Age-related changes in force, stress, and pressure of lower esophageal sphincter of the rat.
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Biomedical subjects
Publications and source records attributed to J Behar.
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The effect of cholecystokinin-octapeptide (CCK-OP) on the lower esophageal sphincter (LES) was studied in 50 cats in vivo. CCK-OP caused a dose-dependent fall in LES pressures in all but 4 animals. Maximal sphincter relaxation was obtained with 200 to 400 ng of CCK-OP per kg of body weight. Atropine sulfate and/or hexamethonium, or adrenergic blocking agents (phentolamine or propranolol), in doses that completely inhibit the action of maximal doses of their respective agonists, failed to block the CCK-OP effect. Tetrodotoxin, however, in doses that denervates the LES, antagonized the CCK-OP-induced sphincter relaxation. In these tetrodotoxin-treated animals, CCK-OP produced LES contraction similar to that observed after pentagastrin. These results suggest that CCK-OP stimulates the postganglionic nonadrenergic, noncholinergic inhibitory neurons responsible for sphincter relaxation. CCK-OP also stimulates the circular muscle by direct action causing LES contraction. The latter becomes apparent when the innervation of the LES is abolished by tetrodoxtin.
A patient with a lifelong history of asthma and hay fever was investigated because of symptoms of esophageal spasm. Esophageal biopsies revealed elongated papillae and basal zone hyperplasia of the epithelial layer with eosinophilic infiltration of the lamina propria and muscularis mucosae. There was no evidence of reflux. Small bowel biopsies revealed a flat mucosal pattern with absent or blunted villi, tall columar surface epithelium, and eosinophilic infiltration of the lamina propria. He did not respond to a gluten-free diet. This patient is thought to have eosinophilic gatroenteritis with esophageal involvement, the first such case reported.
Accelerated cell turnover has been held responsible for the basal zone thickening of the esophageal squamous mucosa of patients with reflux esophagitis. We have studied the in vitro proliferative activity of the basal zone in suction biopsy specimens obtained from normal subjects, from patients with medically treated esophagitis, and from patients who had previously undergone anterior fundoplication. In patients with severe esophagitis, the basal zone showed a significantly elevated [3H]thymidine labeling index in contrast to that of mild esophagitis patients and that of normal subjects. When esophagitis was associated with mucosal lesions at endoscopy, the labeling index was higher than that seen in esophagitis patients without endoscopic abnormalities. Significantly increased thymidine labeling was found only in patients with the most severe changes of papillary length or basal layer thickening. We therefore conclude that there is an increased basal zone uptake of [3H]thymidine in severe esophagitis which suggests increased cell turnover as the mechanism for basal zone hyperplasia. Present techniques for measuring mucosal uptake of [3H]thymidine, however, do not permit the distinction of mild degrees of esophagitis from normal epithelium.
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The interaction of calcium with sugar, sodium, and water absorption was studied in rats fed laboratory chow and in vitamin D-deficient and -repleted rats with the use of intestinal loops in vivo. Calcium absorption in the duodenum was enhanced by D-glucose only in the vitamin D-deficient state. In both vitamin D-deficient and -repleted ileum, calcium absorption decreased when NaCl was replaced by mannitol; however, it remained unchanged when NaCl was replaced by choline chloride or urea. Calcium absorption was enhanced by actively transported sugars and by increasing net water flow generated by differences in osmotic pressure and urea. Under all experimental conditions there was a strong association between net water and calcium absorption in the ileum. These findings suggest that calcium absorption is enhanced by solvent drag, although the role of sodium cannot be excluded entirely.
The sensitivity and specificity of each of five esophageal tests used in the diagnosis of reflux esophagitis were compared with those of six combinations of two tests, one indicating esophagitis and the other indicating sphincter incompetence. The esophageal tests were performed in patients with reflux symptoms, chest pain, and esophagitis without reflux symptoms. Control data were obtained from normal subjects (negative control) and duodenal ulcer patients (positive control). The results indicate that the acid infusion test and esophageal biopsy combined with esophageal pH study after HC1 have similar sensitivity and greater specificity than any test alone. In normal subjects, the cumulative incidence of abnormalities with esophageal tests alone was 30%, but with combinations of two tests it was only 5%. The use of criteria (simultaneous esophagitis and sphincter incompetence) which establish the diagnosis of reflux esophagitis helps to resolve conflicting results obtained with single tests. The most sensitive and specific test combination for the diagnosis of reflux esophagitis appears to be esophageal biopsy with esophageal pH study after HC1.
