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At least 1,711 records · Page 95Linked to original sources

PubMed1999

Mice lacking alpha-calcitonin gene-related peptide exhibit normal cardiovascular regulation and neuromuscular development.

alpha-Calcitonin gene-related peptide (alphaCGRP) is a pleiotropic peptide neuromodulator that is widely expressed throughout the Central and peripheral nervous systems. CGRP has been implicated in a variety of physiological processes including peripheral vasodilation, cardiac acceleration nicotinic acetylcholine receptor (AChR) synthesis and function, testicular descent, nociception, carbohydrate metabolism, gastrointestinal motility, neurogenic inflammation, and gastric acid secretion. To provide a better understanding of the physiological role(s) mediated by this peptide neurotransmitter, we have generated alphaCGRP-null mice by targeted modification in embryonic stem cells. Mice lacking alpha CGRP expression demonstrate no obvious phenotypic differences from their wild-type littermates. Detailed analysis of systemic cardiovascular function revealed no differences between control and mutant mice regarding heart rate and blood pressure under basal or exercise-induced conditions and subsequent to pharmacological manipulation. Characterization of neuromuscular junction in morphology including nicotinic receptor localization, terminal sprouting in response to denervation, developmental regulation of AChR subunit expression, and synapse elimination also revealed no differences in alphaCGRP-deficient animals. These results suggest that alphaCGRP is not required for the systemic regulation of cardiovascular hemodynamics or development of the neuromuscular junction.

Aging↗

PubMed1998

Role of nitric oxide in contraction induced glucose transport.

Nitric oxide (NO) is a vasoactive substance, which was first described as endothelium derived relaxing factor (EDRF). Subsequently, NO has been found to be a messenger molecule abundantly present in the nervous system. Functioning as a neurotransmitter in the peripheral nervous system, NO mediates an array of physiological functions such as gastrointestinal motility, regional blood flow, smooth muscle contraction, neuroendocrine activity and immune function. Recently NO biosynthesis has been found in skeletal muscle, where NO exerts an effect on both the metabolic and contractile processes. This review will focus on the actions of NO in skeletal muscle metabolism. NO donors have been shown to increase glucose transport in skeletal muscle. Inhibition of NOS activity blunts contraction-stimulated glucose transport but has no effect on insulin-stimulated glucose transport. NOS protein expression is enhanced by chronic exercise suggesting that NO may play a role in the improved glucose tolerance and increased insulin sensitivity characteristic of the trained state.

Animals↗

PubMed1993

Structural modification patterns from agonists to antagonists and their application to drug design--a new serotonin (5-HT3) antagonist series.

Structural variations from agonists to their selective antagonists seemed to follow certain patterns. To analyze the variation patterns in the structural modification processes in past examples as well as to utilize the "common" variation patterns as possible principles to design new selective antagonistic drugs, the structures of agonists and their antagonists were superimposed on a two-dimensional grid template composed of regular hexagons and the topological similarities and dissimilarities of substructural elements between agonists and antagonists were examined. Between several pairs of neurotransmitter amines and their "selective" antagonists, similar patterns were disclosed in their structural modification processes. The generalized structural modification patterns were successfully applied as guiding principles to design and identify a new prototype structure of the 5-HT3 antagonist. The prototype structure was optimized by use of QSAR procedures leading to a compound which shows a potent antiemetic activity as well as a powerful gastrointestinal-motility modulation.

Animals↗

PubMed1991

[Postoperative mechanical ileus].

Postoperative GI obstruction is the third most common postoperative complication, after peritonitis and bleeding, leading to laparotomy. The mortality has declined in the last decade from around 20%-35% to 10%-20%. This is probably caused by better intra-operative surgical techniques and better understanding of the pathophysiology of gastrointestinal motility. The problem most frequently lies in the proximal small bowel particularly after operations on the colon, especially in the presence of inflammation or peritonitis. Differentiation between postoperative paralysis and mechanical obstructions is very difficult. Modern diagnostic techniques have not changed this fact. For assessment of the abdomen, repeated surgical investigations is still of more value than laboratory data alone.

Colonic Pseudo-Obstruction↗

PubMed1994

Radiopharmaceuticals and the gastrointestinal tract.

