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PubMed2001

Mechanisms for contractile effect of Dai-kenchu-to in isolated guinea pig ileum.

The mechanisms by which Dai-kenchu-to (TJ-100), a kampo medicine, enhances gastrointestinal motility was investigated using isolated guinea pig ileum. TJ-100 induced contractions accompanied by autonomous contraction at a concentration of more than 3 x 10(-4) g/ml in a dose-related manner. The TJ-100-induced ileal contraction was suppressed by atropine and tetrodotoxin, but not by hexamethonium. This effect was partially suppressed in the presence of high concentrations of ICS 205-930, a serotonin 4 (5-HT4) receptor antagonist. In addition, TJ-100 showed an acetylcholine (ACh)-releasing action in the smooth muscle tissues of ileum. These results suggest that contractile response induced by TJ-100 is partially mediated by ACh released from the cholinergic nerve endings and that 5-HT4 receptors would be involved in the effect of TJ-100.

Acetylcholine↗
PubMed1991

Relationship of serotonin-3 receptor antagonist activity to gastric emptying and motor-stimulating actions of prokinetic drugs in dogs.

Drugs that enhance gastrointestinal motility include the benzamide drugs metoclopramide, cisapride and renzapride (BRL-24924). Because these agents also are serotonin-3 (5-HT3) receptor antagonists, which can promote gastric emptying in some species, the motor-stimulating properties of benzamide agents may be due to this mechanism. Metoclopramide (0.3-3.0 mg/kg i.v.), cisapride (0.03-1.0 mg/kg i.v.) and BRL-24924 (0.01-0.1 mg/kg i.v.) were evaluated for their relative motility-stimulating and 5-HT3 receptor antagonist activities in conscious dogs and were compared with selective 5-HT3 antagonist antiemetic compounds ICS-205-930, (3 alpha-tropanyl)1-H-indole-3-carboxylic acid ester and granisetron (BRL-43694). Gastric antral contractions and intestinal myoelectric motility were determined in response to drugs, as were their effects on solid and liquid emptying in a gamma scintigraphic model of gastroparesis. 5-HT3 receptor antagonist potency was examined by deriving ED50 values for inhibition of cisplatin emesis. All drugs were 5-HT3 antagonists as they blocked cisplatin emesis with relative potencies of BRL-43694 = ICS-205-930 greater than BRL-24924 greater than cisapride = metoclopramide. The order of potency for stimulating fasted dog antral contractile activity, however, was BRL-24924 = cisapride greater than metoclopramide greater than ICS-205-930 = BRL-43694. Maximally effective doses of BRL-24924 (0.1 mg/kg i.v.) and cisapride (0.67 mg/kg i.v.) in the antrum also stimulated intestinal myoelectrical activity, whereas ICS-205-930 (0.5 and 2.0 mg/kg i.v.) was not active.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

Substance P in the gastrointestinal tract of non-obese diabetic mice.

BACKGROUND: Gut dysmotility occurs in most diabetics. Substance P is a neurotransmitter that plays an important role in regulating gastrointestinal motility. The present investigation was carried out to evaluate the possible role of this neurotransmitter in the pathogenesis of dysmotility in diabetics. METHODS: Pre-diabetic and diabetic female non-obese diabetic (NOD) mice aged 22-24 weeks were studied. As controls, BALB/CJ mice of the same age and sex were used. Substance P concentrations in tissue extracts from the antrum, duodenum, and colon were determined with radioimmunoassay. Substance P-immunoreactive nerve elements and endocrine cells were identified by immunocytochemistry and quantified with computerized image analysis. RESULTS: Substance P levels in the antrum of both pre-diabetic and diabetic NOD mice were significantly lower than those of controls. In the duodenum and colon substance P levels were higher than those of the controls in both pre-diabetics and diabetic NOD mice. The relative volume density of substance P-immunoreactive nerve fibres in the colon of diabetic NOD mice was significantly decreased. There was no statistically significant difference between pre-diabetic and diabetic NOD mice and controls with regard to the relative volume density of substance P immunoreactive nerve fibres in the antrum and duodenum. In the antrum the number of substance P-immunoreactive cells decreased significantly in both pre-diabetic and diabetic NOD mice. In the duodenum and colon the numbers of these cells in NOD mice did not differ from those of controls. CONCLUSIONS: The changes in substance P contents in various parts of the gastrointestinal tract of NOD mice seem to be primary to the onset of diabetes. The decreased antral substance P contents in NOD mice seems to be caused by structural change in the mucosal endocrine cells. In the small and large intestine the increase in substance P levels appears to be caused by change in the physiologic activities of the nerve element and/or endocrine cells rather than by structure changes. The abnormalities observed here in an animal model for diabetes type I might have relevance for the gastrointestinal dysmotility displayed in human diabetes.

