Simulation of the electric-control activity of the stomach by an array of relaxation oscillators

An array of bidirectionally coupled relaxation oscillators is proposed as a model of gastric electric-control activity. The characteristics of relaxation oscillators simulating control activity, such as intact and intrinsic frequency gradients and phase-lag patterns, were studied in anesthetized dogs. A marked intrinsic frequency gradient was found along the axis of the stomach, and a slight intrinsic frequency gradient around the circumference. The phase lag/cm decreased distally from the body of the stomach to the antrum. The model showed all these characteristics. Each oscillator in the array was represented by a system of two first-order nonlinear differential equations. The model was programmed on analog and hybrid computers.Supported by the Medical Research Council of Canada, the Alberta Heart Foundation and the National Research Council of Canada.     

Synchronizing genetic relaxation oscillators by intercell signaling

The ability to design and construct synthetic gene regulatory networks offers the prospect of studying issues related to cellular function in a simplified context; such networks also have many potential applications in biotechnology. A synthetic network exhibiting oscillatory behavior has recently been constructed [Elowitz, M. B. & Leibler, S. (2000) Nature (London) 403, 335-338]. It has also been shown that a natural bacterial quorum-sensing mechanism can be used in a synthetic system to communicate a signal between two populations of cells, such that receipt of the signal causes expression of a target gene [Weiss, R. & Knight, T. F. (2000) in DNA6: Sixth International Meeting on DNA-Based Computers, June 13-17, 2000, Leiden, The Netherlands]. We propose a synthetic gene network in Escherichia coli which combines these two features: the system acts as a relaxation oscillator and uses an intercell signaling mechanism to couple the oscillators and induce synchronous oscillations. We model the system and show that the proposed coupling scheme does lead to synchronous behavior across a population of cells. We provide an analytical treatment of the synchronization process, the dominant mechanism of which is "fast threshold modulation."     

Role of cholecystokinin in relaxation of the proximal stomach

Ingestion of a meal causes proximal gastric relaxation (accommodation). The magnitude of accommodation is related to the fat content of the meal. A role for cholecystokinin (CCK) has been suggested. However, under fasting conditions intravenous CCK to postprandial levels does not induce a similar accommodation. This study further explores the role of CCK in accommodation. A gastric barostat was used in eight healthy persons to study accommodation in response to a carbohydrate meal with intravenous CCK (CH-CCK), carbohydrate meal with intravenous placebo (CH-placebo) and a fat rich meal with intravenous placebo (FAT). VAS scores for satiety and plasma CCK levels were obtained. In the first postprandial hour the FAT meal induced a relaxation of 112 +/- 29 ml, the CH-CCK meal 49 +/- 36 ml and the CH-placebo meal 12 +/- 32 ml (FAT versus CH-placebo P = 0.03; FAT versus CH-CCK P = 0.09). In the second postprandial hour, intragastric bag volume returned to baseline with all meals. The FAT meal had the most pronounced effect with respect to satiety, CH-placebo the least. In the first postprandial hour, plasma CCK levels increased with the CH-CCK and FAT meals but not with the CH-placebo meal; in the second postprandial hour, levels remained elevated with the CH-CCK meal. It is concluded that a carbohydrate meal with exogenous CCK does not induce fundic relaxation, whereas a fat-rich meal (endogenous CCK) does, despite similar plasma CCK levels.     

Electrical activity of the normal human stomach

Using monopolar electrodes, the gastric electrical activity was recorded in waking human beings from both the mucosal and the serosal sides of the gastric wall. For each electrode location in a given subject, a mean curve of the regular fluctuations in potential (pacesetter potential) was obtained by an iteration process allowing measurement of characteristic amplitudes. A detailed study of the variations of the electrical period within and between subjects was undertaken. The frequency variations of the normal human gastric pacemaker appear in a slow and gradual fashion rather than in irregularities in the period; rhythm disorders rarely occur. Since frequent shifts of the baseline prevent the routine use of DC recordings, the use of a time constant of 4 seconds allows correct reproduction of the second component of the pacesetter potential. The morphology of the pacesetter potential is dependent on the gastric area and on the recording source—ie, mucosal or serosal. The amplitude and slope of the first component are greater in the antrum than in the corpus; the relative amplitudes of the first and the second component are dependent on the recording source.     

