Doses Of Vasoactive Intestinal Peptide Research Articles

Role of free radical scavenging activity of vasoactive intestinal peptide in the attenuation of mitochondrial dysfunction to ameliorate dextran sulphate sodium‐induced colitis in mice: Implications in ulcerative colitis

To evaluate the efficacy of vasoactive intestinal peptide (VIP) in treating ulcerative colitis (UC), targeting colonic mitochondrial dysfunction by virtue of its free radical scavenging properties for maintenance of colon mucosal integrity. A murine model was administered with dextran sodium sulfate (DSS) to induce colitis in C57BL/6J mice at 3.5%/g bodyweight for 3 cycles of 5 days each, followed by an intraperitoneal dose of VIP at 0.5 nmol/L per mouse per day for 10 days. The post-treatment mice were sacrificed and their colon samples were utilized for further analysis. To substantiate the in vivo findings and identify the reactive species involved in progression of UC, Caco-2 cells were subjected to DSS (5%) for 24 hours at 37 °C with or without VIP (10 nmol/L) in the presence or absence of specific free radical scavengers and antioxidants. Treatment with VIP reduced histopathological severity of colitis and cell death markers in murine model, leading to partial recovery of inhibited mitochondrial respiratory complexes, altered mitochondrial membrane potential and lowered adenosine triphosphate generation. Interestingly, in vitro treatment with VIP restored mitochondrial functions and its efficacy was equal to super oxide dismutase and dimethyl sulfoxide, indicating involvement of superoxide free radical (O2 •-) and hydroxyl radical (•OH) in progression of UC. However, catalase, Nω-nitro-l-arginine methyl ester and mercaptoethylguanidine were ineffective, indicating non-involvement of hydrogen peroxide, nitric oxide and ONOO- in UC. By virtue of its free radical scavenging properties VIP can act as a potent anti-colitogenic agent, reversing colonic mitochondrial dysfunction for treating UC.

The Neuropeptides Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide Control HIV-1 Infection in Macrophages Through Activation of Protein Kinases A and C.

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are highly similar neuropeptides present in several tissues, endowed with immunoregulatory functions and other systemic effects. We previously reported that both neuropeptides reduce viral production in HIV-1-infected primary macrophages, with the participation of β-chemokines and IL-10, and now we describe molecular mechanisms engaged in this activity. Macrophages exposed to VIP or PACAP before HIV-1 infection showed resistance to viral replication, comparable to that observed when the cells were treated after infection. Also, multiple treatments with a suboptimal dose of VIP or PACAP after macrophage infection resulted in a decline of virus production similar to the inhibition promoted by a single exposure to the optimal inhibitory concentration. Cellular signaling pathways involving cAMP production and activation of protein kinases A and C were critical components of the VIP and PACAP anti-HIV-1 effects. Analysis of the transcription factors and the transcriptional/cell cycle regulators showed that VIP and PACAP induced cAMP response element-binding protein activation, inhibited NF-kB, and reduced Cyclin D1 levels in HIV-1-infected cells. Remarkably, VIP and PACAP promoted G-to-A mutations in the HIV-1 provirus, matching those derived from the activity of the APOBEC family of viral restriction factors, and reduced viral infectivity. In conclusion, our findings strengthen the antiretroviral potential of VIP and PACAP and point to new therapeutic approaches to control the progression of HIV-1 infection.

Parasympathetic vasoactive intestinal peptide (VIP): a likely contributor to clozapine‐induced sialorrhoea

The parasympathetic transmitter vasoactive intestinal peptide (VIP) increases salivary gland blood flow and evokes protein secretion and, in some species, such as rats, a small fluid secretion. It interacts synergistically with muscarinics for protein and fluid output. Human salivary acini are supplied with VIP-containing nerves. We hypothesise that VIP and clozapine, acting together, evoke a volume of saliva greater than the sum of those induced by each drug given separately. It was further considered whether, in the current test situation, circulatory events influenced the magnitude of the secretory response. Saliva from parotid glands deprived of their autonomic innervation, and saliva and blood from innervated submandibular glands were collected in adrenoceptor antagonist-pretreated pentobarbitone-anaesthetised rats. Initially, the individual and then the combined effects of intravenous doses of VIP and clozapine were established. The submandibular volume response to the combination was 2-3 times higher, while blood pressure and glandular blood flow did not differ from those to VIP alone. The synergism occurred independent of nerves as shown in denervated parotid glands. From the current preclinical data, we speculate that VIP of parasympathetic origin, by its synergistic interaction with clozapine, may contribute to the clozapine (muscarinic M1-receptor)-induced sialorrhoea in schizophrenics.