Animals↗
PubMed2000

Intercellular coupling mediated by potassium accumulation in peg-and-socket junctions.

Coupling of smooth muscle cells is important for coordination of gastrointestinal motility. Small structures called peg-and-socket junctions (PSJs) have been found between muscle cells and may play a role in electrical coupling due to extracellular potassium accumulation in the narrow cleft between the muscle cells. A model was developed in which an electrical boundary element model of the cell morphology is used in conjunction with a finite difference model which described ionic fluxes and diffusion of extracellular potassium in the PSJ. The boundary element model used a combination of triangular and cylindrical elements to reduce computational demand while ensuring accuracy. Barrier kinetics were used to model the underlying ionic transport mechanisms. Seven ionic transport mechanisms were used to create the transmembrane voltage waveform. Results indicate that PSJs may produce significant coupling between smooth muscle cells under appropriate conditions. Coupling increased exponentially with increasing length and with decreasing intercellular gap.

Adherens Junctions↗
PubMed1998

Defective smooth muscle regulation in cGMP kinase I-deficient mice.

Regulation of smooth muscle contractility is essential for many important biological processes such as tissue perfusion, cardiovascular haemostasis and gastrointestinal motility. While an increase in calcium initiates smooth muscle contraction, relaxation can be induced by cGMP or cAMP. cGMP-dependent protein kinase I (cGKI) has been suggested as a major mediator of the relaxant effects of both nucleotides. To study the biological role of cGKI and its postulated cross-activation by cAMP, we inactivated the gene coding for cGKI in mice. Loss of cGKI abolishes nitric oxide (NO)/cGMP-dependent relaxation of smooth muscle, resulting in severe vascular and intestinal dysfunctions. However, cGKI-deficient smooth muscle responded normally to cAMP, indicating that cAMP and cGMP signal via independent pathways, with cGKI being the specific mediator of the NO/cGMP effects in murine smooth muscle.

Animals↗
PubMed1996

Myoelectrical activity of the gastrointestinal tract of sheep analysed by computer.

The myoelectrical activity of several sections of the digestive tract of sheep has been studied as an estimation of the gastrointestinal motility. Nickel/chromium electrodes were implanted chronically in the reticulum, rumen, omasum, antrum and duodenum. The myoelectrical signals were then recorded simultaneously and stored in a computer which calculated the integrated activity, duration and period (interval) of each separate reticuloruminal spike burst and the integrated activity (over one minute intervals) in the omasum, abomasum and duodenum. The different electromyographic parameters were standardised in sheep during a period of non-ingestion (resting period), and the physiological changes in these parameters associated with rumination and feeding were measured. The main effect induced by rumination was an increase in the myoelectrical parameters in the reticulum. Feeding enhanced the total activity in all regions studied. In the reticulorumen this increase was due to a rise in the frequency of the spike bursts, although there was a decrease in the integrated activity and duration of each individual spike burst.

Animals↗
PubMed1998

Effects of somatostatin on proximal gastric motor function and visceral perception.

