Infusion Of Vasoactive Intestinal Polypeptide Research Articles

Plasma Levels of CGRP During a 2-h Infusion of VIP in Healthy Volunteers and Patients With Migraine: An Exploratory Study

IntroductionThe activation of perivascular fibers and the consequent release of vasoactive peptides, including the vasoactive intestinal polypeptide (VIP), play a role in migraine pathogenesis. A 2-h infusion of VIP provoked migraine, but the mechanisms remain unknown. We investigated whether 2-h infusion of VIP caused alterations in plasma levels of the calcitonin gene-related peptide (CGRP) and whether any changes might be related to the induced migraine attacks.Materials and MethodsWe enrolled individuals with episodic migraine without aura and healthy participants to randomly receive a 2-h infusion of either VIP (8 pmol/kg/min) or placebo (sterile saline) in two randomized, placebo-controlled crossover trials. We collected clinical data and measured plasma levels of VIP and CGRP at fixed time points: at baseline (T0) and every 30 min until 180 min (T180) after the start of the infusion.ResultsBlood samples were collected from patients with migraine (n = 19) and healthy individuals (n = 12). During VIP infusion, mixed effects analysis revealed a significant increase in plasma CGRP (p = 0.027) at T30 (vs. T180, adjusted p-value = 0.039) and T60 (vs. T180, adjusted p-value = 0.027) in patients with migraine. We found no increase in plasma CGRP during VIP-induced migraine attacks (p = 0.219). In healthy individuals, there was no increase in plasma CGRP during VIP (p = 0.205) or placebo (p = 0.428) days.DiscussionPlasma CGRP was elevated in patients with migraine during a prolonged infusion of VIP, but these alterations were not associated with VIP-induced migraine attacks. Given the exploratory design of our study, further investigations are needed to clarify the role of CGRP in VIP-induced migraine.Clinical Trial RegistrationClinicalTrials.gov, identifier: NCT03989817 and NCT04260035.

Effect of Vasoactive Intestinal Polypeptide on Development of Migraine Headaches

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) are structurally and functionally related, yet different in their migraine-inducing properties. It remains unclear whether the lack of migraine induction can be attributed to the only transient vasodilatory response after a 20-minute infusion of VIP. To determine whether a 2-hour infusion of VIP would provoke migraine attacks. A randomized, double-blind, placebo-controlled, crossover study was conducted between May and September 2020 at the Danish Headache Center in Copenhagen, Denmark. Patients were eligible for inclusion if they were ages 18 to 40 years, weighed between 50 and 90 kg, had a diagnosis of migraine without aura as defined by the International Classification of Headache Disorders, and had a migraine frequency of 1 to 6 attacks per month. Patients were randomly allocated to receive a 2-hour infusion of VIP or placebo on 2 different days. The primary end point was the difference in incidence of experimentally induced migraine attacks during the observational period (0-12 hours) between VIP and placebo. Twenty-one patients (17 [81%] women and 4 [19%] men; mean [range] age, 25.9 [19-40] years) were recruited in the study. Fifteen patients (71%; 95% CI, 48%-89%) developed migraine attacks after VIP compared with 1 patient (5%; 95% CI, 0%-24%) who developed a migraine attack after placebo (P < .001). The VIP-induced migraine attacks mimicked patients' spontaneous attacks. The area under the curve (AUC) of headache intensity scores (0-12 hours), as well as the AUC of the superficial temporal artery diameter (0-180 minute) were significantly greater after VIP compared with placebo (AUC0-12h, P = .003; AUC0-180min, P < .001). A 2-hour infusion of VIP caused migraine attacks, suggesting an important role of VIP in migraine pathophysiology. VIP and its receptors could be potential targets for novel migraine drugs. ClinicalTrials.gov Identifier: NCT04260035.

Two-hour infusion of vasoactive intestinal polypeptide induces delayed headache and extracranial vasodilation in healthy volunteers.

