Tu1450 Aberrant Swallow: Swallow Without Pharyngeal Contractile Wave

AGA Abstracts

shown the GI pharmacological effects of allyl isothiocyanate (AITC), a pungent ingredient of wasabi and a TRPA1 channel activator. It was found that 1) AITC impairs tight junction barrier in primary cultures of rat stomachs (Capsaicin 2014, DOI: 10.5772/57289), and 2) no gastric damage by AITC was observed in ex-vivo rat stomachs (Gastroenterology, 138 (5), S-721, 2010). Therefore, this study is to establish a rodent model of impaired gastric motility resulting from gastric low-grade inflammation by AITC, which is reliable produce to evaluate therapeutic agents of FD. METHODS: Gastric low-grade inflammation: Male SD rats were used after 18 h-fasting. Stomachs mounted on ex-vivo chambers under urethaneanesthetized rats treated with omeprazole, were perfused with 50 mM HCl. Vascular permeability (Pontamine Sky blue) was measured during and 90 min after exposure to AITC (0.33~30 mM) for 30 min. A-967079 (10 mM), a TRPA1 channel blocker, was co-applied with AITC. Gastric motility: Male ddY mice were used after 15 h-fasting. Gastric motility was measured by 13C-acetic acid breath test in conscious mice. AITC (1-100 mg/kg, p.o.) was given 30 min before the measurement of motility. Prokinetic agents including itopride (30, 100 mg/kg), mosapride (0.1-1 mg/kg), and neostigmine (30 μg/kg), or a therapeutic agent for FD acotiamide (10, 30 mg/kg) was given s.c. 40 min before the measurement. RESULTS: Gastric low-grade inflammation: AITC increased vascular permeability in exvivo rat stomachs in concentration-dependent manner, which is obviously increased over 10 mM of AITC. However, increased vascular permeability induced by AITC was not inhibited by A-967079. Gastric motility: AITC (%30 mg/kg) impaired gastric motility in dose-dependent manner in conscious mice, those impaired motility was reversible to normal levels for 24 h after treatment of AITC. Decreased gastric motility induced by AITC (80 mg/ kg) was restored by the pretreatment of itopride, mosapride (1 mg/kg), or neostigmine. Acotiamide (100 mg/kg) also recovered decrease of gastric motility. Gastric macroscopic damage was not observed at the end of the experiments and 24 h after treatment of AITC (80 mg/kg). CONCLUSION: These results suggest that AITC induced gastric low-grade inflammation in the rodent stomach, which is independent on TRPA1 channels and no gastric mucosal damage. In addition, AITC produced the impaired gastric motility in conscious mice, whose phenomenon was reversible by prokinetic agents and a therapeutic agent for FD. This rodent model might be useful tool to develop new therapeutic agents for FD.

