Local effect of vasoactive intestinal polypeptide on human sweat-gland function

Physiological significance of vasoactive intestinal polypeptide (VIP), a putative co-transmitter of the cholinergic neuron innervating sweat glands, was investigated by its local effect on drug-induced sweating. VIP, methacholine chloride (MCH), or VIP plus MCH dissolved in 0.1 ml of 0.9% NaCl solution to a specified concentration was injected intradermally at the center of a forearm test area of 15 cm2 and the sweat rate was recorded continuously by capacitance hygrometry. In a cool environment (Ta, 23 degrees C), VIP failed to cause sweat secretion, but increased the rate of MCH-induced sweating, most markedly at a concentration of 10(-5) g/ml, where the rise in local skin temperature was the greatest. On an area anesthetized by nerve block in a hot environment (Ta, 35 degrees C), the effect was less obvious and less consistent, indicating that the sweat-facilitatory effect of VIP is reduced under the condition of passive cutaneous vasodilation. It may be postulated that VIP plays a role in securing ample oxygen supply to functioning sweat glands, especially with a relatively high cutaneous vasoconstrictor tone.     

Distribution of vasoactive intestinal polypeptide in the rat and mouse brain.

The distribution of cell bodies and nerve fibers that combine with antisera to vasoactive intestinal polypeptide (VIP) was studied by immunohistochemistry in combination with radioimmunoassay in the brain of rat and mouse. The highest concentrations (60pmol/g wet wt) of immuno-reactive VIP were found in the cerebral cortex and in certain limbic structures, whereas the concentrations in the basal ganglia, thalamus, lower brain stem, cerebellum and spinal cord were low (<15pmol/g). VIP-immunoreactive cell bodies were found mainly in the cerebral cortex and the limbic system, with the great majority of them in neo- and allocortical areas. In the neocortex the VIP-containing cell bodies were found in layers II-V in all areas. The cells were fusiform or stellate shaped, resembling intracortical and corticocortical association neurones. In the pyriform and entorhinal cortex the cell bodies were located mainly in layer II. In the hippocampal complex VIP-containing cell bodies occurred in both the subiculum, areas CA1 and CA3 and the dentate gyrus. Most of the cells had the appearance of interneurones, some of them probably being identical with basket cells. Of subcortical areas, the amygdala had the largest number of VIP-containing cell bodies; they were numerous in all amygdaloid nuclei except in the central nucleus. Non-cortical areas where there were cell bodies containing VIP included the anterior olfactory nuclei, the bed nucleus of stria terminalis, lateral septum, suprachiasmatic nucleus, superior colliculus, and the mesencephalic periaqueductal gray.VIP-immunoreactive fibres had a distribution which on the whole paralleled that of the cell bodies, suggesting that many of the VIP-containing cells project locally. VIP-containing fibres were numerous in the following areas: the entire neocortex, the pyrifom cortex, the entorhinal cortex, the hippocampal complex, the amygdala (the central nucleus in particular), the anterior olfactory nuclei, the nucleus accumbens, ventral pallidum, bed nucleus of stria terminalis, suprachiasmatic nucleus, medial preoptic nucleus, median eminence, lateral geniculate body, pretectum, superior colliculus, periaqueductal gray, and the lateral parabrachial nucleus. Only few, scattered fibres were seen in other parts of the brain stem, in the striatum, thalamus and spinal cord. The cerebellum was devoid of VIP-containing fibres. VIP-containing neurones seem to form predominantly local projections. In addition, some VIP-containing neurones probably also form long projections, such as descending and transcallosal projections from the cortical cells, and projections from the amygdala to preoptic, hypothalamic and basal forebrain areas.The characteristic telencephalic distribution of the neurones that contain VIP suggests a role for this peptide in cortical and limbic functions.     

Effect of vasoactive intestinal polypeptide on glycogen metabolism in rat hepatocytes

The effects of vasoactive intestinal polypeptide (VIP) on several enzymes of glycogen metabolism in rat hepatocytes were compared with those of glucagon and of vasopressin (ADH). VIP caused phosphorylase activation and glycogenolysis in hepatocytes from fed rats. In hepatocytes from fasted rats incubated with glucose, lactate, and pyruvate, VIP inhibited net glycogen deposition, inactivated glycogen synthase, and activated phosphorylase. VIP was about 100-fold less potent than glucagon and 1,000-fold less potent than ADH in causing activation of phosphorylase. The ability of VIP to activate phosphorylase was not altered by chelation of the calcium in the medium. The half maximal effective doses of VIP for both phosphorylase activation and stimulation of glycogenolysis were 10-30 nM. Treatment with VIP, ADH, or glucagon did not decrease phosphorylase phosphatase activity. Each of these hormones, however, lengthened the lag time before synthase phosphatase activity was expressed in vitro. Other gut hormones tested did not affect hepatocyte glycogen metabolism. These results do not support the concept of physiologic control of hepatic glycogen metabolism by VIP or by other gut hormones.     