Novel, Biocompatible, and Disease Modifying VIP Nanomedicine for Rheumatoid Arthritis

Despite advances in rheumatoid arthritis (RA) treatment, efficacious and safe disease-modifying therapy still represents an unmet medical need. Here, we describe an innovative strategy to treat RA by targeting low doses of vasoactive intestinal peptide (VIP) self-associated with sterically stabilized micelles (SSMs). This spontaneous interaction of VIP with SSM protects the peptide from degradation or inactivation in biological fluids and prolongs circulation half-life. Treatment with targeted low doses of nanosized SSM-VIP but not free VIP in buffer significantly reduced the incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. In addition, SSM associated VIP, unlike free VIP, had no side-effects on the systemic functions due to selective targeting to inflamed joints. Finally, low doses of VIP in SSM successfully downregulated both inflammatory and autoimmune components of RA. Collectively, our data clearly indicate that VIP-SSM should be developed to be used as a novel nanomedicine for the treatment of RA.

Effect of Vasoactive Intestinal Peptide (VIP) on Cytokine Levels and Haemostatic and Biochemical Parameters in A Rat Endotoxaemic Model

Abstract The presented study was planned to determine whether vasoactive intestinal peptide (VIP) could prevent cytokine haemostatic, haematological, and biochemical disturbances in LPS-treated rats. Adult male Wistar rats (weight range: 200-250 g) were used. The study included four groups: group 1 served as a control group (C); animals in group 2 were given intravenously 1.6 mg/100 g of LPS (E. coli, serotype 0.111:B4); in group 3, rats were injected intraperitoneally with 25 ng/kg of VIP; in group 4, the same doses of VIP and LPS were injected simultaneously. Blood samples were collected 6 h after treatments. In endotoxaemic rats, platelet count, fibrinogen, and antithrombin levels were decreased, the activated partial thromboplastin time and prothrombin time were prolonged, and leucopoenia, as well as significant changes in differential leukocyte percentage were demonstrated. In addition, LPS caused statistically significant increases in plasma TNF- , IL-6, and IL-10 levels, and AST, ALT, creatinine, cholesterol, triglyceride concentrations. However, it caused a statistically significant decrease in total protein and albumin levels when compared to control group. The results showed that during endotoxaemia, VIP had moderately therapeutic effect as an antiinflammatory agent, suppressing TNF-α and IL-6, and stimulating IL-10; however, it was not effective against the adverse effect of LPS on investigated haematological and biochemical parameters.

Central pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) decrease the baroreflex sensitivity in trout

Although PACAP and VIP exert diverse actions on heart and blood vessels along the vertebrate phylum, no information is currently available concerning the potential role of these peptides on the regulation of the baroreflex response, a major mechanism for blood pressure homeostasis. Consequently, the goal of this study was to examine in our experimental model, the unanesthetized rainbow trout Oncorhynchus mykiss, whether PACAP and VIP are involved in the regulation of the cardiac baroreflex sensitivity (BRS). Cross-spectral analysis techniques using a fast Fourier transform algorithm were employed to calculate the coherence, phase and gain of the transfer function between spontaneous fluctuations of systolic arterial blood pressure and R–R intervals of the electrocardiogram. The BRS was estimated as the mean of the gain of the transfer function when the coherence between the two signals was high and the phase negative. Compared with vehicle, intracerebroventricular (ICV) injections of trout PACAP-27 and trout VIP (25–100 pmol) dose-dependently reduced the cardiac BRS to the same extent with a threshold dose of 50 pmol for a significant effect. When injected intra-arterially at the same doses as for ICV injections, only the highest dose of VIP (100 pmol) significantly attenuated the BRS. These results suggest that the endogenous peptides PACAP and VIP might be implicated in the central control of cardiac baroreflex functions in trout.

