Altered oesophageal motility following the administration of the 5-HT1 agonist, sumatriptan.
BACKGROUND: The 5-HT1 agonist sumatriptan, used in the treatment of migraine, can cause chest pain. AIM: To investigate the effect of a therapeutic dose of sumatriptan (6 mg s.c.) on oesophageal motility. METHODS: In 16 normal healthy subjects aged 19-32 years (9 males), the manometric response of the lower oesophageal sphincter (sleeve sensor), oesophageal body (four sites), stomach and pharynx (to register swallows) to 5 mL water swallows was assessed before and after a subcutaneous injection of either sumatriptan (6 mg) or saline control. Symptoms and ECGs were also monitored. RESULTS: Sumatriptan 6 mg s.c. altered oesophageal motility in all subjects. This was reflected by a significant increase in the amplitude of oesophageal body contractions (change from pre- to 1 h post-injection: sumatriptan 9.9 (2.8, 17.1) mmHg vs. placebo -0.8 (-4.2, 2.6) mmHg, difference 10.8 (4.4, 17.1) mmHg; P=0.003) and a transient increase in lower oesophageal sphincter pressure (change from pre- to 5 min post-injection: sumatriptan 10.9 (5.2, 16.6) mmHg vs. placebo 5.1 (1.8, 8.4) mmHg, difference 5.8 (-0.7, 12.3) mmHg; P=0.08). Sumatriptan had no effect on the velocity of propagation of oesophageal contractions (change from pre- to 1 h post-injection: sumatriptan -0.1 (-0.3, 0.1) cm/s vs. placebo -0.1 (-0.3, 0.0) cm/s, difference 0.1 (-0.1, 0.2) cm/s; P = 0.40). One subject experienced chest symptoms following sumatriptan and, although motility was altered, this did not reach pathological levels. No ECG abnormalities were observed. CONCLUSION: Sumatriptan (6 mg s.c.) significantly alters oesophageal motor function without affecting the ECG. It is therefore possible that sumatriptan-induced chest symptoms may have an oesophageal origin. The evaluation of similar therapeutic agents for migraine on oesophageal function may be justified. (+info)
Functional esophageal disorders.
The functional esophageal disorders include globus, rumination syndrome, and symptoms that typify esophageal diseases (chest pain, heartburn, and dysphagia). Factors responsible for symptom production are poorly understood. The criteria for diagnosis rest not only on compatible symptoms but also on exclusion of structural and metabolic disorders that might mimic the functional disorders. Additionally, a functional diagnosis is precluded by the presence of a pathology-based motor disorder or pathological reflux, defined by evidence of reflux esophagitis or abnormal acid exposure time during ambulatory esophageal pH monitoring. Management is largely empirical, although efficacy of psychopharmacological agents and psychological or behavioral approaches has been established for several of the functional esophageal disorders. As gastroesophageal reflux disease overlaps in presentation with most of these disorders and because symptoms are at least partially provoked by acid reflux events in many patients, antireflux therapy also plays an important role both in diagnosis and management. Further understanding of the fundamental mechanisms responsible for symptoms is a priority for future research efforts, as is the consideration of treatment outcome in a broader sense than reduction in esophageal symptoms alone. Likewise, the value of inclusive rather than restrictive diagnostic criteria that encompass other gastrointestinal and non-gastrointestinal symptoms should be examined to improve the accuracy of symptom-based criteria and reduce the dependence on objective testing. (+info)
Oesophageal motility defects associated with nocturnal gastro-oesophageal reflux on proton pump inhibitors.
