Effect of sildenafil, a phosphodiesterase-5 inhibitor, on oesophageal peristalsis and lower oesophageal sphincter function in cats.

The propagation of oesophageal peristaltic contractions and lower oesophageal sphincter (LOS) relaxation depends on neural release of nitric oxide (NO) which acts to increase intracellular cGMP. Sildenafil, a phosphodiesterase-5 inhibitor that increases cGMP, reduces basal LOS pressure in patients with achalasia. We investigated the effect of sildenafil on the propagation of oesophageal contractions and LOS relaxation in the cat. Oesophageal manometry was performed in five cats under light sedation. Peristaltic contractions were monitored at 1, 2, 3, 4 and 8 cm proximal to the LOS, at the LOS using a Dent sleeve, and at 3 cm distal to the upper oesophageal sphincter. Swallow-induced oesophageal contractions and LOS relaxation were recorded during 30 min before and 30 min after intravenous administration of sildenafil. Sildenafil reduced the amplitude of oesophageal contractions only in the smooth muscle oesophagus. The latency from swallow to distal oesophageal contractions was significantly delayed. LOS pressure was significantly reduced but the relaxation nadir was not modified by sildenafil. Sildenafil has profound effects on oesophageal motility: it modifies propagation and amplitude of oesophageal contractions and reduces LOS pressure. Slowing down the propagation of contractions in the transitional zone between the striated and smooth muscle can be a useful tool in patients with segmental aperistalsis or intermittent simultaneous contractions, while the effect on the LOS can benefit patients with achalasia.     

Disposable balloon-based oesophageal motility catheters: comparison with solid-state transducers.

BACKGROUND: Current oesophageal manometry systems use either water-perfused or solid-state pressure transducers. Recently developed single-use disposable catheters use small balloons prefilled with air that transmit the pressure of oesophageal contractions to external transducers. AIM: To compare data obtained from single-use disposable balloon catheters to data from solid-state systems. METHODS: Healthy volunteers, patients with ineffective oesophageal motility and nutcracker oesophagus were studied to include a broad range of pressures. A single-use disposable Clinical Innovations (CI) catheter was placed adjacent to a solid-state Konigsberg Instruments (KI) catheter with pressure transducers at 5, 10, 15 and 20 cm above the lower oesophageal sphincter (LOS). Subjects received liquid and viscous swallows at 30-s intervals. Healthy volunteers received additional sets of swallows while having only one catheter in the oesophagus. RESULTS: When both catheters were present in the oesophagus, no differences were noted between mean pressure measurements in the distal oesophagus and there was good correlation between pressures recorded in response to individual swallows. When present alone in the oesophagus the CI catheter recorded lower mean pressures compared with the KI catheter. Overall there was good agreement in classifying swallows as normal, ineffective and simultaneous. CONCLUSION: Single-use oesophageal manometry catheters are promising alternatives to solid-state manometry systems in measuring intra-oesophageal pressures.     

Effect of the 5-HT1 agonist sumatriptan on oesophageal motor pattern in patients with ineffective oesophageal motility