In recent years, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptides (PACAPs) have gained special interest in headache science. VIP and PACAPs (two isoforms, PACAP27 and PACAP38) are related in structure and function, as are their receptors, but they show differences in vasodilating- and headache-inducing properties. Intravenous infusion of PACAP27 or PACAP38, but not VIP, induces a long-lasting dilation of cranial arteries and delayed headache. The relationship between the long-lasting cranial vasodilation and headache development is not fully clarified. In a double-blinded, placebo-controlled, crossover study in 12 healthy volunteers, diameter changes of cranial arteries, occurrence of headache and the parasympathetic system were examined before, during and after a 2-hour continuous intravenous infusion of VIP and placebo. Primary endpoints were the differences in area under the curve for the superficial temporal artery diameter and headache intensity scores, as well as in headache incidence, between VIP and placebo. The superficial temporal artery diameter was significantly larger on the VIP day compared to placebo (p < 0.001) and the dilation lasted for more than 2 h. The incidence of headache was higher (p = 0.003) on the VIP day compared to the placebo day. The difference in headache intensity scores was more evident in the post-infusion period (120-200 min, p = 0.034) and in the post-hospital phase (4-12 h, p = 0.025). Cranial parasympathetic activity, measured through the production of tears, was higher during VIP compared to placebo (p = 0.033). Continuous intravenous infusion of VIP over 2 h induced a long-lasting cranial vasodilation, activation of the cranial parasympathetic system, and delayed mild headaches in healthy volunteers.Trial Registration: The study is registered at ClinicalTrials.gov (NCT03989817).

Change in brain network connectivity during PACAP38-induced migraine attacks: A resting-state functional MRI study.

To investigate resting-state functional connectivity in the salience network (SN), the sensorimotor network (SMN), and the default mode network (DMN) during migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38 (PACAP38). In a double-blind, randomized study, 24 female migraine patients without aura received IV PACAP38 or vasoactive intestinal polypeptide (VIP) over 20 minutes. Both peptides are closely related and cause vasodilation, but only PACAP38 induces migraine attacks. VIP was therefore used as active placebo. Resting-state functional MRI was recorded before and during PACAP38-induced migraine attacks and before and after VIP infusion. We analyzed data by Statistical Parametric Mapping 8 and the Resting-State fMRI Data Analysis Toolkit for Matlab in a seed-based fashion. PACAP38 (n = 16) induced migraine attacks and increased connectivity with the bilateral opercular part of the inferior frontal gyrus in the SN. In SMN, there was increased connectivity with the right premotor cortex and decreased connectivity with the left visual cortex. Several areas showed increased (left primary auditory, secondary somatosensory, premotor, and visual cortices) and decreased (right cerebellum and left frontal lobe) connectivity with DMN. We found no resting-state network changes after VIP (n = 15). PACAP38-induced migraine attack is associated with altered connectivity of several large-scale functional networks of the brain.

Intravenous vasoactive intestinal polypeptide lowers pulmonary-to-systemic vascular resistance ratio in a neonatal piglet model of pulmonary arterial hypertension

Background Several studies of vasoactive intestinal polypeptide (VIP) demonstrated its potent vasodilative effects on pulmonary and systemic circulation. However, no hemodynamic studies were performed to depict the effects of VIP in an in vivo model of pulmonary arterial hypertension (PAH), thereby limiting a complete understanding of the overall hemodynamic effects of VIP in PAH. Methods and Results The pulmonary and systemic hemodynamic effects of intravenous infusion of 100 ng/kg per minute of VIP in control and pulmonary hypertensive piglets at 6 to 8 weeks of age were assessed. Pulmonary arterial hypertension was induced after the instillation of meconium solution in the subjects' trachea and was characterized by the establishment of a persistently elevated pulmonary arterial pressure, diminished cardiac output, and elevated pulmonary-to-systemic vascular resistance (PVR/SVR) ratio. Conclusions Continuous intravenous infusion of VIP markedly decreased PVR/SVR ratio in pulmonary hypertensive subjects; however, it lowered blood pressure without causing any significant changes in PVR/SVR ratio in control subjects. Collectively, these results suggest an overall pulmonary vasodilative effect of VIP in PAH.