then CCK was IP injected. The amounts of the mixture left in the stomach were measured at 2 hours after the injection and gastric emptying rate was calculated. Study on appetite. Rats were fed overnight. CCK was IP injected to the rats who had free access to food and water. The amounts of food were measured at 1 and 2 hours after the injection. In some experiments, CRF or urocortin1 UCN1 was IP injected and the interaction with CCK on gastric emptying was examined. In another study, restraint stress was given to rats and the interaction with CCK was measured. [Results] 1. CCK dose-dependently inhibited gastric emptying (control : CCK10nmol/rat 87.9 : 65.6% p<0.01). 2. CCK (10nmol/rat) significantly inhibited food intake for 1 and 2hours after the injection (control : CCK for 1 hr 1.6±0.21 : 0.4±0.1g, p<0.001). 3. CRF significantly inhibited food intake for 1 and 2 hours after the injection.However, there was no interactive action between CCK and CRF on food intake. 4. UCN1 (3nmol/rat) inhibited food intake at 1 and 2 hours (control : UCN1 for 1 hr 1.6±0.21 : 0.5±0.11g, p<0.001). 5.There was an additive action between CCK and UCN 1 on food intake (control:CCK:CCK+UCN1 2.7±0.25:1.6±0.19:0.9±0.22g p<0.001 or p<0.05). 6. Restraint stress amplified suppressive effect of CCK on gastric emptying (Tmax control : CCK : CCK + stress 81.9±4.3 : 74.6±4.3 : 46.3±6.6%, p<0.01) and food intake (control : CCK : CCK + stress for 1hr 2.48±0.28 : 0.86±2.78 : 0.11±0.05g p<0.001 or p<0.05). [Conclusion] CCK inhibits gastric emptying.CCK also inhibits food intake. The combination of CCK with UCN 1 or restraint stress amplified the suppression of gastric emptying and food intake by CCK. The result suggests that stress might amplify anorexic effects of CCK that might be the possible pathogenesis for postprandial distress syndromes of FD. Tu1450 Aberrant Swallow: Swallow Without Pharyngeal Contractile Wave Daniel Lew, Aniko Szabo, Benson T. Massey, Reza Shaker, Arash Babaei BACKGROUND: Even though pharyngeal and upper esophageal sphincter (UES) data are frequently captured during esophageal high-resolution manometry (HRM), abnormalities of above segments have been poorly studied. Swallows in HRM can be readily identified by several topographic characteristics such as pharyngeal contractile wave, UES relaxation, UES post-deglutitive contraction and ensuing esophageal striated muscle contraction. In certain manometry studies, we have noticed a unique pattern of "aberrant swallows" that have all pressure characteristics of deglutition, except pharyngeal contraction wave. AIM: Retrospective review of clinical HRM studies to identify the prevalence of aberrant swallows and their associated clinical features. METHODS: We reviewed 1784 clinical HRM studies performed from 2007-2014 at a tertiary referral center. Studies were screened for the presence of an adequate number ( >3 sensors) of pharyngeal sensors. Individual manometry studies were reviewed for presence of aberrant swallows during manometry. If aberrant swallows were identified, the following pressure metrics (baseline UES pressure, nadir UES pressure, peak UES pressure, pharyngeal contractile peak pressure) were measured. Electronic medical records of all patients were reviewed to ascertain the associated clinical findings with aberrant swallows. RESULTS: 560 HRM studies were identified that had more than 3 pharyngeal sensors. Only 10/560 patients (1.7%) demonstrated aberrant swallow during esophageal manometry. Prevalence of aberrant swallows in each subject is presented in Table 1. Overall aberrant swallows were more commonly observed during dry swallows (67% vs 35%, p<0.05). Half of patients with aberrant swallow (5/10) had history of Nissen fundoplication (p<0.001) and two had history of cervical fusion and vertebral hardware placement (p<0.01). The remainder of patients had history of total laryngectomy, inclusion body myositis and achalasia. None of these 10 patients had GERD, Laryngopharyngeal reflux, non-cardiac chest pain or ineffective esophageal motility. CONCLUSION: Pharyngeal contractile wave is rarely absent during clinical high-resolution manometry studies. Despite association with certain clinical findings such as prior Nissen fundoplication and cervical vertebral intervention, this retrospective study is unable to suggest causal relationship. None of the patient with aberrant swallow had common gastrointestinal ailments such as GERD or esophageal dysmotility.

Tu1448 Gabapentin/Pregabalin Improves Symptoms in Patients With Upper GI Functional Disease and Gut Dysmotility Andrea H. Thurler, Laurence Guay, Kyle Staller, Braden Kuo Introduction: Current options for the treatment of discomfort in functional upper GI syndromes are limited, especially in the presence of documented motility abnormalities such as gastroparesis and slow-transit constipation. The anticonvulsants gabapentin and pregabalin are thought to treat neuropathic pain with the advantage of having no effects on gut transit. However, there are limited data supporting their use in functional GI disease. We reviewed our clinical experience with the use of these medications for upper GI predominant functional GI disorders. Methods: Patients presenting to a tertiary GI motility clinic with upper gutpredominant symptoms including early satiety, epigastric abdominal pain, bloating, and chronic nausea were considered for treatment with gabapentin or pregabalin. Treated patients were included in the analysis if they completed pre- and post-treatment Patient Assessment of Gastrointestinal Symptom Severity Index (PAGI-SYM) questionnaires (score range from least 0 to 5 worst), which are regularly administered to our patient population. Results: Our cohort consisted of 52 patients treated with gabapentin seen in our clinic from August 2010 to September 2014 with at least 3 months on gabapentin or pregabalin, of which 41 had complete pre- and post-treatment PAGI-SYM data for inclusion in our final analysis. The cohort was predominantly female (n=34, 68.4%) with a mean age of 46.5±16.7 years. Comorbid anxiety was diagnosed in 29 (76.3%) patients and 26 (68.4%) had depression. Presenting complaints included epigastric abdominal pain (92.1%), gas/bloating (89.5%), and chronic nausea (84.2%). Comorbid dysmotility included gastroparesis (n=8, 21.1%), small bowel dysmotility (n=4, 10.5%), constipation (n=29, 76.3%), and diarrhea (n=10, 26.3%). Thirty-seven (90.2%) patients were prescribed gabapentin, and 4 (9.8%) patients received pregabalin over a median on-medication time of 9 months at a median daily dose of 900 mg. Overall PAGI-SYM mean score of 1.99 baseline significantly improved by decrease of 0.32±0.80 (P=0.01). The overall scores were driven primarily by the change in the upper abdominal pain subscale from mean baseline 2.29 (difference of -0.57±0.51, P=0.02), bloating subscale mean baseline 2.71 (difference of -0.55±1.39, P=0.01), and post-prandial fullness subscale mean baseline 2.02 (difference of -0.38±0.82, P=0.004). Conclusion: Our cohort demonstrates significant improvement in upper GI symptoms in patients treated with gabapentin and pregabalin as assessed by the PAGI-SYM. These data suggest that pregabalin or gabapentin, as GI motility-neutral agents, may be emerging options for the treatment of patients with functional upper GI disorders and could carry fewer GI side effects in patients with pre-existing dysmotility. Randomized, placebo-controlled studies are essential to supplement our findings. Tu1449 Stress and Stress-Related Peptide Amplify the Anorexic Actions of Cholecystokinin Naomi Yamaguchi, Eriko Hosomi, Mitsuko Ochiai, Shoki Ro, Kenjiro Hayashi, Sumiko Nagoshi, Koji Yakabi [Background/Aim] Rome III classification of functional dyspepsia (FD) emphasizes postprandial syndromes in FD that suggest an importance of the actions of GI hormones induced by food intake in the pathophysiology of FD. Among many gastrointestinal hormones, cholecystokinin (CCK) has been well known to suppress appetite and gastric emptying. CCK is possible to be involved in the pathophysiology for FD. In the pathophysiology of FD, psychological stress seems to have important roles in the mechanism for FD, we undertook to clarify whether stress and stress-related peptides influence the action of CCK on appetite and gastric emptying. As stress, we gave restraint stress and corticotropinreleasimg factor (CRF) and urocortin1 (UCN1) injection intraperitoneally (IP). [Methods] Study on gastric emptying. Male Sprague-Dawley (SD) rats were fasted overnight, and 1 mL of mixture of food and glass beads was given into the stomach with polyethylene tube and