BACKGROUND: Somatostatin affects gastrointestinal motility and secretion and visceral sensation, but little is known about its effects on the proximal stomach. AIM: To evaluate the effects of somatostatin on proximal gastric motor function and perception of symptoms. METHODS: Six healthy subjects participated in two experiments performed in random order during continuous intravenous infusion of saline or somatostatin (250 microg/h). Proximal gastric motor function was evaluated using a barostat. We performed pressure and volume distensions and a barostat procedure (minimal distending pressure + 2 mmHg). Symptoms were evaluated at regular intervals using visual analogue scales (VAS). RESULTS: Neither minimal distending pressure nor gastric fundal tone were significantly different between somatostatin and saline. Pressure-volume curves during distensions were not influenced by somatostatin. However, phasic volume waves were significantly (P < 0.001) reduced by somatostatin, and somatostatin significantly (P < 0.05) reduced symptom perception of fullness and abdominal pressure during stepwise distensions.

Adult↗
PubMed1994

In utero defecation of the nondistressed fetus: a roentgen study in the goat.

An experimental study was performed to investigate gastrointestinal motility and meconium passage, with simultaneous blood gas measurements, in the fetuses of eight pregnant goats at 110 to 114 days' gestation (full term, 147 to 155 days). With the goats under halothane anesthesia, a nasogastric tube and a heparinized central venous catheter were inserted into the fetuses. 24 hours after surgery, 10 mL of gastric juice from the fetus was replaced with a nonhydrosoluble contrast medium, and serial roentgenograms and blood samples (for pH, PO2, and PCO2 measurement) were taken every 4 hours. All fetuses began to pass the contrast medium into the amniotic cavity within 16 to 22 hours, and central venous blood gas values were normal. The results of this study suggest that the fetus, which urinates routinely, also defecates routinely into the amniotic cavity, even in the absence of distress. The increased incidence of meconium staining in fetal distress conditions may be indicative of impaired clearance of amniotic fluid.

Animals↗
PubMed1993

Review article: promotility drugs in the treatment of gastro-oesophageal reflux disease.

Prokinetic agents are drugs that increase contractile force and accelerate intraluminal transit. They are often used in treating disorders of gastrointestinal motility including gastro-oesophageal reflux disease (GERD). The most widely studied agents include bethanechol, metoclopramide, domperidone and cisapride. These drugs act either by enhancing the effect of acetylcholine or by blocking the effect of an inhibitory neurotransmitter such as dopamine. With the exception of cisapride, the clinical efficacy of the various prokinetic agents in treating GERD has not been confirmed consistently. These agents have variable effects on oesophageal and gastric motor function and are fraught with side-effects. They are effective in relieving mild reflux symptoms but do not predictably heal oesophagitis. On the other hand, cisapride is thus far the most effective prokinetic agent studied for the treatment of GERD. It relieves reflux symptoms and promotes healing of grade I-II oesophagitis, with few side-effects or tachyphylaxis. Its most important role may be in the maintenance treatment of GERD either as a single agent or in combination therapy with an H2-antagonist after oesophagitis healing.

Adult↗
PubMed2004

Human enteric neuropathies: morphology and molecular pathology.

The aim of this study is to review current understanding of the molecular and morphological pathology of the enteric neuropathies affecting motor function of the human gastrointestinal tract and to evaluate the described pathological entities in the literature to assess whether a new nosology may be proposed. The authors used PUBMED and MEDLINE searches to explore the literature pertinent to the molecular events and pathology of gastrointestinal motility disorders including achalasia, gastroparesis, intestinal pseudo-obstruction, colonic inertia and megacolon in order to characterize the disorders attributable to enteric gut neuropathies. This scholarly review has shown that the pathological features are not readily associated with clinical features, making it difficult for a patient to be classified into any specific category. Individual patients may manifest more than one of the morphological and molecular abnormalities that include: aganglionosis, neuronal intranuclear inclusions and apoptosis, neural degeneration, intestinal neuronal dysplasia, neuronal hyperplasia and ganglioneuromas, mitochondrial dysfunction (syndromic and non-syndromic), inflammatory neuropathies (caused by cellular or humoral immune mechanisms), neurotransmitter diseases and interstitial cell pathology. The pathology of enteric neuropathies requires further study before an effective nosology can be proposed. Carefully studied individual cases and small series provide the basic framework for standardizing the collection and histological evaluation of tissue obtained from such patients. Combined clinical and histopathological studies may facilitate the translation of basic science to the clinical management of patients with enteric neuropathies.