Vasoactive Intestinal Polypeptide Evokes Only a Minimal Headache in Healthy Volunteers

The role of the parasympathetic nervous system in the pathogenesis of migraine is disputed. The headache-eliciting effect of the parasympathetic neurotransmitter, vasoactive intestinal polypeptide (VIP), and its effect on cerebral arteries and brain haemodynamics has not been systematically studied in man. We hypothesized that infusion of VIP might induce headache in healthy subjects and cause changes in cerebral haemodynamics. VIP (8 pmol/kg per min) or placebo (0.9% saline) was infused for 25 min into 12 healthy young volunteers in a crossover, double-blind design. Headache was scored on a verbal rating scale from 0 to 10, regional cerebral blood flow (rCBF) was measured with single-photon emission computed tomography and (133)Xe inhalation and mean flow velocity in the middle cerebral artery (V(meanMCA)) was measured with transcranial Doppler ultrasonography. The headache was very mild with a maximum score of 2 and described as a pressing or throbbing sensation. Five participants developed headache during VIP and one during placebo. During the infusion, a significant drop in V(meanMCA) was seen for VIP compared with placebo (P < 0.001), but the effect quickly waned and no difference was found when comparing the time between 30 and 120 min. In addition, no significant difference in the diameter of the MCA could be found during the infusion. No significant differences in rCBF (P = 0.10) were found between VIP and placebo. A marked dilation of the superficial temporal artery was seen (P = 0.04) after VIP in the first 30 min but no difference was found when comparing the time between 30 and 120 min. We found no difference in mean arterial blood pressure between VIP and placebo days but the heart rate increased significantly on a VIP day compared with a placebo day (AUC(0-30 min), P < 0.001). Plasma VIP was significantly higher on a VIP day compared with placebo (AUC(0-80 min), P < 0.001). These results show that VIP causes a decrease in V(meanMCA) without affecting rCBF. In spite of a marked vasodilator effect in the extracranial vessels and increased plasma VIP, healthy subjects developed only a very mild headache.

Nitric Oxide Has Tonic Inhibitory Effect, But Is Not Involved in the Vagal Control or VIP Effects on Motility of the Porcine Antrum

Background: The involvement of nitric oxide (NO) in vagal control and vasoactive intestinal polypeptide (VIP)-induced effects on antral motility was studied using isolated perfused preparations of porcine gastric antrum with intact vagal innervation. Methods: The presence of NO and VIP-producing neurons was studied using immunohistochemistry and histochemical techniques. Widespread, but not total, co-localization of NO and VIP immunoreactivity was found in the submucosa and in the muscle layers. Results: Electrical stimulation of the vagus nerves for 5 r min (8 r Hz, 10 r mA, 4 msec) increased the motility index from 2.47 ± 0.44 to 11.50 ± 2.02 ( n r = r 5). This effect was not influenced by the two NO synthase inhibitors N-nitro- L -arginine methyl ester (10 m 4 r M) and N G -nitro- L -arginine (10 m 5 r M). However, infusion of inhibitors increased the spontaneous motility index from 2.40 ± 0.08 to 5.36 r ± 1.08 ( P r < r 0.05) and 3.05 ± 1.10 to 4.14 ± 1.04 ( P r < r 0.05), respectively. The addition of L -arginine reversed this effect. Infusion of VIP 2 r × r 10 m 9 r M decreased the motility index from 2.32 ± 0.43 to 1.32 ± 0.27 ( P r < r 0.05), an effect that was preserved during NO synthase inhibition. Electrical vagus stimulation increased the release of VIP to the venous effluent, an effect that persisted during NO synthase inhibitors. Conclusion: We conclude that NO-producing nerves seem to have a tonic inhibitory action on the porcine antral motility, but are not involved in the motor effects of vagal stimulation or VIP infusion.

