Gastrointestinal Contractile Activity Research Articles

Study of μ- and δ-Opioid Activities in Agents with Various κ-Receptor Selectivity.

A putative opioid agonist RU-1205 was ineffective within in vitro model of electrically induced contractions of rat ileum assessing the μ- and δ-opioid receptor pathways, while morphine inhibited these contractions in a dose-dependent and naloxone-reversible manners with EC50=2.6×10-7 M. In vivo experiments revealed no significant effects of RU-1205 on respiration and gastrointestinal tract contractile activity. In contrast, butorphanol decreased respiration rate by 25% (25-100 mg/kg) and slowed down the transit of labeled particles along the small intestine by 77.1% (1 mg/kg) and by 45.5% (10 mg/kg). Morphine-induced inhibition of peristalsis was dose-dependent with maximum effect (by 68.6%) observed in the dose of 10 mg/kg. It was concluded that the effects of RU-1205 are not related to activation μ- and δ-opioid receptors known to mediate the effects of non-selective opioid agonist morphine and agonist-antagonist butorphanol.

Gastrointestinal motility and sleep patterns assessed by ambulatory tracking of telemetric capsules combined with polysomnography

Introduction Due to the inaccessibility of the gastrointestinal (GI) tract and lack of proper measurement techniques clinical studies describing gastrointestinal function during sleep are sparse. In the present pilot study we aimed at introducing a novel ambulatory telemetric capsule system (3D-Transit) in conjunction with polysomnography (PSG). Materials and methods 3D-Transit (Motilis Medica SA) consists of ingestible electronic capsules, an extracorporeal portable detector containing 4 magnetic field sensors, and visualization software. The electromagnetic field emitted by each capsule is converted into space–time coordinates defining the distance and angular orientation of each capsule in relation to the detector. Changes in position and orientation of the capsules reflect GI contractile activity and progression. Nine healthy subjects (5 females, age 24–52) ingested a capsule in the morning at 08:00 a.m and another in the evening at 06:30 p.m. Polysomnography was carried out as an unattended portable sleep study with the electrodes placed just before bedtime. Standard placement of electrodes was used (EEG scalp sites: F3/F4, C3/C4, O1/O2, References M1/M2, EOG: E1/E2, EMG: Chin, ECG). The hypnograms were scored using 30- seconds epochs and were synchronized with 3D-Transit recordings. During sleep the first capsule was located in the colon and the second was initially in the stomach but moved to the small intestine (SI) within approximately 4 h (range 2–5.5 h). Propagating movements (PM) were defined as ⩾ 3 cm anterograde displacement of the capsule with a velocity of either ⩾ 15 cm/min (fast movements) or ⩾ 1.5 cm/min (slow movement). Basic colonic activity was defined as the mean standard deviation of the position of capsules during displacement of 3 cm. Results Median sleep time was 6.6 h (range 5.1–7.5 h) with a median arousal index of 7.6 per hour sleep (range 4.9–16.9) and a median WASO of 26 min (range 7–84). From a total of 140 PM observed (85% in the SI and 15% in the colon), 12 (9%) occurred within 30 s after an arousal, 10 (7%) during wake periods and (84%) during stable sleep. There was no association between the sleep stages and the occurrence of PM (REM median 0.5 PM/h (range 0 – 6.9), N1 0 PM/h (0–2.7), N2 1.2PM/h (0.3–5.7) and N3 2.2 PM/h (0–7.0). The speed of progression through the SI did not change with depth of sleep or between REM and NREM sleep. Basic colonic activity was significantly lower during N3 (p = 0.02) than during N2 and also lower during NREM sleep than during REM sleep (p = 0.02). There was no difference between basic colonic activity during REM sleep and wake periods (p = 0.87). Conclusion The novel ambulatory capsule technique (3D-Transit) in combination with PSG allows easy, minor invasive and completely ambulatory investigation of associations between sleep patterns and gastrointestinal motility. This pilot study supports previous findings of deep sleep having an inhibitory effect on colonic activity.