A review is presented of the design of radiolabelled test meals for the evaluation of gastrointestinal function, including oesophageal transit, gastro-oesophageal reflux, gastric emptying, enterogastric reflux and transit through the whole bowel. Descriptions of different systems are presented, together with validations of the procedures used. Published methods for assessment of oesophageal transit show a marked degree of consistency, whereas gastric emptying studies employ a wide range of both liquid and solid test meals. Recommendations are made concerning the optimal system for investigation of each part of the gastrointestinal tract, but whichever system is adopted, it is important to employ some validation procedures, and to establish normal ranges in the population under study.

Bile Reflux↗

PubMed1992

A scintigraphic analysis of colonic movement in patients with colostomy: changes of colonic transit time after acquaintance with irrigation.

For the purpose of making a functional assessment of colostomy irrigation, eight patients were examined. Group A was composed of four patients whose experience of irrigation was less than one year. Group B was composed of four patients who had undergone irrigation for more than two years. The capacity of the remnant colon was determined by a barium enema. Next, 74 MBq of milking technetium 99 diethylene triamine penta-acetic acid (99mTc-DTPA) was instilled with a predetermined amount of water (37 degrees C). A dynamic scan was performed for 45 min. The mean evacuation time of Groups A and B were 6 min 56 s +/- 2 min 33 s and 13 min 27 s +/- 10 min 50 s, respectively. The mean half emptying time of Groups A and B were 142.5 s +/- 7.9 s and 309.0 s +/- 181.9 s. The results suggest that the remnant colon may be habituated with irrigation. Colostomy irrigation which uses a single instillation of a measured volume of tepid water is recommended.

Adult↗

PubMed1993

Effect of metoclopramide and loperamide on the pharmacokinetics of didanosine in HIV seropositive asymptomatic male and female patients.

The pharmacokinetics of orally-administered didanosine were evaluated in 6 male and 6 female HIV seropositive patients to determine the effect of pretreatment with metoclopramide, an inducer of gastrointestinal motility, and loperamide, which retards motility. Using a randomized, balanced, crossover design, each patient received the following three treatments under fasting conditions: didanosine as a single agent, didanosine 5 min after a single 10 mg intravenous dose of metoclopramide, and didanosine 1 h after the final of 4 doses, 4 mg each, of loperamide. Serial blood and urine samples were collected for up to 12 h after each dose. Plasma and urine aliquots were analysed for intact didanosine using HPLC with UV detection. Pharmacokinetic parameter values were calculated using noncompartmental methods. The mean Cmax values were significantly greater for the didanosine single agent (2.04 micrograms.ml-1) and didanosine with metoclopramide (2.30 micrograms.ml-1) treatments than for the combination of didanosine with loperamide (1.57 microgram.ml-1). The t1/2 in males was significantly greater than in females for the didanosine (1.75 vs 1.12 h, respectively) and didanosine with metoclopramide treatments (1.74 vs 1.20 h, respectively). No significant treatment or gender effects were observed for AUC or UR (urinary recovery). The pharmacokinetics of didanosine were not altered appreciably by dosing with metoclopramide. Administration with loperamide affected the rate but not the extent of absorption. There were no clinically relevant differences between males and females in the disposition of didanosine.

Administration, Oral↗

PubMed1985

Improved benefit/risk ratio of higher-dose metoclopramide therapy during cisplatin-induced emesis.

Metoclopramide (Paspertin) was infused intravenously in the high doses of 1.75, 3.5, 7.0, and 14 mg/kg body wt. per treatment cycle as antiemetic therapy for cisplatin-induced emesis (363 cycles, 25-120 mg/m2). The antiemetic potency of metoclopramide increased in a log linear manner, giving from 40% to 95% protection against emesis. Gastrointestinal motility showed a similar increase, i.e. diarrhoea. In contrast, the extrapyramidal reactions, namely akathisia, rigidity and acute dystonia, did not show a dose-dependent increase in frequency and remained constant over the dose range of 3.5-14 mg/kg per cycle. The results suggest increasing benefit of metoclopramide treatment with increasing doses of the drug.

