Vasoactive intestinal peptide stimulates immunoglobulin production and growth of human B cells.

The effect of vasoactive intestinal peptide (VIP) on human lymphoblastoid B cell lines and tonsil B cells was studied. VIP increased immunoglobulin production and proliferation by lymphoblastoid B cell line, GM-1056, in a dose-dependent manner. As little as 10(-12) M of VIP was effective, and higher concentrations of VIP induced an approximately five-fold increase in IgA production. Moreover, this enhancement was blocked by VIP antagonist. Similarly, VIP enhanced IgM and IgG production by other lymphoblastoid B cell lines, CBL and IM-9, respectively. In contrast to VIP, another neuropeptide substance P (SP) or somatostatin failed to enhance immunoglobulin production and thymidine uptake. VIP also enhanced IgA production and thymidine uptake by purified tonsil B cells. However, in contrast to B cell lines, VIP failed to enhance IgM and IgG production by tonsil B cells. SP or somatostatin failed to enhance immunoglobulin production or thymidine uptake by tonsil B cells. These results indicate that VIP acts as B cell stimulatory factor and that VIP may also have preferential effect on IgA production on tonsil B cells.     

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.     

Peptidergic (vasoactive intestinal peptide) nerves in the genito-urinary tract

The feline genito-urinary tract receives a rich supply of nerve fibers displaying immuno-reactivity like that of vasoactive intestinal peptide. Nerves containing vasoactive intestinal peptide are particularly numerous in the trigonum area of the bladder, around the ureteral openings and in the upper part of the urethra in both sexes, in the epididymis, prostate and vas deferens, and in the uterine cervix. Ganglia located close to or within the wall of the trigonum area and of the upper urethra contain numerous immunoreactive nerve cell bodies, which may be the origin of the fibers containing vasoactive intestinal peptide that innervate these regions.     

Vasoactive intestinal peptide receptor localization in rat forebrain by autoradiography

Vasoactive intestinal peptide (VIP) receptors were localized in rat forebrain by in vitro labeling light microscopic autoradiography with 125I-labeled VIP. Binding sites for VIP were found in discrete areas of rat forebrain including lamina I of the neocortex and pyriform cortex, caudate-putamen, the hippocampus and molecular layer of the dentate gyrus, basolateral nucleus of the amygdala, several thalamic nuclei and the magnocellular paraventricular and supraoptic nuclei of the hypothalamus. These results are consistent with earlier findings on the immunohistochemical distribution and proposed sites of action of VIP, and reinforce the concept that endogenous VIP may function as a neuromodulator in brain.     

Vasoactive intestinal peptide impairs leucocyte migration but fails to modify experimental murine colitis

Inflammatory bowel diseases are chronic inflammatory disorders of the gastrointestinal tract. Vasoactive intestinal peptide (VIP) is a neuropeptide with known anti-inflammatory activity. We have demonstrated previously that administration of VIP inhibits leucocyte migration in a murine model of delayed-type hypersensitivity, and anti-inflammatory efficacy is supported by other studies. The aim of this study was to investigate the VIP effects in a murine model of intestinal inflammation. Colitis was induced in BALB/c mice by a 2.5 mg enema of 2,4,6-trinitrobenzenesulphonic acid (TNBS) and the mice were killed on day 7. Mice were administered either a 3-day (therapeutic) or 7-day (prophylactic) constant infusion of VIP by subcutaneously implanted mini-osmotic pumps, or intraperitoneal (i.p.) injection of VIP on alternate days over 7 days. Clinical disease scores, weight changes, histopathology of colon tissues, plasma VIP levels, cytokine levels and chemotaxis of peripheral blood mononuclear cells were evaluated. After administration of TNBS, mice quickly developed severe colitis accompanied by dramatic body weight loss (20% by day 6) and high mortality (30%). Prophylactic treatment using high-dose VIP abrogated leucocyte chemotaxis; however, it failed to ameliorate the weight loss and mortality. Moreover, VIP delivered either by constant infusion or i.p. failed to modify the clinical, histological or cytokine markers of disease. Our studies show that, despite an ability to inhibit chemokine-induced chemotaxis of mononuclear cells, VIP was unable to modulate TNBS-induced colitis. This contrasts with the efficacy of VIP in models of mild inflammatory disease and suggests that VIP is unlikely to provide a useful model for novel anti-IBD therapy.     

