Electrical Stimulation Of Vagus Nerve Research Articles

Abdominal surgery induced gastric ileus and activation of M1-like macrophages in the gastric myenteric plexus: prevention by central vagal activation in rats.

Inflammation plays a role in abdominal surgery (AS)-induced intestinal ileus that is alleviated by electrical vagal stimulation. Intracisternal injection of RX-77368, the stable thyrotropin-releasing hormone agonist, activates dorsal motor nucleus neurons and gastric vagal efferent discharges. We investigated the gastric inflammation induced by AS and the modulation by intracisternal RX-77368 in rats. RX-77368 (50 ng/rat) or saline was injected followed, 1 h later, by laparotomy and small intestinal/cecal manipulation. The sham group had anesthesia alone. After 6 h, gastric emptying (GE) and the inflammation in gastric corpus were determined. AS inhibited GE by 72% vs. control and doubled the number of M1-like macrophage immunoreactive for major histocompatibility complex class II (MHCII; M1 marker) but not for cluster of differentiation 206 (CD206; M2 marker) (MHCII+/CD206-) while there was no change in M2-like macrophages (MHCII-/CD206+). AS increased mRNA levels of interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) by 1.7- and 1.5-fold, respectively, in the gastric submucosa plus muscle layers and the infiltration of neutrophils labeled by myeloperoxidase by 9.5-fold in the muscularis externa. RX-77368 inhibited AS-related gastric changes while not altering these parameters in the sham group. There was a significant negative correlation between GE and IL-1β (r = -0.46), TNF-α (r = -0.44), M1 macrophage (r = -0.82), and neutrophils (r = -0.91). The M2-like macrophages and IL-10 expression were unchanged by AS with intracisternal saline or RX-77368. These data indicate that AS activates gastric M1 macrophages and increases proinflammatory cytokines expression, which are prevented by central vagal activation and may contribute to the correlated dampening of postoperative gastric ileus.NEW & NOTEWORTHY MHCII+/CD206- (M1) and MHCII-/CD206+ (M2) constitute two distinct populations of macrophages that are in close apposition to the cholinergic neurons in the rat gastric myenteric plexus (MP). Abdominal surgery (6 h) activates M1 macrophage leading to inflammation in the gastric MP correlated with the delayed gastric emptying, which was abolished by central vagal stimulation via intracisternal injection of RX-77368. Vagal stimulation linked with the cephalic phase may have potential beneficial effects to curtail postoperative gastric ileus.

Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis.

Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune-mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so-called cholinergic anti-inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL-6 production and improved RA disease severity, even in some patients with therapy-resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.

Potential excitatory role of nitric oxide on 2-deoxy-d-glucose-induced gastric motility in rats.

Previous studies have shown that 2-deoxy-d-glucose (2-DG) increases gastric motility via the vagus nerve, but the underlying mechanism remains elusive. Since nitric oxide (NO) is involved in gastric motility, a possible interplay between 2-DG and NO can be suggested. In the present study, Wistar rats (250-350g) of both sexes were intravenously injected with 2-DG (200mg/kg), and the effects of the intravenous injection of the nitric oxide synthase (NOS) inhibitors; nitro-l-arginine methyl ester (l-NAME, 10mg/kg) and Nω -nitro-l-arginine (l-NNA, 10mg/kg) were investigated. Animals were anaesthetized and cannulated for intravenous drug injections while the left vagal nerve was electrically stimulated (0.1-10Hz, 0.5ms duration, 12V, for 60seconds), and intragastric pressure and gastric motility changes were monitored using a latex gastric balloon. 2-DG increased the mean intragastric pressure (baseline, 5.0±0.4cmH2 O; after 2-DG, 14.4±1.5cmH2 O; P=.0156) and significantly increased the gastric motility index, while NOS inhibitors significantly attenuated both parameters. However, pretreatment with NOS inhibitors significantly augmented the gastric responses to peripheral electrical vagal stimulation. These results suggest that NO plays an excitatory role in gastric responsiveness to 2-DG and that this function may be effected in the central nervous system.

Abdominal vagus nerve stimulation as a new therapeutic approach to prevent postoperative ileus.

