Effect of cholecystokinin-octapeptide on lower esophageal sphincter

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.     

Effect of motilin on the lower esophageal sphincter of the opossum

We have studied the effect of Yajima's synthetic motilin on the lower esophageal sphincter (LES) of the opossum and compared its potency to that of gastrin and its interaction with secretin. Dose-response curves for the LES were constructed from the intravenous bolus injection of graded doses of motilin and gastrin alone and motilin given against a background infusion of secretin. The smallest dose of motilin that elicited a significant response was 0.05 microng/kg, and the highest response was observed with the highest dose used in this study (1.0 microng/kg). Over a wide dose range, both motilin and gastrin were found to be equally potent in stimulating the LES of the opposum, and secretin caused inhibition of the LES pressure to motilin. Therefore, we conclude that (1) motilin is a potent stimulant of the LES; (2) this response is dose dependent; (3) motilin's potency is similar to that of gastrin; and (4) secretin counteracts the effect of motilin on the LES.     

Effect of morphine on gastroesophageal reflux and transient lower esophageal sphincter relaxation

BACKGROUND: Results from animal studies and preliminary data from pilot studies in patients with primary biliary cirrhosis suggest that tauro-ursodeoxycholic acid has metabolic properties that may favour its long-term use as an alternative to ursodeoxycholic acid for patients with chronic cholestatic liver diseases. No direct comparison of tauro-ursodeoxycholic and ursodeoxycholic acids have yet been carried out in primary biliary cirrhosis. METHODS: The effects of ursodeoxycholic and tauro-ursodeoxycholic acids were compared in 23 patients with primary biliary cirrhosis according to a crossover design. Both drugs were administered at the daily dose of 500 mg. in a randomly assigned sequence for two 6-month periods separated by a 3-month wash-out period. RESULTS: Serum liver enzymes related to cholestasis and cytolysis consistently improved, as compared to baseline values, during the administration of both ursodeoxycholic and tauro-ursodeoxycholic acids, but no significant difference between these two bile acids was found. Both treatments were well tolerated and no patient complained of side effects. CONCLUSION: In the short-term, tauro-ursodeoxycholic acid appears to be safe and at least as effective as ursodeoxycholic acid for the treatment of primary biliary cirrhosis.     

Effect of gastrin-17 on lower esophageal sphincter characteristics in man

We studied the effect of gastrin-17 on lower esophageal sphincter (LES) characteristics in man. Nine healthy volunteers participated in two experiments performed in random order during continuous infusion of saline (control) or gastrin-17 (15 pmol/kg/hr). LES pressure (LESP) and transient lower esophageal sphincter relaxations (TLESR), as most the important reflux mechanism, were measured with intraesophageal sleeve manometry combined with pH metry. Infusion of gastrin-17 resulted in plasma gastrin levels comparable to those reached after a mixed meal. During continuous gastrin infusion, LESP decreased significantly (P < 0.05) compared to control. The rate and duration of TLESR was not influenced by gastrin-17. Gastroesophageal reflux and the number of TLESR associated with reflux were significantly (P < 0.05) increased during gastrin infusion. These results suggest that in humans gastrin at physiological postprandial plasma concentrations decreases LESP, does not influence TLESR, but increases the percentage of TLESR associated with reflux.     

Endogenous motilin and lower esophageal sphincter pressure in man: clue to an association

In man (n = 5), after intraduodenal instillation of 50 ml of 0.1 N hydrochloric acid the lower esophageal sphincter pressure (LESP) and plasma motilin concentrations rise concomitantly exceeding basal by about 80% (p less than 0.025) and 90% (p less than 0.05), respectively, at 3 to 4 minutes. These results suggest that the increase in LESP after duodenal acidification may be brought about by endogenously released motilin.     

Transdiaphragmatic pressure gradients and the lower esophageal sphincter after tight abdominal wall plication in the rat