Efffect of vasoactive intestinal polypeptide on gallbladder smooth muscle in vitro

The effect of vasoactive intestinal polypeptide (VIP) on basal and octapeptide of cholecystokinin (OP-CCK) induced tension was examined with guinea pig gallbladder smooth muscle strips in vitro. VIP alone produced dose-related decreases in resting tension and antagonized spontaneous contractile activity where present. In combination with OP-CCK, VIP decreased the expected contractile respone. The degree of antagonism depended upon the concentrations of OP-CCK and VIP. VIP had no effect on acetylcholine-induced contractions. From these observations, we propose that VIP can affect gallbladder motor activity by decreaseing smooth muscle tone and by antagonizing cholecystokinin. These findings lend further support to our proposal that gallbladder motor function may depend upon the action and interaction of the gastrointestinal hormones.     

Down-regulation of vasoactive intestinal polypeptide receptor expression in atopic dermatitis

BACKGROUND: Receptors for vasoactive intestinal polypeptide (VIP) have recently been suggested to play a key role in immunomodulation with genetically modified mice. However, it is not known whether changes in receptor gene regulation are involved in the pathogenesis of human immune disorders. OBJECTIVE: We studied the expression of VPAC(2) in acute lesions of the human immune disease atopic dermatitis. METHODS: By using nonradioactive in situ hybridization, quantitative immunohistochemistry, RT-PCR, and gene array studies, the expression status of VPAC(2) was assessed in atopic dermatitis and control tissues and in the human mast cell line HMC-1. RESULTS: In situ hybridization and immunohistochemistry demonstrated VPAC(2) mRNA and protein expression in human mast cells surrounded by VIP positive nerve fibers. Gene array experiments and RT-PCR studies showed high levels of VPAC(2) mRNA expression in mast cells that were increased compared to other receptors such as VPAC(1) or VIP in the human mast cell line HMC-1. Stimulation of HMC-1 cells led to a downregulation of VPAC(2). Similarly, quantitative immunohistochemistry for VPAC(2) in acute atopic dermatitis lesions showed a significantly decreased VPAC(2) immunoreactivity in mast cells. CONCLUSION: The downregulation of VPAC(2) in human mast cells in acute lesions of atopic dermatitis suggests a role of this G-protein;coupled receptor in the pathophysiology of the disease.     

Effect of vasoactive intestinal polypeptide on cerebral blood flow in the goat

The effect of vasoactive intestinal polypeptide (VIP) on the cerebral blood flow was investigated in the goat. An electromagnetic flow probe was placed around the internal maxillary artery for continuous measurement of ipsilateral blood flow. Intraarterial injection of VIP resulted in a dose-dependent increase in the cerebral blood flow. The effect was not antagonized by any of the antagonists atropine, propranolol, phentolamine and naloxone administered intraarterially 1 min before VIP. It is discussed that VIP may play a physiological role in the local blood flow regulation in the CNS.     

Unique pattern of cleavage of vasoactive intestinal peptide by human lymphocytes.

Human cultured T lymphocytes of the Jurkat line and myeloma cells of the U266 line cleaved the 28 amino acid vasoactive intestinal peptide (VIP1-28) preferentially at three sites with time- and temperature-dependence. The fragments VIP4-28 and VIP23-28) from an endopeptidase activity, and VIP15-28 from a trypsin-like peptidase, together represented a range of 26-65% of the VIP1-28 recovered after 2 hr at 37 degrees C or 4 hr at 22 degrees C, based on the absorbance of purified peptides and the radioactivity of [125I]Tyr10 VIP1-28. The endopeptidase activity was associated with membranes recovered after disruption of U266 cells by nitrogen cavitation. Pretreatment of intact U266 and Jurkat cells with diisopropylfluorophosphate (DFP) and the subsequently isolated subcellular particles with phenylmethylsulphonylfluoride (PMSF) and leupeptin inhibited the trypsin-like enzyme by a mean of 80%, without suppressing endopeptidase activity. In contrast, 0.1 mM DL-thiorphan and phosphoramidon blocked selectively a range of 35-70% of the endopeptidase activity in membrane preparations and intact cells. The capacity of lymphocytes to degrade VIP1-28 may substantially alter the effects of this neuromediator on functions of some subsets of T and B cells.     