Effect of angiotensin II on the hemodynamics after systemic and portal administration

Changes in the general hemodynamics were studied in healthy unanesthetized dogs after injection of angiotensin II for 60 min into the superior vena cava and portal vein at the rate of 27 ng/kg/min. Portal administration of the peptide was found to induce a weaker pressor effect. After systemic injection of angiotensin II the arterial pressure rose as the result of an increase in peripheral vascular resistance, and the minute volume of the circulation was reduced. After portal injection of angiotensin the increase in arterial pressure was due chiefly to an increase in the minute volume of the circulation. The differences in the hemodynamic responses cannot be explained entirely by metabolism of the peptide in the liver. After portal injection of angiotensin II it is possible that depressor substances from the liver enter the blood stream.Laboratory of Clinical and Experimental Surgery, Institute of Cytology and Genetics, Academy of Sciences of the USSR, Siberian Division. Laboratory of Endocrinology, Institute of Clinical and Experimental Medicine, Academy of Medical Sciences of the USSR, Siberian Branch, Novosibirsk. (Presented by Academician of the Academy of Medical Sciences of the USSR V. P. Kaznacheev.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 5, pp. 520–522, May, 1976.     

Vasoactive intestinal peptide-like immunoreactivity in nerves associated with the cardiovascular system of guinea-pigs

The distribution of nerves with vasoactive intestinal peptide (VIP)-like immunoreactivity has been examined in the heart and vascular system of guinea-pigs. There was a very sparse supply of fibres to the heart. No immunoreactive cell bodies were found in the intrinsic cardiac ganglia; however, positive nerve cell bodies were seen along the superior vena cava near the right atrium. There were immunoreactive fibres with most arteries; these fibres were located at the media-adventitia junction. The supply to major distributing arteries, such as the aorta, subclavian, carotid and femoral arteries as well as to the pulmonary arteries, was sparse. Of the individual vascular beds, the most densely supplied arteries were the mesenteric and uterine (or in the male deferential) arteries. Arteries running to other organs or tissues, such as skeletal muscle, kidney, pancreas, spleen and heart were less densely supplied. There were clear differences in the innervation of different cerebral vessels. The greatest density was associated with the anterior and middle cerebral arteries. Fewer nerves accompanied the posterior cerebral, cerebellar and meningeal arteries. There was a sparse innervation of the rostral part of the basilar artery. Throughout the body, veins were sparsely supplied. The distribution of nerves with VIP-like immunoreactivity was not changed when noradrenergic nerves were degenerated by 6-hydroxydopamine or when substance P nerves were disrupted by capsaicin. It is concluded that VIP containing nerves innervating the heart and blood vessels form a population distinct from the substance P-containing and the noradrenergic nerves. It is suggested that the VIP fibres might be efferent vasodilator nerves to the blood vessels.     