The 5-HT1 agonist sumatriptan (SUM) elicits an increase in amplitude of oesophageal motor waves and of lower oesophageal sphincter (LOS) tone in healthy subjects. The aim of the study was to evaluate whether such an effect occurs also in patients with ineffective oesophageal motility (IOM). 16 patients (nine males and seven females, age range 34-55 years) with chest pain and mild to moderate dysphagia were studied; all had undergone previous cardiologic, radiologic and upper gastrointestinal endoscopic exams that were normal. An oesophageal manometry was performed using an electronic probe to record swallows, oesophageal, LOS and gastric motility. The patients whose motor pattern were compatible with IOM (>30% of motor waves with amplitude <30 mmHg and/or non-transmitted) received SUM or placebo 6 mg s.c., injected in the morning and in the afternoon in a random order. The data analysis was limited to 1 h before and 1 h after the drug injections. Ten out of the 16 patients showed an IOM motor pattern. The administration of SUM caused a significant increase in the number of swallows (SUM 99.5 +/- 15.4 vs 78.6 +/- 16.1 basal, P = 0.03) and of primary oesophageal motor waves (SUM 89.6 +/- 13.4 vs 67.2 +/- 12.9 basal, P = 0.04) with no significant changes in the percentage of swallows associated with propagation. Placebo was not associated with increase in the number of swallows (80.3 +/- 14.6, P = 0.9) or of primary oesophageal motor waves (70.1 +/- 12.3, P = 0.7). The amplitude and the percentage of propagated oesophageal motor waves as well as the mean basal LOS tone were unaltered by SUM. There was no change in the symptoms reported after SUM. Although effective in healthy subjects, SUM 6 mg s.c. improves only the numbers but not the amplitude or propagation of oesophageal motility of patients with IOM. The 5-HT1 pathway and its acute stimulation seem to play only a minor role in the pathogenesis of such a disease.     

Effect of an acute intraluminal administration of capsaicin on oesophageal motor pattern in GORD patients with ineffective oesophageal motility

Ineffective oesophageal motility (IOM) is a functional disorder affecting about 50% of gastro-oesophageal reflux disease (GORD) patients. This disease in a severe form limits the clearing ability of the oesophagus and is considered one of the predictive factors for poorer GORD resolution. Capsaicin, the active compound of red pepper, exerts a prokinetic effect on oesophageal motility in healthy subjects by increasing the amplitude of body waves, even if no evidence exists on its possible role in situations of reduced motility. The aim of the study was to evaluate the effect of an acute administration of capsaicin on the oesophageal motor pattern in a group of GORD patients affected by severe IOM. Twelve GORD patients with severe IOM received an intra-oesophageal administration of 2 mL of a red pepper-olive oil mixture and 2 mL of olive oil alone serving as a control during a stationary manometry. The motor patterns of the oesophageal body and lower oesophageal sphincter (LOS) were analysed at baseline and after the infusion of the two stimuli. The administration of capsaicin induced a significant improvement in oesophageal body contractility when compared with baseline. The velocity of propagation of waves and the LOS basal tone remained unchanged. The motor pattern was unaltered by the administration of olive oil alone. An acute administration of capsaicin seems to improve the motor performance of the oesophageal body in patients with ineffective motility. Whether this could represent the basis for further therapeutic approaches of GORD patients needs further study.     

Segmental characteristics of oesophageal peristalsis in paediatric patients.

High-resolution manometry (HRM) in adults identifies a sequential chain of pressure segments that together form normal oesophageal peristalsis. HRM was performed in 40 neonates, infants/toddlers and children (age 1 day-14 years) to see if a similar segmental pattern could be identified in paediatric subjects. A chain of three pressure segments was found with inter-segmental troughs at 27.4 +/- 1.1%, 62.6 +/- 1.3% and 94.9 +/- 0.8% oesophageal length. The first and second pressure troughs were similarly distributed along the oesophagus across age groups; the third was 7.6-8.9% oesophageal length further from the lower oesophageal sphincter in neonates (P < 0.05 compared with other age groups). There were no significant differences in trough locations between subjects with or without oesophageal disease, controlling for age. Consistent presence of all three segments was less common in neonates, primarily because of fewer swallows demonstrating the first (proximal) and third (distal) segments compared with children. HRM in paediatric patients demonstrates, from neonates to children, the distinctive chain of pressure events that also characterizes oesophageal peristalsis in adults. The segmental character to oesophageal peristalsis should be taken into consideration in manometric investigation of all age groups - for example, in testing pharmacological responses and evaluating clearance mechanisms.     