AGA Abstracts

S-894

Tu1451 Correlative Patterns of Upper Esophageal Sphincter Contractility to Skeletal and Smooth Muscle Esophageal Segments: Implications for Neuromuscular Control Megan K. Lutz, Benson T. Massey, Mark Kern, Reza Shaker, Arash Babaei

UES: upper esophageal sphincter

Background: Efferent control of motor activity in the striated and smooth muscle esophageal segments in man reside in separate brainstem nuclei. These different functional units are readily identifiable on high resolution manometry (HRM). Motor responses within the smooth muscle segment are known to be highly variable and dependent upon parameters such as bolus volume. It is unknown whether motor function in the striated muscle segment responds identically to different afferent inputs. Spontaneous "dry" swallows provide a platform to study motor variability that is not artificially constrained by prescribed bolus volumes and times of deglutition. Aim: 1) Define the variability and correlation of pressure phenomena during deglutitive UES after-contraction and proximal esophageal contractions and 2) determine concordance of contractile activity in the striated and smooth segments. Methods: Esophageal HRM of 10 young healthy subjects were studied. Temporally isolated dry swallows without interference of bolus transport, and other swallows were chosen for analysis. We analyzed UES and esophageal pressure parameters using smart mouse tool in color contour plots. Esophageal contractile wave segments above and below the transitional zone were identified. Both temporal and amplitude characteristics of UES after-contraction and segmental esophageal contractile pressure waves were recorded. Linear regression analysis was used to determine correlation of pressure parameters. Results: The manometric length of UES, esophageal proximal striated muscle and distal smooth muscle segments were 3 + 0.5, 4 + 1 cm and 13 + 3 cm respectively. There was significant intra- and inter-subject variability in contractile parameters in the two striated muscle segments. During the first phase of UES postdeglutitive after-contraction pressure dropped down expeditiously from its peak contraction while during the second phase, UES tone declined back to baseline slowly. Duration and vigor of the first phase of UES post-deglutitive contraction significantly correlated with duration and contraction amplitude of proximal striated esophagus. This correlation did not exist with esophageal smooth muscle segment. Conclusion: Despite considerable variability in contractile activity from swallow-to-swallow, the motor activity in upper esophageal sphincter and proximal esophageal striated muscle segment is congruous, consistent with a shared locus of control. The lack of correlation between contractility of the esophageal striated and smooth muscle segments is consistent with being served by two different control centers that are not tightly linked in their response to afferent stimuli.

