Revealing the material basis and mechanism for the inhibition of intestinal peristalsis by Zingiber officinale Roscoe through integrated metabolomics, serum pharmacochemistry, and network pharmacology.

Abnormal relaxation and contraction of intestinal smooth muscle can cause various intestinal diseases. Diarrhea is a common and important public health problem worldwide in epidemiology. Zingiber officinale Roscoe (fresh ginger) has been found to treat diarrhea, but the material basis and mechanism of action that inhibits intestinal peristalsis remain unclear. Metabolomics and serum pharmacology were used to identify differential metabolites, metabolic pathways, and pharmacodynamic substances, and were then combined with network pharmacology to explore the potential targets of ginger that inhibit intestinal peristalsis during diarrhea treatment, and the targets identified were verified using molecular docking and molecular dynamic simulation. We found that 25 active components of ginger (the six most relevant components), 35 potential key targets (three core targets), 40 differential metabolites (four key metabolites), and four major metabolic pathways were involved in the process by which ginger inhibits intestinal peristalsis during diarrhea treatment. This study reveals the complex mechanism of action and pharmacodynamic material basis of ginger in the inhibition of intestinal peristalsis, and this information helps in the development of new Chinese medicine to treat diarrhea and lays the foundation for the clinical application of ginger.

Spasmolytic Effects of Aphanizomenon Flos Aquae (AFA) Extract on the Human Colon Contractility.

The blue-green algae Aphanizomenon flos aquae (AFA), rich in beneficial nutrients, exerts various beneficial effects, acting in different organs including the gut. Klamin® is an AFA extract particularly rich in ß-PEA, a trace-amine considered a neuromodulator in the central nervous system. To date, it is not clear if ß-PEA exerts a role in the enteric nervous system. The aims of the present study were to investigate the effects induced by Klamin® on the human distal colon mechanical activity, to analyze the mechanism of action, and to verify a ß-PEA involvement. The organ bath technique, RT-PCR, and immunohistochemistry (IHC) were used. Klamin® reduced, in a concentration-dependent manner, the amplitude of the spontaneous contractions. EPPTB, a trace-amine receptor (TAAR1) antagonist, significantly antagonized the inhibitory effects of both Klamin® and exogenous ß-PEA, suggesting a trace-amine involvement in the Klamin® effects. Accordingly, AphaMax®, an AFA extract containing lesser amount of ß-PEA, failed to modify colon contractility. Moreover, the Klamin® effects were abolished by tetrodotoxin, a neural blocker, but not by L-NAME, a nitric oxide-synthase inhibitor. On the contrary methysergide, a serotonin receptor antagonist, significantly antagonized the Klamin® effects, as well as the contractility reduction induced by 5-HT. The RT-PCR analysis revealed TAAR1 gene expression in the colon and the IHC experiments showed that 5-HT-positive neurons are co-expressed with TAAR1 positive neurons. In conclusion, the results of this study suggest that Klamin® exerts spasmolytic effects in human colon contractility through ß-PEA, that, by activating neural TAAR1, induce serotonin release from serotoninergic neurons of the myenteric plexus.

Effectiveness of oral phloroglucinol as a premedication for unsedated esophagogastroduodenoscopy: A prospective, double-blinded, placebo-controlled, randomized trial.

BACKGROUND: Anti-spasmodic agents are commonly injected during esophagogastroduodenoscopy (EGD) to improve visualization of the gastric mucosa by inhibiting gastrointestinal (GI) peristalsis. The availability of oral anti-spasmodic agents would increase convenience. In this study, we evaluated the effectiveness of oral phloroglucinol (Flospan®) as a premedication for unsedated EGD. METHODS: A prospective, double-blinded, placebo-controlled, randomized controlled trial was conducted in a tertiary hospital. Individuals scheduled to undergo unsedated EGD were randomly assigned to receive either oral phloroglucinol or matching placebo 15 min before EGD. The primary outcome was the rate of complete gastric peristalsis suppression. Outcomes were assessed by independent investigators according to the classification of gastric peristalsis and ease of intragastric observation at the beginning (Period A) and end (Period B) of EGD. RESULTS: Overall, 71 phloroglucinol-treated and 71 placebo-treated participants (n = 142 total) were included. The phloroglucinol group showed significantly higher proportions of participants with complete gastric peristalsis suppression than the placebo group (22.5% vs. 9.9%, P = 0.040). The ease of intragastric observation was significantly better in the phloroglucinol group than in the placebo group at Periods A (P < 0.001) and B (P = 0.005). Patients in both groups had comparable adverse events and showed willingness to take the premedication at their next examination. CONCLUSIONS: Oral phloroglucinol significantly suppressed gastrointestinal peristalsis during unsedated EGD compared with placebo (Clinical trial registration number: NCT03342118).

