Administration Of Vasoactive Intestinal Polypeptide Research Articles

Influence of vasoactive intestinal polypeptide on growth performance, nutrient digestibility, nitrogen balance, and digestive enzyme activity in lambs.

This study evaluated if vasoactive intestinal polypeptide (VIP) influences growth performance, nutrient digestibility, nitrogen balance, and digestive enzyme activity. Sixteen wether lambs (69.6 ± 1.9kg) were housed in individual pens, adapted to a corn grain-based diet, and randomly assigned to 2 treatment groups. Lambs were injected intraperitoneally every other day for 28 d with saline (0.9% NaCl) containing no VIP (n = 8; control) or containing VIP (n = 8; 1.3 nmol/kg body weight [BW]). All lambs were transferred to individual metabolic crates for the final 7 d of the experiment to measure nitrogen balance and nutrient digestibility. At the end of the treatment period, lambs were slaughtered, and pancreatic tissue, small intestinal tissue, and rumen fluid were collected for protein, digestive enzymes, ruminal pH, and volatile fatty acid (VFA) analyses. Lambs treated with VIP had greater final BW, average daily gain, and gain:feed (P = 0.01, 0.05, 0.03, respectively). No differences between treatment groups were observed (P ≥ 0.25) for nutrient intake, digestibility, nitrogen retention, ruminal pH, and VFA concentrations. Moreover, VIP treatment did not influence (P ≥ 0.19) plasma glucose, urea N, and insulin concentrations. Treatment with VIP increased (P = 0.03) relative cecum weight (g/kg BW) and decreased (P = 0.05) relative brain weight. Pancreatic and intestinal digestive enzyme activities, except for duodenal maltase (P = 0.02), were not influenced (P ≥ 0.09) by VIP treatment. These data suggest that the administration of VIP may have potential to improve average daily gain and gain:feed in lambs fed grain-based diets.

Pituitary adenylate cyclase‐activating peptide and vasoactive intestinal polypeptide bias Langerhans cell Ag presentation toward Th17 cells

Epidermal Langerhans cells (LCs) are dendritic APCs that play an important role in cutaneous immune responses. LCs are associated with epidermal nerves and the neuropeptides vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) inhibit LC Ag presentation for Th1-type immune responses. Here, we examined whether PACAP or VIP modulates LC Ag presentation for induction of IL-17A-producing CD4(+) T cells. Treatment with VIP or PACAP prior to in vitro LC Ag presentation to CD4(+) T cells enhanced IL-17A, IL-6, and IL-4 production, decreased interferon (IFN)-γ and interleukin (IL)-22 release, and increased RORγt and Gata3 mRNA expression while decreasing T-bet expression. The CD4(+) T-cell population was increased in IL-17A- and IL-4-expressing cells and decreased in IFN-γ-expressing cells. Addition of anti-IL-6 mAb blocked the enhanced IL-17A production seen with LC preexposure to VIP or PACAP. Intradermal administration of VIP or PACAP prior to application of a contact sensitizer at the injection site, followed by harvesting of draining lymph node CD4(+) T cells and stimulation with anti-CD3/anti-CD28 mAbs, enhanced IL-17A and IL-4 production but reduced production of IL-22 and IFN-γ. PACAP and VIP are endogenous mediators that likely regulate immunity and immune-mediated diseases within the skin.

Vasoactive Intestinal Polypeptide as Possible Mediator of Relaxation in the Rat Gastric Fundus

Relaxations were induced in longitudinal muscle strips of the rat gastric fundus by stimulation of non-adrenergic non-cholinergic (NANC) neurons and by administration of vasoactive intestinal polypeptide (VIP) or isoprenaline. The effect of antiserum against vasoactive intestinal polypeptide (VIP antiserum) and of control serum on these relaxations was investigated. Incubation with VIP antiserum (dilution 1/50) for 1 h almost completely prevented the relaxation by VIP. It partially prevented the relaxation evoked by electrical stimulation while the relaxation induced by isoprenaline was not influenced. Control serum decreased the VIP- and stimulation-induced relaxations much less than did VIP antiserum. In addition, the effect of the putative VIP antagonist (4Cl-D-Phe6, Leu17) VIP was studied on the relaxations induced by NANC neuron stimulation and by VIP. The VIP antagonist (3 x 10(-5) M, incubation time 10 min) had a relaxatory effect itself but had no influence on either VIP- or stimulation-induced relaxations. The results with VIP antiserum confirm the involvement of VIP in the inhibitory NANC neurotransmission of the rat gastric fundus.