Effect of vasoactive intestinal polypeptide and environmental temperatures on feed intake, digesta flow and nutrient digestion in sheep

Three experiments were conducted to test the hypothesis that vasoactive intestinal polypeptide (VIP) infused into the gastric artery and exposure to a low temperature will increase feed intake, duodenal flow and amino acid supply to the small intestine of sheep, both effects as a result of increased ruminal outflow. A total of eight sheep (55 ± 2.7 kg) with rumen and duodenal cannulae and eight sheep without digestive cannulae were provided with continuous access to a diet of alfalfa pellets. Water and salt licks were accessible 24 h d-1. Two infusion treatments, VIP (1 nmol min-1) solution or a saline control (0.9% NaCl solution) were given through a left gastric-artery catheter for 10 min each hour for the first 3 h after feeding each day for 3 to 4 consecutive days in a crossover arrangement during experimental periods. Sheep were exposed to 1 ± 2°C in exp.1, to a thermoneutral (21 ± 2°C) environment in exp. 3 and to both thermoneutral (21 ± 1.5°C) and cold environments (1 ± 2°C) in exp. 2. These studies demonstrated that a VIP infusion of short duration did not increase dry matter intake (DMI) (P &gt; 0.05) and did not influence duodenal passage of DM, OM, CP, amino acids (AA) or bacterial protein (P &gt; 0.05). The exposure of animals to a cold environment stimulated (P &lt; 0.05) intake of DM, OM and AA and duodenal passage of DM, OM, AA and microbial protein. There was an interaction (P &lt; 0.05) between VIP and environmental temperature such that VIP improved duodenal AA passage in the thermoneutral, but not in the cold, environment. The data suggest that short-term VIP treatment does not induce a change in feed intake when sheep have access to feed for 24 h d-1. Cold environmental temperature stimulates significant increases in feed intake and passage of protein and AA into the small intestine of sheep fed ad libitum, such that there was enrichment of intestinal supply of AA relative to digestible organic matter. Key words: Sheep, vasoactive intestinal peptide, feed intake, environmental temperature

Vasoactive Intestinal Polypeptide and Gastrin-Releasing Peptide Attenuate Hepatic Microvasculatory Disturbances following Intestinal Ischemia and Reperfusion

Background/Aims: In addition to the primarily affected small bowel, intestinal ischemia and reperfusion (IIR) also leads to a marked decrease in hepatic microcirculation. The aim was to determine the potentially protective effect of the vasoactive hormones vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide (GRP) on hepatic microcirculation following IIR. Methods: Using a rat model, three animal groups were subjected to 40 min of intestinal ischemia, two of which were infused with either VIP or GRP (n = 12 each). Following reperfusion, hepatic intravital microscopy was performed. Portal venous perfusion, activities of serum glutamate pyruvate transaminase and alkaline phosphatase, mucosal injury in the small intestine and the expression of antioxidant enzymes glutathione peroxidase, copper-zinc-superoxide dismutase (Cu-Zn-SOD), glutathione reductase and catalase (CAT) in the liver were investigated. Results: Infusion of either VIP or GRP improved hepatic microcirculation and bile flow when compared with the untreated IIR group. VIP and GRP increased portal venous blood flow during reperfusion. VIP reduced the extent of mucosal damage resulting from IIR. GRP caused a decrease in expression of CAT and Cu-Zn-SOD, whereas VIP simply reduced CAT expression. Conclusion: This study indicates that vasoactive hormones may attenuate intestinal and hepatic injuries and circulatory disturbances following IIR.