Effect of Cassia nomame on Small Intestine Movement, Diuresis, and Anti-inflammation in Rats

ObjectiveTo investigate the preliminary pharmacological screening of Cassia nomame. MethodsThe effect of aqueous extract from C. nomame on gastrointestinal motor function was investigated by assessing the intestinal transit rate (ITR) of charcoal modeled into gastrointestinal motility dysfunction (GMD) by the administration of dopamine, atropine, or noradrenaline to the rats, respectively. Diuresis was studied in vivo by estimating the urine output. The anti-inflammatory activity was expressed as the percentage of swelling reduction by comparison on the mean thickness of ear swelling in mice. ResultsThe ITR in these GMD animals was significantly retarded compared to that in normal animals. The retardation, however, was significantly inhibited by the ig administration of C. nomame (2 g/kg) for all GMD animals. The results suggested that C. nomame had the potential for development into a prokinetic agent that could prevent or alleviate GMD in patients. C. nomame increased urine output and suppressed significantly ear swelling induced by dirnethyl benzene in mice. ConclusionC. nomame could increase the gastrointestinal contractile activity of rats and has the effects of diuresis and anti-inflammation.

An orally active motilin receptor antagonist, MA-2029, inhibits motilin-induced gastrointestinal motility, increase in fundic tone, and diarrhea in conscious dogs without affecting gastric emptying

The pharmacological properties of MA-2029, a selective and competitive motilin receptor antagonist, were investigated in conscious dogs after oral administration. Gastrointestinal contractile activity was recorded by chronically implanted force transducers. The proximal gastric volume was measured with a barostat under constant pressure. Gastric emptying was examined using the paracetamol absorption test. MA-2029 (0.3–10 mg/kg, p.o.) administered in the interdigestive state inhibited gastrointestinal contractions induced by motilin (3 µg/kg, i.v.) in a dose-dependent manner. MA-2029 (0.3–3 mg/kg, p.o.) also inhibited the occurrence of spontaneous phase III contractions, even though MA-2029 had no effect on basal gastrointestinal motility or basal gastric emptying even at 10 and 30 mg/kg p.o. The inhibitory effect of MA-2029 on motilin-induced gastrointestinal motility corresponded to its plasma concentration. Motilin (0.3 µg/kg/h, i.v. infusion) reduced the proximal gastric volume by about 50% of control during isobaric distension. This effect was also inhibited by MA-2029 (1–10 mg/kg, p.o.) in a dose-dependent manner. In the digestive state, injection of motilin (3 µg/kg, i.v.) induced diarrhea in 9 of 11 dogs. MA-2029 (1–30 mg/kg, p.o.) reduced the incidence of diarrhea induced by motilin in a dose-dependent manner. The results indicate that MA-2029 inhibits hypermotility induced by motilin in conscious dogs without having an effect on the basal gastrointestinal tone or gastric emptying rate. MA-2029 may be useful in treating gastrointestinal disorders in which the pathogenesis involves the elevation of circulating motilin.

The effect of growth hormone releasing peptide-2 on upper gastrointestinal contractile activity and food intake in conscious dogs

The aim of this study was to evaluate the effect of growth hormone releasing peptide (GHRP)-2, a synthetic ligand for the growth hormone secretagogue receptor, on upper gastrointestinal motility and food intake. Five neurally intact dogs and five dogs with vagotomy and pyloroplasty were equipped with strain gauge force transducers on the stomach, duodenum and jejunum. GHRP-2 (0.5-10 microg/kg) was administered intravenously in neurally intact dogs in the interdigestive state and after feeding. To study the mechanism of GHRP-2-induced inhibition on postprandial contractions, various antagonists were administered intravenously prior to GHRP-2. The effect of GHRP-2 on postprandial contractions was also studied in dogs with vagotomy. GHRP-2 was also administered immediately before feeding in each group, and its effect on food intake was assessed. GHRP-2 did not evoke gastrointestinal contractions in the interdigestive state. GHRP-2 induced contractile inhibition continuing for 2-3 min in neurally intact dogs and dogs with vagotomy. This inhibitory effect was reversed by the alpha- and alpha(2)-blockers. GHRP-2 increased food intake in neurally intact dogs, but not in dogs with vagotomy. These results indicate that in the upper gut GHRP-2 inhibits postprandial contractions via alpha(2)-receptors on the enteric nervous system, whereas an intact vagal nerve is necessary for a GHRP-2-induced increase in food intake.