Physiology of the oesophageal transition zone in the presence of chronic bolus retention: studies using concurrent high resolution manometry and digital fluoroscopy

Abstract  Distinct contraction waves (CWs) exist above and below the transition zone (TZ) between the striated and smooth muscle oesophagus. We hypothesize that bolus transport is impaired in patients with abnormal spatio-temporal coordination and/or contractile pressure in the TZ. Concurrent high resolution manometry and digital fluoroscopy were performed in healthy subjects and patients with reflux oesophagitis; a condition associated with ineffective oesophageal contractility and clearance. A detailed analysis of space–time variations in bolus movement, intra-bolus and intra-luminal pressure was performed on 17 normal studies and nine studies in oesophagitis patients with impaired bolus transit using an interactive computer based system. Compared with normal controls, oesophagitis patients had greater spatial separation between the upper and lower CW tails [median 5.2 cm (range 4.4–5.6) vs 3.1 cm (2.2–3.7)], the average relative pressure within the TZ region (TZ strength) was lower [30.8 mmHg (28.3–36.5) vs 45.8 mmHg (36.1–55.7), P  < 0.001], and the risk of bolus retention was higher (90% vs 12%; P  < 0.01). The presence of bolus retention was associated with a wider spatial separation of the upper and lower CWs (>3 cm, the upper limit of normal; P  < 0.002), independent of the presence of oesophagitis. We conclude that bolus retention in the TZ is associated with excessively wide spatial separation between the upper and lower CWs and lower TZ muscle squeeze. These findings provide a physio-mechanical basis for the occurrence of bolus retention at the level of the aortic arch, and may underlie impaired clearance with reflux oesophagitis.     

Clinical correlates of dysphagia to oesophageal dysmotility: studies using combined manometry and impedance

Abstract  This study aimed to elucidate the mechanism of dysphagia by determining the simultaneous relationships between subjective perception of swallow with oesophageal motility and bolus transport in patients with non-obstructive dysphagia (NOD). Combined oesophageal manometry and impedance was performed in 18 consecutive NOD patients and 14 healthy controls. Swallow was abnormal if the amplitude of distal oesophageal contractions was less than 30 mmHg or simultaneous contractions occurred. Bolus transit was abnormal if bolus exit was not found at one or more of the measuring sites. Perception of each swallow was assessed using a standardized scoring system and was enhanced if score was >1. The prevalence of complete bolus transit was lower in NOD patients compared with healthy controls ( P  = 0.001). Abnormal liquid bolus transit was found in 40% of patients with normal motility and 38% of patients with abnormal motility, whereas abnormal viscous bolus transit was observed in 38% of patients with normal motility and 70% of patients with abnormal motility. Agreement between enhanced perception and impedance was poor during liquid (κ = 0.12, 95% CI: −0.003 to 0.233) and viscous swallowing (κ = 0.12, 95% CI: −0.004 to 0.244). Agreement between enhanced perception and manometry was even poorer during liquid (κ = −0.16, 95% CI: −0.302 to 0.022) and viscous swallowing (κ = −0.12, 95% CI: −0.25 to 0.002). NOD patients show poor correlation between dysphagia and oesophageal motility parameters. The results suggest that, in patients with NOD, oesophageal motor dysfunction may play a limited role, if any, in the generation of dysphagia.     

Effect of baclofen on oesophageal motility and transient lower oesophageal sphincter relaxations in GORD patients: a 48-h manometric study

Abstract  Little is known about prolonged effect of baclofen on oesophageal and lower oesophageal sphincter (LOS) motility. We aimed at investigating the oesophageal motility in gastro-oesophageal reflux disease (GORD) patients 24 h before and after the administration of multiple doses of baclofen. Twenty-one GORD patients underwent a 48-h manometry recording the swallows, the oesophageal and the LOS motility. During the second 24-h period, patients received baclofen 10 mg or placebo four times per day in a double-blind randomized fashion. Baclofen increased the LOS basal tone in comparison with baseline ( P  = 0.02), with a concomitant reduction in the number of transient LOS relaxations (TLOSRs) ( P  = 0.01). Moreover, baclofen induced a decrease of the swallows ( P  = 0.02) and of primary oesophageal body waves ( P  = 0.04) with no changes in the amplitude. Multiple doses of baclofen determine a reduction in the number of TLOSRs and an increase in the LOS tone throughout the 24 h. The concomitant decreased number of swallows and of primary peristalsis could depend on the well-known lower amount of reflux episodes induced by the drug. The potential therapeutic effect of baclofen could be expressed not only postprandially, but also in the fasting state when reflux episodes are present as well.     