Vasoactive intestinal peptide in rats with focal cerebral ischemia enhances angiogenesis

We studied the effect of vasoactive intestinal peptide (VIP) on angiogenesis in the ischemic boundary area after focal cerebral ischemia. Adult male Sprague–Dawley rats underwent middle cerebral artery occlusion for 2 h. A single dose of VIP was given via i.c.v. injection at the beginning of reperfusion. Immunohistochemistry and Western blotting were performed to assay angiogenesis and brain levels of vascular endothelial growth factor (VEGF) protein, respectively. In addition, the expression of VEGF and its receptors (flt-1 and flk-1), as well as endothelial proliferation, was measured using rat brain microvascular endothelial cells. Immunohistochemical analyses revealed significant (P<0.05) increases in the numbers of bromodeoxyuridine (BrdU) positive endothelial cells and microvessels at the boundary of the ischemic lesion in rats treated with VIP compared with rats treated with saline. Western blotting analysis showed that treatment with VIP significantly (P<0.05) raised VEGF levels in the ischemic hemisphere. In addition, treatment with VIP increased flt-1 and flk-1 immunoreactivity in endothelial cells. In vitro, incubation with VIP significantly (P<0.01) increased the proliferation of endothelial cells and induced the expression of VEGF, flt-1 and flk-1 in endothelial cells. The stimulatory effect of VIP on the proliferation of endothelial cells was significantly (P<0.01) inhibited by SU5416, a selective inhibitor of VEGF receptor tyrosine kinase. Our data suggest that treatment with VIP enhances angiogenesis in the ischemic brain, and this effect may be mediated by increases in levels of VEGF and its receptors.

Prolactin release and response to vasoactive intestinal peptide in an opportunistic breeder, the zebra finch ( Taeniopygia guttata)

Zebra finches in arid regions of Australia are opportunistic breeders that time their breeding cycles to coincide with nonseasonal rainfall. Hormonal profiles associated with reproductive behaviors may differ from those observed in seasonal breeders because these birds need to be reproductively competent on short notice. This study measured plasma prolactin (PRL) levels in nonbreeding and breeding zebra finches and in birds with and without prior reproductive experience. We also investigated the change in plasma PRL following injection with vasoactive intestinal peptide (VIP), the avian PRL-releasing hormone. PRL was lowest in non-paired birds, increased after pair bonds had formed, and was highest in incubating birds. No differences in PRL levels were found between males and females in these biparental care-givers. A single injection of VIP resulted in a rapid increase in plasma PRL in nonbreeding zebra finches, while PRL remained unchanged in incubating birds. When escalating doses of VIP were administered, nonbreeders responded with a maximal response in PRL release, but PRL levels in breeders remained unchanged following even the highest VIP dose. Among nonbreeders, inexperienced birds had significantly lower PRL levels than birds that had successfully reared a clutch, but both groups responded with an equally robust increase in PRL following a VIP challenge. This pattern differs from that observed in most photosensitive species in which only during a breeding cycle do birds secrete significant levels of PRL in response to exogenous VIP. Zebra finches, even when not actively breeding, must maintain competent pituitary lactotrophs that can secrete PRL at maximal rates. This is part of the suite of characters enabling these birds to respond to favorable breeding conditions at any time.