Animals↗
PubMed1994

Use of gastroduodenal manometry to differentiate mechanical and functional intestinal obstruction: an analysis of clinical outcome.

OBJECTIVES: Our aim was to assess the outcome of patients whose gastrointestinal motility recording suggested intestinal mechanical obstruction. METHODS: Medical records were reviewed for operative reports and alternative diagnoses during at least 1-yr follow-up. RESULTS: During 1988-1992, 27 of 890 consecutive manometric recordings suggested mechanical obstruction: 20 with non-propagated, prolonged contractions, seven with a pattern of non-propagated clustered contractions that lasted > 30 min. Obstruction was confirmed at laparotomy in 17 (including two with progressive systemic sclerosis) and by radiology in one. In confirmed obstruction, 12 of 18 contrast radiographs performed prior to manometry were either normal or nondiagnostic. One laparotomy was negative for obstruction; nine patients who did not undergo laparotomy were classified as unobstructed. Manometric recordings showed prolonged contractions in two, clustered contractions in three, and a mixed pattern in four. Positive predictive values of these patterns for obstruction were: prolonged contractions, 82%; clustered contractions, 57%; and mixed pattern, 56%. CONCLUSIONS: Thus, non-propagated, prolonged contractions in small bowel should prompt a search for obstruction, even when this is equivocal on barium small bowel radiography.

Adolescent↗
PubMed1983

Campylobacter jejuni enteritis: efficacy of antimicrobial and antimotility drugs.

We analyzed retrospectively the illnesses of 82 patients with Campylobacter jejuni enteritis to ascertain the efficacy of antimicrobials and drugs that inhibit gastrointestinal motility. Forty-four patients were treated with only supportive measures consisting of diet modification and fluids; 22 others received an antimotility agent for at least 48 h; the remaining 16 were given an antimicrobial at or near the time of therapeutic intervention. The three groups were similar in terms of severity of symptoms and signs. There was a greater need for secondary antimicrobial therapy because of static or worsening illness in the group treated with antimotility agents (8/22, 36%) than in the others (4/44,9%; 2/16, 13%: p less than 0.02). Furthermore, six patients treated initially and 10 treated secondarily with erythromycin or tetracycline had illnesses of shorter duration than did untreated controls paired by age, sex, length and severity of symptoms and signs, hematochezia, and antimotility therapy (p less than 0.05). Thus treatment of C. jejuni enteritis with erythromycin or a tetracycline shortened the illness, but antimotility agents impeded the resolution of the infection.

Adolescent↗
PubMed2003

Electrical stimulation reveals complex neuronal input and activation patterns in single myenteric guinea pig ganglia.

The myenteric plexus plays a key role in the control of gastrointestinal motility. We used confocal calcium imaging to study responses to electrical train stimulation (ETS) of interganglionic fiber tracts in entire myenteric ganglia of the guinea pig small intestine. ETS induced calcium transients in a subset of neurons: 52.2% responded to oral ETS, 65.4% to aboral ETS, and 71.7% to simultaneous oral and aboral ETS. A total of 41.3% of the neurons displayed convergence of oral and aboral ETS-induced responses. Responses could be reversibly blocked with TTX (10(-)6 M), demonstrating involvement of neuronal conduction, and by removal of extracellular calcium. omega-Conotoxin (5 x 10(-7) M) blocked the majority of responses and reduced the amplitude of residual responses by 45%, indicating the involvement of N-type calcium channels. Staining for calbindin and calretinin did not reveal different response patterns in these immunohistochemically identified neurons. We conclude that, at least for ETS close to a ganglion, confocal calcium imaging reveals complex oral and aboral input to individual myenteric neurons rather than a polarization in spread of activity.