Electrical stimulation of the cervical vagus nerve (VNS) prevents postoperative ileus (POI) in mice. As this approach requires an additional cervical procedure, we explored the possibility of peroperative abdominal VNS in mice and human. The effect of cervical and abdominal VNS was studied in a murine model of POI and lipopolysaccharide (LPS)-induced sepsis. Postoperative ileus was quantified by assessment of intestinal transit of fluorescent dextran expressed as geometric center (GC). Next, the effect of cervical and abdominal VNS on heart rate was determined in eight Landrace pigs to select the optimal electrode for VNS in human. Finally, the effect of sham or abdominal VNS on LPS-induced cytokine production of whole blood was studied in patients undergoing colorectal surgery. Similar to cervical VNS, abdominal VNS significantly decreased LPS-induced serum tumor necrosis factor-α (TNFα) levels (abdominal VNS: 366±33pg/mL vs sham: 822±105pg/mL; P<.01). In line, in a murine model of POI, abdominal VNS significantly improved intestinal transit (GC: sham 5.1±0.2 vs abdominal VNS: 7.8±0.6; P<.01) and reduced intestinal inflammation (abdominal VNS: 35±7 vs sham: 80±8 myeloperoxidase positive cells/field; P<.05). In pigs, heart rate was reduced by cervical VNS but not by abdominal VNS. In humans, abdominal VNS significantly reduced LPS-induced IL8 and IL6 production by whole blood. Abdominal VNS is feasible and safe in humans and has anti-inflammatory properties. As abdominal VNS improves POI similar to cervical VNS in mice, our data indicate that peroperative abdominal VNS may represent a novel approach to shorten POI in man.

Single vagus nerve stimulation reduces early postprandial C-peptide levels but not other hormones or postprandial metabolism

A recent study in rheumatoid arthritis (RA) patients using electrical vagus nerve stimulation (VNS) to activate the inflammatory reflex has shown promising effects on disease activity. Innervation by the autonomic nerve system might be involved in the regulation of many endocrine and metabolic processes and could therefore theoretically lead to unwanted side effects. Possible effects of VNS on secretion of hormones are currently unknown. Therefore, we evaluated the effects of a single VNS on plasma levels of pituitary hormones and parameters of postprandial metabolism. Six female patients with RA were studied twice in balanced assignment (crossover design) to either VNS or no stimulation. The patients selected for this substudy had been on VNS therapy daily for at least 3 months and at maximum of 24 months. We compared 10-, 20-, and 30-min poststimulus levels to baseline levels, and a 4-h mixed meal test was performed 30 min after VNS. We also determined energy expenditure (EE) by indirect calorimetry before and after VNS. VNS did not affect pituitary hormones (growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone, prolactin, follicle-stimulating hormone, and luteinizing hormone), postprandial metabolism, or EE. Of note, VNS reduced early postprandial insulin secretion, but not AUC of postprandial plasma insulin levels. Cortisol and catecholamine levels in serum did not change significantly. Short stimulation of vagal activity by VNS reduces early postprandial insulin secretion, but not other hormone levels and postprandial response. This suggests VNS as a safe treatment for RA patients.

Acute Electrical Vagal Nerve Stimulation Exerts Powerful Anti‐inflammatory Effects Through its Nicotinic Action in Rats with Pulmonary Arterial Hypertension

BackgroundsThe inflammatory mechanism plays a crucial role in the pathogenesis of pulmonary arterial hypertension (PAH). Since autonomic dysregulation, that has been reported in PAH, aggravates the inflammatory responses, we hypothesized that electrical vagal nerve stimulation (VNS) may help restore autonomic balance, thereby prevent the worsening of PAH. To clarify the beneficial mechanism of VNS, we investigated how acute VNS impacts on the inflammatory mechanism involved in PAH.MethodsWe used Fischer344 rats weighing 180–200g. As a model of PAH, Sugen5416 was injected (VEGF receptor inhibitor, 20mg/kg, subcutaneously), followed by hypoxia (O2 10%) for 3 weeks and normoxia for 2 weeks. We attached the electrode to the right cervical vagal nerve, applied VNS (20Hz, 0.1–0.15mA, n=5) or sham stimulation (n=4) for 90 minutes, measured hemodynamics and sampled tissues of lung at the end of experiment. We performed western blotting for eNOS and real time PCR for pro‐inflammatory cytokines, anti‐inflammatory cytokine, endothelin‐1 (ET‐1), and α7 nicotinic acetylcholine receptor (α7nAchR).ResultsVNS significantly reduced heart rate by about 10 % from baseline, while did not change mean pulmonary arterial pressure (before VNS: 39.3±8.8, after VNS: 35.9±8.7 mmHg, n.s.) or pulmonary vascular resistance (Fig. 1). Compared to sham, VNS did not alter the eNOS level or mRNA level of ET‐1, whereas attenuated the expressions of pro‐inflammatory cytokines, especially in Tnfa (p&lt;0.05), and that of Il10, an anti‐inflammatory cytokine (p&lt;0.01). In addition, VNS upregulated α7nAchR, the upstream regulatory factor of pro‐inflammatory cytokines (p&lt;0.05) (Fig. 2).ConclusionsVNS exerted the powerful anti‐inflammatory effect through the nicotinic action in PAH model rats. Because the excessive inflammatory responses accelerate pulmonary vascular remodeling in PAH, VNS may serve as a potential therapeutic strategy for PAH. However, how those acute anti‐inflammatory effect of VNS translates into the improvement of PAH remains to be seen.Support or Funding InformationNothing to declare.