Behavioral and Genetic Dissection of a Mouse Model for Advanced Sleep Phase Syndrome

Vasoactive intestinal polypeptide (VIP) has been implicated in sleep regulation as a promoter of rapid eye movement (REM) sleep. Previous work has shown that the amount of time spent in REM sleep is increased by intracerebroventricular administration of VIP, and reduced by treatment with VIP antagonists or antibodies against VIP. A variety of evidence suggests that VIP is critical for normal expression of circadian rhythmicity of diverse physiological and behavioral parameters. In the present study, we investigated the role of this peptide in sleep regulation using VIP-deficient (VIP-/-) mice. EEG/EMG sleep-wake patterns were recorded in VIP-/- mice and their wild-type littermate controls under normal light-dark (LD), constant darkness (DD) and sleep deprivation conditions. VIP-/- mice exhibited reduced REM sleep time over the 24-h cycle while total daily amounts of NREM sleep and wakefulness were not altered significantly. The reduced REM sleep time in VIP-/- mice occurred entirely during the day due to a reduction in the duration, but not the frequency, of REM sleep bouts. In response to sleep deprivation, compensatory rebounds in NREM sleep and REM sleep were also attenuated in VIP-/- mice. Finally, the loss of VIP altered the temporal distribution of sleep in that the VIP -/- mice exhibited smaller amplitude rhythms in total sleep, NREM sleep, and REM sleep under both LD and DD. These results indicate that VIP regulates the duration of REM sleep, sleep homeostatic mechanisms as well as the temporal patterning of sleep.

Involvement of vasoactive intestinal polypeptide in the parasympathetic vasodilatation of the rat masseter muscle

The parasympathetic vasodilatory fibres are known to innervate vessels in a rat masseter muscle via both cholinergic and non-cholinergic mechanisms. However, the non-cholinergic mechanisms are still unclear. Recently, vasoactive intestinal polypeptide (VIP) was convincingly shown to be involved in the parasympathetic vasodilatation in orofacial areas, such as submandibular glands and lower lip. However, very little is known about the rat masseter muscle. The present study was designed in the rat masseter muscle to assess (1) whether the parasympathetic nerve innervating vessels have VIP immunoreactivities, (2) whether intravenous administration of VIP induces the vasodilatation, and (3) effects of selective VIP receptor antagonist ([4Cl- d-Phe 6, Leu 17] VIP) in the presence or absence of atropine on the parasympathetic vasodilatation. The VIP immunoreactivities were found at two sites of the parasympathetic otic ganglion and nerve fibres located around vessels. The intravenous administration of VIP induced the vasodilatation, and [4Cl- d-Phe 6, Leu 17] VIP markedly decreased the vasodilatation evoked by VIP administration. The parasympathetic vasodilatation was not inhibited by [4Cl- d-Phe 6, Leu 17] VIP. However, treatment with [4Cl- d-Phe 6, Leu 17] VIP markedly decreased the parasympathetic vasodilatation when [4Cl- d-Phe 6, Leu 17] VIP was administered together with atropine. These results suggest that (1) VIP exists in the postganglionic parasympathetic nerve innervating the vessels in the masseter muscle, (2) the intravenous administration of VIP induces the vasodilatation in the masseter muscle, and (3) VIP may be involved in the parasympathetic vasodilatation in the masseter muscle when muscarinic cholinergic receptors are deactivated by either atropine or the suppression of the ACh release.