BACKGROUND: Gastroesophageal reflux (GER) is increasingly recognized as a complication of surgical closure of gastroschisis and omphalocele. AIM: This study tests the hypothesis that forceful abdominal wall closure reinforces the transdiaphragmatic pressure gradients that constitute the main GER-driving force and challenges the antireflux barrier. MATERIALS AND METHODS: Abdominal and esophageal pressures as well as lower esophageal sphincter pressures (LESP) and length (LESL) were measured in 17 adult rats before tight abdominal wall plication, after it, and 1 week later. RESULTS: This maneuver increased the transdiaphragmatic expiratory gradient from 0.67 +/- 1.31 to 6.97 +/- 2.68 mm Hg (P < .01) and the inspiratory gradient from 4.36 +/- 1.13 to 10.79 +/- 2.31 mm Hg (P < .01) by markedly increasing both the expiratory (from 1.47 +/- 0.74 to 9.44 +/- 1.85 mm Hg; P < .01) and inspiratory (from 0.98 +/- 0.69 to 6.83 +/- 1.55 mm Hg; P < .01) intraabdominal pressures. These changes were transient, and all pressures became normal after 1 week. The antireflux barrier functioned properly under these new conditions because both LESP and the diaphragmatic pinch-cock pressure (DPP) increased, from 20.3 +/- 3.63 to 26.5 +/- 4.31 mm Hg (P < .01) and from 16.4 +/- 7.25 to 22.5 +/- 4.36 mm Hg (P < .01), respectively, while LESL remained unchanged. CONCLUSION: Tight abdominal wall plication in the rat generates high intraabdominal pressures and thus reinforces the transdiaphragmatic pressure gradients, but these conditions elicit a healthy barrier response with sphincteric reinforcement. In addition, these changes are transient and fade out some time after operation. These facts should be taken into account for understanding the pathogenesis of GER after repair of abdominal wall defects in human babies.     

Mechanism of action of metoclopramide on opossum lower esophageal sphincter muscle

The purpose of this study was to investigate the mechanism of action of metoclopramide on the lower esophageal sphincter (LES) muscle of the opossum. Metoclopramide gave a dose-related increase in LES muscle active tension. A peak response of 12.5 +/- 2.1 g (mean +/- SEM) was achieved at 3.1 X 10(-4) M. The maximal and submaximal LES muscle response to metoclopramide could not be antagonized by atropine, hyoscine, hexamethonium, tetrodotoxin, phentolamine, diphenhydramine, or propranolol. Metoclopramide did not augment the submaximal muscle responses to gastrin I, acetylcholine, or norepinephrine. These studies suggest that in the opossum, metoclopramide acts through a direct action on the smooth muscle.     

Characterization and mediation of inhibitory junction potentials from opossum lower esophageal sphincter

BACKGROUND: Activating nonadrenergic, noncholinergic (NANC) nerves of the lower esophageal sphincter (LES) hyperpolarizes and relaxes its circular smooth muscle. This relaxation is mediated by nitric oxide (NO) or an NO-containing compound. These studies were undertaken to compare the electrophysiological responses of circular smooth muscle from the LES and esophagus in response to NANC nerve stimulation and to test the hypothesis that NO mediates LES hyperpolarization. METHODS: The transmembrane potential difference was recorded with glass microelectrodes. Nerve-mediated membrane responses were evoked by electrical pulses of 0.5 msec duration and 50 V amplitude. RESULTS: Responses of LES muscle differed from those of the esophageal muscle. The duration of hyperpolarization was much longer in sphincteric muscle. The depolarization that followed hyperpolarization of esophageal muscle was not observed in sphincteric muscle. NG-nitro-L-arginine, an inhibitor of NO synthase, attenuated the nerve-induced hyperpolarization. L-arginine, the substrate for NO synthase, antagonized the effect of NG-nitro-L-arginine. Exogenous NO hyperpolarized of the smooth muscle membrane. CONCLUSIONS: These data support the hypothesis that NO or an NO-like compound may mediate nerve-induced hyperpolarization of the opossum LES.     

Relationship of cervical and abdominal vagal activity to lower esophageal sphincter function

The purpose of this study was to compare the effects of electrical stimulation of the abdominal and cervical portions of the vagus on lower esophageal sphincter (LES) pressure in the anesthetized opossum. Unilateral or bilateral abdominal vagotomy gave no significant change in basal LES pressure or in the sphincteric response to swallowing. Electrical stimulation of the peripheral end of the sectioned cervical vagus gave a frequency-related decrease in LES pressure with a maximum reduction of 93.5 +/- 2.5% at 10 HZ, 10 V. Stimulation of the central end of the cervical vagus increased LES pressure, with a maximum response of 34.0 +/- 1.9 mm Hg. Neither peripheral nor central stimulation of the sectioned abdominal vagus had significant effect on LES pressure (P greater than 0.05). Additionally, LES relaxation in response to swallowing or cervical vagal stimulation was intact after bilateral abdominal vagotomy. These studies suggest that whereas the cervical portion of the vagus mediates inhibitory and excitatory changes in LES pressure, the abdominal vagus has no demonstrable role in the control of LES function.     

Comparison of the effects of atropine and glycopyrrolate on lower oesophageal sphincter pressure

Lower oesophageal sphincter pressure (LOSP) has been measured on three separate occasions in nine healthy volunteers using oesophageal pressure transducers. Atropine 0.6 mg decreased LOSP significantly at 5 min after i.v. injection (P less than 0.025) and this change was sustained for 40 min. Glycopyrrolate 0.3 mg or 0.2 mg decreased LOSP significantly at 3 min after i.v. injection (P less than 0.0025). This change was sustained for 60 min and was similar for both doses and also similar in magnitude to the change produced by atropine.     