Inhibitory responses mediated by vagal nerve stimulation are diminished in stomachs of mice with reduced intramuscular interstitial cells of Cajal

Intramuscular interstitial cells of Cajal (ICC-IM) are closely associated with enteric motor nerve terminals and electrically coupled to smooth muscle cells within the gastric musculature. Previous studies investigating the role of ICC-IM in motor neurotransmission have used indiscriminate electric field stimulation of neural elements within the gastric wall. To determine the role of ICC-IM in transduction of vagally-mediated motor input to gastric muscles electrical and mechanical responses to selective electrical vagal stimulation (EVS) were recorded from gastric fundus and antral regions of wild type and W/WV mice, which lack most ICC-IM. EVS evoked inhibitory junction potentials (IJPs) in wild type muscles that were attenuated or abolished by L-NNA. IJPs were rarely evoked in W/WV muscles by EVS, and not affected by L-NNA. EVS evoked relaxation of wild type stomachs, but the predominant response of W/WV stomachs was contraction. EVS applied after pre-contraction with bethanechol caused relaxation of wild type gastric tissues and these were inhibited by the nitric oxide synthase inhibitor L-NNA. Relaxation responses were of smaller amplitude in W/WV muscles and L-NNA did not attenuate relaxation responses in W/WV fundus muscles. These data suggest an important role for ICC-IM in vagally-mediated nitrergic relaxation in the proximal and distal stomach.

Cardiac vagal control in a knock-in mouse model of dilated cardiomyopathy with a troponin mutation.

The aim of this study was to evaluate cardiac vagal nerve activity and identify the abnormality of cardiac vagal control in heart failure caused by dilated cardiomyopathy (DCM) using a knock-in mouse model with a ΔK210 mutation in the cardiac troponin T gene. The effects of electrical stimulation of the cervical vagal nerve at 5 and 10Hz (peripheral vagal control) and α2-adrennoceptor stimulation by intravenous medetomidine at 0.1mg/kg (central vagal control) were examined in wild-type (WT) mice and DCM mice. Microdialysis technique was applied to the left ventricular myocardium of anesthetized mice and myocardial interstitial acetylcholine (ACh) levels were measured by HPLC as an index of ACh release from cardiac vagal nerve endings. Electrical vagal nerve stimulation increased cardiac interval and myocardial interstitial ACh level in both WT and DCM mice, and these responses did not differ between WT and DCM mice. In contrast, intravenous medetomidine increased cardiac interval and myocardial interstitial ACh level in both WT and DCM mice, but the responses of cardiac interval and myocardial interstitial ACh level were significantly suppressed in DCM mice compared to WT mice. Medetomidine did not affect the myocardial interstitial ACh response induced by vagal nerve stimulation in WT mice. In this mouse model of DCM, peripheral vagal control including ACh release from vagal nerve endings and the postsynaptic response of pacemaker cells was preserved, but central vagal control through α2-adrenoceptors was impaired.