Effects of Motilin and Mitemcinal (GM-611) on Gastrointestinal Contractile Activity in Rhesus Monkeys In Vivo and In Vitro

Neither the presence of motilin receptors nor their action has been investigated in monkeys. The object of this study was to determine the effects of motilin and mitemcinal (GM-611), an erythromycin derivative, on the gastrointestinal tract in rhesus monkeys in vivo and in vitro. In in vivo investigations in conscious monkeys, both motilin and mitemcinal induced migrating motor complex-like contractions in the interdigestive state and also accelerated gastric emptying. In in vitro investigations, the presence of motilin receptors in the gastrointestinal tract was demonstrated by receptor binding assays. Motilin and mitemcinal contracted isolated duodenum strips in a concentration-dependent manner. In conclusion, rhesus monkeys may be useful for studying the physiological and pharmacological roles of the motilin agonistic mechanism because they show reactivity to motilin both in vivo and in vitro.

Effects of Mitemcinal (GM-611), an Acid-Resistant Nonpeptide Motilin Receptor Agonist, on the Gastrointestinal Contractile Activity in Conscious Dogs

The effects of mitemcinal (GM-611) on the gastrointestinal contractile activity were investigated using chronically implanted force transducers in conscious dogs and were compared with the effects of porcine motilin (pMTL), EM-523 and EM-574. In the interdigestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 induced the gastrointestinal contractile activity in a manner similar to pMTL. The contractile activity caused by mitemcinal was suppressed by continuous intravenous infusion of a motilin receptor antagonist. In the digestive state, intravenous and oral administration of mitemcinal, EM-523 and EM-574 also stimulated the gastrointestinal contractile activity. Mitemcinal, EM-523 and EM-574 given intravenously increased the gastric contractile activity in a similar dose range; however, mitemcinal was approximately 10 times more potent than EM-523 and EM-574 when administered orally in the digestive state. These results indicate that the mitemcinal-induced gastrointestinal contractile activity operates via motilin receptors and possesses a higher activity than EM-523 and EM-574 when administered orally in conscious dogs in the digestive state. Mitemcinal may therefore be useful in the treatment of several gastrointestinal disorders involving dysmotility, such as gastroparesis and functional dyspepsia, even when administered orally.

Altered Gastrointestinal and Metabolic Function in the GPR39-Obestatin Receptor–Knockout Mouse

The G-protein-coupled receptor GPR39 is a member of a family that includes the receptors for ghrelin and motilin. Recently the peptide obestatin was identified as a natural ligand for GPR39. The objective of this study was to gain insight into the biological function of the GPR39 receptor. GPR39(-/-) mice were generated and analyzed. Endogenous GPR39 expression was detected in the brain (septum-amygdala) and the gastrointestinal system (parietal cells, enterocytes, neurons, and pancreas). Gastric emptying of a solid meal (measured by the (14)C octanoic breath test) in GPR39(-/-) mice was accelerated significantly with a gastric half-emptying time of 49.5 +/- 2.2 minutes compared with 86.9 +/- 8.4 minutes in GPR39(+/+) mice. A more effective expulsion of distally located pellets (30%-75% of length) was observed in the colon of GPR39(-/-) mice. Four hours after pylorus ligation, the volume of gastric secretion was increased significantly (GPR39(-/-): 638 +/- 336 microL; GPR39(+/+): 225 +/- 170 microL), but gastric acid secretion was unchanged. The mature body weight and body fat composition of GPR39(-/-) mice was significantly higher compared with GPR39(+/+) mice, but this was not related to hyperphagia because 24-hour food intake did not differ between both genotypes. In contrast, deficiency of the GPR39 receptor led to reduced hyperphagia after fasting. The cholesterol levels were increased significantly in the GPR39(-/-) mice. Our data partially confirm and extend the described in vivo effects of obestatin and suggest that this peptide plays a functional role in the regulation of gastrointestinal and metabolic function through interaction with the GPR39 receptor.

