking water (1 g/L prepared fresh each day). The ileums were processed according to the immunohistochemistry technique for whole-mount preparation in order to detect the presence of VIP immunoreactive in the cellular bodies and nervous fibers in the neurons of the submucous plexus. We have verified their immunoreactivity and measured the cellular profile of 80 cellular bodies of VIP-ergic neurons from each studied group. RESULTS: The ascorbic acid supplementation did not alter physiological parameters such as water intake and food consumption of the three studied groups. We observed a significant increase of the cellular profile of VIP-ergic neurons in untreated control with 210 days when compared to untreated control with 90 days. The cellular profile of VIP-ergic neurons in ascorbic acid-treated rats with 210 days was bigger than those observed in others groups. CONCLUSION: The ascorbic acid had a neurotrophic effect on VIP-ergic neurons on the ileum after period 120 days of supplementation.

Effects of ascorbic acid on the vasoactive intestinal peptide synthesis in the ileum submucous plexus of normal rats

RACIONAL: O envelhecimento é um processo deteriorativo que acomete o trato gastrointestinal, provocando alterações no número e tamanho dos neurônios do sistema nervoso entérico. A ação dos radicais livres nos neurônios entéricos é favorecida pela diminuição significativa de antioxidantes. OBJETIVO: Avaliar o efeito da suplementação com ácido ascórbico sobre os neurônios submucosos do íleo de ratos normais que produzem o peptídio intestinal vasoativo (VIP) por um período de 120 dias. MÉTODOS: Quinze ratos foram divididos em três grupos: controles com 90 dias, controles com 210 dias e tratados com ácido ascórbico com 210 dias. O ácido ascórbico foi administrado durante 16 semanas a partir de 90 dias de idade pela adição em água (1 g/L/dia). O íleo foi processado para obtenção de preparados totais empregados na realização de técnica imunoistoquímica para detectar a presença de corpos celulares e fibras VIP imunoreativas nos neurônios do plexo submucoso. O perfil celular e a imunoreatividade de 80 corpos celulares de neurônios VIP-érgicos de cada grupo estudado foi verificada. RESULTADOS: A suplementação com ácido ascórbico não alterou parâmetros fisiológicos tais como a água ingerida e alimento consumido nos três grupos estudados. Observou-se aumento significativo do perfil celular dos neurônios VIP-érgicos dos animais controles com 210 dias, quando comparados com os controles com 90 dias. O perfil celular dos neurônios VIP-érgicos no grupo de animais tratados com ácido ascórbico foi maior do que aqueles observados nos grupos controles. CONCLUSÃO: O ácido ascórbico teve efeito neurotrófico sobre os neurônios VIP-érgicos do íleo após 120 dias de suplementação.

Pharmacology of erectile function and dysfunction.

Central regulation of the erectile process involves several transmitters, including dopamine, serotonin, noradrenaline, and nitric oxide, and peptides, such as oxytocin and ACTH/alpha-MSH. These systems may be targets for future drugs designed to treat erectile dysfunction. Peripherally, the different steps involved in neurotransmission, impulse propagation, and intracellular transduction of neural signals in penile smooth muscles need further investigation. Continued studies of the interactions between different transmitters/modulators may reveal new combination therapies. Increased knowledge of the changes in penile tissues associated with erectile dysfunction may explain the pathogenetic mechanisms and help to prevent the disorder.

Leptin and TGF-beta synergistically regulate VIP cytokine response element transcription.

Leptin was originally described as an adipocyte-derived cytokine that signals to the hypothalamus to regulate food intake and energy expenditure. Leptin signals through the Ob receptor, which is closely related to the gp130 cytokine receptor. Here we show that leptin can induce expression of the neuropeptide gene vasoactive intestinal peptide (VIP) through the VIP cytokine response element, the same element that mediates the response to the gp130 cytokines. Leptin acts synergistically with TGF-beta to activate transcription through this element. Transcriptional responses to leptin are increased when transmitted through ObR mutated at Tyr986, the SHP-2 docking domain, yet this mutation does not alter the synergy between TGF-beta and leptin. These data emphasize the functional similarity between leptin and the gp130 cytokines.

Effects of enalapril on vasoactive intestinal peptide metabolism and tissue levels.

Angiotensin converting enzyme inhibitor therapy results in an increase in cardiac output without an increase in heart rate suggesting a positive inotropic effect. This cannot be explained by changes in angiotensin II and bradykinin concentrations. Angiotensin converting enzyme may also metabolise vasoactive intestinal peptide (VIP), a vasodilator and positive inotrope whose concentration in the heart declines in heart failure. We sought to determine whether changes in plasma VIP or its metabolism might explain the positive inotropic effect of angiotensin converting enzyme inhibitors. We also measured VIP in the heart to determine whether a local increase in VIP might explain this effect. Male Sprague-Dawley rats were randomised to control and enalapril groups (2 mg kg(-1) day(-1)). After 7 days, rats were anaesthetised and underwent metabolic clearance studies for VIP or had hearts, lungs and kidneys removed and snap frozen. VIP concentrations in plasma, infusate and tissue extracts were measured by radioimmunoassay. Plasma concentrations of VIP were unchanged by treatment with enalapril (control: 7.7 +/- 0.8 pmol l(-1); enalapril: 7.9 +/- 0.8 pmol l(-1) ), while the metabolic clearance rate of) VIP increased significantly (control: 10.4 +/- 1.4 ml min(-1) 100 g(-1); enalapril: 17.3 +/- 1.6 ml min(-1) 100 g(-1); p < 0.005). Secretion rate) also increased in enalapril treated rats (139.1 +/- 25.0 pmol min(-1) 100 g(-1) compared with controls (96.3 +/- 13.4 pmol min (-1) 100 g(-1); P< 0.01). VIP in the heart increased after enalapril (control: 208.4 +/- 39.0 pmol g (-1); enalapril: 928.9 +/- 123.6 fmol g(-1); P < 0.0005). Angiotensin converting enzyme inhibition increases the metabolism of VIP. However, the significant increase in the myocardial concentration of VIP may contribute to the beneficial haemodynamic inotrope effects of angiotensin converting enzyme inhibitors.