Effect Of Vagus Nerve Stimulation Technique On Ventilatory Function In Acute Exacerbation Of Bronchial Asthma

Background: Asthma when uncontrolled, can severely limit the patient's daily life.Little, no, or excess delivery of the active drug substance will place patients with asthma at substantial risk. As physical therapist it is our responsibility to find physical techniques as substitutions or complementary for medications to reduce its use, dose and/or side effects. Purpose: to measure the efficacy of bilateral non invasive cervical vagus nerve stimulation technique on ventilatory function in acute exacerbation of patient diagnosed with bronchial asthma. Subjects and procedures: 30 patients aged between 21-70 years were assigned randomly into two groups 2/1ratio:vagus nerve stimulation group (A) and placebo group (B) both groups underwent pulmonary function test (flow-volume curve)to measure parameters of pulmonary function test (FVC,FEV1,PEF and FEF25-75%) as a percentage of predicted ,after that the vagus nerve stimulation group underwent positioning of four adhesive electrodes for bilateral non invasive cervical vagus nerve stimulation for 20 minutes and the placebo group underwent positioning of four adhesive electrodes without vagus nerve stimulation for 20 minutes after that spirometry was repeated to measure any changes in both groups. Results: for vagus nerve stimulation group (FVC,FEV1,PEF and FEF25-75%) as a percentage of predicted showed significant increase and reversibility of 10.76% ,10.19% ,10.43% and 10.40% respectively . For sham vagus nerve stimulation group FVC, FEV1 and PEF as a percentage of predicted showed insignificant differences and decline of 0.4%, 1.7% and 5.5% respectively and FEF25-75% showed significant decline of 6.8% . Comparing between the two groups in relative changes %;FVC as % of predicted was indicative of insignificant difference ,for FEV1, PEF and FEF25-75% as % of predicted relative changes % were indicative of statistically significant difference conclusion: a technique bilateral vagus nerve electrical stimulation in patients diagnosed with bronchial asthma in acute exacerbation is an effective technique in reversibility of FVC ,FEV1,PEF and FEF25-75% the improvement may be attributed to stimulation of afferent vagus with central desensitization.

Intravenous electrical vagal nerve stimulation prior to coronary reperfusion in a canine ischemia-reperfusion model markedly reduces infarct size and prevents subsequent heart failure

BackgroundReducing myocardial damage is a prerequisite to prevent chronic heart failure after acute myocardial infarction (AMI). Although vagal nerve stimulation (VNS) has been repeatedly demonstrated to have potent anti-infarct effect, technical difficulties have precluded its clinical application. We developed a novel therapeutic strategy of intravenous VNS (iVNS) and examined whether iVNS administered prior to coronary reperfusion in a canine AMI model reduces infarct size and prevents heart failure. Methods and resultsIn 35 mongrel dogs, we induced ischemia by ligating the left anterior descending coronary artery and then reperfused 3h later (I/R). We transvenously placed a catheter electrode in the superior vena cava and adjusted the stimulation intensity to a level that induced bradycardia but maintained stable hemodynamics (continuous, 5.1±2.1V, 10Hz). We administered iVNS from onset (iVNS-0, n=7) or 90min after onset (iVNS-90, n=7) of ischemia until one hour after reperfusion. Four weeks after ischemia–reperfusion, iVNS markedly reduced infarct size (iVNS-0: 2.4±2.1%, p<0.05 and iVNS-90: 4.5±4.5%, p<0.05) compared with I/R control (I/R: 13.3±2.5%), and improved cardiac performance and hemodynamics. Atrial pacing (n=7) to abolish iVNS-induced bradycardia significantly attenuated the beneficial effects of iVNS. ConclusionsShort-term iVNS delivered prior to coronary reperfusion markedly reduced infarct size and preserved cardiac function one month after AMI. The bradycardic effect plays an important role in the beneficial effect of iVNS. How other mechanisms contribute to the reduction of infarct size remains to be studied.

PWE-001 Transcutaneous Cervical Vagal Nerve Stimulation Exerts an anti-TNF-Alpha Effect in Healthy Humans: Abstract PWE-001 Table 1