Impacting patient-centred outcomes in COPD: exacerbations and hospitalisations

Graded doses of 0.6, 1.3, and 3.3 pmol/kg/min of vasoactive intestinal peptide (VIP) were intravenously infused over 30 minute periods in four healthy volunteers and plasma VIP levels were measured by radioimmunoassay. Even with the smallest dose of VIP, plasma concentrations rose markedly above normal values. Infusion of higher VIP doses resulted in mean plateau levels of circulating VIP which were in the range of VIP values found in the Verner-Morrison syndrome. After cessation of the VIP infusions, plasma VIP levels fell strikingly by first order kinetics with an average disappearance half-time of one minute. The apparent metabolic clearance rate was about 9 ml/kg/min and the apparent volume of distribution for VIP was approximately 14 ml/kg. During infusion of the highest VIP dose, previously shown to induce one-fifth maximum pancreatic juice secretion, plasma concentrations of glucose, free fatty acids, and calcium were slightly but significantly raised, the pulse rate and the amplitude of blood pressure were increased, and cutaneous flushing occurred. The spectrum of effects accords well with some abnormalities seen in the Verner-Morrison syndrome. The present data, however, do not support a role for VIP as a circulating hormone, at least under physiological conditions.

Expression of vasoactive intestinal peptide and functional VIP receptors in human prostate cancer: Antagonistic action of a growth-hormone-releasing hormone analog

Vasoactive intestinal peptide (VIP) functions as a mitogenic agent in the human prostate gland acting by autocrine/paracrine mechanisms. Here we extend knowledge on the VIP system (expression of VIP and VIP receptors, functionality of VIP receptors) at this level by analyzing the differences between human normal prostate and prostate carcinoma specimens. RT-PCR showed the expression of mRNA for VIP in normal and malignant tissues, whereas VIP levels, as measured by enzyme immuno-analysis, were about two times higher in adenocarcinoma samples. Real-time RT-PCR indicated a minor expression of VPAC2 receptors in the prostate gland, as well as the overexpression of VPAC1 and PAC1 receptors in malignant tissue specimens. Radio-labeled binding experiments with [125I]VIP showed an increased number of VIP binding sites (2.5 times for the high- and 1.7 times for the low-affinity sites) during malignant transformation, whereas the affinity values were unaffected. The receptors were functional in control and cancer tissues as shown by the ability of increasing VIP doses to stimulate adenylate cyclase activity. Interestingly, JV-1-53 (a GHRH-related peptide analog) (at 0.1 microM) behaved as a potent VIP antagonist since it inhibited by 60% the maximal VIP effect upon the enzyme activity. The results further explain the mechanisms of the autocrine/paracrine actions of VIP in human prostate and prostatic carcinoma through the observation of differences between healthy tissue and malignant transformation. Moreover, present data support the potential usefulness of VIP and/or synthetic peptide analogs for diagnostic or radiotherapeutic purposes as well as for long-term peptide therapy in this malignancy.

The role of joint nerves and mast cells in the alteration of vasoactive intestinal peptide (VIP) sensitivity during inflammation progression in rats

The present study examined the peripheral effects of vasoactive intestinal peptide (VIP) on rat knee joint blood flow during acute and chronic inflammation. The involvement of joint nerves and synovial mast cells on these effects was also investigated. Prior to blood flow assessment, animals were deeply anaesthetised with ethyl carbamate (urethane; 2 mg kg(-1) i.p.). Local application of VIP (10(-13)-10(-9) mol) onto the capsular surface of normal rat knee joints caused a dose-dependent increase in synovial perfusion with an ED50 of 1.2 x 10(-11) mol. The dilator effect of the peptide was transient with the maximal response occurring approximately 1 min after drug administration. VIP-induced vasodilatation was blocked by co-administration of the VIP receptor antagonist VIP(6-28) (10(-9) mol). The inhibitory effect of the antagonist was consistent across the entire VIP dose range (P=0.01). The vasoresponsiveness to VIP was significantly attenuated in acutely inflamed joints; however, surgical denervation of acutely inflamed knees re-established the vasodilator effect of the neuropeptide. Topical application of VIP to 1- and 3-week adjuvant monoarthritic knees produced a hyperaemic response, which was not significantly different from normal (P=0.06 and 0.73 for 1- and 3-week adjuvant treated joints, respectively). Stabilisation of synovial mast cells by disodium cromoglycate (cromolyn) pretreatment did not alter the vasoresponsiveness to VIP in acute or chronically inflamed joints. The vasodilatatory effect of VIP is lost during acute knee joint inflammation and this abrogated effect is neurally dependent. In the chronic phase of knee joint inflammation, VIP-mediated hyperaemia recovers to normal levels. Synovial mast cells do not influence the vasomotor effects of exogenously applied VIP in inflamed knee joints.

