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Slow waves are known to originate orally in the stomach and to propagate toward the antrum, but the exact location of the pacemaker and the precise pattern of propagation have not yet been studied. Using assemblies of 240 extracellular electrodes, simultaneous recordings of electrical activity were made on the fundus, corpus, and antrum in open abdominal anesthetized dogs. The signals were analyzed off-line, pathways of slow wave propagation were reconstructed, and slow wave velocities and amplitudes were measured. The gastric pacemaker is located in the upper part of the fundus, along the greater curvature. Extracellularly recorded slow waves in the pacemaker area exhibited large amplitudes (1.8 +/- 1.0 mV) and rapid velocities (1.5 +/- 0.9 cm/s), whereas propagation in the remainder of the fundus and in the corpus was slow (0.5 +/- 0.2 cm/s) with low-amplitude waveforms (0.8 +/- 0.5 mV). In the antrum, slow wave propagation was fast (1.5 +/- 0.6 cm/s) with large amplitude deflections (2.0 +/- 1.3 mV). Two areas were identified where slow waves did not propagate, the first in the oral medial fundus and the second distal in the antrum. Finally, recordings from the entire ventral surface revealed the presence of three to five simultaneously propagating slow waves. High resolution mapping of the origin and propagation of the slow wave in the canine stomach revealed areas of high amplitude and rapid velocity, areas with fractionated low amplitude and low velocity, and areas with no propagation; all these components together constitute the elements of a gastric conduction system.

5-Hydroxytryptamine(4) (5-HT(4)) receptors are an interesting target for the management of patients in need of gastrointestinal (GI) promotility treatment. They have proven therapeutic potential to treat patients with GI motility disorders. Lack of selectivity for the 5-HT(4) receptor has limited the clinical success of the agonists used until now. For instance, next to their affinity for 5-HT(4) receptors, both cisapride and tegaserod have appreciable affinity for other receptors, channels or transporters [e.g. cisapride: human ether-a-go-go-related gene (hERG) is K(+) channel and tegaserod: 5-HT(1) and 5-HT(2) receptors]. Adverse cardiovascular events observed with these compounds are not 5-HT(4) receptor-related. Recent efforts have led to the discovery of a series of selective 5-HT(4) receptor ligands, with prucalopride being the most advanced in clinical development. The selectivity of these new compounds clearly differentiates them from the older generation compounds by minimizing the potential of target-unrelated side effects. The availability of selective agonists enables the focus to shift to the exploration of 5-HT(4) receptor-related differences between agonists. Based on drug- and tissue-related properties (e.g. differences in receptor binding, receptor density, effectors, coupling efficiency), 5-HT(4) receptor agonists are able to express tissue selectivity, i.e. behave as a partial agonist in some and as a full agonist in other tissues. Furthermore, the concept of ligand-directed signalling offers great opportunities for future drug development by enlarging the scientific basis for the generation of agonist-specific effects in different cell types, tissues or organs. Selective 5-HT(4) receptor agonists might thus prove to be innovative drugs with an attractive safety profile for better treatment of patients suffering from hypomotility disorders.

1. We aimed to characterize the 5-HT receptors involved in the 5-HT-induced effect on electrically induced contractions of dog antrum longitudinal muscle in vitro. 2. In the presence of L-NOARG (0.1 mM), electrical field stimulation (EFS) induced atropine- and tetrodotoxin-sensitive contractions. Tetrodotoxin or atropine left any agonist tested ineffective. These EFS-induced contractions were on average enhanced by 5-HT (0.3 microM), however, pronounced variation in the response to 5-HT was observed. There were non-significant trends of the selective 5-HT3 receptor antagonist granisetron (1 microM), and methysergide (1 microM; preventing interactions of 5-HT with 5-HT1, 5-HT2, 5-ht5, 5-HT6 and 5-HT7 receptors) to increase the response to 5-HT. The selective 5-HT4 receptor antagonist GR 113808 (0.1 microM) displayed a non-significant trend to inhibit the 5-HT-induced increase. 3. Combination experiments with methysergide (1 microM), granisetron (1 microM) and GR 113808 (0.1 microM) revealed that the 5-HT (0.3 microM)-induced response consisted of (1) an excitatory component blocked by GR 113808, (2) excitatory and inhibitory components both blocked by methysergide. 4. The selective 5-HT4 receptor agonist prucalopride (0.3 microM) increased EFS-induced contractions, an effect prevented by GR 113808 (0.1 microM). 5. The increase of EFS-induced contractions by the preferential 5-HT2 receptor agonist alpha-Me-5-HT (0.3 microM) was antagonized by 5-HT2B receptor antagonists. 6. The 5-HT1/5-HT7 receptor agonist 5-carboxamidotryptamine (5-CT; 0.3 microM) inhibited EFS-induced contractions. This was prevented by methysergide (1 microM), the 5-HT7 receptor antagonist mesulergine (0.3 microM) and the selective 5-HT7 receptor antagonist SB-269970 (0.3 microM). 7. In the presence of GR 113808 (0.1 microM), alpha-Me-5-HT (1 microM) increased EFS-induced contractions. The 5-HT (0.3 microM)-induced inhibition of the stimulation by alpha-Me-5-HT was prevented by SB-269970 (0.3 microM). 8. In conclusion, dog antral longitudinal muscle is endowed with (1) excitatory neuronal 5-HT4 receptors and 5-HT2B receptors and (2) inhibitory smooth muscle 5-HT7 receptors.