The effect of oral metoclopramide (15 mg), AlMgOH (30 ml), and placebo on the cumulative duration of gastroesophageal reflux induced by a protein-rich meal was compared in 15 patients with reflux esophagitis. Oral metoclopramide was found to be more effective than AlMgOH in reducing the cumulative duration of reflux after placebo over a 3-hr period. The same dose of oral metoclopramide increased resting lower esophageal sphincter pressures in all 15 patients for at least 1 hr and prevented gastroesophageal reflux after an intragastric acid load (300 ml of O.1 N HCl) in 8 of 10 of these patients. Oral metoclopramide, however, failed to increase the amplitude of esophageal contractions and acid clearing of the distal esophagus. These findings suggest that oral metoclopramide in the dose of 15 mg may be potentially valuable in the management of reflux esophagitis.
We compared the surgical and medical managements of reflux esophagitis in a prospective managements of reflux esophagitis in a prospective clinical trial. Patients wissigned to surgical (15 patients) and medical (16 patients) groups. A non-randomized medical group (20 patients) was also studied. Seventy three per cent of the surgical and 19 per cent of the medical group had an excellent to good response. A fair to poor response was observed in 81 per cent of medical and 27 per cent of surgical patients. Symptomatic improvement was accompanied by normal findings on acid infusion test and esophagoscopy. The histologic appearance of the squamous mucosa, however, remained abnormal in all but one patient. In patients who did well after operation there was improvement in resting lower-esophageal-sphincter pressures and absence of gastroesophageal reflux. The relative increases in pphincter pressure to graded increases in gastric pressure, however, remained abnormal in all but one patient.
The effect of calcium on magnesium absorption was studied in the rat ileum in vivo. The increase in the luminal concentration of calcium led to a progressive decrease in magnesium absorption, which was accompanied by a parallel decrease in net sodium absorption. This calcium effect was also observed when sodium chloride was replaced by urea. However, a consistent correlation was observed between the magnitude of net magnesium absorption and the rates of net water absorption of all calcium concentrations. These findings suggest that calcium decreases magnesium absorption by a nonspecific reduction in membrane permeability to solutes that induce net water flow and are consistent with the concept that magnesium is transported by solvent "drag". The increase in the luminal concentration of calcium resulted in an increase in tissue accumulation of magnesium. This increase in tissue accumulation of magnesium was associated with a decrease in net sodium absorption and in the negativity of the transmural PD. These findings suggest an additional mechanism of magnesium transport operating independently of net water flow.
The mechanical characteristics of the circular muscle of the human lower esophageal sphincter and esophagus were studied in subjects with competent and incompetent sphincters. Pressure-diameter curves were constructed by producing various degrees of circumferential stretch with pressure-measuring probes of increasing diameter. The circumferential membrane tension (force of closure) and the circumferential stress (muscle tension) of the circular muscle layer were also calculated from these data. The pressure-diameter curves of competent and incompetent sphincters were different in magnitude and shape. Incompetent sphincters had lower pressures at all diameters, with pressure gradually increasing with larger probe diameter. In contrast for competent sphincters the pressure was highest near closure, with an initial decline and then an increase in pressure with increasing probe diameter. Both shape and magnitude of pressure-diameter curves of competent and incompetent sphincters were interchangeable when manipulated by pharmacologic agents. Urecholine increased the pressures and changed the incompetent pressure-diameter curve to the levels of the competent sphincter; conversely. Pro-Banthine decreased pressures and changed the shape of the competent pressure-diameter curve to the levels of the incompetent sphincter. Force of closure and circular muscle tension curves of competent and incompetent sphincters were similar in shape but were higher at all diameters for competent sphincters. Force of closure and circular muscle tension increased with larger probe diameter. However, the diameter of optimal tension development was larger than the largest probe used and certainly far from closure. Fundoplication increased the magnitude and changed the shape of the incompetent pressure-diameter curve to one similar to a competent curve. This pressure change was associated with an increase in the force of closure, suggesting that fundopliation modified the length-force of closure characteristics of the incompetent spincter.
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Metoclopramide tablets were compared with placebo in the treatment of gastrointestinal symptoms in 40 patients with diabetic gastroparesis. Results of a 3-wk double-blind study indicate that metoclopramide at a dosage of one 10-mg tablet four times daily reduced nausea, vomiting, fullness, and early satiety and improved meal tolerance better than placebo. Statistically significant differences were noted for nausea and postprandial fullness. Mean gastric emptying assessed by radionuclide scintigraphy was significantly improved in the metoclopramide-treated group when compared with their baseline result. Metoclopramide is an effective agent for improving the upper gastrointestinal motor function in diabetic patients with gastroparesis.
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.