Introduction The vagus nerve is the main neural substrate of the parasympathetic nervous system and has a role in modulating inflammation through the cholinergic anti-inflammatory pathway, via inhibition of the production of pro-inflammatory cytokines at the level of both the spleen and the intestinal muscularis. Animal studies have demonstrated that in vagotomised mice, electrical vagal nerve stimulation (VNS), applied distal to the severance, ameliorates the pro-inflammatory cytokine response to lipopolysaccharide. The cervical vagus nerve is located directly under the skin, making it a suitable target for transcutaneous non-invasive VNS (n-VNS). In this pilot study, we sought to evaluate the effect of non- n-VNS on pro-inflammatory cytokines and cardiometrically derived autonomic parameters in humans. Methods In healthy volunteers, heart rate, blood pressure and validated sympathetic, (cardiac sympathetic index) and vagal, (cardiac vagal tone (CVT)) indices were measured directly before, and 24 hours after, 2 minutes of n-VNS applied bilaterally. Venous blood was also drawn and assayed for pro-inflammatory cytokines (tumour necrosis factor-alpha (TNF-a) and interferon-gamma (IFN-g)) and the anti-inflammatory cytokine (interleukin-10) directly prior to, and 24 hours after n-VNS. Results 20 healthy volunteers (13 females, median age 34 years, range 23–55) all tolerated the n-VNS. Table 1 details the changes in the recorded parameters. There was a negative correlation between change in CVT and change TNF-a (rs = 0.45, p Conclusion These results, for the first time in humans, provide preliminary evidence for an anti-TNF-a in response to n-VNS, potentially mediated by an increase cardiac vagal tone. These data, warrant further investigation in immune mediated inflammatory disorders such as those with inflammatory bowel disease. Disclosure of Interest None Declared

OC-069 Randomised Controlled Trial – Transcutaneous Auricular Electrical Vagal Nerve Stimulation Prevents the Development of Acid Induced Esophageal Hypersensitivity

Introduction We have previously demonstrated that physiologically increasing vagal tone, with deep breathing, prevents the development of acid induced oesophageal pain hypersensitivity.1 We aimed to determine whether electrical manipulation of parasympathetic tone influences the development of hypersensitivity in a validated model of acid induced oesophageal pain. Methods Prior to, and following, a 30 minute distal oesophageal infusion of 0.15 M hydrochloric acid, pain thresholds to electrical stimulation were determined in the proximal non-acid exposed oesophagus in 15 healthy subjects (11 male, mean age 30 years, range 21–42). Validated sympathetic (cardiac sympathetic index) and parasympathetic (cardiac vagal tone) parameters were measured at baseline and continuously thereafter. Subjects were randomised in a blinded crossover design to receive either external auricular electrical vagal nerve stimulation (VNS), or sham stimulation, during acid infusion. Results VNS increased cardiac vagal tone (31.6% ± 58.7 vs. -9.6 ± 20.6, p = 0.02) in comparison to sham stimulation. Mixed effects linear regression, controlling for age and gender, demonstrated that VNS prevented the development of acid-induced oesophageal hypersensitivity in comparison to sham stimulation (coefficient 15.4 mA /unit time (95% confidence interval 8.8 to 22.2), p = 0.001). Figure 1 demonstrates the percentage change in pain thresholds following a 30 distal oesophageal acid infusion. Conclusion The development of oesophageal hyperalgesia is prevented by electrically stimulating the vagus nerve by increasing parasympathetic tone. This study provides further evidence of the anti-nociceptive role of the parasympathetic nervous system within the oesophagus. Further work is warranted in patients groups such as those with recalcitrant non-erosive reflux disease. Reference 1 Botha C, et al . Gut 2014. Disclosure of Interest None Declared

Effect of electric vagal stimulation on postoperative cognitive dysfunction in aged rats

Objective To evaluate the effect of electric vagal stimulation on postoperative cognitive dysfunction in aged rats. Methods Thirty healthy Sprague-Dawley rats of both sexes, aged 18-20 months, weighing 390-550 g, were randomly divided into 3 groups(n=10 each)using a random number table: control group(group C), surgery group(group S), and electric vagal stimulation group(group V). Incision of the right carotid sheath was performed, and the vagal nerve was exposed after anesthesia in S and V groups.The right vagus nerve was stimulated for 30 min with continuous electric rectangular pulses(1 ms, 10 Hz, 1-2 V)after surgery in group V. The Morris water maze place navigation test was performed at 4, 3, 2 and 1 days before surgery and 2 days after surgery.The cognitive function was assessed using spatial probe and open field tests conducted at 2 days after surgery.The escape latency, the number of crossing the platform, the number of crossing the grid, the number of standing on the back legs, and the time animals spent in the central square were recorded.After the end of behavioral testing, venous blood samples were collected from the jugular vein for determination of concentrations of serum tumor necrosis factor-alpha(TNF-α), interleukin(IL)-1β and IL-6 using enzyme-linked immunosorbent assay. Results Compared with group C, the number of crossing the platform, the number of crossing the grid, and the number of standing on the back legs were significantly decreased, the escape latency and the time animals spent in the central square were significantly prolonged, and the concentrations of serum TNF-α, IL-1β and IL-6 were significantly increased at 2 days after surgery in group S(P<0.05). Compared with group S, the number of crossing the platform, the number of crossing the grid, and the number of standing on the back legs were significantly increased, the escape latency and the time animals spent in the central square were significantly shortened, and the concentrations of serum TNF-α, IL-1β and IL-6 were significantly decreased at 2 days after surgery in group V(P<0.05). Conclusion Electric vagal stimulation can improve the postoperative cognitive dysfunction in aged rats. Key words: Vagus nerve; Electric stimulation therapy; Aged; Cognitive dysfunction; Postoperative complications