Animals↗
PubMed1989

The gastrointestinal prokinetic benzamide derivatives are agonists at the non-classical 5-HT receptor (5-HT4) positively coupled to adenylate cyclase in neurons.

We have previusly shown that a non-classical 5-hydroxytryptamine (5-HT4) receptor mediates the stimulation of adenylate cyclase activity in mouse embryo colliculi neurons in primary culture. The pharmacological characteristics of this receptor exclude the possibility that it belongs to the known 5-HT1, 5-HT2 or 5-HT3 receptor types. Here we report that this 5-HT receptor can be stimulated by 4-amino-5-chloro-2-methoxy substituted benzamide derivatives. All these compounds have been reported to be potent stimulants of gastrointestinal motility and some of them are 5-HT3 receptor antagonists. The rank order of potency of these substituted benzamide derivatives in stimulating cAMP formation was: cisapride greater than BRL 24924 greater than 5-HT greater than zacopride greater than BRL 20627 greater than metoclopramide. The non-additivity of benzamide and 5-HT activities suggests that 5-HT and the substituted benzamide derivatives act on the same receptor. Only ICS 205930, a recognized 5-HT3 receptor antagonist, competitively antagonized the stimulatory effect of cisapride, zacopride and BRL 24924. However, its pKi (6-6.3) for this new receptor was very different from its pKi for 5-HT3 receptors (pKi = 8-10). Other selective 5-HT3 receptor antagonists with an indole group (BRL 43694 and GR 38032F), with a benzoate group (cocaïne, MDL 72222) or with a piperazine group (quipazine) were ineffective in reversing the stimulatory effect of benzamide derivatives. Exposure of neuronal cells to potent agonists at this receptor such as BRL 24924 rapidly reduces its capacity to stimulate cAMP production.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed2002

Clinical perspectives, mechanisms, diagnosis and management of irritable bowel syndrome.

This consensus document reviews the current status of the epidemiology, social impact, patient quality of life, pathophysiology, diagnosis and treatment of irritable bowel syndrome. Current evidence suggests that two major mechanisms may interact in irritable bowel syndrome: altered gastrointestinal motility and increased sensitivity of the intestine. However, other factors, such as psychosocial factors, intake of food and prior infection, may contribute to its development. Management of patients is based on a positive diagnosis of the symptom complex, careful history and physical examination to exclude 'red flags' as risk factors for organic disease, and, if indicated, investigations to exclude other disorders. Therapeutic choices include dietary fibre for constipation, opioid agents for diarrhoea and low-dose antidepressants or infrequent use of antispasmodics for pain, although the evidence basis for efficacy is limited or in some cases absent. Psychotherapy and hypnotherapy are the subject of ongoing study. Treatment should be tailored to patient needs and fears. Novel therapies are emerging, and drugs acting on serotonin receptors have proven efficacy and a scientific rationale and, if approved, should be useful in the overall management of patients with irritable bowel syndrome. Patient and physician education, early identification of psychosocial issues and better therapies are important strategies to reduce the suffering and societal cost of irritable bowel syndrome.

Adult↗
PubMedDate not supplied

Myo-electrical and motor activity of the stomach in the first days after abdominal surgery: evaluation by electrogastrography and impedance gastrography.