The Effect of Propofol on Human Gastric and Colonic Muscle Contractions

Although propofol is widely used for sedation in the intensive care unit, there are limited data on its effects on gastrointestinal motility. For that reason, we studied the in vitro effects of propofol on human gastric and colonic smooth muscle. Grossly normal human gastric and colonic muscle strips were mounted in an organ bath set-up for isometric contraction and stimulated by acetylcholine (Ach), using a cumulative dose schedule in the absence or presence of different concentrations of propofol [1.7 x 10(-6) M (0.3 microg/mL) to 4.4 x 10(-4) M (78 microg/mL)]. Ach led to concentration-dependent contraction of both gastric and colonic muscle strips, whereas propofol, at a concentration 6.7 x 10(-6) M (1.2 microg/mL) and above, significantly depressed Ach-induced contraction in a concentration-dependent manner for both smooth muscle preparations. In addition, propofol, at a concentration 2.7 x 10(-5)M (4.8 microg/mL) and above, depressed spontaneous contractile activity of both smooth muscle preparations. Fat emulsion 10% (Intralipid), the solvent for propofol, had no effect on either the spontaneous activity or the Ach-induced contraction of gastric and colonic smooth muscles. The success of enteral feeding requires a normal gastrointestinal motility. We found that, at clinically relevant concentrations, propofol impaired gastrointestinal contractile activity. Further investigations are required to determine the clinical significance of this change.

Effect of endotoxin on canine colonic motility and transit

Diarrhea is a common problem in patients who have episodes of sepsis and are being fed enterally. Endotoxemia results in gastrointestinal motor dysfunction characterized by slowed gastric emptying and rapid intestinal transit; however, the effect of endotoxin on colonic motility is unknown. The aim of our study was to determine the effects of a single sublethal dose of endotoxin on colonic motility and transit. Seven dogs underwent construction of a 50 cm colonic Thirty-Vella fistula. Five manometry catheters were sewn into the colonic lumen at 8 cm intervals along the fistula. Following recovery, the fistula was perfused with an isotonic solution at 2.9 ml/min, and fasting and postprandial colonic motility was determined. Liquid transit was assessed by bolus of a nonabsorbable marker instilled into the proximal end of the Thirty-Vella fistula. Recordings of gastrointestinal contractile activity were made digitally to determine contractile frequencies and motility indexes. Following completion of the baseline studies, each dog was given a single dose of E. coli lipopolysaccharide, 200 μg/kg intravenously, and studies were repeated daily for the next 3 days. Endotoxin doubled the fasting colonic contractile frequency on postendotoxin day 1 and also increased motility indexes on that same day. Fasting motility indexes and contractile activity were decreased on postendotoxin days 2 and 3. The postprandial frequency of contractions and motility indexes were decreased on postendotoxin day 3. Fasting colonic liquid transit was rapid on postendotoxin day 1, whereas postprandial liquid transit was rapid on both postendotoxin days 1 and 2. Endotoxin temporarily speeds liquid transit and increases both the frequency and strength of colonic contractions. These effects may contribute to the diarrhea that occurs during episodes of sepsis.

The Effect of Endotoxin on Canine Jejunal Motility and Transit

Intestinal transit is rapid during endotoxemia; however, little is known regarding the small intestinal motility changes which produce this rapid intestinal transit. The aim of our study was to determine the degree and duration of disrupted jejunal transit, and changes in jejunal motility following a sublethal dose of endotoxin. Eight dogs underwent construction of jejunal Thiry-Vella fistulas (TVF) with manometry catheters to record motility along the TVF. Following recovery, a 240-kcal liquid meal was given and the TVF was perfused with an isotonic solution. Liquid transit was assessed by bolus of a nonabsorbable marker instilled into the proximal end of the TVF. Recordings of gastrointestinal contractile activity were made digitally to determine postprandial motility. Following completion of the baseline studies, each dog was given a single dose ofEscherichia colilipopolysaccharide (200 μg/kg, iv) and the postprandial studies were repeated for the next 3 days. Endotoxin decreased the frequency of jejunal contractions for 2 days while the strength of jejunal contractions was diminished for 1 day. Jejunal transit of liquids was rapid on Postendotoxin Day 1. The rapid transit was associated with a greater percentage of single pressure waves propagating aborally on Postendotoxin Day 1 than the baseline percentages established prior to endotoxin. We conclude that endotoxemia temporarily disrupts postprandial jejunal motility and transit. The rapid liquid intestinal transit seen with endotoxemia may be due to changes in contractile propagation.