Ambulatory oesophageal pressure,pH and ECG recording in patients with normal and pathological coronary angiography and intermittent chest pain

Abstract The present study was performed to compare pain-related oesophageal motility, gastro-oesophageal reflux and ST-segment deviations in patients with intermittent chest pain and normal or pathological coronary angiography. Thirty patients (11 males, 19 females; mean age 54.8 years) with normal and 15 patients (12 males, 3 females; mean age 66.7 years) with pathological coronary angiography were investigated by 24-h oesophageal pressure, pH and ECG recording. Chest pain correlated with motility abnormalities or gastro-oesophageal reflux occurred in 33% (10/30) of patients with normal coronary arteries and in 26% of patients with pathological coronary angiography. Symptomatic and asymptomatic ST-segment changes were less frequently observed in patients with normal angiography (4/30) than in patients with pathological coronary angiography (7/14; P = 0.02). Oesophageal dysfunction coincided with ST-segment deviation in 6.7% (2/30) of patients with normal and 40% (6/15) of patients with pathological coronary angiography (P = 0.02). The conclusions reached were: (1) pain-correlated abnormal motility or gastro-oesophageal reflux occurred in patients with normal and pathological coronary angiography at the same frequency; (2) ambulatory motility and pH recording alone does not appear to differentiate between cardiac and non-cardiac chest pain; (3) simultaneous ECG recording reveals a significant correlation of ST-segment deviation and gastro-oesophageal reflux or abnormal motility in patients with coronary artery stenosis.     

Morphometric evaluation of oesophageal wall in patients with nutcracker oesophagus and ineffective oesophageal motility

Abstract  The pathogenesis of nutcracker oesophagus (NE) and ineffective oesophageal motility (IEM) is unclear. Damage to the enteric nervous system or smooth muscle can cause oesophageal dysmotility. We tested the hypothesis that NE and IEM are associated with abnormal muscular or neural constituents of the oesophageal wall. Oesophageal manometry was performed in patients prior to total gastrectomy for gastric cancer. The oesophageal manometries were categorized as normal ( n  = 7), NE ( n  = 13), or IEM ( n  = 5). Histologic examination of oesophageal tissue obtained during surgery was performed after haematoxylin and eosin (H&E) and trichrome staining. Oesophageal innervation was examined after immunostaining for protein gene product-9.5 (PGP-9.5), choline acetyltransferase (ChAT) and neuronal nitric oxide synthase (nNOS). There were no significant differences in inner circular smooth muscle thickness or degree of fibrosis among the three groups. Severe muscle fibre loss was found in four of five patients with IEM. The density of PGP-9.5-reactive neural structures was not different among the three groups. The density of ChAT immunostaining in the myenteric plexus (MP) was significantly greater in patients with NE ( P  < 0.05) and the density of nNOS immunostaining in the circular muscle (CM) was significantly greater in IEM patients ( P  < 0.05). The ChAT/nNOS ratio in both MP and CM was significantly greater in NE patients. NE may result from an imbalance between the excitatory and inhibitory innervation of the oesophagus, because more than normal numbers of ChAT-positive myenteric neurones are seen in NE. Myopathy and/or increased number of nNOS neurones may contribute to the hypocontractile motor activity of IEM.     