Electrical activity of the stomach and upper intestine

Thecontrol andresponse electrical activities of the stomach and upper intestine have been described. Control activities are spontaneous, rhythmic activities which do not induce contractions directly but which do control contractions by controlling the appearance of response activities. Properties of the control activity (pacesetter potentials) of the stomach have been described and compared to the properties of the control activity of the upper duodenum. Differences between these control activities were stressed: only in the stomach can single pacesetter potentials be induced locally as desired (by intraarterial acetylcholine) and obliterated locally as desired (by intraarterial catecholamines). Using these procedures, it was shown that the pacesetter potential of the stomach is followed by a refractory period; can be abolished temporarily by collision with a premature potential which spreads in a retrograde direction, or by a local injection of catecholamines proximal to a recording site. These findings and other evidence suggest that the pacesetter potentials of the stomach may differ from those of the intestine, and present a challenge to current models (eg, coupled relaxation oscillators) for the control activities of the gastrointestinal tract. The electrical activity of the stomach can be manipulated experimentally, and this would be advantageous in testing the applicability of models to gastrointestinal electrical activity.Supported by a grant from the Life Insurance Medical Research Fund.     

Mechanoreceptors of the proximal stomach: Role in triggering transient lower esophageal sphincter relaxation

BACKGROUND AND AIMS: The role of fundic tension and stretch mechanoreceptors in triggering transient lower esophageal sphincter (LES) relaxation is still unknown. This information would be useful for the development of effective pharmacologic strategies. To elucidate this topic, gastric contractile activity was modified during isovolumetric gastric distention at 2 different volumes. METHODS: LES (Dentsleeve) and gastric (barostat) motility were recorded in 21 healthy subjects during studies comprising two 30-minute isovolumetric gastric distentions (placebo and glucagon or erythromycin). Glucagon (bolus of 4.8 microg/kg plus infusion of 9.6 microg x kg(-1) x h(-1)) was administered at high intragastric volume (i.e., 75% of the threshold volume for discomfort; n = 7) and erythromycin (3 mg/kg) at high (n = 7) and low intragastric volume (i.e., at perception threshold; n = 7). RESULTS: Glucagon decreased (P < 0.05) baseline intragastric pressure and abolished gastric contractions (0 vs. 16.7 +/- 2.3), whereas erythromycin increased (P < 0.05) baseline pressure and doubled (P < 0.05) the rate of gastric contractions at both volumes. Neither drug affected the rate of transient LES relaxations. Low intragastric volume induced a lower rate of transient LES relaxations (1.7 +/- 0.3 vs. 5.7 +/- 1.1; P < 0.01) and gastric contractions (11.8 +/- 2.5 vs. 20.5 +/- 3.1; P < 0.05) compared with high volume but similar baseline intragastric pressure (10.6 +/- 0.6 vs. 11.9 +/- 0.9 mm Hg). CONCLUSIONS: Stretch receptors (gastric volume) seem to be more relevant than tension receptors in triggering transient LES relaxation.     

Nitroxergic nerves mediate vagally induced relaxation in the isolated stomach of the guinea pig.

Here we show that the relaxation induced by stimulation of the vagus nerve in the presence of cholinergic (muscarinic) and adrenergic blockade in the isolated stomach of the guinea pig is mediated by nitric oxide (NO). This is substantiated by inhibition of vagal relaxation by NG-monomethyl-L-arginine, an inhibitor of NO synthesis. The effect of NG-monomethyl-L-arginine was partially reversed by coincubation with L-arginine but not with D-arginine. NO activates soluble guanylate cyclase, and relaxation of the stomach induced by vagal stimulation was prevented by an inhibitor of soluble guanylate cyclase, methylene blue, further supporting our conclusions. The relaxant effect of vagal stimulation was also ablated by hexamethonium, an inhibitor of ganglionic nicotinic receptors, thereby showing that ganglionic transmission did not rely on NO, through its release from preganglionic neurons. However, hexamethonium did not inhibit the gastric relaxation brought about by increasing the intragastric pressure, which is also mediated by NO as previously described by us. The selective inhibition by hexamethonium of only the vagally mediated relaxation but not of the pressure-induced relaxation of the stomach indicates the existence of at least two separate neuronal pathways able to generate NO and bring about gastric accommodation of food or fluid.     

Inhibition of interdigestive contractile activity in the stomach by peptide YY in Heidenhain pouch dogs

The inhibitory effect of peptide YY on contractile activity in the innervated main stomach and the vagally denervated fundic pouch in conscious Heidenhain pouch dogs was investigated. Peptide YY was given in i.v. bolus injections of doses between 12.5 and 100 pmol/kg body wt. During the digestive state, 2-3 h after feeding, peptide YY was found to have no effect on contractile activity in either the innervated or the vagally denervated stomach. In the interdigestive state, it was found that peptide YY inhibited the interdigestive migrating contractions in the innervated main stomach dose-dependently for 1.2 +/- 0.1 to 5.8 +/- 0.3 min, but did not affect pouch contractions at all. This peptide, however, did not influence the cycle of the interdigestive migrating contractions. Pentagastrin, on the other hand, suppressed the interdigestive migrating contractions in the innervated main stomach when the bolus doses were greater than 300 pmol/kg body wt, but did not inhibit pouch contractions completely with this dose. Atropine (0.05 mg/kg body wt) suppressed contractions in both the main stomach and the vagally denervated pouch. Peptide YY inhibits the interdigestive migrating contractions in the stomach through the extrinsic nerves.     