Development of a new telemetry recording system for measuring of gastrointestinal contractile activity in unrestrained and conscious small animals

Myoelectrogram, strain gauge force transducer or manometry has been commonly used to record contractile activity of the gastrointestinal (GI) tract in small animals, but protecting the lead wires and tubes is troublesome when conducting experiments. To solve this problem, we have developed a new telementric recorder which can be implanted in the abdominal cavity of a small animal. The elemeter is a cylinder (phi 10 x 35 mm) with a strain gauge force transducer (4 x 3 mm) connected by fine lead wires. The telemeter includes a battery and amplification, transmission and power supply circuit to the transducer. The battery has a 1,500 hr life and is designed to be turned on and off from outside the body by means of a magnetic switch. The device weights 4 g and is waterproofed with silicon. Five male Wister rats weighing 300-400 g were used. Under general anesthesic, the force transducer was sutured onto the serosa in the gastric antrum, and the telemeter was fixed in the corner of the peritoneal cavity. During measurement, the rats were housed in individual cages under unrestrained conditions and the cage was placed on the receiver. Gastric motility could be continuously recorded for up to 60 days, although body movements sometimes affected the recordings slightly due to adhesion. There was no noticeable trouble related to the device implanted in the abdominal cavity. Gastric motility recorded with this telemeter was identical with that measured by other devices, and consisted of two different patterns, the fasted and fed patterns divided into two phases, as reported previously. In the fasted state, cyclic occurrence of intense contractions was observed, and regular phasic contractions were observed in the fed state. Bethanechol induced strong contractions and atropine inhibited contractile activity. The newly developed telemeter is a useful and reliable device to use in measuring GI motility in small animals.

Effect of TSK159, a novel 5-hydroxytryptamine 4 agonist, on gastrointestinal contractile activity in conscious dogs: [formula omitted], Y. Shiba, E. Mochiki and Z. Itoh. GI Res. labs., Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan

Effect of TSK159, a novel 5-hydroxytryptamine 4 agonist, on gastrointestinal contractile activity in conscious dogs: [formula omitted], Y. Shiba, E. Mochiki and Z. Itoh. GI Res. labs., Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan

Effect of erythromycin on interdigestive gastrointestinal contractile activity and plasma motilin concentration in humans

The effects of erythromycin (EM) on gastrointestinal contractile activity during the interdigestive period were investigated in seven healthy subjects using an infused catheter system, and the changes in the plasma motilin concentration were also determined. Graded EM doses (0.1-1.5 mg/kg) were administered intravenously over 5 min, usually during gastric phase I. EM induced interdigestive migrating contractions (IMCs). Their induction rate was low after low doses of EM, but gradually increased as the dose increased to reach 71.4% at an EM dose of 0.375 mg/kg. Strong contractions, which were quite similar to phase III activity of the stomach but did not migrate or migrated incompletely to the duodenum, were observed at EM doses above 0.375 mg/kg. Therefore, the optimum dose of EM for inducing an IMC was established to be 0.375 mg/kg. In comparison with spontaneous IMCs, EM-induced IMCs had a significantly longer duration in the stomach and a significantly lower amplitude in the duodenum. These observations indicate that EM induced phase III activity more intensively in the stomach than in the duodenum. The plasma motilin concentration increased significantly during EM-induced IMCs, and this suggested a close relationship between this hormone and induction of the IMC. The increase in motilin levels was also observed of the strong gastric contractions which did not migrate or migrated incompletely to the duodenum. Therefore, it seems reasonable to suggest that motilin is involved in phase III activity of the stomach rather than in that of the duodenum.

Effects of cisapride on gastrointestinal motor activity and gastric emptying of disopyramide.