Effects of VIP and NO on the motor activity of vascularly perfused rat proximal colon

The effects of vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) on the motor activity of the rat proximal colon were examined in an ex vivo model of vascularly perfused rat proximal colon. VIP reduced motor activity and this inhibitory effect was not altered by either atropine, hexamethonium, tetrodotoxin (TTX) nor TTX plus acetylcholine (ACh), but was completely antagonized by NO synthase inhibitor N G-nitro-L-arginine (L-NA) and by VIP receptor antagonist, VIP(10–28). These results suggest that VIP may exert a direct inhibitory effect on the motor activity of the rat proximal colon via a VIP receptor located on the smooth muscle and this effect is mediated by NO but not by cholinergic pathways. Atropine and hexamethonium reduced but ACh stimulated motor activity and the effect of ACh was not changed by TTX, suggesting that the cholinergic pathway may exert a direct stimulatory effect on motor activity. Single injection of TTX, VIP(10–28) or L-NA induced a marked increase in motor activity, suggesting that the motor activity of rat proximal colon is tonically suppressed by VIP and NO generating pathways, and elimination of inhibitory neurotransmission by TTX may induce an abnormal increase of the motor activity. The interaction between VIP and NO in regulation of motor activity was further examined by a measurement of NO release from vascularly perfused rat proximal colon. Results showed that NO release was significantly increased during infusion of VIP and this response was reversed by L-NA. These results suggest that VIP generating neurons may inhibit colonic motility by stimulating endogenous NO production in either smooth muscle cells or nerve terminals.

Effect of vasoactive intestinal polypeptide and environmental temperature on forestomach electromyographic activity and gastrointestinal contraction in sheep

Four crossover design experiments were conducted with sheep to test the hypothesis that vasoactive intestinal polypeptide (VIP) affects gastrointestinal motility with implications for digesta flow. Sheep were shorn and surgically prepared with electrodes implanted on the forestomach, cannulae in the rumen, duodenum or/and ilieum, and a left gastric artery catheter. VIP (1 or 1.5 nmol min−1) or saline (control) was infused for 10 min at half-hour or hour intervals for 4 or 7 d during treatment periods. VIP transiently inhibited electromyographic (EMG) activity of the reticulum, reticulo-omasal orifice (ROO) and omasum for 3 to 8 min during the 10-min infusion periods. VIP infusion extended the duration of ROO opening (P &lt; 0.01). The gastrointestinal lumen pressure pattern was also transiently influenced by VIP, with an increase of quiescent time. Cold exposure of sheep stimulated a relatively higher motility in the ROO and omasum. The results indicate that the inhibitory effect of VIP on the reticulum, ROO and omasum electrical activity is transient; however, its action to extend the duration of opening of the ROO may facilitate digesta passage. Key words: Sheep, vasoactive intestinal polypeptide, electromyographic activity, reticulo-omasal orifice

3333 VIP INFUSION INHIBITS DUODENAL MOTILITY DURING ENDOSCOPY: VIDEOMETRIC AND MANOMETRIC ANALYSIS.

Vasoactive Intestinal Polypeptide (VIP) is 28 amino acid polypeptide hormone found throughout the enteric nervous system. VIP is a powerful gastrointestinal and vascular smooth muscle relaxant. In addition, VIP has a short duration of action because it is rapidly metabolized by tissue proteases. Because of the potent relaxant effects and short half-life, VIP may be useful as an inhibitor of gastrointestinal motility during endoscopy and ERCP. To determine the action of VIP on endoscopic duodenal motility, VIP was administered intravenously to patients undergoing endoscopy and manometry and video-motility of the duodenum were measured. Volunteers underwent routine upper endoscopy with a forward viewing endoscope and a pressure-transducing catheter was placed in the duodenum. VIP doses of 0.2-0.5 μg/kg were administered as two separate infusions and duodenal motility measured by continuous manometric recording and simultaneous time-stamped video-recording. Blood pressure, pulse, duodenal manometry and video-recordings were obtained for at least four minutes prior to, during and after each infusion. The second infusion of VIP was performed only if vital signs and motility returned to baseline. In five volunteers with active duodenal motility VIP significantly decreased contraction frequency from 5.5 to 1.9 contractions/min as measured by manometry and from 3.7 to 1.3 contractions/min as measured by video-motility. The VIP-stimulated decrease in contraction frequency was dose-dependent and lasted for a minimum of seven minutes. To assess the effect of VIP on the intensity of contractions VIP-stimulated incomplete contractions and intraduodenal pressure were analyzed. VIP infusion increased partial occlusion of the duodenal lumen as measured by videomotility 0.9 to 2.0 partial contractions/min and decreased the height of manometric contractions. VIP infusion increased heart rate and decreased both systolic and diastolic blood pressure in a dose-dependent manner. The VIP effect on vital signs was transient and judged to be not clinically significant. This study demonstrates that VIP is a potent inhibitor of duodenal motility. VIP significantly decreases duodenal motility by decreasing the frequency and intensity of contractions during endoscopy. The VIPstimulated effect on duodenal motility can be quantified using both manometric and video-recording techniques. In conclusion, VIP infusion may be useful in ERCP for cases where there is active duodenal motility.