*-P<0.001 Tu1453 Pharyngeal Bolus Transit in a Human Model of Restricted Swallowing; A Multi-Channel Intraluminal Impedance Study Ling Mei, Gokulakrishnan Balasubramanian, Rachael Manderle, Mark Kern, Patrick Sanvanson, Hongmei Jiao, Reza Shaker Impedance changes during swallow have been proposed to reflect the bolus kinematics as a surrogate. Using this technique, our Aim was to determine and characterize the pharyngeal bolus kinematics/transit in a human model of Restricted Swallowing (RS). Methods: We studied 10 heathy volunteers (6 males, 49 ± 26 years). To induce restricted swallowing, we used a handmade device. This device is comprised of an inflatable concave cushion (13.5x9.5cm) that molds over the larynx and a Velcro strap that could be comfortably worn around the neck holding the device in place and in full contact with the larynx. Inflation of the cushion, results in cupping of the convexity of the larynx inducing resistance to the anterior and superior excursion of the hyo-laryngeal complex during swallowing. Magnitude of the restriction to laryngeal excursions and swallowing is controlled by the pressures applied to inflate the molding cushion. Using this technique, we studied the effect of 0 and 40mmHg restricting pressure on the pharyngeal bolus transit during swallowing of 5 and 10ml half-normal saline in upright position. Pharyngeal and UES impedance changes were recorded by four and two impedance couplets, respectively. Bolus transit time was measured as the time between the 50% drop (representing head of the bolus) in impedance of the most proximal couplets to 50% recovery (representing tail of the bolus) in impedance of the most distal couplets in the pharynx. UES transit time was measured by similar approach. Results: In the pharynx, the bolus transit time for both 5 and 10ml volumes were significantly shorter in the restricted swallows compared to non-restricted swallows, p<0.05 (table). Within the segment of UES, there was no statistical difference in bolus transit time between restricted and non-restricted swallows. Bolus volume did not affect the transit time in either pharynx or the UES significantly. Conclusions: The proposed human model of restricted swallowing significantly affects the kinematics of the swallowed bolus in the pharynx as evidenced by reduction in the bolus transit time. This effect is absent in the UES. This model has the potential to help in better understanding of the pathophysiology of a number of clinical conditions associated with abnormal laryngeal excursions and pharyngeal shortening such as those observed after radiation therapy and stroke. Supported in part by R01DK025731 and P01DK068051. Pharyngeal and UES bolus transit time

Tu1452 Dynamics of Pharyngeal Contraction During Vocalization, Cough and Swallowing Maneuvers Using High Resolution Manometry Gokulakrishnan Balasubramanian, Mark Kern, Rachael Manderle, Ling Mei, Patrick Sanvanson, Arash Babaei, Reza Shaker Introduction: Pharynx is anatomically a complex organ comprised of several muscle groups with different neural control mechanisms. This anatomical complexity mirrors the functional complexity of the pharynx being essential for deglutition, phonation and several respiratory functions such as coughing and breathing. Despite the availability of electromyographic and radiologic data, manometric data on contribution of different muscle component of the pharynx to the above mentioned functions remains scarce The reason for this scarcity has been the lack of a reliable recording device with acceptable sensitivity and specificity for measuring a wide range of pressures with different rise rates from the entire length of the pharynx during various function. With advent of HRM these shortcomings are remedied. The Aim of the present study therefore was to characterize and compare the pharyngeal pressure phenomena during swallowing, coughing and vocalization. Methods: We studied 9 healthy volunteers (mean age: 51± 25Y, 4F) using a high resolution manometry catheter with 36 sensor spaced 1 cm apart positioned such that it spanned the entire pharyngeal contractile zone, upper esophageal sphincter (UES) and proximal esophagus. We studied each of the followingsX3: vocalization maneuvers (AAA, OOO, EEE and KKK) for ten seconds cough and near dry swallow (0.5ml). We evaluated the pressure waves at each site in the

*p<0.05 RS: Restricted Swallow by 40mmHg pressure No RS: Without restricting pressure

S-895

AGA Abstracts

AGA Abstracts

pharynx and used e-sleeve for evaluation of UES during each of the above mentioned tasks. Statistical analysis was done using repeated measure ANOVA adjusted for multiple comparisons by Bonferroni method. Results: Vocalization maneuvers caused increased pharyngeal pressures in the most distal sensors from UES. Pharyngeal contraction was initiated in the distal sensors from UES while proximal sensors from UES showed pharyngeal pressurization during vocalization maneuvers like AAA, OOO, EEE, and KKK while there was simultaneous contraction of UES and pharynx overlying the distal sensors from UES during cough. Peak pharyngeal pressures in the distal channels from UES are comparable during each of the vocalization maneuvers while KKK maneuver produced higher peak pharyngeal pressures in the proximal sensors from UES when compared with peak pharyngeal pressures during other vocalization maneuvers (AAA, OOO, and EEE). Increase in baseline UES pressure during cough was significantly higher than those during vocalization maneuvers (P=0.03). Conclusion: Pharyngeal pressure wave and UES contraction were significantly different during deglutition compared to vocalization and coughing maneuvers. Pharyngeal muscles involved in vocalization maneuvers may not be the same as that of deglutition. Supported in part by R01DK025731 and P01DK068051. Table 1: Change in UES Pressure during vocalization and cough