Effects of codeine on esophageal peristalsis in humans using high resolution manometry.

BACKGROUND AND AIM: Opioid receptors agonists have been demonstrated to impair lower esophageal sphincter (LES) relaxation and induce spastic esophageal dysmotility, but little was known for their impact on distension-induced secondary peristalsis. The aim of the study was to investigate the hypothesis whether acute administration of codeine can influence physiological characteristics of primary and secondary peristalsis in healthy adults. METHODS: Eighteen healthy volunteers (13 men, mean age 27.5 years, aged 20-43 years) underwent high resolution manometry (HRM) with a catheter containing an injection port in mid-esophagus. Secondary peristalsis was performed with 10 and 20 mL rapid air injections. Two different sessions including acute administration of codeine (60 mg) or the placebo were randomly performed. RESULTS: Codeine significantly increased 4-s integrated relaxation pressure (IRP-4s) (P = 0.003) and shortened distal latency (DL) (P = 0.003) of primary peristalsis. The IRP-4s of secondary peristalsis was also significantly higher after codeine than the placebo during air injections with 10 mL (P = 0.048) and 20 mL (P = 0.047). Codeine significantly increased the frequency of secondary peristalsis during air injections with 10 mL than the placebo (P = 0.007), but not for air injection with 20 mL (P = 0.305). CONCLUSIONS: In addition to impair LES relaxation and reduce distal latency of primary peristalsis, codeine impairs LES relaxation of secondary peristalsis and increases secondary peristaltic frequency. Our study supports the notion in human esophagus that the impact of opioids on peristaltic physiology appears to be present in both primary and secondary peristalsis.

The bitter tastant denatonium benzoate has no influence on the number of transient lower esophageal sphincter relaxations in health.

BACKGROUND: Administration of a bitter compound can alter the intragastric pressure (IGP) after a meal. Additionally, a negative correlation between IGP and the number of transient lower esophageal sphincter relaxations (TLESRs) has been demonstrated. However, the effect of a bitter tastant on the number of TLESRs and subsequent reflux episodes has never been investigated and it is unclear whether bitter food items should be avoided in gastro-esophageal reflux disease. We hypothesize that bitter administration in healthy volunteers (HVs) will lead to an increase in the number of TLESRs. METHODS: After an overnight fast, 20 female HVs (36 years [21-63]) underwent a high-resolution impedance manometry (HRiM) measurement. After placement of the HRiM probe, 0.1 ml/kg of a 10 mM denatonium benzoate solution (bitter) or an identical volume of water (placebo) was administered directly into the stomach. The number of TLESRs and reflux episodes was quantified 30 min before and 2 h after consumption of a high caloric meal. KEY RESULTS: There was no significant difference in the number of TLESRs or reflux episodes between the bitter and placebo condition. Additionally, no differences were observed in the nature (gas or liquid) and extent of reflux events. Lower esophageal sphincter pressures dropped significantly in the first postprandial hour to start recovering slowly back to baseline values during the second postprandial hour (p < 0.0001), without any difference between both conditions. CONCLUSIONS & INTERFERENCES: Administration of the bitter tastant denatonium benzoate has no influence on the number of TLESRs or reflux episodes.

Effect of prucalopride on sildenafil-induced inhibition of esophageal peristalsis in healthy adults.

