Vasoactive intestinal polypeptide biologic role in health and disease.

Vasoactive intestinal polypeptide (VIP), a neuropeptide with wide distribution in the central and peripheral nervous systems, has a broad spectrum of biologic actions. Usually acting as a neurotransmitter or neuromodulator but sometimes also as a blood-borne hormone, it participates in the regulation of a variety of major body functions and may be an important factor in the pathogenesis of several diseases.     

Vasoactive intestinal polypeptide in obesity

Twenty-six patients who were more than 35 per cent above their ideal weight were examined before the introduction of a weight reduction programme. At the end of a three-month period, seven patients had lost more than 10 per cent of their body weight. These patients had significantly lower triglyceride levels, fasting gastric inhibitory polypeptide levels (GIP) and prolactin levels. Fasting vasoactive intestinal polypeptide levels (VIP) before commencing diet were raised in six of the 19 patients who subsequently did not lose weight whereas the seven patients who lost weight had normal VIP levels (X2 = 3.07, P less than 0.05). Patients with high VIP levels had higher triglyceride levels, higher mean C-terminal glucagon-like immunoreactivity (C-GLI) and higher post glucose infusion secretin levels. There was a significant correlation between triglycerides and VIP. The significance of abnormally high VIP levels in obesity and the inability of these patients to lose weight is discussed.     

Vasoactive intestinal polypeptide: measurement, distribution and putative neurotransmitter function.

Vasoactive intestinal polypeptide (VIP) is a highly basic octacosapeptide isolated from porcine small intestine. VIP was originally considered to be a gut hormone, but radioimmunochemical and immunohistochemical studies have revealed that VIP has a widespread distribution localized in neurons. VIP-containing neurons are present in the central nervous system including the cerebral arteries, the digestive tract, the genitourinary tract and the adrenal glands. In the nerve terminals VIP is localized in synaptic vesicles. VIP fulfils a number of criteria to be a neurotransmitter both in central and peripheral nerves. Whilst the role of VIP in the central nervous system is unknown, it is likely that VIP is the mediator of gastrointestinal and pancreatic functions, which are controlled by non-cholinergic, non-adrenergic nerve fibres.     

Vasoactive intestinal peptide (VIP) protects against acid-induced acute lung injury in isolated perfused rat lungs

Acute, diffuse lung injury, the principal lesion in ARDS, is often refractory to treatment. Recently, pretreatment with several pulmonary vasodilators that increase cAMP levels: isoproterenol, terbutaline, theophylline, and prostacyclin, was found to reduce the severity of lung injury in animal models. We have investigated the possible modulation of HCl-induced pulmonary edema in rats by VIP, a lung neuropeptide with potent vasodilator and cAMP-producing properties. The lungs of rats were perfused in situ at 10 ml/min with Krebs-4% albumin solution, and ventilated at constant tidal volume (6.5 ml/kg). Peak airway pressure (PAW), mean pulmonary arterial pressure (PPA) were measured throughout the experiment, and wet to dry lung weight ratio (W/D), afterwards. All animals were observed for one hour. In 6 rats receiving HCl only, 0.2 N-HCl was instilled intratracheally at 2 ml/kg. Four rats received 2 ml/kg of physiological saline intratracheally as control. In 6 other animals, VIP was infused into the pulmonary artery at 1 micrograms/kg/min, beginning 10 minutes before HCl and for the rest of the experiment. Another 6 rats were pretreated with atrial natriuretic peptide (ANP, atriopeptin II) just like the VIP group. Lungs of saline control animals showed little or no chage in PAW or PPA. With HCl alone, PAW increased immediately and continued to rise for the rest of the hour, reaching 500% of basal value at 30 minutes. PPA increased by 68% and W/D by 74% compared to saline-instilled lungs. In the VIP + HCl group, all abnormalities were significantly reduced relative to the HCl group. The rise in PAW was attenuated by 79% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasoactive intestinal polypeptide levels in sigmoid colon in idiopathic constipation and diverticular disease.