Vasoactive intestinal polypeptide-immunoreactive neurons in rat visual cortex

An antibody to vasoactive intestinal polypeptide (VIP) was used to examine the forms of VIP-positive neurons and the synapses made by VIP-positive axon terminals. Vasoactive intestinal polypeptide-positive cells are most common in layers II and III and the majority of them are typical bipolar neurons, with two primary dendrites which emanate from the upper and lower poles of the cell body. Their somata, which have only a few symmetric and asymmetric synapses, generally have a fusiform or "tear-drop" shape and contain nuclei with a vertically oriented cleft. The dendritic trees are arranged vertically and often extend through five cortical layers. The axons are thin and extend either from the soma or from one of the primary dendrites. The axons also follow a vertical trajectory. Other VIP-positive neurons are modified bipolar cells and a few of them are multipolar cells. The synapses formed by the VIP-positive axon terminals in the neuropil are symmetric in form, and although the synaptic clefts are narrow, the junctions are usually long and continuous, rather like those described for asymmetric synapses. Most of the VIP-positive axon terminals synpase with small dendritic shafts, but a few synapse with neuronal cell bodies. Since the majority of the VIP-positive neurons are bipolar cells it is concluded that these are the source of most of the VIP-positive axon terminals. If this is so, then the VIP-positive bipolar cells form symmetric synapses. This is in contrast to the observations of Peters and Kimerer (1981. J. Neurocytol. 10, 921-946) for the bipolar cells they examined in a Golgi-electron microscopic study had axon terminals forming asymmetric synapses. It is suggested that this disparity can be reconciled if it is assumed that the bipolar cell population consists of subgroups which have different biochemical characteristics and different synaptic relationships.     

VIP调节LPS激活的树突状细胞免疫功能

目的 研究神经肽VIP能否调节LPS激活的树突状细胞(DC)的免疫功能.方法 联合应用rm GM-CSF和rmIL-4自C57BL/10.A小鼠骨髓细胞制备DC;以LPS和/或VIP刺激DC;收集DC及其上清夜行ELISA分析;自DC提取总RNA行RNAse分析.结果 VIP明显抑制LPS激活的DC分泌细胞因子IL-2、IL-12和TNF-α,但对IL-6的抑制作用则不明显;VIP明显抑制LPS激活的DC表达化学因子MIP-2和-10,但对化学因子Rantes、MIP-1α和MIP-β的抑制作用并不明显.结论 VIP对LPS激活的DC的免疫功能有负性调节作用.     

Vasoactive intestinal peptide suppresses macrophage‐mediated inflammation by downregulating interleukin‐17A expression via PKA‐ and PKC‐dependent pathways

Interleukin (IL)‐17A is a pro‐inflammatory cytokine that markedly enhances inflammatory responses in the lungs by recruiting neutrophils and interacting with other pro‐inflammatory mediators. Reducing the expression of IL‐17A could attenuate inflammation in the lungs. However, whether VIP exerts its anti‐inflammatory effects by regulating the expression of IL‐17A has remained unclear. Here, we show that there is a remarkable increase of IL‐17A in bronchoalveolar lavage fluid (BALF) and lung tissue of mice with acute lung injury (ALI). Moreover, lipopolysaccharides (LPS) stimulated elevated expression of IL‐17A, which was evident by the enhanced levels of mRNA and protein observed. Furthermore, we also found that VIP inhibited LPS‐mediated IL‐17A expression in a time‐ and dose‐dependent manner in an in vitro model of ALI and that this process might be mediated via the phosphokinase A (PKA) and phosphokinase C (PKC) pathways. Taken together, our results demonstrated that VIP might be an effective protector during ALI by suppressing IL‐17A expression.     

Activation of the hyperpolarization-activated current (if) in sino-atrial node myocytes of the rabbit by vasoactive intestinal peptide

Vasoactive intestinal peptide (VIP) is a putative neurotransmitter found in extrinsic and intrinsic nerves of the heart. VIP can be released by vagal stimulation but, contrary to ACh, causes positive chronotropic effects as a result of binding to cardiac receptors which stimulate adenylate cyclase, and thus has been implicated in vagal tachycardias. Since the rate of diastolic depolarization of sinoatrial (SA) node myocytes depends on the hyperpolarization-activated current (i_f), which is directly activated by cytoplasmic cAMP, we studied the action of VIP on i f in myocytes isolated from the SA node of the rabbit. VIP (0.65 M) reversibly increased i_f at –65 mV but had no effect at –115 mV suggesting that its primary effect was to shift the activation curve to more positive voltages. Hyperpolarizing ramp and voltage compensation protocols indicated that VIP shifts the activation curve of i_f by approximately 5–6 mV in the positive direction with no change in maximal conductance. This shift may be the mechanism by which VIP produces its positive chronotropic effect and supports a negative feedback role for this peptide during elevated vagal activity.     