BACKGROUND AND AIM: Prucalopride, a high-affinity 5-hydroxytryptamine 4 receptor agonist, promotes esophageal peristalsis, while phosphodiesterase type 5 inhibitor sildenafil inhibits esophageal peristalsis. The present study was aimed to evaluate whether prucalopride would augment esophageal peristalsis subsequent to the application of sildenafil. METHODS: Seventeen healthy adults underwent high-resolution manometry by a catheter with one injection port located in the mid-esophagus. Secondary peristalsis was assessed by rapid air injections after water swallows. Two sessions were randomly performed including acute administration of sildenafil 50 mg after pretreatment with prucalopride or the placebo. RESULTS: The frequency of primary peristalsis subsequent to the administration of sildenafil was significantly increased by prucalopride (P = 0.02). Prucalopride also significantly increased distal contractile integral of primary peristalsis subsequent to the administration of sildenafil (P = 0.03). No difference in the frequency of secondary peristalsis subsequent to the administration of sildenafil for air injects of 10 mL (P = 0.14) or 20 mL (P = 0.21) was found between prucalopride and placebo. Prucalopride did not change distal contractile integral of secondary peristalsis subsequent to the administration of sildenafil for air injections of 10 mL (P = 0.09) or 20 mL (P = 0.12). CONCLUSIONS: Prucalopride modulates sildenafil-induced inhibition of primary peristalsis by increasing its effectiveness and peristaltic wave amplitude. Our findings suggest that activation of 5-hydroxytryptamine 4 receptors plays a role in mediating sildenafil-induced inhibition of esophageal primary peristalsis rather than secondary peristalsis.

Effects of phosphodiesterase-5 inhibitor sildenafil on esophageal secondary peristalsis: Studies with high-resolution manometry.

BACKGROUND AND AIM: Secondary peristalsis contributes to the clearance of retained refluxate from the esophagus. Sildenafil, a phosphodiesterase-5 inhibitor, inhibits primary esophageal peristalsis, but its effects on secondary peristalsis remain unknown. This study sought to investigate whether sildenafil could influence physiological characteristics of secondary peristalsis by applying high-resolution manometry (HRM). METHODS: Seventeen healthy volunteers (15 men and 2 women, aged 30.2 ± 6.4 years) underwent two HRM studies on separate days following the administration of either a placebo or 50 mg of sildenafil in a random order. Both studies were performed using a water-perfused HRM catheter containing one air injection channel positioned in the mid-esophagus. Secondary peristalsis was stimulated by a rapid mid-esophageal injection of 10 or 20 mL of air 1 h after the administration of either the placebo or sildenafil. The frequency and distal contractile integral of secondary peristalsis were then compared. RESULTS: Complete secondary peristalsis triggered by the 20-mL air injection was more frequent than observed with the 10-mL air injection (P < 0.001). The vigor of secondary peristalsis triggered by the injection of either volume of air was lower than that of primary peristalsis (P < 0.001). Sildenafil significantly reduced the success rate (P ≤ 0.001) and vigor (P < 0.001) of secondary peristalsis relative to the effects of the placebo at both distension volumes. CONCLUSIONS: Secondary peristalsis can be successfully triggered by rapid air injection during HRM. Sildenafil reduces both the success rate and the vigor of secondary peristalsis, similar to that seen with primary peristalsis.

High-resolution manometry reveals different effect of polyethylene glycol, bisacodyl, and prucalopride on colonic motility in healthy subjects: An acute, open label, randomized, crossover, reader-blinded study with potential clinical implications.