Mechanism for the Cardiovascular Action of Intracerebroventricularly Administered Vasoactive Intestinal Polypeptide in Rats

It was investigated whether the secretion of epinephrine, norepinephrine, and arginine vasopressin from the adrenal medulla, sympathetic nerve endings, and posterior pituitary gland, respectively, was involved in the mediation of the pressor effect of intracerebroventricular (icv) administration of vasoactive intestinal polypeptide (VIP) in anesthetized rats. Icv administration of 1 microgram VIP increased mean blood pressure by 21% and heart rate by 17% in Wistar rats although the lesser dose was effective only for increasing heart rate. Simultaneously with the change in blood pressure and heart rate, the concentrations of plasma epinephrine and norepinephrine rose 4 and 10 min after VIP administration. After adrenalectomy, the action of VIP on mean blood pressure or heart rate was unchanged or partially reduced, respectively. Although the cardiovascular action of VIP was observed in control Long-Evans rats as well as in Brattleboro rats homozygous or heterozygous for diabetes insipidus, which hereditarily lacked vasopressin completely or partially, the increase in mean blood pressure after icv administration of VIP was more marked in homozygous than heterozygous rats or Long-Evans rats. These results suggest that the cardiovascular action of centrally administered VIP is mediated by increased sympathetic nerve outflows including stimulation of adrenal epinephrine secretion and is enhanced by the chronic absence of vasopressin secretion from the posterior pituitary gland.

Vasoactive Intestinal Polypeptide Entrains Circadian Rhythms in Astrocytes

Many mammalian cell types show daily rhythms in gene expression driven by a circadian pacemaker. For example, cultured astrocytes display circadian rhythms in Period1 and Period2 expression. It is not known, however, how or which intercellular factors synchronize and sustain rhythmicity in astrocytes. Because astrocytes are highly sensitive to vasoactive intestinal polypeptide (VIP), a neuropeptide released by neurons and important for the coordination of daily cycling, the authors hypothesized that VIP entrains circadian rhythms in astrocytes. They used astrocyte cultures derived from knock-in mice containing a bioluminescent reporter of PERIOD2 (PER2) protein, to assess the effects of VIP on the rhythmic properties of astrocytes. VIP induced a dose-dependent increase in the peak-to-trough amplitude of the ensemble rhythms of PER2 expression with maximal effects near 100 nM VIP and threshold values between 0.1 and 1 nM. VIP also induced dose- and phase-dependent shifts in PER2 rhythms and daily VIP administration entrained bioluminescence rhythms of astrocytes to a predicted phase angle. This is the first demonstration that a neuropeptide can entrain glial cells to a phase predicted by a phase-response curve. The authors conclude that VIP potently entrains astrocytes in vitro and is a candidate for coordinating daily rhythms among glia in the brain.

The Role of Vasoactive Intestinal Polypeptide and Pituitary Adenylate Cyclase-Activating Polypeptide in the Neural Pathways Controlling the Lower Urinary Tract

Vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are expressed in the neural pathways regulating the lower urinary tract. VIP-immunoreactivity (IR) is present in afferent and autonomic efferent neurons innervating the bladder and urethra, whereas PACAP-IR is present primarily in afferent neurons. Exogenously applied VIP relaxes bladder and urethral smooth muscle and excites parasympathetic neurons in bladder ganglia. PACAP relaxes bladder and urethral smooth muscle in some species (pig) but excites the smooth muscle in other species (mouse). Intrathecal administration of VIP in cats with an intact spinal cord suppresses reflex bladder activity, but intrathecal administration of VIP or PACAP in rats enhances bladder activity and suppresses urethral sphincter activity. PACAP has presynaptic facilitatory effects and direct excitatory effects on lumbosacral parasympathetic preganglionic neurons. Chronic spinal cord transection produces an expansion of VIP-IR (cats) and PACAP-IR (rats) in primary afferent axons in the lumbosacral spinal cord and unmasks spinal excitatory effects of VIP on bladder reflexes in cats. Intrathecal administration of PACAP6-38, a PAC1 receptor antagonist, reduces bladder hyperactivity in chronic spinal-cord-injured rats. These observations raise the possibility that VIP or PACAP have a role in the control of normal or abnormal voiding.