Effect of vasoactive intestinal polypeptide infusion on feed intake, digesta flow and nutrient digestion in sheep with access to feed for limited time

Two experiments were conducted to test the hypothesis that vasoactive intestinal polypeptide (VIP) infusion into the gastric artery increases feed intake, duodenal flow and amino acid supply to the small intestine of sheep. Four sheep in exp. 1 and five sheep in exp. 2 were fistulated with rumen and duodenal cannulae. Sheep in exp. 2 also had an ileal cannula. In both experiments animals were fed a diet of alfalfa pellets ad libitum for 8 h per day in a thermoneutral environment (20 ± 2 °C) and had free access to water and mineralized salt blocks. In exp. 1, VIP was infused at 1 nmol min−1 through a gastric-artery catheter for 10 min duration each hour for 3 h each day for 4 consecutive days. In exp. 2, VIP was infused at 1.5 nmol min−1 for 10 min duration each half-hour for 3 h each day for 7 consecutive days. Control sheep were infused with saline. Vasoactive intestinal polypeptide infusion increased (P &lt; 0.05) feed intake by 14.3 and 26.1% in exp. 1 and exp. 2, respectively. In exp. 2, there was a positive regression (P &lt; 0.01) between intake and duodenal passage of dry matter (DM) (n = 5, r2 = 0.67), organic matter (OM) (n = 5, r2 = 0.68), and amino acids (AA) (n = 5, r2 = 0.85). The present results suggest that VIP may play a role as a physiological regulator of feed intake in sheep and also has potential to increase the supply of nutrients to the animal. Key words: Digesta passage, intake, sheep, vasoactive intestinal polypeptide

Nicorandil, its denitrated metabolite, SG-86 and naturally occurring vasodilators synergistically interact on adenosine-induced vasodepression in rats: special reference to adrenomedullin.

To investigate synergistic effects among nicorandil, its main metabolite, SG-86 and endogenous vasodilators such as adrenomedullin (ADM), vasoactive intestinal polypeptide (VIP) and calcitonin gene-related peptide (CGRP), the effects of ADM, VIP and CGRP as well as nicorandil and SG-86 alone, and their low-dose combination were examined on adenosine-induced vasodepression in anesthetized rats. Single bolus i.v. injections of adenosine (3-100 micrograms/kg) caused a dose-dependent reduction of arterial blood pressure, accompanied by slight decreases (except for 100 micrograms/kg) in heart rate. i.v. infusion of nicorandil (10 micrograms/kg/min), SG-86 (100 micrograms/kg/min) ADM (1 ng/kg/min), VIP (30 ng/kg/min) or CGRP (1 ng/kg/min) alone, or the low-dose combination of either nicorandil (1 microgram/kg/min), and SG-86 (10 micrograms/kg/min) or either nicorandil or SG-86 and endogenous vasodilators, significantly potentiated the vasodepression produced by bolus i.v. adenosine, but not that by bolus i.v. acetylcholine (0.1 microgram/kg). The observed enhancement did not occur in the presence of glibenclamide (20 mg/kg i.v.). The present results indicate that nicorandil, SG-86 and endogenous vasodilators reciprocally interact, partly in link with KATP channels in vascular smooth muscle.

Effect of intraseptal vasotocin and vasoactive intestinal polypeptide infusions on courtship song and aggression in the male zebra finch (Taeniopygia guttata).