BACKGROUND: Polyethylene glycol (PEG), bisacodyl, and prucalopride have been reported to be more effective than placebo in treating patients with constipation but about 50% of the patients still do not respond to these medications. Only bisacodyl and prucalopride are expected to directly stimulate the colonic motility in humans in vivo. As no previous study has done this, the aim of the study was to investigate the effect of PEG, bisacodyl, and prucalopride as compared to placebo on colonic motility assessed by means of the high-resolution manometry (HRM) in healthy subjects. METHODS: Ten healthy subjects have been enrolled in an acute, open label, randomized, reader-blinded, crossover study and requested to undergo a colonoscopy-assisted HRM measuring their colonic motility before and after oral administration of 13.8 g (two doses) PEG, 10 mg bisacodyl, 2 mg prucalopride, and placebo. KEY RESULTS: In the human prepared colon, oral administration of PEG significantly increases the number of low-amplitude long distance propagating contractions (p = 0.007 vs placebo) while bisacodyl significantly increases the number of high-amplitude propagating contractions (HAPCs) (all p < 0.01 vs PEG, prucalopride, and placebo). Prucalopride has no major effect on the number of propagating contractions but increases HAPCs amplitude (p = 0.01). CONCLUSIONS & INFERENCES: In humans, PEG, prucalopride, and bisacodyl have distinct effects on colonic motility. This information has clinical implication, as it indicates that the combination of prucalopride and bisacodyl, normally not considered in clinical practice, could be effective in treating patients with constipation refractory to single medications.

Esophageal hypercontractility is abolished by cholinergic blockade.

BACKGROUND: Esophageal hypercontractility (EHC) is considered a major esophageal motor disorder of unclear etiology. Different mechanisms have been proposed, including an imbalance in inhibitory and excitatory esophageal innervation. We hypothesized that patients with EHC suffer from cholinergic hyperactivity. AIM: To interrogate the excitatory and inhibitory neurotransmission in EHC by assessing the esophageal motor response to atropine (ATR) and cholecystokinin (CCK), respectively, in EHC patients. METHOD: We retrospectively reviewed patients who underwent high-resolution manometry (HRM) with pharmacologic challenge in a tertiary referral center between 2007 and 2017. We identified 49 EHC patients who were categorized based on frequency of hypercontractile peristaltic sequence into "frequent" and "infrequent" and motility diagnosis groups. Deglutitive pressure metrics and esophageal motor responses to ATR (12 mcg/kg iv) and CCK (40 ng/kg iv) were analyzed across groups. RESULTS: Atropine abolished hypercontractility across all groups studied, converting nearly half of patients to a motor pattern of ineffective esophageal motility. Abnormal CCK responses primarily occurred in the patient groups with concomitant outflow obstruction. CONCLUSIONS: Hypercontractility is cholinergically mediated in all esophageal motor disorders. Most patients with isolated EHC appear to have excessive cholinergic drive, rather than loss of inhibitory innervation, and might be candidates for treatment with anticholinergic agents.

Comparison of the chemical constituents of raw Fructus Aurantii and Fructus Aurantii stir-baked with bran, and the biological effects of auraptene.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Aurantii (FA) is a Chinese herbal medicine commonly used in clinical practice to improve gastrointestinal motility, treat dyspepsia, and relieve constipation. More than 20 processing methods of FA have been recorded, among which FA stir-baked with bran is the earliest, most time consuming, and the most popular one. Raw FA has a strong ability to promote qi-moving and has middle-energizer-soothing effects; therefore, it is often used to relieve hypochondrium distension and pain, and to relax the stagnation of the liver Qi. FA stir-baked with bran is more effective in nourishing the stomach and curing indigestion. AIM OF THE STUDY: In this study, the chemical composition and differences between raw FA and FA stir-baked with bran were systematically compared. The chemical components that increased after stir-baking FA and bran were separated and their pharmacodynamic characteristics were determined. Lastly, the processing mechanism of FA was further explained. MATERIALS AND METHODS: Twelve main chemicals in raw FA and FA stir-baked with bran were compared using high-performance liquid chromatography (HPLC). The main differential components were identified, separated, purified, and then analyzed using pharmacodynamic tests. The intestine-pushing test, in vitro smooth muscle test, and in vitro acetylcholinesterase (AchE) activity test in mice were performed to explain the mechanism of auraptene in improving gastrointestinal motility. RESULTS: Using HPLC, the primary chemical that differed between raw FA and FA stir-baked with bran was identified as auraptene. The processed FA was extracted, separated, and purified to obtain pure auraptene. The intestine-pushing test in mice showed that low (0.6 mg·kg-1) and medium doses (1.2 mg·kg-1) of auraptene could promote peristalsis of the small intestine, whereas a high dose (2.4 mg·kg-1) inhibited peristalsis. In vitro studies on the smooth muscle of mice showed that a low dose of auraptene (0.2 mmol·L-1, 10-800 µL) could promote contraction, whereas a high dose (0.2 mmol·L-1, >1000 µL) had the opposite effect. Auraptene has a mechanism of action similar to that of the acetylcholinesterase inhibitor, neostigmine. Additionally, auraptene could inhibit AchE activity in vitro. CONCLUSIONS: Auraptene is the main chemical constituent that differs between raw FA and FA stir-baked with bran. Pharmacodynamic tests showed that auraptene has a cholinergic effect, by virtue of its role as an acetylcholinesterase inhibitor. Moreover, auraptene could dually regulate the gastrointestinal smooth muscle. Auraptene was present in low levels and its content varied in FA stir-baked with bran, depending on the origin and source of FA, and the treatment procedures it was subjected to. In the Chinese Pharmacopoeia, the recommended dose of FA stir-baked with bran is a low dose of 3-10 g, which effectively promotes small-intestinal peristalsis. The mechanism of action is attributed to an increase in the relative content of acetylcholine by the inhibition of AchE activity to promote gastrointestinal motility. The increased levels of auraptene in FA stir-baked with bran are the main reason and the primary purpose for the change in its medicinal properties. This technique, therefore, has potential to be used as one of the main processing mechanisms of raw FA.