Basal Ganglia Diseases↗

PubMed1993

Loperamide. Survey of studies on mechanism of its antidiarrheal activity.

In castor oil challenged rats, low doses of loperamide inhibit diarrhea and normalize intestinal propulsion. Unlike other opioids, loperamide is devoid of central opiate-like effects, including blockade of intestinal propulsion, up to the highest subtoxic oral dose. Nevertheless, the antidiarrheal action of loperamide can be considered to be mu-opiate receptor mediated, only a few in vitro effects at rather high concentrations being not naloxone-reversible. There is little evidence that interactions with intestinal opiate receptors directly change epithelial cell function. When secretory stimuli increase mucosal tension, however, loperamide may reverse the elevated hydrostatic tissue pressure that opposes normal absorption. This antisecretory effect at the mucosal level is accompanied by motor effects when loperamide reaches the myenteric mu-opiate receptors. At therapeutic doses for the treatment of acute diarrhea, it is likely that the mucosal effect prevails.

Animals↗

PubMed1993

Impaired colonic motor response to cholinergic stimulation in patients with severe chronic idiopathic (slow transit type) constipation.

Chronic idiopathic constipation, especially the slow transit type, is a troubling problem often afflicting young women. The pathophysiological basis for this entity is unknown, although a defective cholinergic innervation has been postulated. We tested the hypothesis that cholinergic colonic innervation is deranged in this condition by studying colonic motor activity after strong cholinergic stimulation with edrophonium chloride in 14 women complaining of slow transit constipation. Unlike healthy subjects, constipated patients showed minimal or no response to edrophonium injection. It is concluded that in slow transit constipation there is an important alteration of colonic cholinergic activity and that edrophonium chloride may represent a useful test drug for colonic pathophysiological investigations.

Adult↗

PubMed1991

Physiology and pathophysiology of colonic motor activity (2).

The basic motor function of the colon is to mix and knead its contents, propel them slowly in the caudad direction, hold them in the distal colon until defecation, and provide a strong propulsive force during defecation. Infrequently, it also produces mass movements in the proximal colon. These motor functions are achieved in most species by three different types of contractions: the individual phasic contractions that include the short- and long-duration contractions, organized groups of contractions that include the migrating and nonmigrating motor complexes, and special propulsive contractions (giant migrating contractions). The spatial and temporal patterns of all of these contractions are controlled by myogenic, neural, and chemical control mechanisms. The individual phasic contractions are highly disorganized in time and space in the colon. For this reason, they are effective in mixing and kneading and slow distal propulsion. The underlying cause of the disorganization of short duration contractions is the irregularity in the frequency and waveshape of colonic electrical control activity and its phase unlocking throughout the colon. The individual contractions in many species occur in cyclic bursts called contractile states. At least in some species, these contractile states exhibit mostly caudad and sometimes orad migration. However, there are also nonmigrating or randomly migrating contractile states in the colon. These two patterns of contractile states are called colonic migrating motor complexes and colonic nonmigrating motor complexes, respectively. The giant migrating contractions provide the strong propulsive force for defecation and mass movements. The neural control of colonic contractions is organized at three levels--enteric, autonomic, and central. The enteric nervous system contains cholinergic and peptidergic neurons and plays a major role in the control of colonic contractions. The autonomic nerves, the vagi, pelvic, lumbar colonic, hypogastric, and splanchnic nerves, seem to continuously monitor the state of the colon and provide a modulatory input when necessary. These nerves play a major role in the reflexive control of colonic motor function. The voluntary input from the central nervous system coordinates the motor activity of the colon, rectum, anal canal and sphincters for orderly evacuation of feces during defecation. The role of acetylcholine, nonadrenaline, and the yet to be completely identified nonadrenergic, noncholinergic neurotransmitter, possibly VIP, in the control of contractions is fairly well established. Besides these, there are several other peptides and chemicals that are localized in the colonic wall; their physiological roles remain unknown. Colonic motor activity has been studied in several disease states. The findings have not always been consistent.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗

PubMed1995

Secretoneurin: a new peptide in the human enteric nervous system.