Patterns of c-fos expression induced by fluvoxamine are different after acute vs. chronic oral administration.

Fluvoxamine is a selective serotonin (5-HT) reuptake inhibitor (SSRI) with a broad spectrum of behavioral and therapeutic effects, e.g. in depressive illness. We used the expression of c-fos, after both acute and chronic oral administration of fluvoxamine in the rat, to study its immediate and long-term effects, in relation to the distribution of Galanin (GAL) and Vasoactive Intestinal Polypeptide (VIP). After acute oral administration, most consistent increases were apparent in (parts of); the nucleus of the solitary tract, medial part; the lateral parabrachial nucleus, external part; the bed nucleus of the stria terminalis, dorsolateral part; and the central nucleus of the amygdala, lateral part. After chronic administration, distribution of Fos-IR was similar to acute administration, although numbers of Fos-IR neurons were no longer significantly different from control values. It is concluded that activation of 5-HT3-receptors in the caudal brainstem or gastro-intestinal afferents of the vagal nerve may play a role in the observed pattern of Fos-IR after fluvoxamine administration. The relationship with the antidepressant effects of fluvoxamine needs further investigations.

Cholecystokinin, beta-endorphin and vasoactive intestinal peptide in peripheral blood mononuclear cells of drug-naive schizophrenic patients treated with haloperidol compared to healthy controls.

Cholecystokinin (CCK), beta-endorphin (BE), and vasoactive intestinal peptide (VIP) in peripheral blood mononuclear cells from 30 drug-naive schizophrenics compared to 22 healthy controls were studied. Patients were evaluated with the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of the Negative Symptoms (SANS) at baseline (TO), and after four weeks (T4) in nine patients who were subsequently treated with haloperidol (HL). Neuropeptide concentrations in peripheral blood mononuclear cells (PBMC) were measured at TO and, for the treated patients, at T4. There was a negative correlation between CCK and SANS baseline scores and a trend for patients who responded poorly to HL (i.e. patients with a prevalence of negative symptomatology) to have lower CCK basal values.

Evidence that vasoactive intestinal polypeptide is a parasympathetic neurotransmitter in the endocrine pancreas in dogs.

Vasoactive intestinal polypeptide (VIP) has been found in pancreatic nerves in several species. Studies were conducted to determine if VIP could be a parasympathetic neurotransmitter in the canine endocrine pancreas. To verify that VIP is localized in pancreatic parasympathetic nerves, sections of canine pancreas were immunostained for VIP. VIP staining was identified in the majority of neuronal cell bodies in intrapancreatic parasympathetic ganglia. In addition. VIP was localized in nerve fibers innervating pancreatic islets in the proximity of alpha cells. Next, to determine if VIP is released during electrical stimulation of parasympathetic nerves, pancreatic spillover of VIP was measured during vagal nerve stimulation (VNS) in anesthetized dogs. VIP spillover increased from a baseline of 630+/-540 pg/min to 2580+/-540 pg/min (delta = +1950+/-490 pg/min, p <0.01). Pancreatic VIP release during VNS was not affected by atropine, whereas ganglionic blockade with hexamethonium nearly abolished the VIP response to VNS (p<0.005 vs control), suggesting that VIP is a postganglionic neurotransmitter in the dog pancreas. To examine the effects of VIP on pancreatic hormone secretion, synthetic VIP was infused locally into the pancreatic artery. VIP, at a low dose (5 pmol/min), increased glucagon secretion from 1750+/-599 to 3800+/-990 pg/min (delta = +2060+/-870 pg/min, p<0.05), but did not affect insulin secretion (delta = -1030+/-760 microU/min, NS). Thus, VIP is contained in and released from pancreatic parasympathetic nerves in proximity to islet alpha cells and exogenous VIP, at a dose which approximates the increase of VIP spillover during VNS, preferentially stimulates glucagon vs insulin secretion. Therefore, VIP is likely to function as a parasympathetic neurotransmitter in the endocrine pancreas in dogs. We hypothesize that VIP could mediate the glucagon response to parasympathetic activation which has been shown to resistant to cholinergic blockade with atropine in several species.

Nitric oxide and release of the peptide VIP from parasympathetic terminals in the submandibular gland of the anaesthetized cat.

The role of nitric oxide (NO) in mediating various submandibular responses to stimulation of the parasympathetic innervation has been investigated in anaesthetized cats, in which N omega-nitro-L-arginine methyl ester (L-NAME; 30 mg kg-1 I.A.) was used to block the synthesis of NO. L-NAME significantly reduced the vasodilator response and the flow of saliva, together with the output of salivary protein that occurred during stimulation of the chorda lingual nerve (20 Hz for 1 s at 10 s intervals), without significantly reducing the output of vasoactive intestinal peptide (VIP) from the gland. The results show that NO is implicated not only in the release of VIP, as established previously, but also in mediating its actions following release in the submandibular gland of the cat.