The transient receptor potential A1 ion channel (TRPA1) modifies in vivo autonomous ureter peristalsis in rats.

AIMS: The current study aimed to explore the expression of transient receptor potential A1 ion channels (TRPA1) in the rat ureter and to assess if TRPA1-active compounds modulate ureter function. METHODS: The expression of TRPA1 in rat ureter tissue was studied by immunofluorescence. The TRPA1 distribution was compared to calcitonin gene-related peptide (CGRP), α-actin (SMA1), anoctamin-1 (ANO1), and c-kit. For in vivo analyses, a catheter was implanted in the right ureter of 50 rats. Ureter peristalsis and pressures were continuously recorded by a data acquisition set-up during intraluminal infusion of saline (baseline), saline plus protamine sulfate (PS; to disrupt the urothelium), saline plus PS with hydrogen sulfide (NaHS) or cinnamaldehyde (CA). Comparisons were made between rats treated systemically with vehicle or a TRPA1-antagonist (HC030031). RESULTS: TRPA1-immunoreactive nerves co-expressed CGRP and were mainly located in the suburothelial region of the ureter. Immunoreactivity for TRPA1 was also encountered in c-kit-positive but ANO1-negative cells of the ureter suburothelium and wall. In vivo, HC030031-treated rats had elevated baseline peristaltic frequency (p < 0.05) and higher intraluminal pressures (p < 0.01). PS increased the frequency of ureter peristalsis versus baseline in vehicle-treated rats (p < 0.001) but not in HC030031-treated rats. CA (p < 0.001) and NaHS (p < 0.001) decreased ureter peristalsis. This was counteracted by HC030031 (p < 0.05 and p < 0.01). CONCLUSIONS: In rats, TRPA1 is expressed on cellular structures considered of importance for peristaltic and mechanoafferent functions of the ureter. Functional data indicate that TRPA1-mediated signals regulate ureter peristalsis. This effect was pronounced after mucosal disruption and suggests a role for TRPA1 in ureter pathologies involving urothelial damage.

Impact of Feeding Strategies With Acid Suppression on Esophageal Reflexes in Human Neonates With Gastroesophageal Reflux Disease: A Single-Blinded Randomized Clinical Trial.