Secretoneurin is a functional neuropeptide derived from secretogranin II (chromogranin C). This proprotein is processed to varying degrees in neuroendocrine tissues. In the present study we established by gel filtration high performance liquid chromatography that in human intestinal wall and mucosa an antiserum against secretoneurin detects as the major immunoreactive moiety the free peptide secretoneurin. In the mucosa some larger immunoreactive peptides were also present, however, a significant amount of the intact proprotein secretogranin II could not be detected. By immunohistochemistry we studied the distribution of secretoneurin within the gut. Antibodies to protein gene product 9.5 and chromogranin A were used to identify all neurons and endocrine cells, respectively, whilst those to the peptides substance P, CGRP and somatostatin were used for the further characterization of individual secretoneurin-positive structures. Secretoneurin immunoreactivity was found in nerve fibres in all layers of the gut wall. In both myenteric and submucous plexuses, nerve fibres and the majority of ganglion cells were secretoneurin-immunoreactive. In the mucosa, some secretoneurin-positive nerve processes ran parallel to the basal membrane of epithelial cells, occasionally invading the epithelial layer. Secretoneurin immunoreactivity was found in endocrine cells, mostly D cells, in the following regions in descending order of density: stomach/duodenum; rectum; colon; ileum. Thus, secretoneurin is a new major peptide within the human enteric neuroendocrine system. Its presence in abundant myenteric ganglion cells may imply a role in the modulation of gastrointestinal motility. The chemotactic properties of secretoneurin and its possible localization in sensory fibres suggest that this peptide may be involved in the genesis of intestinal inflammation.

Adult↗

PubMed1988

Megarectum.

Evaluation of the rectum by barium enema does not correlate well with rectometrographic studies and is not predictive of bowel function. The purpose of the present study was to describe clinical and functional data in patients with chronic idiopathic constipation, where a megarectum was diagnosed by a rectometrogram. Among 355 patients who underwent rectal elasticity studies, 35 were found to have a megarectum (maximum tolerable volume above 320 ml in women and 440 in men) for which no specific etiology was recognized. They, and a group of 11 healthy controls who were not sensitive to stress, underwent studies of stool frequency, colonic transit time of radiopaque markers, rectal elasticity, and anorectal pressures and reflexes. The elasticity coefficient of the rectal wall was decreased in patients as compared to controls (P less than 0.01). Seven patients had onset of symptoms at birth, with maximum tolerable volume in the rectum between 460 and 900 ml, and all were incontinent for feces. Studies of colonic transit times demonstrated normal function in the right and left colon, but there was rectosigmoid stagnation (transit time of 122 +/- 17 hr vs 8 +/- 2 in stress-free controls; X +/- SE; P less than 0.001). In the other 28 patients (late-onset megarectum), in contrast to the congenital group, there was a marked female preponderance, and their recorded stool frequency (4 +/- 0.7/week) was greater than the recalled frequency (1.4 +/- 0.2/week; P less than 0.001). Only half suffered from fecal incontinence. They did not have a greater rectal capacity when colonic transit times were prolonged (455 +/- 27 ml) than when normal (422 +/- 27). Rectal pressure was similar at the level of conscious sensation of filling, regardless of rectal capacity, suggesting a motor, rather than a sensory, abnormality. The amplitude of the rectoanal inhibitory reflex was decreased (P less than 0.001) as compared to controls, sometimes mimicking the findings of Hirschsprung's disease, but increasing rectal distension always induced a relaxation of the internal anal sphincter. The notion of a megarectum, which tolerates large amounts of fluid without sensation, lacks elasticity, and is accompanied by an abnormal rectoanal inhibitory reflex, provides an explanation for one of the mechanisms of constipation by outlet obstruction.

Adult↗

PubMed1990

Effect of cholera toxin on small intestinal motor activity in the fed state.

We sought to determine the effect of cholera toxin on small intestinal transit and motor activity in the fed state. Mean transit time increased after cholera toxin, but there was no change in mean amplitude, duration, and area of contractions. In contrast, there was a reduction in the total amplitude, duration, and area of contractions, and this was due to a decrease in frequency of contractions. The reduction in the total parameters of all contractions could be accounted for by a reduction in the same parameters for propagating contractions. The parameters of nonpropagating contraction were not different after cholera toxin. Also, there was a decrease in the distance of propagation of contractions. Our findings demonstrate that during the secretory state due to cholera toxin the small intestinal motor activity works in a compensatory mode to decrease transit and allow more time for absorption.