The effects of cisapride on the gastrointestinal contractile activity and pharmacokinetics of disopyramide were determined in beagle dogs and patients with arrhythmia. In the animal experiments, the gastric motor index was significantly decreased by i.v. administration of disopyramide in a dose-dependent fashion. The peak decrease of the motor index was observed within 5 min after i.v. injection of disopyramide; the motor index then recovered gradually to the level present prior to drug administration. I.v. administration of cisapride (0.5 mg/kg) markedly increased gastrointestinal contractile activity following the decrease induced by disopyramide pretreatment (5 mg/kg, i.v.). In the clinical studies, the gastric emptying test was performed using the acetaminophen method. A significant correlation between plasma concentrations of disopyramide and gastric emptying time has been found (p < 0.001). The combination of disopyramide (100 mg t.i.d.) and cisapride (2.5 mg t.i.d.) significantly increased gastric emptying compared with that induced by disopyramide alone. The peak plasma concentration of disopyramide in association with cisapride oral administration was significantly higher, and the apparent absorption rate constant and lag time of disopyramide were about 2-fold higher and 2-fold shorter, respectively, than for disopyramide alone. Cisapride, acting as a cholinergic agonist, may counteract the anticholinergic effect of disopyramide on gastric motility. As a factor influencing drug absorption, gastric emptying is of importance, as it determines the rate of drug delivery to the small intestine. Therefore, the oral administration of disopyramide with cisapride may be useful for patients with delayed gastric emptying.

Involvement of 5-hydroxytryptamine 3 receptors in regulation of interdigestive gastric contractions by motilin in the dog

The effects of IV injection of 5-hydroxytryptamine 3 receptor antagonists (BRL 43694 and GR38032F) on gastrointestinal contractile activity were studied in dogs with vagally denervated fundic pouch in the conscious state by means of chronically implanted force transducers in the gastrointestinal tract and the pouch. In the interdigestive state, 5-hydroxytryptamine 3 receptor antagonists (0.01–0.1 mg/kg), if given during phase III contractions, instantly and dose-dependently inhibited the spontaneous and motilin-induced phase III contractions in the intact stomach and altered the duodenal phase III contractions to a pattern of continuous contractions, the contractile force of which was 65% of the spontaneous phase III contractions in the duodenum and caused immediate caudad migration of phase III contractions along the small intestine. However, the spontaneous and motilin-induced phase III-like contractions in the denervated pouch were not affected at all by 5-hydroxytryptamine 3 receptor antagonists. When 5-hydroxytryptamine 3 receptor antagonists (0.1–3.0 mg/kg) were given during the phase I period, they did not directly stimulate gastrointestinal contractions. The cyclic fluctuation of the plasma motilin concentration with phase III activity in the stomach was also not influenced by 5-hydroxytryptamine 3 receptor antagonists, but the next phase III contractions in the stomach were inhibited. During the digestive state, however, 5-hydroxytryptamine 3 receptor antagonists (0.1–3.0 mg/kg) did not influence contractile activity in the gastrointestinal tract and in the vagally denervated fundic pouch. On the basis of recent pharmacological studies showing that the distribution of 5-hydroxytryptamine 3 receptors is recognized in the area postrema, peripheral neurons of vagal afferents, and the enteric nervous system, the results of the current study provide a basis for a hypothesis that 5-hydroxytryptamine 3 receptor antagonists are most likely to block motilininduced signals at 5-hydroxytryptamine 3 receptors on the vagal afferents. In conclusion, the present findings suggest the possible involvement of 5-hydroxytryptamine 3 receptors on vagal afferents especially in terms of endogenous release of acetylcholine in the control of interdigestive phase III activity in the stomach by motilin.

A novel water-soluble dopamine-2 antagonist with anticholinesterase activity in gastrointestinal motor activity: Comparison with domperidone and neostigmine