INTRODUCTION: Aims were to test hypothesis that esophageal provocation-induced reflexes are superior with acid suppression plus feeding modifications vs acid suppression alone among infants treated for gastroesophageal reflux disease (GERD). METHODS: Infants (N = 49, 41.3 ± 2.6 of postmenstrual age) with acid reflux index >3% underwent longitudinal motility testing (weeks 0 and 5) with graded midesophageal provocation to test randomly allocated therapies (4 weeks' proton pump inhibitor [PPI] ± feeding modifications) on sensory-motor aerodigestive reflexes. Feeding modification included restricted fluid volume <140 mL/kg per day, fed over 30 minutes in right lateral position and supine postprandial position. Primary motility outcome was frequency-occurrence of peristaltic reflex. Secondary outcomes included upper esophageal sphincter contractile reflex, lower esophageal sphincter (LES) relaxation reflex, respiratory change, and symptom characteristics. RESULTS: Treatment groups did not differ for primary outcome (odds ratio = 0.8, 95% confidence interval 0.4-1.6, P = 0.99) or secondary outcomes (all P > 0.05). For both treatment groups at follow-up, distal esophageal contraction and LES tone decreased, and LES relaxation reflex occurrence is less frequent (all P < 0.05). In a subgroup analysis, comparing infants with PPI washout (N = 40) vs with continued (N = 9) PPI therapy, no differences were noted for aerodigestive reflex response frequency-occurrence (all P > 0.05). DISCUSSION: In infants with GERD, feeding modification with acid suppression is not superior to acid suppression alone in modifying aerodigestive reflexes (frequency, sensation, or magnitude). Contiguous areas targeted by GER, i.e., LES and distal esophageal functions, worsened at follow-up for both groups despite PPI therapy. Maturation is likely the key factor for GERD resolution in infants, justifying the use of placebo in clinical trials for objectively determined GERD.

L-Menthol for Gastrointestinal Endoscopy: A Systematic Review and Meta-Analysis.

INTRODUCTION: In randomized controlled trials, L-menthol inhibits gastrointestinal peristalsis during endoscopy. Our goal was to quantitatively synthesize the available evidence to evaluate the efficacy and safety of L-menthol for gastrointestinal endoscopy. METHODS: We comprehensively searched for relevant studies published up to January 2020 in PubMed, EMBASE, Web of Science, and Cochrane Library. The main outcomes consisted of the proportion of no peristalsis, proportion of no or mild peristalsis, adenoma detection rate, and adverse events. RESULTS: Eight randomized controlled trials analyzing 1,366 subjects were included. According to the pooled data, L-menthol significantly improved the proportion of no peristalsis (odds ratio [OR] = 6.51, 95% confidence interval [CI] = 4.94-8.57, P < 0.00001), and the proportion of no or mild peristalsis (OR = 7.89, 95% CI = 5.03-12.39, P < 0.00001) compared with the placebo, whereas it was not associated with an improvement in the adenoma detection rate (OR = 1.03, 95% CI = 0.54-1.99, P = 0.92). Adverse events did not differ significantly between the 2 groups (OR = 1.40, 95% CI = 0.75-2.59, P = 0.29). DISCUSSION: The findings of this study support the use of L-menthol to suppress gastrointestinal peristalsis during endoscopic procedure.

Anticholinergic, anti-depressant and other medication use is associated with clinically relevant oesophageal manometric abnormalities.

BACKGROUND: Medications can affect gastrointestinal tract motility. However, their effects on oesophageal motility in particular are often not as widely known or may be underestimated. AIM: To review the effect of existing medication use on high-resolution oesophageal manometry (HRM) in a 'real-world' setting. METHODS: Adult patients with upper gut symptoms and normal endoscopy or imaging who had HRM over a 22-month period were analysed. Achalasia and major disorders of peristalsis were excluded. All medications taken within 24 hours of the procedure were prospectively recorded and compared with HRM results, controlling for age, gender and proton pump inhibitor use. RESULTS: A total of 502 patients (323 female, mean age 51) were recruited. Of these, 41.2% had normal oesophageal HRM, while 41.4% had ineffective oesophageal motility (IOM) and 7.6% had oesophagogastric junction outflow obstruction (OGJOO). Serotonin/norepinephrine reuptake inhibitors (SNRI) and opioids were associated with significantly higher resting lower oesophageal sphincter pressure. Benzodiazepines and opioids were associated with elevated integrated relaxation pressure. SNRI and inhaled beta-agonists were associated with increased distal contractile index, whereas calcium channel blockers were associated with a lower distal contractile index. Odds ratio of being on anticholinergics was higher in IOM patients vs normal (3.6, CI 1.2-10.8). Odds ratio for anticholinergics, inhaled beta-agonists, anticonvulsants, SNRIs and opioids (trend) were all > 3 for OGJOO patients vs normal. CONCLUSION: Many medication classes are associated with abnormal HRM variables and diagnoses such as OGJOO and IOM; some of these associations are probably causal. These possible links should be taken into consideration during manometry interpretation.