血管活性肠肽在MPTP帕金森病模型小鼠的抗氧化应激作用

目的:研究血管活性肠肽(VIP)对1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的帕金森病(PD)模型小鼠发挥抗氧化应激和神经保护作用。方法:雄性C57BL/6J小鼠随机分为生理盐水(NS)组、MPTP组和MPTP+VIP组。Elisa法检测纹状体丙二醛(MDA)以及超氧化物歧化酶(SOD)、过氧化氢酶(CAT)的变化;免疫组织化学法观察中脑黑质纹状体系统酪氨酸羟化酶(TH)、星形胶质细胞特异性标记物胶质细胞纤维酸性蛋白(GFAP)和小胶质细胞标志物离子钙结合蛋白(Iba-1)的表达变化;透射电子显微镜观察中脑黑质多巴胺能神经元的超微结构变化。结果:MPTP组与对照组相比,MDA水平显著增高,SOD和CAT的表达显著降低;给予VIP可显著抑制MDA的水平(P0.01),增强SOD和CAT的表达(P0.05)。与对照组相比,MPTP组小鼠GFAP和Iba-1的表达明显上升,TH表达明显下降;给予VIP可显著降低GFAP和Iba-1的表达(P0.05),而TH表达明显增强。透射电镜观察显示:NS组神经细胞和细胞器结构清晰完整;MPTP组神经细胞核膜内陷,线粒体空泡样变;MPTP+VIP组神经细胞和细胞器结构基本正常。结论:VIP能够抑制MPTP诱导PD小鼠中脑黑质星形胶质细胞和小胶质细胞的活化,对抗氧化应激,发挥神经保护作用。     

Developmental studies on vasoactive intestinal peptide,substance P and calcitonin gene-related peptide in salivary glands of postnatal rats

The development of vasoactive intestinal peptide, substance P and calcitonin gene-related peptide in parotid, submandibular and sublingual glands of the male rat was followed by immunochemistry and immunocytochemistry. The total amounts of these peptides increased in surges during the first 8 weeks of the animal's life; one within 2–4 weeks and the other beginning 1–2 weeks later. Nerve fibres containing these peptides were present at birth showing a pattern of distribution similar to that in adults. During the first 4 weeks the nerve fibres increased in number.     

Interaction of cholecystokinin with vasoactive intestinal peptide in body shaking response to ice-water immersion in rats

Interaction of cholecystokinin (CCK) with vasoactive intestinal peptide (VIP) in body shaking response to ice-water immersion was observed in pentobarbital-anesthetized rats. Although CCK itself had no influence on the response, VIP suppressed it and this effect of VIP was antagonized by simultaneous administration of sulfated octapeptide of CCK, but not by non-sulfated CCK.     

Atrial natriuretic peptide attenuates pressor but enhances natriuretic responses to angiotensin II in pregnant conscious goats