The present experiments were conducted to test the hypothesis that septal arginine vasotocin (AVT) and vasoactive intestinal polypeptide (VIP) modulate directed song (a courtship behaviour) and aggression in male zebra finches (Taeniopygia guttata). Subjects were surgically fitted with a guide cannula directed at the septum. Following recovery they were tested for aggression and directed song following infusions of AVT, its antagonist (anti-vasopressin, AVP), and saline volume control. Infusion of the AVT antagonist significantly reduced all three aggressive behaviours measured (pecks, beak fences and chases); and AVT infusion significantly facilitated beak fencing. Vasoactive intestinal polypeptide treatment significantly reduced pecking. No treatment produced a change in directed song. Comparison with findings in mammals suggests that modulation of aggression by septal AVT (or AVP) is evolutionarily conserved in vertebrates, but modulation of aggression by VIP has not previously been reported for any vertebrate.

Neural mediation of vasoactive intestinal polypeptide inhibitory effect on jejunal alanine absorption.

It was recently shown that vasoactive intestinal polypeptide (VIP) inhibits rat jejunal alanine absorption, an effect that was significantly reduced by vagotomy. This study assesses the role of capsaicin-sensitive primary afferents (CSPA) and the myenteric plexus in the inhibition of rat jejunal alanine absorption by VIP. Continuous intravenous infusion of VIP (11.2 ng . kg-1 . min-1) reduced alanine absorption by 60% in sham control rats and by 20% in rats neonatally treated with capsaicin (P < 0.01). In in vitro experiments, VIP decreased alanine uptake by jejunal strips isolated from sham control rats in a dose-dependent manner. In the presence of 40 nM VIP, alanine uptake by full-thickness jejunal strips was reduced by 54% in sham control rats and by 25% in rats neonatally treated with capsaicin (P < 0.001). On the other hand, VIP reduced alanine uptake by mucosal scrapings by 25% in sham rats compared with 9% reduction in neonatally treated rats. Chemical ablation of the extrinsic innervation and jejunal myenteric plexuses by pretreatment with benzalkonium chloride significantly (P < 0.001) reduced basal alanine absorption and the inhibitory effect of VIP. Moreover, incubation of intestinal strips with tetrodotoxin and atropine reduced significantly (P < 0.05) the inhibitory effect of VIP on alanine absorption. These data suggest that VIP exerts its inhibitory effect on alanine absorption through the CSPA fibers and the myenteric plexus. The neuronal circuitry of this inhibitory process may involve cholinergic muscarinic mechanisms.

Territorial Aggression and Dawn Song are Modulated by Septal Vasotocin and Vasoactive Intestinal Polypeptide in Male Field Sparrows (Spizella pusilla)

Previous experiments demonstrate that lesions of the septum produce opposite effects on intraspecific male aggression in the territorial field sparrow (Spizella pusilla) and the colonial zebra finch (Taeniopygia guttata; facilitate vs inhibit, respectively) and intraseptal infusions of arginine vasotocin (AVT) and vasoactive intestinal polypeptide (VIP) modulate aggression in the male zebra finch (facilitate and inhibit, respectively). The present experiments were conducted to test the hypotheses that (1) septal AVT and VIP modulate both overt territorial aggression and the production of territorial song during the dawn chorus in male field sparrows and (2) these neuropeptides will exert effects opposite of those observed in the zebra finch, consistent with the prediction that social organization is associated with septal neuropeptide function. Wild-caught male field sparrows were fitted with chronic guide cannulae directed at the septum and were tested in outdoor aviaries placed in their natural habitat. Intrusion tests (introduction of a stimulus male) and dawn song observations were conducted following infusion of AVT, VIP, or saline control. Consistent with predictions, infusion of AVT significantly inhibited chases and significantly increased chase latency. No significant effects of VIP on chasing or chase latency were observed, although most subjects were more aggressive following infusion of VIP. Both AVT and VIP produced significant, selective effects on the complex (agonistic) song type (facilitation and inhibition, respectively) and produced no effect on the simple (multipurpose) song type. Thus, song and overt aggression appear be modulated independently by septal neuropeptides, and septal AVT and VIP function may differ between species which differ in the expression of territorial or colonial social organizations.