Placental Expression of Substance P and Vasoactive Intestinal Peptide: Evidence for a Local Effect on Hormone Release

The present study evaluated vasoactive intestinal peptide (VIP) and substance P (SP) mRNA expressions and the localization of both peptides in first- and third-trimester human placentas. VIP and SP mRNAs were detected by slot blot analysis in first- and third-trimester placental tissues. By immunohistochemistry both neuropeptides were localized in the trophoblast (syncytium and cytotrophoblastic cells) of the chorionic villi. Because little information is available on the role of VIP and/or SP on the secretion of placental hormones, we investigated the effect of these neuropeptides on human chorionic gonadotropin (hCG) and progesterone release from primary cultured human trophoblastic and JEG-3 cells. The addition of increasing doses of VIP resulted in a dose-dependent stimulation of hCG release from cultured human trophoblast and JEG-3 cells. Increasing doses of VIP also dose-dependently stimulated progesterone secretion from primary cultured trophoblastic cells at all time points evaluated and from JEG-3 cells only after 3 h. SP did not affect hCG and progesterone secretion either in cultured human trophoblast or in JEG-3 cells. In conclusion, the present study demonstrates that VIP and SP are mainly expressed in human trophoblasts, and that VIP modulates the in vitro secretion of hCG and progesterone, suggesting a different role in trophoblastic function of the two peptides.

Long-lasting enhancement of rapid eye movement sleep and pontogeniculooccipital waves by vasoactive intestinal peptide microinjection into the amygdala temporal lobe.

The effect of a vasoactive intestinal peptide (VIP) microinjection into the amygdaloid central (CN) and basal nuclei (BN) on sleep organization and on the number and pattern of occurrence of pontogeniculooccipital (PGO) waves was analyzed. One group of 8 cats was studied in baseline conditions and after the microinjection of two doses of VIP applied into the CN and BN. Sleep research laboratory. PARTCIPANTS AND INTERVENTIONS: Eight cats were prepared with sleep-recording electrodes and with guide tubes in both amygdalae for saline and VIP microinjections. Neuropeptide doses of 0.10 microg/1 microl (30 microM) and 0.33 microg/1 microl (99.24 microM) were employed. Once the microinjection was applied, 23-hour polygraphic sleep recordings were performed for 5 consecutive days. Concomitantly the PGO waves were tape-recorded on each day and computationally analyzed. Results show that the 0.10 microg/1 microl microinjection produced no change. Unilateral VIP 0.33 microg/1 microl injection into the CN provoked a significant and lasting increase in the percentage of slow-wave sleep with PGO waves. Bilateral application of VIP increased the percentage of slow-wave sleep with PGO waves and rapid eye movement sleep for 5 days. Bilateral microinjection of the neuropeptide into the BN only enhanced the percentage of slow wave sleep with PGO waves. For both amygdaloid nuclei, we observed that VIP increased the number and modified the PGO wave pattern of occurrence during slow-wave sleep with PGO waves and during rapid eye movement sleep. The VIP microinjection into both the CN and BN induces increased amounts of rapid eye movement sleep, PGO waves, and slow-wave sleep with PGO waves, having a more robust effect on all of these three variables when applied into the CN.

Recent studies of cutaneous nociception in atopic and non-atopic subjects.