Electrophysiological and pharmacological responses of chronically denervated lower esophageal sphincter of the opossum

BACKGROUND & AIMS: Achalasia is characterized by loss of myenteric neurons and incomplete relaxation of the lower esophageal sphincter (LES). The aim of this study was to develop an achalasia model in the opossum using the surfactant benzyldimethyltetradecylammonium chloride (BAC). This study further characterizes the achalasia model. METHODS: BAC or saline was injected circumferentially into the LES of 14 adult opossums. Eight months after injection, manometry, isolated muscle bath studies, electrical field stimulation, and histochemical analysis were performed. RESULTS: Manometrically, the LES of BAC-treated opossums showed higher pressures (38.7 +/- 12 mm Hg vs. 17 +/- 3.0 mm Hg) and reduced esophageal body contraction amplitudes (4.2 +/- 3 mm Hg vs. 27.4 +/- 12 mm Hg). Isolated muscle strips challenged with carbachol and sodium nitroprusside contracted and relaxed similarly to controls. Electrical field stimulation failed to induce relaxation in BAC-treated tissue but did induce contraction. Contractile responses were markedly reduced by tetrodotoxin and atropine in BAC-treated animals and controls. An altered nitric oxide system was shown by the lack of response to L-arginine and N omega-nitro-L-arginine. Histology showed loss of myenteric neurons and increased cholinergic nerve bundles. CONCLUSIONS: Loss of NO inhibitory myenteric neurons markedly reduces the relaxation of the LES, and histology and pharmacological responses suggest a proliferation of cholinergic nerves into the LES contributing to the static elevated pressures of the amyenteric LES.     

Different protein kinase C isozymes mediate lower esophageal sphincter tone and phasic contraction of esophageal circular smooth muscle

Circular muscle of the esophagus (ESO) is normally relaxed and contracts phasically in response to neural stimuli. In contrast, lower esophageal sphincter (LES) circular muscle maintains spontaneous tone and relaxes in response to neural stimuli. We have previously shown that in vitro, spontaneous LES tone and contraction of ESO in response to acetylcholine (ACh) are antagonized by protein kinase C (PKC) inhibitors, suggesting that PKC activation is responsible for these functions. In the current study, Western blot analysis of LES and ESO revealed PKC-alpha, -betaII, and -gamma isozymes in LES circular muscle, but only PKC-betaII translocated from the cytosolic to the membrane fraction in response to ACh. In contrast, ESO contained PKC-betaII, -gamma, and -epsilon, and only PKC-epsilon translocated to the membrane fraction in response to ACh. In LES single cells isolated by enzymatic digestion and permeabilized by saponin, 1-2-dioctanoylglycerol-mediated contraction was inhibited by preincubation with PKC-betaII antiserum but not by other PKC antisera. In esophageal cells, contraction was inhibited by the PKC-epsilon antiserum but not by antisera against other PKC isozymes. N-Myristoylated peptides derived from the pseudosubstrate sequences of PKC isozymes were used to inhibit saponin, 1-2-dioctanoylglycerol-induced contraction of LES and ESO smooth muscle cells. Contraction of LES cells was reduced by the alpha beta gamma pseudosubstrate but not by the alpha, delta, or epsilon pseudosubstrate. Contraction of ESO cells was reduced by the epsilon pseudosubstrate but not by the alpha, delta, or alpha beta gamma pseudosubstrate. We conclude that different types of contractile activity in the ESO and LES are mediated by different PKC isozymes. LES contraction is mediated by the calcium-dependent PKC-betaII, whereas contraction of ESO is mediated by the calcium-independent PKC-epsilon.     

Effect of halothane, isoflurane and desflurane on lower oesophageal sphincter tone

We have studied the effects of volatile anaesthetics on lower oesophageal sphincter (LOS) tone in three groups of eight pigs allocated randomly to receive end-tidal concentrations of 0.5, 1.0 and 1.5 MAC of desflurane, isoflurane or halothane for 15 min. LOS and oesophageal barrier pressures (BrP = LOSP - gastric pressure) were measured using a manometric method. The decrease in BrP paralleled the decrease in LOS pressure and was significant at 0.5 MAC for isoflurane and at 1.0 MAC for halothane. At 1.5 MAC, BrP values were approximately 62% of baseline values for halothane, 37% for isoflurane and 83% for desflurane. Inter-group comparisons showed that BrP did not differ at baseline and at 0.5 MAC. At 1.0 MAC the effect of isoflurane on BrP was significantly different from desflurane (P < 0.001) and halothane (P < 0.02) whereas the effect of desflurane on BrP was not significantly different from halothane. At 1.5 MAC the effect of isoflurane on BrP was significantly different from desflurane (P < 0.01) and halothane (P < 0.05) whereas the effect of desflurane on BrP was not significantly different from halothane. We conclude that desflurane maintained BrP and this may be clinically important in patients at high risk of regurgitation.     