Hippocampal asymmetry in exploratory behavior to vasoactive intestinal polypeptide

The effects of vasoactive intestinal polypeptide (VIP) microinjected uni- or bilaterally into the CA1 hippocampal area of male Wistar rats at a dose of 10, 50 and 100 ng on exploratory behavior were examined. VIP microinjected bilaterally at a high dose (100 ng) significantly decreased the horizontal movements, while at low doses (10 and 50 ng) had no effect on the exploratory activity. Microinjections of VIP into the left hippocampal CA1 area at doses 50 and 100 ng suppressed the exploratory activity, while right-side VIP administration at a dose 100 ng significantly increased horizontal movements compared to the respective controls. Vertical activity was stimulated only by VIP administered into the right hippocampal CA1 area at the three doses used. Neither bilateral nor left injections of VIP induced changes in the vertical movements. The main finding was the presence of hippocampal asymmetry in exploratory behavior to unilateral microinjections of VIP depending on the dose and the microinjected hemisphere.

Effects of Pituitary Adenylate Cyclase‐Activating Polypeptide and Vasoactive Intestinal Polypeptide on Food Intake and Locomotor Activity in the Goldfish, Carassius auratus

We investigated the effects of intracerebroventricular (ICV) and intraperitoneal (IP) administration of pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) on food intake in the goldfish, Carassius auratus. Cumulative food intake was significantly decreased by ICV injection of PACAP or VIP. Similarly, IP administration of PACAP or VIP induced a significant decrease in food intake. ICV injection of PACAP or VIP also induced a significant decrease in locomotor activity. These results suggest that PACAP and VIP may be involved in the regulation of feeding in goldfish.

Electrophysiological evidence that the vasoactive intestinal peptide receptor antagonist VIP 6–28 reduces nociception in an animal model of osteoarthritis

The present study examined whether local administration of the neuropeptide vasoactive intestinal polypeptide (VIP) could modulate joint nociception in normal rat knee joints and if the VIP antagonist VIP(6-28) could ameliorate joint mechanosensitivity in an animal model of osteoarthritis (OA). OA was induced in male Wistar rats by intra-articular injection of 3mg sodium monoiodo-acetate with a recovery period of 14 days. Electrophysiological recordings were made from knee joint primary afferents in response to normal rotation and noxious hyper-rotation of the joint both before and following close intra-arterial injection of different doses of VIP and VIP(6-28). Local application of VIP to normal knees caused afferent firing rate to be significantly enhanced during normal rotation (up to 180% P<0.01; n=17) and during hyper-rotation (up to 37% P<0.01; n=17) of the knee. VIP-induced sensitization was blocked by pre-administration of the VIP receptor antagonist VIP(6-28). In the OA group, application of VIP(6-28) caused afferent firing rate to be significantly reduced during normal rotation (up to 45% P<0.05; n=17) and during hyper-rotation (up to 34% P<0.01; n=15) of the knee joint. These findings indicate that VIP is involved in peripheral sensitization of knee joint afferents especially in response to normal joint movements. OA-induced sensitization of knee joint afferents was inhibited by local administration of VIP(6-28), indicating that VIP is released into OA knee joints, potentially contributing to joint pain. As such, VIP(6-28) may prove to be a beneficial agent for the treatment of arthritis pain.

Impact of vasoactive intestinal polypeptide and gastrin-releasing peptide on small bowel microcirculation and mucosal injury after hepatic ischemia/reperfusion in rats

Alterations in microvascular perfusion of the intestine after hepatic ischemia/reperfusion have been suggested as an important cause of postoperative septic complications. We therefore investigated small bowel microcirculation and mucosal injury after liver ischemia/reperfusion in a rat model. Furthermore, we analyzed the effects of the regulatory peptides vasoactive intestinal polypeptide and gastrin-releasing peptide for their splanchnic vasoactivity. Hepatic ischemia was induced by clamping of the left hepatic artery and vein for 40 min, followed by 60 min of reperfusion. The control group was treated similarly, but without clamping of the liver vessels. Ten minutes after clamping of the hepatic vessels, vasoactive intestinal polypeptide or gastrin-releasing peptide, respectively, were continuously infused intravenously in the experimental groups. Small bowel microcirculation and mucosal injury were assessed using intravital microscopy and the Chiu-score, respectively. The functional capillary density of the small intestine following ischemia and reperfusion of the left hepatic lobe significantly decreased compared to normal controls in both the mucosa and the smooth intestinal muscle. Red blood cell velocity decreased, whereas leukocyte-endothelium adherence, stasis index and the mucosal injury score increased. Administration of vasoactive intestinal polypeptide resulted in an increase of functional capillary density in the mucosa and of the red blood cell velocity and a decrease in the stasis index. The mucosal injury score was significantly higher in reperfused animals without treatment. The application of gastrin-releasing peptide resulted in an isolated increase of the red blood cell velocity. Leukocyte adherences could not be altered by the regulatory peptides. We conclude that hepatic ischemia/reperfusion injury leads to significant alterations of small bowel microcirculation and mucosal injury. Vasoactive intestinal polypeptide and gastrin-releasing peptide attenuate the damage in a different manner.