Influence of sildenafil on esophageal motor function in humans: Studies using high-resolution manometry.

BACKGROUND/AIM: Sildenafil induces smooth muscle relaxation of the esophagus by blocking type 5 phosphodiesterase that degrades cyclic guanine monophosphate. We aimed to characterize the effects of sildenafil on esophageal peristalsis and contraction reserve using high-resolution manometry (HRM). METHODS: Fifteen healthy adults (12 men, age 21-39, mean 27 years) participated in this study using HRM following either sildenafil 50 mg or placebo. HRM with ten wet swallows and five multiple rapid swallows was performed in all participants. HRM metrics included esophagogastric junction contractile integral (EGJ-CI), basal lower esophageal sphincter (LES) pressure, 4-second integrated relaxation pressure (IRP-4s), distal contractile integral (DCI), distal latency, resting upper esophageal sphincter pressure (UESP), and the response to MRS. RESULTS: Sildenafil significantly lowered EGJ-CI (P < .001), LES pressure (P = .04), IRP-4s (P = .02), and DCI (P < .001). There was no difference in UESP (P = .87) between sildenafil and placebo. Sildenafil significantly decreased peristaltic vigor, inducing absent peristalsis in 12 subjects and ineffective esophageal motility in 3 subjects. Peristaltic response and augmentation following MRS were significantly inhibited following sildenafil (7% vs 100%, P < .001, and none vs 73%, P < .001). CONCLUSIONS: Sildenafil attenuates EGJ barrier function, resting LES pressure, and LES relaxation. Both esophageal body contractility and contraction reserve are inhibited by sildenafil in healthy adults.

Gastrointestinal Neurons Expressing HCN4 Regulate Retrograde Peristalsis.

Peristalsis is indispensable for physiological function of the gut. The enteric nervous system (ENS) plays an important role in regulating peristalsis. While the neural network regulating anterograde peristalsis, which migrates from the oral end to the anal end, is characterized to some extent, retrograde peristalsis remains unresolved with regards to its neural regulation. Using forward genetics in zebrafish, we reveal that a population of neurons expressing a hyperpolarization-activated nucleotide-gated channel HCN4 specifically regulates retrograde peristalsis. When HCN4 channels are blocked by an HCN channel inhibitor or morpholinos blocking the protein expression, retrograde peristalsis is specifically attenuated. Conversely, when HCN4(+) neurons expressing channelrhodopsin are activated by illumination, retrograde peristalsis is enhanced while anterograde peristalsis remains unchanged. We propose that HCN4(+) neurons in the ENS forward activating signals toward the oral end and simultaneously stimulate local circuits regulating the circular muscle.

Controlled Delivery of Bile Acids to the Colon.

INTRODUCTION: Bile acids, such as chenodeoxycholic acid, play an important role in digestion but are also involved in intestinal motility, fluid homeostasis, and humoral activity. Colonic delivery of sodium chenodeoxycholate (CDC) has demonstrated clinical efficacy in treating irritable bowel syndrome with constipation but was associated with a high frequency of abdominal pain. We hypothesized that these adverse effects were triggered by local super-physiological CDC levels caused by an unfavorable pharmacokinetic profile of the delayed release formulation. METHODS: We developed novel release matrix systems based on hydroxypropyl methylcellulose (HPMC) for sustained release of CDC. These included standard HPMC formulations as well as bi-layered formulations to account for potential delivery failures due to low colonic fluid in constipated patients. We evaluated CDC release profiles in silico (pharmacokinetic modeling), in vitro and in vivo in swine (pharmacokinetics, rectal manometry). RESULTS: For the delayed release formulation in vitro release studies demonstrated pH triggered dose dumping which was associated with giant colonic contractions in vivo. Release from the bi-layered HPMC systems provided controlled release of CDC while minimizing the frequency of giant contractions and providing enhanced exposure as compared to standard HPMC formulations in vivo. DISCUSSION: Bi-phasic CDC release could help treat constipation while mitigating abdominal pain observed in previous clinical trials. Further studies are necessary to demonstrate the therapeutic potential of these systems in humans.