Relationship between motor function of the proximal stomach and transient lower oesophageal sphincter relaxation after morphine

BACKGROUND: Morphine reduces the rate of transient lower oesophageal sphincter (LOS) relaxations but its site of action is presently unknown. There are no data available concerning its motor effects on the proximal stomach, an important site for triggering transient LOS relaxations. AIM: To evaluate the effect of morphine on the rate of transient LOS relaxations and motor function of the proximal stomach. SUBJECTS AND METHODS: In 19 healthy subjects, concurrent transient LOS relaxations with a sleeve sensor and motor function of the proximal stomach with a bag connected to an electronic barostat were recorded during pressure controlled (n = 9) and volume controlled (n = 10) gastric distensions after intravenous administration of placebo and morphine 100 microg/kg. RESULTS: During pressure controlled distensions, intrabag volume was markedly decreased by morphine (median 189 ml (interquartile range 101-448) v 404 (265-868) after placebo; p<0.01) as was the rate of transient LOS relaxations (0.5/30 minutes (0.4-2) v 2.5 (2-4); p<0.01). When intrabag volume was kept constant (525 ml (490-600)) (that is, in volume controlled distensions), the rate of transient LOS relaxations was not affected by morphine (2/30 minutes (2-3) v 2.5 (2-3)). Gastric contractions decreased after morphine similarly during pressure controlled and volume controlled distensions (8.5/30 minutes (4-10) v 15.5 (9.5-20.5), p<0.02; and 6.5 (0-24) v 19.5 (12-22), p<0.05). CONCLUSIONS: The effect of morphine on transient LOS relaxations is dependent on the decrease in volume of the proximal stomach. Our data suggest that pharmacological interventions which decrease fundal volume should result in control of transient LOS relaxation mediated gastro-oesophageal reflux.     

Effect of gastric dysrhythmias on postcibal motor activity of the stomach

The effect of electrical dysrhythmias on the mechanical activity of the fed stomach was investigated in 5 conscious dogs implanted with Ag-AgCl electrodes and strain gauge force transducers. Each dog was fed 1 can of ALPO^® and electromechanical activities of the stomach were recorded for the next 120 min. The results show that intraarterial boluses of met-enkephalin (75 g/kg), PGE₂ (36 g/kg), and epinephrine (36 g/kg) induced episodes of antral dysrhythmias whereas saline (1 cc) did not. The postcibal antrat motility index for the test period was not altered following saline injection, but it was reduced by 61%, 70%, and 81% following the administration of met-enkephalin, epinephrine, and PGE₂, respectively (p<0.01 vs. baseline period). During periods of normal electrical rhythm, PGE₂ and epinephrine significantly reduced the antral motility index (2.07±0.93 and 3.24±0.79, respectively) vs. saline (7.92±0.44) (p<0.05 for both drugs) whereas met-enkephalin (4.98±0.56) did not. In contrast, during episodes of dysrhythmia, met-enkephalin significantly depressed antral motility (1.70±0.74) (p<0.05 vs. periods with normal electrical rhythm) whereas neither epinephrine nor PGE₂ caused a further reduction in antral motility from what was seen during periods of normal electrical rhythm (1.84±0.72 and 1.34±0.37, respectively). We thus conclude that intraarterial administration of met-enkephalin, PGE₂, or epinephrine induce gastric dysrhythmias postcibally and depress antral contractile activity. The relaxatory effect of met-enkephalin on antral contractions is primarily due to its dysrhythmic effect whereas PGE₂ and epinephrine inhibit antral motility even when the electrical rhythm is undisturbed.This work was supported in part by the USPHS, NIH grants AM26428, AM07198, and AM34988 and the Mayo Foundation.     

Spontaneous penetration of an antireflux prosthesis into the stomach

The Angelchik antireflux prosthesis is a ringlike device used in the surgical treatment of sliding hiatal hernia and gastroesophageal reflux. This article describes an unusual postoperative complication whereby the prosthesis had migrated into the lumen of the stomach.     

Muriatic secretion and acid-proteolytic activity of the stomach in vivo]

The study of the basal (BAP) and stimulated (SAP) acid production effect on the average daily acidity and speed of proteolysis in the stomach in vivo was conducted in 498 patients with various functional states of the stomach. It was established that the aforesaid muriatic secretion indices influence the acidity and speed of proteolysis in natural conditions of digestion only within the low and normal range of their values. In the condition of HCl hypersecretion, the dependence between the muriatic secretion and acidity and proteolytic stomach activity in vivo gets lost. This can be explained by the autoregulation effect supporting the introgastral pH optimal for pepsin activity irrespective of the intensity of the acid glands hyperplasia.