Vasoactive intestinal polypeptide- and pituitary adenylate cyclase activating polypeptide-mediated control of catecholamine release from chromaffin tissue in the rainbow trout, Oncorhynchus mykiss.

The aim of the present investigation was to assess the relative contributions of cholinergic (acetylcholine) and non-cholinergic vasoactive intestinal polypeptide (VIP), and pituitary adenylate cyclase activating polypeptide (PACAP) neurotransmitters in the neuronal control of catecholamine secretion from the chromaffin tissue lining the posterior cardinal vein of the rainbow trout (Oncorhynchus mykiss). Using an in situ saline-perfused posterior cardinal vein preparation, it was demonstrated that exogenous administration of chicken VIP or human PACAP-27 caused a dose-dependent increase in adrenaline secretion; noradrenaline secretion was unaffected. Analysis of dose-response curves indicated that VIP and PACAP stimulated the secretion of adrenaline with a similar degree of potency (ED(50) for VIP=1.90x10(-11) mol/kg; ED(50) for PACAP=1.03x10(-11) mol/kg). The VIP/PACAP-elicited secretion was diminished in the presence of the VIP receptor antagonist, VIP 6-28, but was unaffected by the PACAP receptor antagonist, PACAP 6-27, or the cholinergic antagonists, hexamethonium and atropine. Thus, this is the first study to demonstrate a direct stimulatory role for VIP or PACAP in catecholamine secretion from piscine chromaffin cells. The relative contribution of cholinergic and non-cholinergic neurotransmitters in the neuronal control of catecholamine secretion from the chromaffin tissue was evaluated using an in situ nerve-stimulating technique previously validated by us in the rainbow trout. This was accomplished by comparing catecholamine secretion in the presence or absence of cholinergic and the VIP and PACAP receptor antagonists during different levels of electrical stimulation. The results demonstrated that cholinergic stimulation predominated during high frequency of electrical stimulation (20 Hz) while the non-cholinergic component prevailed at low frequency (1 Hz). Overall, the results of the present investigation demonstrate that VIP and/or PACAP may directly stimulate adrenaline secretion from trout chromaffin cells at low levels of neuronal activity. Therefore, the neuronal control of catecholamine secretion in teleosts may not be confined to cholinergic-evoked events.

Inhibition by vasoactive intestinal polypeptide (VIP) of angiogenesis induced by murine Colon 26-L5 carcinoma cells metastasized in liver.

We investigated the effect of VIP on the liver metastases and angiogenesis by Colon 26-L5 carcinoma cells in mice. Daily systemic administration of VIP, beginning 3 days after tumor inoculation into a portal vein of mice, inhibited significantly the development of their liver metastases. Immunohistochemical staining for factor VIII-related antigen in the sections of liver metastases showed that the systemic administration of VIP caused significant prevention of angiogenesis within tumor masses. VIP (10-(10) to 10(-6) M) inhibited the invasion of reconstituted basement membrane (Matrigel) by hepatic sinusoidal endothelial (HSE) cells in a concentration-dependent manner in a Transwell chamber assay in vitro and achieved approximately 50% reduction of control at 10(-6) M. VIP (10(-6) M) also significantly suppressed the haptotactic migration of HSE cells to fibronectin, laminin or type I collagen substrates with a similar inhibition rate to the invasion assay. Exposure of VIP to HSE cells induced accumulation of intracellular cAMP in a concentration-dependent manner. The inhibitory effect of VIP (10(-6) M) on HSE cell migration was significantly abrogated in the presence of 3 x 10(-6) M H-89, a cAMP-dependent protein kinase inhibitor. VIP (10(-6) M) inhibited the morphogenesis of HSE cells into capillary-like structures on Matrigel-coated wells. VIP did not affect the proliferation of HSE cells and the production of gelatinases in HSE cells in vitro at the concentrations used in the invasion assay. These observations suggest that the anti-metastatic effect of VIP on liver metastases by Colon 26-L5 carcinoma cells in mice is partly due to the prevention of tumor angiogenesis probably through suppression of the motility of endothelial cells.