The electrical and motor activities of the stomach were studied in the early postoperative phase after abdominal surgery by means of surface recording techniques: electrogastrography (EGG) and impedance gastrography (IGG). EGG and IGG recordings were made pre-operatively and on the first and second postoperative days. Physical signs and symptoms related to gastrointestinal motility were assessed. Two patient groups were studied; a group of patients undergoing cholecystectomy (n = 9) was compared with a group with major colonic surgery (n = 14). After colonic surgery, resumption of a normal oral diet was later and nausea and vomiting were seen more frequently than after cholecystectomy. Other physical signs concerning intestinal motility did not differ between the groups. Gastric myo-electrical activity (0.04-0.06 Hz), recorded electrogastrographically, tended to decrease in the postoperative phase in both groups, and return to pre-operative values later in the colonic surgery group. However, none of the differences reached statistical significance. Abnormal gastric activity (tachyarrhythmia) was observed in one pre-operative patient but in 6 patients (2 cholecystectomy, 4 colonic surgery) after operation. IGG variables were not significantly affected by the operation and were not significantly different between the groups. No correlation between the symptoms nausea and vomiting in the postoperative phase and the incidence of tachyarrhythmias could be demonstrated in this study. It is concluded that antral myo-electrical and motor activity, measured with non-invasive techniques (EGG and IGG), are not grossly abnormal on the first and second postoperative day after abdominal surgery. It is further concluded that abnormal gastric frequencies do not appear to play a major role in the genesis of postoperative nausea and vomiting.

Cholecystectomy↗
PubMed2005

Effect of SC-435 on the gastrointestinal migrating myoelectric complex in guinea pigs.

OBJECTIVE: To determine whether SC-435, a new ileal apical sodium-codependent bile acid transporter (IBAT) inhibitor, can alter the gastrointestinal motility in guinea pigs. METHODS: Sixty guinea pigs received regular diet or IBAT inhibitor (SC-435) diet for 2, 4, and 8 weeks, respectively. At the end of the feeding period, the gallbladder motility was assessed and then four bipolar silver electrodes were implanted on the antrum, duodenum, jejunum, and ileum. Seven days later, migrating motor complex (MMC) was recorded and the total bile acid pool size was measured according to the isotope dilution principle in the meantime. RESULTS: After feeding SC435, the gallbladder motility was declined in the 4-week group and the 8-week group. The bile acid pool size decreased by 17.11% (P <0.05) in the 4-week group and 48.35% (P < 0.05) in the 8-week group. The places of origin of MMC were changed where antral origins (37%) and duodenal origins (46%) decreased whereas jejunal origins (17%) increased. The MMC cycle period was prolonged in the duodenum (1.16 times in the 4-week group, P < 0.05; 1.38 times in the 8-week group, P < 0.05) whereas MMC amplitude fell in the duodenum (10.58% in the 4-week group, P <0.05; 49.17% in the 8-week group, P <0.05). There were not significant differences in all parameters of MMC between the control group and the 2-week group in guinea pigs. CONCLUSION: The IBAT inhibitor (SC-435) reduces the bile acid pool size and inhibits the MMC cycle activity. MMC is related to the enterohepatic circulation of bile acids, which is consistent with the changes of the bile acid pool size in guinea pigs.

Animals↗
PubMed1983

[Pharmacological studies of guanabenz. Effects on the peripheral nervous and other organ systems].

General pharmacological properties of guanabenz (GUB), a new anti-hypertensive agent, were studied in comparison with those of clonidine (CLD) and guanethidine (GUD). Intravenous or peroral administration of GUB caused a contraction of the nictitating membrane in cats and mydriasis in mice, while it produced an inhibitions of the gastrointestinal motility in dogs; the motility of isolated rabbit ileum; and chacol transport, salivation and gastric acid secretion in rats. GUB had no or slight inhibitory actions on contractile responses induced by peripheral sympathetic or parasympathetic nerve stimulation in various organs; however, it had antagonistic actions against the norepinephrine-induced contraction of isolated guinea-pig vas deferens. The contractile responses to epinephrine and tyramine in the nictitating membrane and to sympathetic nerve stimulation in isolated guinea-pig vas deferens were potentiated by GUB. GUB specifically antagonized the serotonin-induced contraction of the isolated rat fundus strip and nonspecifically inhibited acetylcholine, histamine or Ba2+-induced contractions of isolated guinea-pig ileum at higher concentrations. GUB exhibited local anesthetic actions and diuretic effects, but had no particular actions on neuromuscular transmission, isolated rat uterus, guinea-pig tracheal muscle and the hematic system. These effects of GUB were found to be almost identical with but less potent than those of CLD. The effects of GUD were basically different from GUB.

Animals↗