Production of secretory diarrhea by intravenous infusion of vasoactive intestinal polypeptide

We attempted to reproduce the diarrhea of pancreatic cholera syndrome with prolonged (10-hour) administration of vasoactive intestinal polypeptide (VIP) in five healthy nonfasting subjects. The polypeptide was given as a continuous intravenous infusion at a rate of 400 pmol per kilogram of body weight per hour. By two hours the plasma VIP concentration had risen from a normal basal value of 15.3 +/- 0.2 (mean +/- S.E.M.) to 129 +/- 40 pmol per liter--within the range found in patients with pancreatic cholera syndrome. In each subject profuse watery diarrhea developed within 4.3 +/- 0.8 hours (range, 2.0 to 6.3), and the mean stool weight at 10 hours was 2441 +/- 600 g (normal 24-hour stool weight, less than 200 to 250 g). The results of stool analysis were consistent with secretory diarrhea. Between the first and last stool, there were significant increases in fecal sodium and bicarbonate concentrations and in pH. The large fecal bicarbonate loss induced hyperchloremic metabolic acidosis, which is characteristic in patients with pancreatic cholera syndrome. Our study suggests that VIP is not merely a marker of pancreatic cholera, but is the mediator of watery diarrhea in this syndrome.     

The significance of vasoactive intestinal polypeptide (VIP) in immunomodulation

Evidence for VIP influences on immune function comes from studies demonstrating VIP-ir nerves in lymphoid organs in intimate anatomical association with elements of the immune system, the presence of high-affinity receptors for VIP, and functional studies where VIP influences a variety of immune responses. Anatomical studies that examine the relationship between VIP-containing nerves and subpopulations of immune effector cells provide evidence for potential target cells. Additionally, the presence of VIP in cells of the immune system that also possess VIP receptors implies an autocrine function for VIP. The functional significance of VIP effects on the immune system lies in its ability to help coordinate a complex array of cellular and subcellular events, including events that occur in lymphoid compartments, and in musculature and intramural blood circulation. Clearly, from the work described in this chapter, the modulatory role of VIP in immune regulation is not well understood. The pathways through which VIP can exert an immunoregulatory role are complex and highly sensitive to physiological conditions, emphasizing the importance of in vivo studies. Intracellular events following activation of VIP receptors also are not well elucidated. There is additional evidence to suggest that some of the effects of VIP on cells of the immune system are not mediated through binding of VIP to its receptor.Despite our lack of knowledge regarding VIP immune regulation, the evidence is overwhelming that VIP can interact directly with lymphocytes and accessory cells, resulting in most cases, but not always in cAMP generation within these cells, and a subsequent cascade of intracellular events that alter effector cell function. VIP appears to modulate maturation of specific populations of effector cells, T cell recognition, antibody production, and homing capabilities. These effects of VIP are tissue-specific and are probably dependent on the resident cell populations within the lymphoid tissue and the surrounding microenvironment. Different microenvironments within the same lymphoid tissue may influence the modulatory role of VIP also. Effects of VIP on immune function may result from indirect effects on secretory cells, endothelial cells, and smooth muscle cells in blood vessels, ducts, and respiratory airways. Influences of VIP on immune function also may vary depending on the presence of other signal molecules, such that VIP alone will have no effect on a target cell by itself, but may greatly potentiate or inhibit the effects of other hormones, transmitters, or cytokines. The activational state of target cells may influence VIP receptor expression in these cells, and therefore, may determine whether VIP can influence target cell activity.Several reports described in this chapter also indicate that VIP contained in neural compartments is involved in the pathophysiology of several disease states in the gut and lung. Release of inflammatory mediators by cells of the immune system may destroy VIP-containing nerves in inflammatory bowel disease and in asthma. Loss of VIPergic nerves in these disease states appears to further exacerbate the inflammatory response. These studies indicate that altered VIP concentration can have significant consequences in terms of health and disease. In addition, the protective effects of VIP from tissue damage associated with inflammatory processes described in the lung also may be applicable to other pathological conditions such as rheumatoid arthritis, anaphylaxis, and the swelling and edema seen in the brain following head trauma. While VIP degrades rapidly, synthetic VIP-like drugs may be developed that interact with VIP receptors and have similar protective effects. Synthetic VIP-like agents also may be useful in treating neuroendocrine disorders associated with dysregulation of the hypothalamic—pituitary—adrenal axis, and pituitary release of prolactin.     