Oxytocin enhances the prolactin response to vasoactive intestinal polypeptide in healthy women

Objective: To establish whether oxytocin modifies the stimulatory effect of vasoactive intestinal polypeptide (VIP) on prolactin secretion in healthy women. Design: Controlled clinical study. Setting: Healthy women in an academic research environment. Patient(s): Seven healthy women (aged 24–32 years) were tested on the 22nd day of two consecutive normal menstrual cycles. Intervention(s): Vasoactive intestinal polypeptide (4 pmol · kg −1 · min −1 in 50 mL of normal saline infused IV for 60 minutes) was administered in either the presence or absence of concurrent treatment with oxytocin (2 IU injected plus 0.07 IU/min infused for 60 minutes). Main Outcome Measure(s): Serum prolactin levels. Result(s): The administration of VIP induced a significant increase in serum prolactin levels, with a mean peak response 1.6 times higher than baseline at 45 minutes after injection. In the presence of oxytocin, the prolactin response to VIP was significantly higher, with a mean peak response 2 times higher than baseline. Conclusion(s): These data suggest that in healthy women, oxytocin facilitates the regulation of the stimulating effect of VIP on prolactin secretion.

Effect of vasoactive intestinal peptide on pacemaker location and heart rate in the dog atrium

Vasoactive intestinal polypeptide (VIP) was either injectedintravenously (300 pmol·kg–1) or perfused (1 nmol in 1 min) into the sinusnode artery (SNA) in anesthetized dogs to study its effect on subsidiary atrial pacemakers.Isochronal maps were obtained from 128 unipolar electrograms recorded on the epicardialsurface of both atria in nine animals. When VIP was perfused into the SNA or injectedintravenously, heart rate increased by 29 ± 16% and 12 ± 12%, and blood pressure decreased by16 ± 15 mmHg (1 mmHg = 133.3 Pa) and 24 ± 18 mmHg, respectively. Nosignificant change in heart rate (3 ± 6% decrease) accompanied a similar decrease in bloodpressure after an intravenous sodium nitroprusside perfusion. The perfusion of VIP into the SNAas well as the intravenous injection of VIP induced a shift of the pacemaker site to the region ofBachmann’s bundle in a third of the preparations, while the pacemaker remained in the sinusnode area in two thirds. A perfusion of isoproterenol into the SNA produced a similar heart rateincrease (32 ± 14%, NS vs. VIP), and shifted the pacemaker site rostrally within the sinus node inthree of five preparations, or to the region of Bachmann’s bundle in two of five preparations.The response to VIP in the location of the pacemaker was significantly different from theresponse to isoproterenol. Repeated perfusions of VIP into the SNA after 10-, 25-, 40-, and60-min intervals produced 2 ± 13% (p &lt; 0.005 vs. the effect of first VIP administration),14 ± 12% (p &lt; 0.05), 10 ± 12% (p &lt; 0.05) and 30 ± 13% (NS) heart rateincreases, respectively, thereby demonstrating a tachyphylactic effect. In conclusion, VIP seemsto exert its positive chronotropic effect directly (probably via specific VIP receptors), althoughthe phenomenon of tachyphylaxis may suggest an indirect sympathomimetic mechanism.Key words: vasoactive intestinal peptide,subsidiary atrial pacemakers, sinus node artery, atrial mapping.