Vasotocin and Vasoactive Intestinal Polypeptide Modulate Aggression in a Territorial Songbird, the Violet-Eared Waxbill (Estrildidae:Uraeginthus granatina)

Previous research demonstrates that intraseptal administrations of arginine vasotocin (AVT) inhibit male aggression in the territorial field sparrow (Emberizidae:Spizella pusilla) but facilitate aggression in the colonial zebra finch (Estrildidae:Taeniopygia guttata). In order to determine whether this difference may be related to the territorial and colonial social organizations of these two species, the effect of AVT infusions was examined in a territorial Estrildid species, the violet-eared waxbill (Uraeginthus granatina). This species is more closely related to the zebra finch than to the field sparrow and shares most critical features of breeding ecology in common with zebra finches, but differs in social organization. AVT infusions administered via chronic guide cannulae directed at the septum significantly inhibited aggressive behavior, consistent with results in the territorial field sparrow, supporting the hypothesis that social organization is correlated with AVT function. Similar experiments with mesotocin and substance P produced no effects on any of the behaviors measured, but infusions of vasoactive intestinal polypeptide (VIP) significantly facilitated aggression. This result contrasts with the inhibitory effect of septal VIP obtained in the colonial zebra finch, suggesting that VIP function may be correlated with social organization as well.

Involvement of nitric oxide in vasoactive intestinal peptide-stimulated prolactin secretion in normal men

To establish whether nitric-oxide (NO) participates in the regulation of prolactin (PRL) secretion in humans in basal conditions and/or under stimulation with vasoactive intestinal polypeptide (VIP), seven normal men were treated with a placebo (normal saline) or the NO synthase (NOS) inhibitor L-NAME (40 μg/kg injected plus 50 μg/kg infused intravenously over 60 minutes), which in previous studies has been found able to modify other pituitary hormone secretions. Experiments were performed either in basal conditions or during stimulation of PRL secretion with an intravenous infusion of VIP (4 pmol/kg min over 60 minutes). The administration of L-NAME was unable to change the basal secretion of PRL. In contrast, L-NAME significantly enhanced the PRL increase induced by VIP. These data argue against an involvement of NO in regulation of basal PRL secretion. In contrast, the stimulatory effect of L-NAME on VIP-induced PRL secretion suggests that NO exerts an inhibitory control of the PRL response to VIP.

Synergism between low-dose nicorandil and neuropeptides on adenosine-induced vasodepression in rats

We hypothesized that the effect of nicorandil may be enhanced by interaction with naturally occurring vasodilators. To clarify this hypothesis, the effects of low-dose nicorandil alone and in combination with low doses of vasoactive intestinal polypeptide (VIP) or calcitonin gene-related peptide (CGRP) on adenosine-induced vasodepression were studied in rats. Intravenous (i.v.) bolus injections of adenosine (3–100 μg kg −1) elicited dose-dependent decreases in blood pressure, accompanied by slight decreases (except for 100 μg kg −1) in heart rate. Simultaneous i.v. infusion of either nicorandil (1 μg kg −1 min −1) and VIP (0.003 μg kg −1 min −1) or CGRP (0.1 ng kg −1 min −1) significantly enhanced the adenosine-induced vasodepression, although each agent alone in the dose used had no effects on vasodepressor responses to adenosine. The potentiation of the effect of adenosine was not observed in the presence of 3,7-dimethyl-1-propargylxanthine (DMPX) (1 mg kg −1, i.v.) or glibenclamide (20 mg kg −1, i.v.). The present results suggest that low-dose nicorandil modifies the response to adenosine in interaction with low levels of endogenous neuropeptides such as VIP and CGRP, and that the reciprocal interaction is mediated partly through K ATP channel activation in vascular smooth muscle.