Animals↗

PubMed1991

Vincristine-induced recurrent laryngeal nerve paralysis in children.

Stridor developed in 2 children during vincristine therapy for malignancies. Indirect laryngoscopy revealed left vocal cord paralyses in both patients. One child had generalized neurotoxicity from vincristine including hypotonia, decreased gastrointestinal motility, and painful paresthesias while laryngeal nerve paralysis was the only neurotoxic manifestation in the other patient. Stridor resolved in both patients after discontinuing or decreasing the dose of vincristine. Visualization of the airway not only confirms the diagnosis, but also rules out treatable causes of stridor in the febrile, immunocompromised patient.

Child↗

PubMed1985

[Benefit and risk of high-dose metoclopramide in comparison to high-dose haloperidol or triflupromazine in cisplatin-induced vomiting].

The antiemetic efficacy of metoclopramide (MCL, Paspertin, loading infusion 0.5 mg/kg body wt./h over 2 h, maintenance infusion 0.25 mg/kg/h over 24 h) has been compared with haloperidol (HAL, Haldol, 1/10 of MCL dosage) and with triflupromazine (TFP, Psyquil, 1/2 of MCL dosage) in two sequential analyses, against the emetic effects of cisplatin (60-90 mg/m2). After treating 14 and 8 pairs of patients respectively, MCL was significantly (alpha = 0.05) more effective than HAL or TFP. Only 1 of the 14 patients in the HAL group and 0 of 8 in the TFP group were totally protected against emesis, in contrast to 6 of 14 patients and 3 of 8 in the MCL groups. In order to quantify the benefit/risk relationship of the antiemetic drugs studied the number of prevented emetic episodes (in comparison to previous insufficient treatment) was related to the incidence of major undesired effects (i.e. dystonia and/or akathisia). This relationship was 17.8 and 12.1 for the two MCL groups; for HAL and TFP it was only 5.8 and 4.6, respectively. The high antiemetic selectivity of MCL against cisplatin-induced emesis is probably related to the still unknown action of MCL on the gastrointestinal motility. A high neuroleptic potency, with or without additional anticholinergic activity, is apparently not essential for high antiemetic protection against cisplatin.

Cisplatin↗

PubMed1984

[Ultrastructure of diabetic autonomic neuropathy of the gastrointestinal tract].

Gastrointestinal motility disorders induced by diabetes mellitus are most commonly manifested in the colon, and are considered to be an expression of diabetic autonomic polyneuropathy. In this study, for the first time, the intrinsic nervous system of the bowel has been subjected to an ultrastructural and morphometric examination in rectal biopsy material obtained from diabetics with and without diabetic enteropathy. In patients with diabetic enteropathy, the nerves of the submucous plexus (Meissner's plexus) revealed significant swelling of the axons, as an expression of neural degeneration. Furthermore, in about a half of these patients, thickening of the basal membrane of Schwann's cells was also detected. Additional, although unspecific, changes found in the diabetics were a quantitative increase in the lysosomes, lipofuscin and glycogen in the Schwann cells. The ultrastructural findings represent evidence for the presence of an intrinsic autonomic polyneuropathy in diabetics with diabetic enteropathy. At the same time, they indicate that the diagnosis of diabetic enteropathy is no longer merely an "exclusion" diagnosis.

Adult↗

PubMed1992

Abnormal rectosigmoid myoelectric response to eating in patients with severe idiopathic constipation (slow-transit type).

Pathophysiologic mechanisms responsible for severe chronic constipation are poorly understood. In particular, most of the published studies have lumped together patients having different subtypes of constipation, with different and often conflicting results. We studied six patients complaining of severe idiopathic constipation and displaying homogeneous clinical and pathophysiologic features (i.e., patients with slow-transit type constipation) to evaluate their myoelectric spiking responses to food ingestion. Ten healthy subjects acted as controls. The constipated patients failed to show the increase in myoelectric spiking activity that was seen in controls immediately following the meals, suggesting the possibility of a neurogenic defect in this condition.

Action Potentials↗