Neural motor complexes propagate continuously along the full length of mouse small intestine and colon.

Cyclical propagating waves of muscle contraction have been recorded in isolated small intestine or colon, referred to here as motor complexes (MCs). Small intestinal and colonic MCs are neurogenic, occur at similar frequencies, and propagate orally or aborally. Whether they can be coordinated between the different gut regions is unclear. Motor behavior of whole length mouse intestines, from duodenum to terminal rectum, was recorded by intraluminal multisensor catheter. Small intestinal MCs were recorded in 27/30 preparations, and colonic MCs were recorded in all preparations (n = 30) with similar frequencies (0.54 ± 0.03 and 0.58 ± 0.02 counts/min, respectively). MCs propagated across the ileo-colonic junction in 10/30 preparations, forming "full intestine" MCs. The cholinesterase inhibitor physostigmine increased the probability of a full intestine MC but had no significant effect on frequency, speed, or direction. Nitric oxide synthesis blockade by Nω-nitro-l-arginine, after physostigmine, increased MC frequency in small intestine only. Hyoscine-resistant MCs were recorded in the colon but not small intestine (n = 5). All MCs were abolished by hexamethonium (n = 18) or tetrodotoxin (n = 2). The enteric neural mechanism required for motor complexes is present along the full length of both the small and large intestine. In some cases, colonic MCs can be initiated in the distal colon and propagate through the ileo-colonic junction, all the way to duodenum. In conclusion, the ileo-colonic junction provides functional neural continuity for propagating motor activity that originates in the small or large intestine.NEW & NOTEWORTHY Intraluminal manometric recordings revealed motor complexes can propagate antegradely or retrogradely across the ileo-colonic junction, spanning the entire small and large intestines. The fundamental enteric neural mechanism(s) underlying cyclic motor complexes exists throughout the length of the small and large intestine.

Effects of L-Menthol and Carbon Dioxide on the Adenoma Detection Rate during Colonoscopy: L-Menthol and Carbon Dioxide on Colonoscopy.

BACKGROUND AND AIMS: We examined the efficacy of the combined use of L-menthol spraying (L-mentholS) as an antispasmodic agent and carbon dioxide insufflation (CO2I) on the adenoma detection rate (ADR) in a prospective, single-center trial with a 2 × 2 factorial design. METHODS: We randomly assigned 611 patients scheduled to undergo colonoscopy to 4 groups: (1) the L-mentholS + CO2I (n = 153), (2) L-mentholS + air insufflation (AI; n = 156), (3) CO2I (n = 153), and (4) AI (n = 149) groups. We used 20 mL of 0.8%-L-menthol solution for the L-mentholS. The primary outcome was the difference in the ADR, and the secondary outcomes were the differences in colonic peristalsis and abdominal pain. -Results: The ADRs were not different among the groups: 1/2/3/4; 39.9%/43.6%/41.2%/51.0%. CO2I was associated with a significant decrease in the ADR (OR 0.57; 95% CI 0.35- 0.93) with a multiple logistic regression. The interaction between L-mentholS and CO2I was associated with a suppression of the decrease in the ADR. Both L-mentholS and CO2I were associated with a significant decrease in abdominal pain, and L-mentholS was associated with a significant improvement of peristalsis. CONCLUSIONS: The fact that CO2I was associated with significant decreases in the ADR was a problem. The combined use of L-mentholS and CO2I could help to suppress the decrease in the ADR.