Su1563 Electrical Stimulation of the Abdominal Vagus Nerve Is as Effective as Cervical Nerve Stimulation in Reducing Postoperative Ileus

Su1563 Electrical Stimulation of the Abdominal Vagus Nerve Is as Effective as Cervical Nerve Stimulation in Reducing Postoperative Ileus

520 Randomized Controlled Trial: Transcutaneous Electrical Vagal Nerve Stimulation Prevents the Development of Acid Induced Esophageal Hyperalgesia

520 Randomized Controlled Trial: Transcutaneous Electrical Vagal Nerve Stimulation Prevents the Development of Acid Induced Esophageal Hyperalgesia

Mo1787 Electrical Vagus Nerve Stimulation As an Innovative Treatment in Inflammatory Bowel Diseases

Mo1787 Electrical Vagus Nerve Stimulation As an Innovative Treatment in Inflammatory Bowel Diseases

Vagus nerve electrical stimulation inhibits serum levels of S100A8 protein in septic shock rats.

The vagus nerve and the released acetylcholine exert anti-inflammatory effects and inhibit septic shock. However, their detailed mechanisms remain to be elucidated. The present study aimed to investigate the effects of vagus nerve electrical stimulation on serum S100A8levels in septic shock rats. A total of36male Sprague-Dawley rats were randomly divided into six equal groups: i)Sham group, receiving sham operation; ii)CLP group, subjected to cecal ligation and puncture (CLP) to establish a model of polymicrobial sepsis; iii)VGX group, subjected to CLP and bilateral cervical vagotomy; iv)STM group, subjected to CLP, bilateral cervical vagotomy and electrical stimulation on the left vagus nerve trunk; v)α‑bungarotoxin (BGT) group was administered α‑BGT prior to electrical stimulation; vi)Anti‑receptor for advanced glycation end products (RAGE) group, administered intraperitoneal injection of anti‑RAGE antibody prior to electrical stimulation. The right carotid artery was cannulated to monitor mean artery pressure (MAP). The serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were measured to assess the liver function. Serum S100A8and advanced glycation end product (AGE) levels were measured using enzyme‑linked immunosorbent assays. The expression of hepatic RAGE was determined by western blotting. The present study revealed that Sprague‑Dawley rats exhibited progressive hypotension and significantly increased serum AST and ALT levels following CLP challenge compared with the sham group. The levels of S100A8and AGEs, and the protein expression of hepatic RAGE were significantly increased following CLP compared with the sham group. Vagus nerve electrical stimulation significantly prevented the development of CLP‑induced hypotension, alleviated the hepatic damage, reduced serum S100A8 and AGEs production, and reduced the expression of hepatic RAGE. The inhibitory effect of vagus nerve electrical stimulation was reversed by pre-treatment with α-BGT and enhanced by pre-treatment with anti-RAGE antibody. In conclusion, vagus nerve electrical stimulation may produce a protective effect on septic shock in rats by decreasing the production of S100A8.

DOP024. Electrical vagus nerve stimulation as an innovative treatment in inflammatory bowel diseases

DOP024. Electrical vagus nerve stimulation as an innovative treatment in inflammatory bowel diseases

Modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity

The parasympathetic nervous system, whose main neural substrate is the vagus nerve, exerts a fundamental antinociceptive role and influences gastrointestinal sensori-motor function. Our research question was to whether combined electrical and physiological modulation of vagal tone, using transcutaneous electrical vagal nerve stimulation (t-VNS) and deep slow breathing (DSB) respectively, could increase musculoskeletal pain thresholds and enhance gastroduodenal motility in healthy subjects. Eighteen healthy subjects were randomized to a subject-blinded, sham-controlled, cross-over study with an active protocol including stimulation of auricular branch of the vagus nerve, and breathing at full inspiratory capacity and forced full expiration. Recording of cardiac derived parameters including cardiac vagal tone, moderate pain thresholds to muscle, and bone pressure algometry, conditioned pain modulation using a cold pressor test and a liquid meal ultrasonographic gastroduodenal motility test were performed. Cardiac vagal tone increased during active treatment with t-VNS and DSB compared to sham (p=0.009). In comparison to sham, thresholds to bone pain increased (p=0.001), frequency of antral contractions increased (p=0.004) and gastroduodenal motility index increased (p=0.016) with active treatment. However, no effect on muscle pain thresholds and conditioned pain modulation was seen. This experimental study suggests that this noninvasive approach with combined electrical and physiological modulation of vagal tone enhances gastroduodenal motility and reduces somatic pain sensitivity. These findings warrant further investigation in patients with disorders characterized with chronic pain and gastrointestinal dysmotility such as functional dyspepsia and irritable bowel syndrome.

Cholinergic Stimulation Improves Hemostasis in a Hemophilia Mouse Model

Background: Management of bleeding in hemophilia patients that develop inhibitors remains a challenging clinical problem. Current bypassing agents are expensive, not universally effective and have pro-thrombotic potential. New approaches, including bispecific antibodies and others have shown potential but still require additional testing in clinical trials. As such, there is a clear need for alternative therapeutic options.The inflammatory reflex is an endogenous neuro-immune pathway that monitors and regulates systemic inflammation via the vagus nerve. The afferent vagus nerve can inform the brain of increased peripheral inflammation. The brain then down-regulates systemic inflammation via increased efferent vagus nerve signaling to the spleen, a mechanism referred to as the cholinergic anti-inflammatory pathway (KJ Tracey, Nat Rev Imm 9(6), 2009). Our previous work has demonstrated that activation of the cholinergic anti-inflammatory pathway via direct electrical vagus nerve stimulation (VNS) or by systemic administration of a pharmacological cholinergic agonist inhibits proinflammatory cytokine production and protects against lethal systemic inflammation (JR Fritz, Bioelectron Med 1(1), 2014).While studying the cholinergic anti-inflammatory pathway in mice, we observed that cholinergic stimulation reduces traumatic hemorrhage. To explore this observation further, we developed a porcine model of soft tissue trauma and hemorrhage. Electrical stimulation of the cervical vagus nerve significantly reduces total blood loss and bleeding time in pigs. Electrical vagus nerve stimulation also significantly increases local thrombin generation at the site of injury, whereas systemic thrombin concentrations remain unchanged (CJ Czura, Shock 33(6), 2010).Aim: To evaluate the beneficial hemostatic effects of cholinergic stimulation on tail hemorrhage in a mouse model of hemophilia A.Methods: Male 8-12-week-old, factor VIII knockout mice (B6;129S-F8<tm1Kaz>/J, Jackson Labs) receive either electrical cervical vagus nerve stimulation (1 V, 30 Hz, 2 ms pulse for 5 minutes) or sham stimulation under anesthesia (ketamine/xylazine 140/16 mg/kg, ip) five minutes before 2 mm distal tail transection. In separate experiments, nicotine (2 mg/kg, ip) or saline is administered 17 minutes before injury. Mouse tails are placed into a 37¡ÆC normal saline bath for five minutes prior to injury. After injury, tails are placed into 50 mL conical tubes filled with 37¡ÆC normal saline and allowed to bleed freely for a total of ten minutes. Total shed blood volume and active bleeding time are recorded, and systemic and local thrombin generation (thrombin-antithrombin complex) is measured via ELISA. Complete blood counts are measured via standard clinical assay.Results: Vagus nerve stimulation significantly reduces total blood loss and bleeding time by 75% and 18%, respectively. Administration of nicotine significantly reduces total blood loss and bleeding time by 79% and 41%, respectively (Fig. 1). Nicotine significantly increases local thrombin generation compared with vehicle controls, whereas systemic thrombin generation is unchanged. There are no differences in circulating platelet counts or hematocrit levels.Conclusions: Cholinergic stimulation results in rapid and specific improvements in hemostasis during traumatic hemorrhage in a mouse model of hemophilia A. The molecular mechanisms of localized thrombin generation remain an active area of research. Future clinical trials are necessary to determine if cholinergic stimulation is an efficacious, safe and cost-effective therapy for hemophilia A patients. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.