Itching reflects a distinct quality of cutaneous nociception elicited by chemical or other stimuli to neuronal receptors at the superficial layers of the skin and muco-cutaneous orifices. Although recent experimental studies of the conduction and perception of itch have yielded deeper insight into the physiology of this sensory quality, little is known about the neuromechanisms involved in pruritus accompanying many inflammatory skin diseases, in particular, in atopic eczema. Previous case-control studies of our research group with patients suffering from atopic eczema (AE) revealed significantly diminished itch perception after iontophoretic application of different doses of histamine as well as substance P (i.c. injected). Further experiments using acetylcholine (ACh, i.c.) clearly demonstrated that ACh elicits pruritus instead of pain in patients with AE. The first part of the present review deals with the results of our most recent case-control studies on histamine-induced itch perception in atopics devoid of eczema as well as in patients with urticaria or psoriasis compared to atopics with or without manifest eczema. We demonstrated that both focal itch and perifocal alloknesis (i.e., itch elicited by a slight mechanical, otherwise non-itching stimulus) were significantly reduced in eczema-free atopics yet were normal in non-atopics suffering from urticaria or psoriasis. In further studies using ACh i.c. injected into the uninvolved skin of patients with AE, lichen ruber, psoriasis, type IV contact eczema, or non-specific nummular eczema (n = 10/each group), all the atopics and 6/10 psoriatics felt itch instead of burning pain, but none of the others did. Different doses of vasoactive intestinal peptide (VIP) i.c. applied to the controls and the atopics with or without eczema did not markedly increase the intensity of nociceptive sensations. However, ACh induced pain in the controls, pure pruritus in the atopics with acute eczema, and a 'mixture' of pain and itch in the atopics just free from eczema. Obviously, the quality of sensations evoked by ACh and VIP depends on the inflammatory or non-inflammatory state of the atopic skin. In a placebo-controlled, double blind study on histamine-induced focal itch and alloknesis with healthy subjects (n = 15) using naltrexone (opioid receptor antagonist) and cetirizine (H1-blocking agent), naltrexone was found to significantly reduce both itching and alloknesis. Cetirizine reduced focal itch but failed to influence the alloknesis phenomenon. The wheal and flare reaction was suppressed only by cetirizine. These different effects point to a mainly CNS-based activity of naltrexone but a peripheral level effect of cetirizine. Due to long-lasting experience with group sport as a supporting adjuvant for inpatients with AE, we evaluated, by clinical, psychometric, and physiological studies, the therapeutic efficacy of controlled physical exercise in addition to otherwise equal anti-eczematous therapy for both voluntary participants and non-participants in sports by performing several case-control studies, one followed-up to 6 months after the patients' discharge from the hospital. Regular moderate exercises neither deteriorated nor impeded the recovery from AE, ameliorated the participants' scratch controlling ability and significantly their depressed emotional mood. The non-participants failed to achieve these aims. Sweating-induced itch was inhibited in almost all participants if simple skin care (clearing by warm shower, ointment) and short-term rest were used by informed patients. In conclusion, there are several indications that itching is elicited in individuals inclined to cutaneous atopy, regardless of their eczematous or just eczema-free state, by a different physiological pathway from that in non-atopic individuals. Therefore, antipruritic agents influencing the centrally altered nociception of atopics are needed and may be expected in near future. (ABSTRACT TRUNCATED)

Effects of vasoactive intestinal peptide (VIP) on the testicular vasculature of the rat.

Using laser Doppler flowmetry, the effects of unilateral intratesticular injection of vasoactive intestinal peptide (VIP) on testicular blood flow and mean arterial blood pressure were studied in anaesthetized adult rats. At doses of 50 and 500 ng, VIP increased blood flow by 29 +/- 8 and by 77 +/- 25% (p < 0.05), respectively (means +/- SEM) at 5 mm, but not at 15 mm, from the injection site. Blood pressure was not significantly affected by 50 ng, but was slightly reduced (by -8 +/- 2%) after treatment with 500 ng VIP. The highest dose of VIP (5 micrograms) reduced blood pressure (by -30 +/- 9%), and decreased blood flow at 15 mm, but not at 5 mm, from the injection site. It is concluded that VIP can act as a vasodilator in the rat testis.