The distribution in the bowel wall of vasoactive intestinal polypeptide-, neuropeptide Y-, and substance P-containing nerve cell bodies and nerve fibers has been described in human sigmoid colon by immunohistochemical examination. In patients with chronic idiopathic constipation, diverticular disease, and in controls (of tissue taken from patients with carcinoma, from a site distant from the tumor that appeared macroscopically normal), the concentrations of vasoactive intestinal polypeptide, neuropeptide Y, and substance P have been measured by immunoassay in the following preparations of sigmoid colon: mucosa, whole colonic wall with mucosa dissected away, circular muscle, and taenia coli. In idiopathic constipation, the vasoactive intestinal polypeptide content of the whole wall minus mucosa was reduced when compared with controls (P less than 0.05) but was unaltered in the mucosa, circular muscle, and taenia coli. In diverticular disease, the vasoactive intestinal polypeptide content of the mucosa and whole wall minus the mucosal layer was increased when compared with control tissue (P less than 0.05 and P less than 0.02, respectively) but was unaltered in the circular muscle and taenia coli. Substance P and neuropeptide Y levels in all layers of colonic wall were unaltered in these two diseases. The disturbances in the normal neural content of vasoactive intestinal polypeptide in the bowel wall in idiopathic constipation and diverticular disease may initiate or contribute to the functional changes seen in these disorders.     

Localization of vasoactive intestinal polypeptide (VIP) to central and peripheral neurons.

The localization of the vasoactive intestinal polypeptide (VIP) has been studied with immunohistochemistry and radioimmunoanalysis. VIP immunoreactivity is present in gastrointestinal nerves, which constitute a quantitatively important nerve population that may be intrinsic to the gut wall. VIP-immunoreactive neurons are also found within the ventromedial hypothalamus and give off processes that travel latteral to the third ventricle. Results of radioimmunoanalysis strongly indicate that the immunoreactive material represents true VIP. Thus VIP, at present a gastrointestinal hormone candidate, appears to represent a new neuronal peptide occurring in both the central and peripheral nervous system.     

Vasoactive intestinal polypeptide as mediator of asthma

Vasoactive intestinal polypeptide (VIP) is one of the most abundant, biologically active peptides found in the human lung. VIP is a likely neurotransmitter or neuromodulator of the inhibitory non-adrenergic non-cholinergic airway nervous system and influences many aspects of pulmonary biology. In human airways VIP-immunoreactive nerve fibres are present in the tracheobronchial airway smooth muscle layer, the walls of pulmonary and bronchial vessels and around submucosal glands. Next to its prominent bronchodilatory effects, VIP potently relaxes pulmonary vessels. The precise role of VIP in the pathogenesis of asthma is still uncertain. Although a therapy using the strong bronchodilatory effects of VIP would offer potential benefits, the rapid inactivation of the peptide by airway peptidases has prevented effective VIP-based drugs so far and non-peptide VIP-agonists did not reach clinical use.     

Vasoactive intestinal polypeptide is synthesized in anterior pituitary tissue

Previous studies have suggested that vasoactive intestinal polypeptide (VIP) is involved in regulation of PRL secretion within the pituitary gland. In order to determine whether VIP is synthesized in anterior pituitary tissue, we performed three experiments. In all experiments, anterior pituitaries were obtained from male rats. The tissue was then labeled by incubation in leucine-free minimum essential medium containing [3H]leucine, 14 microCi/ml. In Exp I, the labeled tissue was homogenized, centrifuged, and the supernatant was chromatographed on Sephadex G-50F. The fractions indicated a large peak of counts near the void volume and another peak coeluting with VIP. These latter fractions were pooled and subjected to reverse phase HPLC. Fractions from the HPLC indicated: a protein peak, VIP immunoreactivity, and maximum counts immunoprecipitated by anti-VIP serum at the retention time of synthetic porcine VIP. Exp II consisted of perifusion of labeled pituitary quarters over a 120-min period followed by an additional 60 min in the presence of 56 mM KCl. During this latter period of KCl depolarization, a large amount of 3H-labeled material was secreted. These fractions were then chromatographed on Sephadex G-50F, and the fractions coeluting with [125I]porcine VIP were subjected to immunoprecipitation with anti-VIP serum. In addition, all fractions from the Sephadex column were assayed for VIP, and the only activity was at the elution volume of [125I]porcine VIP. In Exp III, the pituitary labeling procedure included 3.6 X 10(-5) M cycloheximide. Subsequently, the tissue was perifused and the perifusate collected during the 60-min 56 mM KCl perifusion phase was pooled and immunoprecipitated with anti-VIP serum. No immunoprecipitable counts were obtained. These experiments indicate that anterior pituitary tissue synthesizes VIP on the basis of the HPLC profile and immunoprecipitation with specific anti-VIP antiserum. These results, in addition to other studies by our laboratory and others, suggest that intrapituitary VIP may be an important regulator of anterior pituitary hormone secretion, particularly PRL.     