Static and dynamic function of the lower esophageal sphincter before and after laparoscopic Nissen fundoplication

SUBJECT: We analysed the periprosthetic bone mineral density (BMD) in a prospective longitudinal study over two years after operation and in a separate cross-sectional study more than five years after implantation of cementless total hip arthroplasty (CLS-stem, Mecron threaded acetabular cup) by using dual-energy X-ray absorptiometry (DEXA). MATERIALS AND METHODS: In n = 53 patients (29 women, 24 men) we analysed the periprosthetic BMD prospectively in certain periods. All patients had an uncomplicated postoperative course and good clinical outcome (Merle d'Aubigne score > 12). In the cross-sectional study we analysed 23 patients (13 women, 10 men). Regions of Interest (ROI) were defined according to Gruen et al. for the periprosthetic femur and to De Lee and Charnley for the periprosthetic acetabulum. RESULTS: BMD significantly decreases in the periprosthetic femur as well as in the periprosthetic acetabulum during the first three months. In men BMD reaches its lowest values between six months (femur) and one year (acetabulum) after operation and then increases to 96.2% at the femur and 93.8% at the acetabulum. In women BMD decreases during the entire follow-up to 89.4% at the periprosthetic femur and 80.0% at the periprosthetic acetabulum. In the proximal zones 1 and 7 of the femur and the cranial-medial zone II of the acetabulum we observed the highest decrease of mineralisation. More than five years after implantation of the prosthesis BMD in the femur showed only little changes. On the other side BMD around the threaded acetabular cup significantly decreased to 67.4% in women and 79.1% in men. CONCLUSION: The results reflect the different stress on the periprosthetic bone after implantation of the prosthesis and fit to earlier reported good clinical results of the CLS-stem and to increased loosening rate of threaded acetabular cups after five years. Analysing changes of mineralisation in cementless total hip arthroplasty DEXA together with the analization scheme according to Gruen at the femur and to De Lee and Charnley at the acetabulum is a useful method and has been reliable in clinical practise.     

Simultaneous study of tones of the lower esophageal sphincter and proximal stomach in healthy humans

OBJECTIVES: The aim of this study was to determine the feasibility and tolerance of simultaneous assessment of the proximal gastric and lower esophageal sphincter tones in healthy humans, in fasting and fed conditions. METHODS: Esophageal motility and lower esophageal sphincter tone were measured on two separate days in 7 healthy subjects. During one of these sessions, proximal gastric tone was simultaneously assessed with a balloon placed in the proximal stomach and connected to an electronic barostat. Motility was monitored 1 hour before and 4 hours after a liquid fat meal (400 mL/600 kcal). In four other healthy subjects, simultaneous assessment of proximal gastric and lower esophageal sphincter tones was performed after, suggestion of a 200 mL/200 kcal liquid meal. RESULTS: Simultaneous use of gastric barostat and esophageal motility device was well tolerated in 10/11 healthy subjects. The presence of the barostat balloon did not significantly affect basal lower esophageal sphincter tone and the rate of transient lower esophageal sphincter relaxations. The important fall of lower esophageal sphincter basal tone after ingestion of the 400 mL/600 kcal meal did not allow to detect a post-prandial increase of transient lower esophageal sphincter; relaxations. After ingestion of the 200 mL/200 kcal meal, the incidence of transient lower esophageal sphincter relaxations increased (p < 0.02 vs. fasting). Maximal gastric relaxation was reached 15 min after meal, and appeared shorter (112 +/- 17 min vs. 167 +/- 24 min) and more pronounced (292 +/- 26 mL vs. 190 +/- 51 mL) than after the 400 mL meal, but differences were not statistically significant. CONCLUSIONS: Simultaneous assessment of proximal gastric and lower esophageal sphincter tone is feasible, after oval ingestion of a meal. Since the 400 mL meal induces in important inhibition of lower esophageal sphincter basal tone, the 200 mL meal seems more adequate for assessment of the transient lower esophageal sphincter relaxations.     

The effect of intravenous infusion of synthetic human gastrin-I on lower esophageal sphincter (LES) pressure in the dog and its relation to gastrin level

To demonstrate the relation between gastrin level and lower esophageal sphincter (LES) pressure, experiments with intravenous infusions of synthetic human gastrin-I (SHG-I) were performed in anaesthetized dogs. The results show that infusions with 5 mug-kg-1-h-1 SHG-I have an initially increasing effect on LES pressure but produce unphysiologically high gastrin blood levels. Physiological levels of gastrin were measured only using an infusion dose of 0.5 mug-kg-1-h-1, which was below the threshold for increasing LES pressure.