Primary duodenal small-cell neuroendocrine carcinoma with production of vasoactive intestinal polypeptide

A primary duodenal small-cell neuroendocrine carcinoma was found in an elderly man who presented with upper abdominal pain. Although metastatic small-cell carcinoma was documented by liver biopsy, the primary lesion was not identified until postmortem examination. The latter tumor, which ulcerated the duodenal mucosa, was composed of small ovoid cells with sparse cytoplasm and granular chromatin. Electron microscopy revealed cytoplasmic dense-core granules. Immunocytochemical study demonstrated the presence of neuron-specific enolase, Leu 7 antigen, chromogranin, epithelial membrane antigen, and vasoactive intestinal polypeptide within tumor cells. However, there was no evidence of a clinical endocrinopathy. This case emphasizes the need to include the duodenum as a possible primary site when metastatic small-cell neuroendocrine carcinoma is seen in the absence of apparent pulmonary disease.     

正常关节软骨和骨关节炎关节软骨细胞中血管活性肠肽表达的比较

背景：神经肽的发现给骨关节炎的治疗带来了新的希望,但神经肽的表达与骨关节炎发病以及软骨退变程度的关系尚不清楚。 目的：观察血管活性肠肽在正常关节软骨和不同退变程度骨关节炎软骨中的表达,以及血管活性肠肽表达与骨关节炎发病及软骨退变程度的关系。 方法：选取2007-03/11中南大学湘雅医院骨科进行关节置换的骨关节炎患者的关节软骨标本26个,选取因外伤行截肢的膝关节软骨或股骨颈暴力骨折的股骨头正常关节软骨标本10个为对照,根据大体观察凿取正常和骨关节炎不同退变程度软骨块50个,再根据关节软骨改良Mankin病理评分法进行分组,采用免疫组织化学染色检测软骨组织中血管活性肠肽的表达和分布。 结果与结论：各关节软骨中均可见到血管活性肠肽阳性神经纤维,正常关节软骨中血管活性肠肽的表达明显高于骨关节炎关节软骨(P < 0.05)。且血管活性肠肽表达与软骨改良Mankin病理评分呈负相关(r=-0.896,P < 0.05)。说明血管活性肠肽低表达与关节软骨退变程度、骨关节炎病程进展有关,可能是关节软骨退变、骨关节炎发病的机制之一。     

Fasting and prolonged exercise increase vasoactive intestinal polypeptide (VIP) in plasma.

6 young men had venous blood drawn during 4 experiments. The concentration of VIP in plasma increased markedly (from 1.8 (0--4.5) to 22.3 (7.8--43.8) pmol.1(-1), mean and range) during 3 h of mild bicycle exercise but not at all during an equivalent period of rest or during short term submaximal and maximal exercise. During 59 h of fasting, VIP increased from 3.6 (0.6--6.6) to 10.2 (6.6--13.8) pmol.1(-1) (p less than 0.05). The concentration of glucose in plasma decreased significantly during the prolonged exercise as well as during fasting. The known metabolic actions of VIP and the demonstrated increases in its plasma concentration during negative energy balance indicate that VIP is "a polypeptide of substrate need".     

Effect of intraventricular administration of vasoactive intestinal polypeptide on body temperature in the rat

Intracerebroventricular injection of vasoactive intestinal polypeptide (VIP) into rat caused a temporary elevation of body temperature followed by a decrease to below the control level. Hypothermia induced by cholecystokinin octapeptide was abolished by simultaneous administration of VIP. Hypothermia following pentobarbital administration was reduced by successive injections of VIP. The results suggest that multiple interactions of neuropeptides are involved in central thermoregulation.     

Localization and release of immunoreactive vasoactive intestinal polypeptide in bovine adrenal medulla

The concentration of immunoreactive (IR) vasoactive intestinal polypeptide (VIP) in extracts from bovine adrenal medulla was 29.9 +/- 7.2 pmol/g wet wt., which was about 100 times that of IR neurotensin and 30 times that of IR somatostatin. Chromatographic analysis showed that most of the IR-VIP was the same molecular size as synthetic VIP(1-28). On retrograde perfusion of isolated bovine adrenal gland, release of VIP with catecholamine (CA) was marked on stimulation with high K+, but slight on stimulation with acetylcholine, which induced marked release of CA. These results suggest that most of the VIP is localized not in CA storing granules in chromaffin cells, but in other intraadrenal neuronal components. In immunohistochemical studies, IR VIP fibers with large varicosities were observed around the vessels in the adrenal medulla.     