Evidence for roles of vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) receptors in modulating the responses of rat dorsal horn neurons to sensory inputs

The extracellularly recorded electrophysiological activity of single multireceptive dorsal horn neurons was markedly increased by ionophoretic administration of vasoactive intestinal polypeptide (VIP) or pituitary adenylate cyclase activating polypeptide (PACAP)-38. Some cells responded selectively to PACAP-38 (suggesting mediation by a PACAP receptor), whereas others responded to both VIP and PACAP-38 (suggesting a VIP 1 and/or VIP 2 receptor). Most non-nociceptive cells were unaffected by PACAP-38 and all were unaffected by VIP. The selectivity of VIP/PACAP receptor antagonists was established on cloned rat VIP 1, VIP 2 and PACAP receptors in vitro before their utilization to indicate the likely involvement of VIP 1, and possibly PACAP receptors, in VIP- and PACAP-38-mediated responses of dorsal horn neurons. The VIP/PACAP receptor antagonists inhibited responses of multireceptive cells to sustained innocuous (brush) and noxious (mustard oil) stimuli, with a selectivity suggesting the involvement of VIP 1 and PACAP receptors, although the participation by VIP 2 receptors cannot be excluded. These data implicate both VIP and PACAP in regulating the basal responsiveness of multireceptive dorsal horn neurons to sensory stimuli.

PACAPs stimulate duodenal bicarbonate secretion at PACAP receptors in the rat.

We investigated the effects of pituitary adenylate cyclase-activating polypeptides (PACAPs) on gastroduodenal HCO(3)- secretion in anesthetized rats and characterized their effects by comparison with the effects of vasoactive intestinal polypeptide (VIP). Under urethan anesthesia, a rat proximal duodenal loop or a rat stomach mounted in an ex vivo chamber (in the absence of acid secretion) was perfused with saline, and HCO(3)- secretion was measured at pH 7.0 using a pH-stat method and by addition of 10 mM HCl. Intravenous injection of PACAP-27 stimulated HCO(3)- secretion in a dose-dependent manner in the duodenum, but not in the stomach, although this peptide had no effect on duodenal HCO(3)- secretion after intracisternal administration. The duodenal HCO(3)- stimulatory action was similarly observed after intravenous administration of PACAP-38 and VIP, and the potency of action was in the following order: PACAP-27 > PACAP-38 = VIP. The duodenal HCO(3)- stimulatory action of PACAP-27 was potentiated by pretreatment with 3-isobutyl-1-methylxanthine, similar to that of prostaglandin E2, and was significantly attenuated by PACAP-(6--27) (PACAP antagonist) or Ac-Tyr1,D-Phe2-VIP (VIP antagonist) but was not affected by bilateral vagotomy or prior administration of atropine, verapamil, and indomethacin. Forskolin, the stimulator of adenylate cyclase, also increased HCO(3)- secretion in the duodenum, but not in the stomach. These results suggest that 1) PACAP is a potent stimulator of HCO(3)- secretion in the duodenum, but not in the stomach, and may be involved in the peripheral regulation of duodenal HCO(3)- secretion, 2) this action is mediated by adenosine 3',5'-cyclic monophosphate, probably through PACAP and VIP receptors, and 3) adenosine 3',5'-cyclic monophosphate is a mediator in duodenal, but not in gastric, HCO(3)- secretion.

Effects of vasoactive intestinal polypeptide on heart rate in relation to vagal cardioacceleration in conscious dogs.