BACKGROUND: Recent studies from our laboratory reveal that 70% of patients with gastro-oesophageal reflux disease (GERD) on proton pump inhibitors twice daily (b.d.) have nocturnal gastric acid breakthrough (gastric pH < 4 > 1 h) which is often accompanied by oesophageal acid exposure. The pathogenesis of GER during gastric acid breakthrough is not clear. AIM: To determine the prevalence of oesophageal motility abnormalities in patients with nocturnal GER associated with nocturnal acid breakthrough on proton pump inhibitor b.d. METHODS: We reviewed the pH-metry and manometric studies of 100 consecutive patients with GERD who were on proton pump inhibitor b.d. pH tracings were analysed for the nocturnal period (10.00 hours until 06.00 hours). Nocturnal GER was defined as> 0.5% time distal oesophageal pH < 4. Manometric tracings were reviewed for lower oesophageal sphincter (LES) pressure and oesophageal body motility. Chi-squared and Fischer's test were used for statistical analysis. RESULTS: Of the 100 patients, 74 (74%) had nocturnal gastric acid breakthrough. Thirty-one (42%) had concurrent abnormal nocturnal GER (refluxers) and 43 out of 74 (58%) had no GER (non-refluxers). The prevalence of ineffective oesophageal motility, and low LES pressure was significantly higher in refluxers than in non-refluxers (P < 0. 05, P < 0.001, respectively). Ineffective-oesophageal motility has a high specificity (91%), but low sensitivity (45%) as a diagnostic predictor for patients who are more likely to develop nocturnal GER on proton pump inhibitor b.d. CONCLUSION: Ineffective oesophageal motility is a risk factor for proton pump inhibitor refractory GER. (+info)
Signal transduction in esophageal and LES circular muscle contraction.
Contraction of normal esophageal circular muscle (ESO) in response to acetylcholine (ACh) is linked to M2 muscarinic receptors activating at least three intracellular phospholipases, i.e., phosphatidylcholine-specific phospholipase C (PC-PLC), phospholipase D (PLD), and the high molecular weight (85 kDa) cytosolic phospholipase A2 (cPLA2) to induce phosphatidylcholine (PC) metabolism, production of diacylglycerol (DAG) and arachidonic acid (AA), resulting in activation of a protein kinase C (PKC)-dependent pathway. In contrast, lower esophageal sphincter (LES) contraction induced by maximally effective doses of ACh is mediated by muscarinic M3 receptors, linked to pertussis toxin-insensitive GTP-binding proteins of the G(q/11) type. They activate phospholipase C, which hydrolyzes phosphatidylinositol bisphosphate (PIP2), producing inositol 1,4,5-trisphosphate (IP3) and DAG. IP3 causes release of intracellular Ca++ and formation of a Ca++-calmodulin complex, resulting in activation of myosin light chain kinase and contraction through a calmodulin-dependent pathway. Signal transduction pathways responsible for maintenance of LES tone are quite distinct from those activated during contraction in response to maximally effective doses of agonists (e.g., ACh). Resting LES tone is associated with activity of a low molecular weight (approximately 14 kDa) pancreatic-like (group 1) secreted phospholipase A2 (sPLA2) and production of arachidonic acid (AA), which is metabolized to prostaglandins and thromboxanes. These AA metabolites act on receptors linked to G-proteins to induce activation of PI- and PC-specific phospholipases, and production of second messengers. Resting LES tone is associated with submaximal PI hydrolysis resulting in submaximal levels of inositol trisphosphate (IP3-induced Ca++ release, and interaction with DAG to activate PKC. In an animal model of acute esophagitis, acid-induced inflammation alters the contractile pathway of ESO and LES. In LES circular muscle, after induction of experimental esophagitis, basal levels of PI hydrolysis are substantially reduced and intracellular Ca++ stores are functionally damaged, resulting in a reduction of resting tone. The reduction in intracellular Ca++ release causes a switch in the signal transduction pathway mediating contraction in response to ACh. In the normal LES, ACh causes release of Ca++ from intracellular stores and activation of a calmodulin-dependent pathway. After esophagitis, ACh-induced contraction depends on influx of extracellular Ca++, which is insufficient to activate calmodulin, and contraction is mediated by a PKC-dependent pathway. These changes are reproduced in normal LES cells by thapsigargin-induced depletion of Ca++ stores, suggesting that the amount of Ca++ available for release from intracellular stores defines the signal transduction pathway activated by a maximally effective dose of ACh. (+info)
Vincristine-induced dysphagia suggesting esophageal motor dysfunction: a case report.