Vasoactive intestinal peptide stimulates prostate-specific antigen secretion by LNCaP prostate cancer cells

The secretion of prostate-specific antigen (PSA) by prostate cancer provides an important tool in the diagnosis and management of this disorder. While androgens are required for PSA synthesis, the neuroendocrine regulation of PSA secretion is less understood. Human prostate is extensively innervated with vasoactive intestinal peptide (VIP)-containing neurons, while both normal and malignant prostate cells contain VIP receptors. Therefore, we investigated the effects of VIP on PSA secretion by LNCaP prostate cancer cells. We found that 1–4 VIP treatment produces 60–100% increases in PSA secretion by LNCaP cells. Increases in PSA secretion were seen with as little as 10 −10 M VIP with maximum effects at 10 −7 M. The predominant acute effect of VIP was to increase the secretion of stored PSA without increasing PSA mRNA. VIP's effect on PSA secretion involved the production of intracellular cAMP since all doses of VIP which increased secretion were associated with increased cyclic AMP and since dibutyryl-cyclic AMP treatment increased secretion similarly to VIP. These results suggest that VIP regulates PSA secretion by prostate cancer cells and also suggest a role for VIP to regulate PSA secretion by normal prostate epithelial cells.

Roles of the suprachiasmatic nucleus and vasoactive intestinal peptide in the response of plasma arginine vasopressin to osmotic challenge.

To clarify the role of neurons containing a vasoactive intestinal peptide (VIP)-like substance (VIP neurons) in the hypothalamic suprachiasmatic nucleus (SCN) in regulation of the plasma arginine vasopressin (AVP) concentration, we examined the effects of bilateral lesions of the SCN and intracranial injection of VIP on the increase in the plasma AVP concentration caused by ip injection of hypertonic (3.6%) saline in rats. The increase in the plasma AVP concentration after ip injection of hypertonic saline was significantly suppressed in rats with bilateral lesions of the SCN. Furthermore, the increase in the plasma AVP concentration elicited by ip injection of hypertonic saline was enhanced by intracerebro-ventricular injection of VIP and suppressed by a VIP antagonist, [Lys1,Pro2,5,Arg3.4,Tyr6]VIP. However, the same dose of VIP injected into the heart had no effect on the increase in the plasma AVP concentration caused by ip injection of hypertonic saline. These results suggest that the SCN and intracranial VIP play important roles in the regulation of the plasma AVP concentration and support the possibility that VIP neurons in the SCN enhance the response of plasma AVP to osmotic challenge.

Stimulatory effects of vasoactive intestinal peptide and pituitary adenylate cyclase-activating peptide on tuberoinfundibular dopaminergic neuron activity in estrogen-treated ovariectomized rats and their correlation with prolactin secretion.

The effects of central administration of vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) on hypothalamic tuberoinfundibular dopaminergic neuron activity and serum prolactin (PRL) levels were reported. Adult female Sprague-Dawley rats overiectomized for 2 weeks, implanted with subcutaneous estrogen-containing capsules and intracerebroventricular (i.c.v.) cannulae for 6 days were used for experiments. I.c.v. injections of VIP or PACAP were performed in conscious rats in the morning, and the injected rats were decapitated at various times afterwards. Serum sample and the median eminence tissue were collected from each rat. The levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 3,4-dihydroxyphenylalanine (DOPA) in the median eminence were determined by high-performance liquid chromatography with electrochemical detection. Serum PRL levels were determined by radioimmunoassay. I.c.v. administration of VIP (1 microgram/3 microliter) significantly increased median eminence DOPAC/DA ratio at 30 min, and serum PRL level at 15 min. The same dose of VIP (1 microgram), but not higher (10 micrograms) or lower (0.1 microgram), was also effective in stimulating the median eminence DOPA accumulation 35 min after the injection. The effect of VIP (1 microgram) on median eminence DOPA could be blocked by coadministration of a VIP antagonist, VIP6-28 in 10- and 30-, but not in 1- or 0.1-microgram doses. On the other hand, i.c.v. administration of PACAP (10 micrograms) stimulated median eminence DOPAC and lowered serum PRL levels at 30 min. All doses of PACAP used (0.1, 1 and 10 micrograms/ rat, i.c.v.) significantly increased median eminence DOPA concentrations at 60 min. The stimulatory effect of PACAP (0.1 microgram) on median eminence DOPA could also be blocked by coadministration of a PACAP antagonist, PACAP6-38 (in 10 to 100 x higher doses). In summary, central administration of either VIP or PACAP exhibited a stimulating effect on TIDA neuron activity through specific receptors. Serum PRL levels, however, were stimulated and inhibited by VIP and PACAP, respectively.