This study was designed to examine the actions of ANP in acute, ANGII-mediated hypertension during pregnancy. Effects on blood pressure, blood volume, and renal Na and K excretion were evaluated in conscious goats (n= 6). ANP (2 μrg min^-1), ANGII (0.5 μg min^-1), or ANGII + ANP (doses the same as for each peptide alone) was infused intravenously for 60 min. The pressor response to ANGII was reduced in pregnant goats. This reduction was seen in systolic, but not in diastolic pressure. ANP decreased pressure by 5–10 mmHg both in pregnancy and in non-pregnancy. When ANGII + ANP was infused, blood pressure initially rose as with ANGII but then declined. ANP suppressed only the elevated systolic pressure. Plasma protein concentration and haematocrit was reduced by ANGII but increased by ANP alone or together with ANGII, thereby implying fluid shift into the vasculature by ANGII and opposite movement by ANP. ANGII increased renal Na excretion to 1500 μmol min^-1in non-pregnancy, but only to half of that in pregnancy. ANP alone caused small natriuresis, but enhanced ANGII-induced natriuresis to near 3000 μmol min^-1in both non-pregnant and pregnant goats. In summary, ANP further attenuated the blunted blood-pressure rise due to ANGII in pregnant goats, and reduced plasma volume, but enhanced renal Na excretion as in non-pregnant goats. This implies that with the present combination ANP and ANGII caused a near maximal natriuretic response that was not modified by the systemic cardiovascular changes occurring in pregnant goats.     

Substance P and vasoactive intestinal peptide in serotonin-induced nasal secretions in normal subjects

The aim of this study was to examine if nasal secretions contained substance P and/or vasoactive intestinal peptide. Serotonin nasal challenge was performed in 14 normal subjects 15 min after intranasal pretreatment (double-blind) with atropine, methysergide, chlorpheniramine or isotonic saline. Serotonin induced a dose dependent increase in secretion (P less than 0.05), and only pretreatment with atropine reduced the secretion (P less than 0.02). Substance P, measured by radioimmunoassay, was found in all of the examined secretions (n = 100) with a median concentration of 13.7 pmol/l (range 1.7-125.0). Serotonin challenge increased the concentration or content of substance P in a dose-related fashion (P less than 0.01). The different pretreatments did not affect the concentration of substance P. Vasoactive intestinal peptide was found in low concentration in 37% of the secretions with a median concentration of 0 pmol/l (range 0-50.0).     

肠血管活性多肽或生长抑素抑制大鼠肠CD8~+淋巴细胞归巢

为观察肠血管活性多肽 (VIP )及生长抑素 (SST )对大鼠肠淋巴细胞在肠相关淋巴组织归巢的影响 ,本实验将 18只大鼠随机分为三组 ,每组 6只 ,分别从股静脉输入生理盐水、VIP组或SST ,从肠系膜淋巴管插管引流淋巴液。结果显示 ,大鼠经静滴VIP或SST后 ,5h内肠系膜淋巴管淋巴细胞总数降低 (P <0 0 5 ) ;肠淋巴液量和对照组比较无显著改变 (P >0 0 5 ) ;每毫升淋巴液中细胞数降低 (P <0 0 5 )。VIP组和SST组肠淋巴液中CD8+ 细胞比例降低 (P <0 0 5 )。两实验组回肠粘膜CD8+ 细胞数降低 (P <0 0 5 )。VIP或SST能减少肠粘膜CD8+ 淋巴细胞与其他器官及系统免疫的沟通 ,也抑制从其他器官及系统免疫中归巢至肠粘膜的CD8+ 细胞     

胎儿小肠生长抑素、胃泌素及血管活性肠肽免疫反应细胞的个体发生

目的：探讨生长抑素（SS）、胃泌素（Gas）、血管活性肠肽（VIP）免疫反应（IR）细胞在胎儿小肠中的个体发生及其分布。方法：免疫组织化学方法和图像分析技术。结果：SS-IR细胞和Gas-IR细胞于11周即可见于小肠三段绒毛上皮和尚未分化完全的肠腺细胞间。随着胎龄增长,SS-IR细胞数量和细胞内SS由少至多,其中以十二指肠细胞最多,回肠最少。Gas-IR细胞和细胞内的Gas在十二指肠中随胎龄增长逐渐增多;21周后空肠中则有所减少,回肠中则消失。VIP-IR细胞数量少,整个胎期细胞数量、形态及免疫染色强度均未见明显变化。结论：SS、Gas和VIP在胎儿小肠的内分泌细胞中表达,提示内分泌激素在胎儿小肠的发育过程中起调节作用。