Oesophageal peristaltic transition zone defects: real but few and far between

Abstract This study analysed the association between oesophageal transition zone (TZ) defects [characterized by a delay and/or spatial gap between the terminus of the proximal oesophageal (striated muscle) contraction and the initiation of the distal oesophageal (smooth muscle) contraction] and dysphagia in a large patient cohort. Four hundred consecutive patients (178 with dysphagia) and 75 controls were studied with 36‐channel high‐resolution manometry (HRM). The resultant pressure topography plots were first analysed for impaired oesophagogastric junction (OGJ) relaxation, distal segment contractile abnormalities, and proximal contractile abnormalities using normal values from the 75 controls. If these aspects of oesophageal motility were deemed normal, the TZ was characterized by length and duration between the proximal and distal contractions using a 20 mmHg isobaric contour to establish the segment boundaries. Patients were then classified according to whether or not they exhibited TZ defects (spatial separation or delay) and the occurrence of unexplained dysphagia. Of the 400 patients, 267 were suitable for TZ analysis and of these 55 had a spatial or temporal TZ measurement exceeding the 95th percentile of the controls (2 cm, 1 s). Exactly 34.6% of the patients (n = 19) with spatial and/or temporal TZ defects had unexplained dysphagia, which was significantly more than seen with normal TZ dimensions (19.8%). Although far less common than distal peristaltic or OGJ abnormailites, TZ defects may be related to dysphagia in a minority of patients (<4% in this series) and should be considered a distinct oesophageal motility disorder.     

Effect of successive swallows on oesophageal motility of normal volunteers, patients with Chagas'' disease and patients with idiopathic achalasia

Most frequently, ten swallows of a 5-mL bolus of water are performed during oesophageal manometry. Our hypothesis is that five swallows may produce the same results. We studied the oesophageal contraction parameters of 40 volunteers, 75 patients with Chagas' disease and 14 patients with idiopathic achalasia. Motility was recorded at 5, 10 and 15 cm above the lower oesophageal sphincter. The subjects performed ten swallows of a 5-mL bolus of water alternated with ten dry swallows with an interval of at least 30 s. We measured the amplitude, duration, peristaltic velocity, number of failed and number of simultaneous contractions of the initial five and final five dry and wet swallows. The comparison of dry and wet swallows showed the differences already known. The comparison of the parameters of the initial five swallows with those of the final five swallows showed no differences. Thus, when the initial five or the final five swallows were considered, there was no change in the conclusions reached by the comparison of patients and volunteers and of dry and wet swallows. We conclude that five swallows may be sufficient for the manometric examination of oesophageal parameters in Chagas' disease and idiopathic achalasia.     

Neural regulation of tone in the oesophageal body: in vivo barostat assessment of volume–pressure relationships in the feline oesophagus

Recent combined manometric-barostat studies demonstrated that the oesophageal body exhibits both peristaltic contractions and tone. This study further characterized the neural modulation of tone in the feline oesophageal body. Simultaneous oesophageal barostat and manometry were performed in 20 adult cats under ketamine sedation. Oesophageal tone and peristalsis were assessed in the distal smooth muscle oesophagus. Cholinergic modulation was studied using neostigmine, erythromycin, atropine and vagotomy. Nitrergic regulation was assessed using sildenafil to increase cellular cyclic guanosine monophosphate and the nitric oxide synthase blocker Nomega-nitro-l-arginine (l-NNA). The presence of a tonic contractile activity in the distal oesophageal body was confirmed. Peristaltic contractions proceeded along the oesophageal body over the background tonic contraction. Neostigmine and erythromycin enhanced (20-30%) whereas bilateral vagotomy and atropine strongly decreased oesophageal tone (50-60%). However, l-NNA increased (40%) and sildenafil decreased oesophageal tone (30%). Therefore, tonic contractile activity in the oesophageal body is mainly caused by a continuous cholinergic excitatory input. A nitric oxide inhibitory mechanism may have a complementary role in the regulation of oesophageal tone.