The vagal cardiac accelerator (VCA) system takes part in the nervous control of the heart rate. In the present study we tried to adduce evidence that vasoactive intestinal polypeptide (VIP) contributes to vagally induced cardioaccelerations. The effect of VIP on heart rate and arterial blood pressure was investigated after unmasking the inherent VCA activity by blocking the sympathetic accelerator and vagal decelerator influences on heart rate in conscious dogs. Following intravenous administration of VIP (10 micrograms i.v.) the heart rate increased by 43.6 +/- 6.7 (28.1 +/- 4.7%), from 165.6 +/- 8.5 to 209.1 +/- 7.0 beats/min (P < 0.001) and the mean arterial blood pressure decreased by 47.5 +/- 3.2 (37.9 +/- 3.0%), from 126.6 +/- 2.6 to 79.1 +/- 4.9 mmHg (P < 0.001) (n = 11). After VCA activity was reflexly enhanced by alpha 1-adrenoceptor stimulation with methoxamine, VIP increased heart rate by 36.9 +/- 7.3 (21.5 +/- 4.6%), from 179.8 +/- 5.2 to 216.7 +/- 5.8 beats/min (P < 0.001) and decreased mean arterial pressure by 79.1 +/- 6.4 (46.7 +/- 3.5%), from 168.2 +/- 4.1 to 89.1 +/- 5.0 mmHg (P < 0.001). Hence, the VIP-induced tachycardia, expressed in relative values, shows a significant attenuation after the administration of methoxamine (P < 0.05). The increase in heart rate induced by VIP appeared to be inversely related to the prevailing VCA activity, both before (r = -0.744, P = 0.009) and after methoxamine (r = -0.689, P = 0.019). The VIP-induced tachycardia is certainly not reflexly induced by the fall in arterial pressure, because intracoronary administration of VIP (0.5 microgram i.c.) caused an appreciable increase in the heart rate by 63.7 +/- 13.0 (46.4 +/- 10.4%), from 143.0 +/- 8.1 to 208.7 +/- 12.0 beats/min (P < 0.005), whereas the mean arterial pressure only slightly changed (-7.7 +/- 2.0 mmHg) (P < 0.05) (n = 6). In addition, VIP (10 micrograms i.v.) also caused a tachycardia in vagotomized dogs with blocked beta-adrenergic and muscarinic receptors. The administration of the VIP antagonists [D-p-CI-Phe6, Leu17]-VIP (50-150 micrograms i.c.) and [Lys1, Pro2,5, Leu17]-VIP (20 micrograms i.c.) did not result in alterations in VCA activity nor did the VIP antagonists block the VCA reflex response to a rise in arterial pressure. However, none of the VIP antagonists reduced the VIP-induced tachycardia either. Vasoactive intestinal polypeptide is likely to play a part in the vagal cardiac accelerator system. However, conclusive evidence for its role as the terminal transmitter in the VCA pathway will have to wait for the availability of a specific cardiac VIP receptor antagonist.

Bilateral lesions of the hypothalamic suprachiasmatic nucleus eliminated sympathetic response to intracranial injection of 2-deoxy- d-glucose and VIP rescued this response

We previously found that bilateral lesions of the suprachiasmatic nucleus abolished hyperglycemic response to intracranial injection of 2-deoxy- d-glucose in rats. Because the hyperglycemia due to 2-deoxy- d-glucose was shown to be dependent on the functions of the adrenal medulla and sympathetic nervous system, the effect of bilateral lesions of the suprachiasmatic nucleus on changes in the nervous activity of sympathetic efferents to the adrenal after intracranial injection of 2-deoxy- d-glucose was examined in rats. It was found that bilateral lesions of the nucleus eliminated the increase in nerual activity of the sympathetic efferent that occurred after the injection of 2-deoxy- d-glucose. Because the suprachiasmatic nucleus posseses neurons containing a vasoactive intestinal polypeptide-like substance, the effects of vasoactive intestinal polypeptide and 2-deoxy- d-glucose, administered alone or in combination, on the sympathetic activity were examined in intact control rats and in rats with bilateral lesions of the suprachiasmatic nucleus. It was found that in the normal control rats, vasoactive intestinal polypeptide alone increased the sympathetic activity, whereas it dramatically enhanced the sympathetic response to 2-deoxy- d-glucose. However, in rats with bilateral lesions of the suprachiasmatic nucleus, vasoactive intestinal polypeptide alone elicited no increase in the nervous activity of the sympathetic efferents to the adrenal, but combined administration of vasoactive intestinal polypeptide and 2-deoxy- d-glucose caused an increase in the nervous activity of sympathetic efferents to the adrenal. These findings suggest that the suprachiasmatic nucleus is involved in the enhancement of sympathetic activity caused by intracranial injection of 2-deoxy- d-glucose, and that neurons containing a vasoactive intestinal polypeptide-like substance in the suprachiasmatic nucleus play an important role in the sympathetic enhancement that occurs after intracranial injection of 2-deoxy- d-glucose. This role might be a permissive and facilitative one.