Effect of cholecystokinin octapeptide and vasoactive intestinal polypeptide on adrenocortical secretion in the rat

Intraperitoneal (i.p.) injection of C-terminal octapeptide of cholecystokinin (CCK-8) produced a dose-related increase in plasma corticosterone levels in intact rats, but not in vagotomized ones. Intracerebroventricular (i.c.v.) injection of CCK-8 was ineffective in stimulating the secretion of corticosterone, and in vitro experiment on ACTH release indicated that CCK-8 could not affect pituitary tissue directly. Since i.p. injection of non-sulfated CCK-8 failed to elevate plasma corticosterone levels, sulfated tyrosine residue in the CCK molecule is assumed to be indispensable for the stimulation of visceral organs. On the other hand, vasoactive intestinal polypeptide (VIP) was found to cause a dose-dependent increase in plasma corticosterone levels when administered centrally, but not after i.p. injection. However, VIP could not stimulate the release of ACTH from the pituitary tissue directly. The results suggest that VIP, but not CCK, stimulates the hypothalamic CRF neurons either directly or indirectly.     

A long ascending projection in the rat brain containing vasoactive intestinal polypeptide

The effects of knife cut lesions of the medial forebrain bundle on the distribution of forebrain vasoactive intestinal polypeptide (VIP)-like immunoreactivity (VIP-LI) in the rat has been studied with radioimmunoassay and immunocytochemistry. The extent of depletion of tyrosine hydroxylase activity from corpus striatum was used to monitor lesion efficiency. Medial forebrain bundle lesions produced substantial depletions of VIP-LI from nucleus accumbens, hypothalamus, amygdala and bed nucleus of the stria terminalis ipsilateral to the lesion. No changes were seen in frontal cortex, olfactory tubercle, striatum and hippocampus. Possible origins of this long ascending projection, including an extensive group of cell bodies containing VIP-LI in the mesencephalic central grey matter, are discussed.     

Developmental changes in vasoactive intestinal polypeptide immunoreactivity in the human paravertebral ganglia

Vasoactive intestinal polypeptide (VIP) belongs to the glucagon-secretin family of polypeptides and possesses numerous functions. Its existence in the mammalian central and peripheral nervous system has been widely documented. However, there are no reports on the developmental aspects of VIP-like immunoreactivity (VIP-IR) in the human postganglionic sympathetic neurons. In this study the availability and distribution of vasoactive intestinal polypeptide has been localized in human stellate ganglia neurons and nerve fibers from neonates, children and adults using the immunohistochemical method. In neonatal ganglia VIP-immunoreactive postganglionic neurons were revealed in a marked population compared to others age-groups. These nerve cells are both small and large in size and are distributed in small clusters or singly in the area of ganglia sections. In children, VIP-IR in ganglionic neurons decreases. In adult stellate ganglia, VIP-immunoreactive postganglionic neurons rarely occur. In ganglia of an individual human only varicosities of VIP-positive nerve fibers were observed. These results provide the age-dependent reduction of VIP-like immunoreactivity in human stellate ganglia neurons and suggest the different role of this peptide in the function of sympathetic ganglia neurons with age.     

Radioimmunologic localization of vasoactive intestinal polypeptide in hypothalamic and extrahypothalamic sites in the rat brain.

Using a specific radioimmunoassay (RIA), we have quantitated the hypothalamic and extrahypothalamic distribution of vasoactive intestinal polypeptide (VIP) in the rat brain. Highest concentrations of VIP were found in cerebral cortex, suprachiasmatic nucleus, and medial amygdaloid nucleus. Lower concentrations were found in the anterior hypothalamic area, medial preoptic area, peri- and paraventricular nuclei, and hippocampus. Significant levels of VIP were also found in the anterior pituitary. Very little VIP was detected in median eminence and cerebellar cortex. This distribution of VIP in areas of the rat brain known to be important to neuroendocrine function suggests a role for VIP in the control of anterior pituitary events.     

Melatonin potentiates cyclic AMP production stimulated by vasoactive intestinal peptide in human lymphocytes.

The present paper demonstrates the effect of melatonin on cyclic AMP production in human lymphocytes from peripheral blood. Melatonin by itself did not influence cyclic AMP accumulation in these cells at any dose studied; however, the drug potentiated the effect of vasoactive intestinal peptide (VIP) on the cyclic nucleotide production. In the presence of physiological concentrations of VIP (either 1, 10 or 100 pM), melatonin potentiated cyclic AMP production. However, at high doses of VIP (either 1, 10 or 100 nM), melatonin exhibited no such effect. The results suggest that human lymphocytes are a target for melatonin and that it may participate, jointly with VIP, in the regulation of immune function.