Transient esophageal motor dysfunction with dysphagia was observed in a 62-year-old man receiving vincristine-containing chemotherapy for non-Hodgkin's lymphoma. Neurological examinations, including muscle strength of extremities, deep tendon reflexes and cranial nerves, were normal. However, the patient complained of severe numbness in the fingertips and toes. The results of esophagogram and esophagoscopy were unremarkable. However, a significantly prolonged esophageal transit time was observed. Vincristine was considered as the causative agent. Empirical vitamin and metoclopramide were prescribed for his neurological symptoms but there was no improvement. The symptoms of dysphagia subsided spontaneously 2 weeks later. However, prompt recurrence of severe dysphagia was observed again after administration of the second and third courses of treatment, which again disappeared upon discontinuation of the drug. Peripheral nerves and the gastrointestinal tract are often affected by vincristine. Common gastrointestinal tract symptoms of vincristine neuropathy may be colicky abdominal pain and constipation. However, vincristine-induced esophageal motor dysfunction with dysphagia is uncommon but generally reversible. The oncologist and chemotherapist should be aware of this complication. (+info)
Esophagitis-related esophageal shortening in opossum is associated with longitudinal muscle hyperresponsiveness.
Acute intraluminal acid perfusion induces esophageal shortening in humans and opossums. Lower esophageal sphincter (LES) hypotension and peristaltic dysfunction occur in patients and animal models of reflux esophagitis. This study examined whether similar shortening and motor dysfunction occur in anesthetized opossums after repeated esophageal acid exposure and whether this is associated with longitudinal muscle (LM) hyperresponsiveness. Manometry used before and after 3 consecutive days of 45-min perfusion with 100 mmol/l HCl or normal saline measured esophageal length and motor responses to induced swallows. LM electrical and mechanical responses were assessed using standard isometric tension and intracellular recording techniques. Compared with controls, repeated acid perfusion induced erosive esophagitis and significant esophageal shortening, associated with enhanced LM responses to carbachol, a significantly depolarized resting membrane potential, and abnormal spike patterns. LES resting pressure and swallow-induced peristalsis were unaffected. In this model of reflux esophagitis, marked persistent esophageal shortening and associated LM hyperresponsiveness occur before significant LES or peristaltic dysfunction, suggesting that esophageal shortening is the earliest motor disorder induced by acid injury. (+info)
Two cases of severe non-specific oesophageal dysmotility showing different response to botulinum injection therapy.
We report 2 cases where treatment of achalasia type symptoms due to severe non-specific oesophageal dysmotility have shown symptom resolution and manometric improvement to intrasphincteric botulinum injections either by itself or in combination with oesophageal dilatation. (+info)
Effect of graded running on esophageal motility and gastroesophageal reflux in fed volunteers.
The effects of different grades of running on esophageal motility and gastroesophageal reflux in the fed state were evaluated. We studied healthy volunteers (male: 12, age: 27 +/- 5 yr) using ambulatory esophageal manometry, pH catheter and portable digital data recorder. Each exercise was performed 30 min after meal, with 20 min of rest between exercises. Subjects exercised on a treadmill at 40% and 70% maximal heart rate. The number of gastroesophageal reflux episodes, the duration of esophageal acid exposure and percent time pH below 4 were significantly (p < 0.01) increased during exercise at 70% maximal heart rate. The frequency of contraction (contraction/min) (p < 0.05), frequency of repetition (p < 0.01), percent of simultaneous contraction (p < 0.01), percent of above 100 mmHg amplitude (p < 0.05), and frequency of 2-peak contraction (p < 0.01) were significantly increased during exercise at 70% maximal heart rate. However, median amplitude and median duration showed no significant changes between each exercise session. Postprandial running exercises induce gastroesophageal reflux, which correlates with exercise intensity. These effects are mediated by disorganized esophageal motility. (+info)