A novel water-soluble dopamine-2 antagonist, N-[4-[2-(dimethylamino) ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride (HSR-803) was synthesized and assayed for its gastrointestinal smooth muscle stimulating activity in vivo and in vitro. In the in vivo study, gastrointestinal contractile activity was measured by means of chronically implanted force transducers in conscious dogs; it was found that HSR-803 at 3.0 mg/kg IV probably stimulated gastric contractile force twice during the digestive state and significantly antagonized dopamine- (1.0 mg/kg per hour) inhibited gastric contractions in doses of 0.3,1, and 3 mg/kg IV. With a background IV infusion of HSR-803 at 3 mg/kg per hour, the contraction-stimulating activity of acetylcholine (0.05 mg/kg per minute) was greatly enhanced while the response to bethanechol was not changed. As a result, HSR-803 was found to have a strong anticholinesterase activity besides the antidopamine-2 activity; i.e., the anticholinesterase activity of HSR-803 at 3 mg/kg per hour was equivalent to that of neostigmine at 10 μg/kg per hour, and dopamine-2 antagonistic activity of HSR-803 was similar to that of domperidone on a weight basis. No symptom suggesting actions on the central nervous system was noticed in HSR-803 up to 10 mg/kg IV in conscious dogs. In the in vitro study, HSR-803 inhibited cholinesterase dose-dependently, and IC50 was 2.9 × 10 −6 mol/L, while those of neostigmine and domperidone were 2.3 × 10−8 mol/L and 1.7 × 10−5 mol/L, respectively. In conclusion, HSR-803 stimulates endogenous acetylcholine release by antagonizing the dopamine-2 receptor on the postsynaptic cholinergic neurons, and the anticholinesterase activity of HSR-803 may cause the released acetylcholine to accumulate at cholinergic receptor sites. Thus, HSR-803 is potentially capable of enhancing cholinergic activity in the gastrointestinal region.

Effect of 5‐Hydroxytryptamine on Gastrointestinal Contractile Activity in Conscious Dogs

The effect of intravenous infusion of 5‐hydroxytryptamine (5‐HT) on gastrointestinal contractile activity was studied in conscious dogs during the digestive and interdigestive states. It was found that 30 to 300 μg/kg per hour of 5‐HT induced phasic contractions mainly in the gastric antrum, duodenum, jejunum, and mid‐intestine. However, when doses greater than 100 μg/kg per hour were used, a stimulatory effect was seen in the ileum and colon. The dose‐dependent stimulatory effect of 5‐HT on gastrointestinal motor activity was observed in both the frequency and amplitude of contractions. Atropine‐resistant 5‐HT‐induced contractions in the stomach were completely inhibited by methysergide. This fact strongly suggests the existence of 5‐HT receptor on the smooth muscle. The stimulatory effect of 5‐HT given intravenously quickly disappeared with the cessation of infusion. No significant side effects such as nausea, vomiting, diarrhea, or other symptoms suggesting abdominal pain were observed during or after the intravenous infusion of 5‐HT in doses between 10 and 300 μg/kg per hour in any of the dogs.

Metoclopramide reversal of decreased gastrointestinal myoelectric and contractile activity in a model of canine postoperative ileus.

Postoperative ileus is characterized by decreased gastrointestinal myoelectric activity and motility. Metoclopramide was used to treat experimentally induced postoperative ileus in six dogs. Contractile activity was monitored by extraluminal strain gages on the pyloric antrum and proximal segment of the duodenum, and myoelectric activity was measured by recording bipolar electromyograms (EMGs) at the pyloric antrum, pyloric canal, proximal segment of the duodenum, proximal and distal parts of the jejunum, and ileum. Measurements were obtained from animals without ileus (baseline) and those with ileus that were either untreated or treated with metoclopramide. Adynamic ileus was induced by rubbing a 50 cm segment of jejunum with a dry sponge for 5 minutes and exposing the bowel to the air for 30 minutes. Treated dogs received metoclopramide (0.4 mg/kg 4 times daily [QID] intravenously [IV]), whereas untreated dogs received a saline placebo, starting 1 hour after celiotomy closure. Recordings were made for 26 hours after induction of ileus. The phases of the migrating myoelectric complex (MMC) were identified and motility index values were determined. During ileus, the MMC phase II duration was increased at the duodenum and phase III duration was decreased at the antrum, pylorus, duodenum, and proximal segment of the jejunum (p less than 0.05). Motility index values were decreased at the antrum and duodenum during ileus (p less than 0.05). Treatment with metoclopramide reversed the MMC phase III inhibition at the antrum and pylorus, and partially reversed the inhibition at the duodenum and jejunum (p less than 0.05). Motility index values were restored to preoperative baseline values with metoclopramide treatment (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

S10-2 - Continuous measurements of gastrointestinal contractile activity in dogs

S10-2 - Continuous measurements of gastrointestinal contractile activity in dogs