Vasoactive intestinal peptide (VIP) induces transactivation of EGFR and HER2 in human breast cancer cells

We analyzed the cross-talk between receptors for vasoactive intestinal peptide (VIP) and the human epidermal growth factor family of tyrosine kinase receptors (HER) in oestrogen-dependent (T47D) and oestrogen-independent (MDA-MB-468) human breast cancer cells. VIP treatment slowly increased the expression levels of EGFR but it rapidly augmented phosphorylation of EGFR and HER2 in both cell lines. This pattern of HERs transactivation was blocked by the specific VIP antagonist JV-1-53, supporting the direct involvement of VIP receptors in formation of P-EGFR and P-HER2. VIP-induced transactivation was also abolished by H89 (protein kinase A inhibitor), PP2 (Src inhibitor) or TAPI-1 (inhibitor of matrix metalloproteases), following a differential pattern. These results shed a new light on the specific signalling pathways involved in EGFR/HER2 transactivation by VPAC receptors and suggest the potential usefulness of VIP receptor antagonists together with current antibodies against EGFR/HER2 and/or tyrosine kinase inhibitors for breast cancer therapy.     

Effects of vasoactive intestinal polypeptide (VIP) on lower esophageal sphincter in awake baboons

The effects of vasoactive intestinal polypeptide (VIP), glucagon, and secretin on lower esophageal sphincter pressure were investigated in awake baboons. The three hormones were compared with respect to effect on (1) resting lower esophageal sphincter pressure and (2) maximal stimulatory response to pentagastrin. VIP was shown to reduce resting and pentagastrin-stimulated lower esophageal sphincter pressure with significantly greater potency than either secretin or glucagon. For reduction of resting lower esophageal sphincter pressure, the potency ratio of VIP to secretin was 16:1 and of VIP to glucagon was 32:1 (P<0.05). For inhibition of pentagastrin-stimulated sphincter pressure, the potency ratio of VIP to secretin was 32:1 and of VIP to glucagon ws 64:1 (P<0.02). This demonstration of significantly increased potency of VIP over known inhibitory hormones strengthens the suggestion that VIP may have a physiologic role in the control of lower esophageal sphincter function.This paper was presented in part at the National Meeting of the American Federation for Clinical Research, San Francisco, California, May 1, 1978.The opinions or assertions contained herein are those of the authors and are not to be construed as reflecting the views of the Departments of the Army, Navy, or Department of Defense.     

Hypothyroidism increases vasoactive intestinal polypeptide (VIP) immunoreactivity and gene expression in the rat hypothalamic paraventricular nucleus.

Vasoactive intestinal polypeptide (VIP) is produced by neurons in the rat hypothalamic paraventricular nucleus (PVN) and may have an important role as a prolactin-releasing factor. Recent work from our laboratories has shown that thyroid hormone regulates the content of VIP and VIP mRNA in the rat anterior pituitary, but its effect on VIP in the PVN is not known. To determine whether thyroid hormone alters VIP biosynthesis in the PVN, we studied the effect of hypothyroidism on the content of immunoreactive (IR)-VIP and VIP mRNA in PVN neurons using histochemical techniques. By immunocytochemistry, only scattered IR-VIP fibers were present in the PVN of control animals whereas IR-VIP perikarya and fibers were present in hypothyroid rats. By in situ hybridization histochemistry, no labeled neurons were recognized in the PVN in control animals whereas PVN neurons were labeled in hypothyroid rats. These findings raise the possibility that hypothyroidism exerts negative feedback regulation on VIP-producing neurons in the PVN and suggest that this may be important to modulate the stimulatory effects of VIP on anterior and/or posterior pituitary function.     

Vasoactive intestinal polypeptide: specific binding to rat brain membranes.

The binding of radiolabeled vasoactive intestinal polypeptide (VIP) to rat brain membranes was investigated. Specific binding of 125I-labeled VIP was reversible and saturable (Bmax = 2.2 pmol/g of wet tissue). Brain membranes exhibited a high affinity for 125I-labeled VIP (KD = 1 nM) at a single class of noninteracting sites. Binding of 125I-labeled VIP paralleled its immunohistochemical localization, being enriched in cerebral cortex, hippocampus, striatum, and thalamus, with the notable exception of the hypothalamus, which had low levels of binding. The density of sites was greater in synaptosomal fractions relative to mitochondrial or nuclear fractions. Secretin and partial sequences of it and VIP inhibited binding to brain membranes with an order of potency similar to that found in other systems. The findings suggest the existence of a unique new class of brain receptors.