Presence and effects of pituitary adenylate cyclase activating peptide in the submandibular gland of the ferret

Pituitary adenylate cyclase activating peptide (PACAP), a recently described vasoactive intestinal peptide-like neuropeptide, was found to be present in neurons in the submandibular gland of the ferret, where PACAP-immunoreactive nerve fibers were distributed around blood vessels, acini and ducts. Most of the PACAP-immunoreactive fibres were distinct from those storing vasoactive intestinal peptide. PACAP occurs in tissues as PACAP1-38 and PACAP1-27. PACAP1-38 and PACAP1-27 but not PACAP16-38 displayed biological activity with about the same potency. They exerted vasodilator effects on the submandibular vasculature, which resulted in a greater fall in vascular resistance than an equimolar dose of vasoactive intestinal peptide. The vasodilator response was independent of muscarinic receptor activation. Neither vasoactive intestinal peptide nor PACAP alone evoked any flow of saliva. However, both vasoactive intestinal peptide and PACAP enhanced the fluid response to acetylcholine, and the flow of saliva as well as the output of protein in response to parasympathetic nerve stimulation, vasoactive intestinal peptide being more potent than PACAP. In vitro, protein was released from submandibular gland tissue in response to both vasoactive intestinal peptide and PACAP, vasoactive intestinal peptide being more potent than PACAP. PACAP (and vasoactive intestinal peptide) exerted its in vitro effect following adrenoceptor and muscarinic blockade and following degeneration of sympathetic nerves. Sympathetic denervation combined with parasympathetic preganglionic denervation resulted in supersensitivity to both vasoactive intestinal peptide and PACAP. The fact that PACAP and vasoactive intestinal peptide occur in different nerve fibre populations suggests different roles for the two peptides in the submandibular gland.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of vasoactive intestinal peptide receptors on rat alveolar macrophages.

In view of the evidence that vasoactive intestinal peptide (VIP) may modulate acute inflammatory injury in the lung, we investigated the presence and characteristics of VIP receptors on alveolar macrophages (AMs). We examined the binding of monoiodinated [Tyr(125I)10]-labeled VIP (125I-VIP) to rat AMs (> 96% pure), obtained from Sprague-Dawley rats by bronchoalveolar lavage (BAL). At 23 degrees C, the interaction of 125I-VIP with AMs was rapid, reversible, saturable, and linearly proportional to the number of cells. At equilibrium, the binding was competitively inhibited by 10(-11)-10(-6) M of native peptide [half-maximal inhibition (IC50) = 0.53 +/- 0.34 nM, n = 8], with evidence for two classes of binding sites: one with a high affinity (Kd = 0.20 +/- 0.09 nM) and a low capacity (1,190 +/- 640 sites/cell) and another with a low affinity (Kd = 43.2 +/- 13.8 nM) and a high capacity (51,700 +/- 14,000 sites/cell). VIP-related peptides inhibited the binding with the order of potency: VIP > peptide histidine isoleucine > helodermin >> secretin; glucagon was ineffective. In the presence of 3-isobutyl-1-methylxanthine, VIP dose dependently stimulated adenosine 3',5'-cyclic monophosphate accumulation in intact AMs, with maximal stimulation (6.3 times basal level) at 1 nM, and half-maximal accumulation at 0.23 +/- 0.11 nM VIP (Kd for high-affinity sites). For determination of the mass of the VIP receptor, 125I-VIP was covalently bound to AMs with the cross-linking agent dithiobis succinimidyl propionate. Autoradiographic studies after sodium dodecyl sulfate/polyacrylamide gel electrophoresis of solubilized affinity-labeled cells revealed a single major band of M(r) 76,400. We conclude that VIP binds to specific receptors on rat AMs that are coupled to adenylate cyclase, through which VIP may modulate inflammatory responses within the lung.