The novel enterokinetic drug prucalopride was tested at various intravenous and oral doses in fasted dogs to assess: (i) the effects on colonic contractile motility patterns; and (ii) the mediation of these effects by 5-hydroxytryptamine (5-HT4) receptors. Colonic motility patterns were assessed in conscious dogs with four chronically implanted strain-gauge force transducers that were sutured on the serosal side of the colon. Prucalopride altered colonic contractile motility patterns in a dose-dependent fashion by stimulating high-amplitude clustered contractions in the proximal colon and by inhibiting contractile activity in the distal colon. Prucalopride was equipotent after oral and intravenous administration, as reflected by the values for the effective dose that induced 50% of maximum effect (95% confidence limits): 0.04 mg kg(-1) p.o. (0.01-0.1 mg kg(-1)) and 0.01 mg kg(-1) i.v. (0.006-0.04 mg kg(-1)). Prucalopride also caused a dose-dependent decrease in the time to the first giant migrating contraction (GMC); at higher doses of prucalopride, the first GMC generally occurred within the first half-hour after treatment. Subcutaneous pretreatment with the 5-HT4 receptor antagonist GR125487 (40 microg kg(-1) bodyweight) completely prevented the effects of orally administered prucalopride (0.31 mg kg(-1) bodyweight). Prucalopride, given orally or intravenously, alters colonic motility in the fasted conscious dog in a dose-dependent fashion. It induces GMCs and causes proximal colon stimulation and distal colon inhibition of contractile motility patterns by stimulating 5-HT4 receptors.

Gastrin delays gastric emptying of liquids probably by reducing gastric tone. The mechanism responsible for the relaxatory effect induced by pentagastrin was unknown. The aim of this study was to investigate the effects of pentagastrin and the underlying mechanisms responsible for these effects. Could nitric oxide (NO) be involved as a mediator. Gastric tone was monitored with a flaccid bag introduced into the stomach via a gastric cannula and connected to a barostat. A series of pressure-volume curves with a 30-min interval were constructed by increasing intragastric pressure to a maximum of 14 mmHg (2-mmHg steps). Pentagastrin (4 micrograms kg-1 s.c.) facilitated the volume increases induced by isobaric gastric distension. This effect could be completely blocked by pretreatment with cimetidine (10 mg kg-1 s.c.) or by omeprazole (10 mg kg-1 p.o.). The effect induced by pentagastrin could be mimicked by histamine (0.16 mg kg-1 s.c.) and to a lesser extent by insulin (0.2 IU kg-1 i.v.). Cimetidine and omeprazole had no intrinsic effect on gastric tone. With an opened cannula, allowing the gastric secretions to leave the stomach, no increased gastric relaxation could be observed either in the presence of pentagastrin or in the presence of histamine or insulin. Nitro-1-arginine (L-NNA, 5 mg kg-1 i.v.) reduced the volume increases induced by distension. Unexpectedly, even in the presence of L-NNA, pentagastrin remained effective. In conclusion, pentagastrin induces a gastric relaxation via a mechanism which involves gastric secretion but not nitric oxide.

The effects of xenin 25, a peptide of the neurotensin/xenopsin family, were examined on the motility of the guinea pig jejunum and colon in vitro. In the jejunum, xenin induced a biphasic response: first a small relaxation and then a large contraction. In the colon, xenin induced relaxation. The tenia coli was contracted. Deletion or amidation of the C-terminal leucine inactivated xenin. A peptide sequence of 16 C-terminal amino acids was necessary to elicit a full response in the jejunum, whereas in the colon, the potencies of all fragments of xenin 25, including the 6 C-terminal amino acid sequence (xenin 6), were not significantly different from that of xenin 25. In the jejunum, contraction was abolished or reduced by tetrodotoxin, by atropine, by met-enkephalin, by antagonists to the tachykinin receptors NK1 and NK2 and by the P2-purinoceptor antagonist suramin. L-NNA, phentolamine, methysergide, hexamethonium and apamin had no effect. In the colon, all actions of xenin were tetrodotoxin-resistant; the potency of xenin to relax was reduced by apamin and suramin. The actions of xenin on small and large bowel were attenuated by the neurotensin receptor antagonist SR 48692. The xenin analog neurotensin was significantly less potent than xenin 25 in contracting the jejunum and more potent than xenin 25 in relaxing the colon. We conclude that xenin exerts excitatory effects on a neuronal subtype receptor in the jejunum, with participation of muscarinic, purinergic and tachykinin-related mechanisms. Xenin exerts relaxing effects on the colon by interaction with a myokinetic subtype receptor involving Ca(++)-dependent K+ channels and the P2-purinoceptor.

Pharmacotherapy of gastrointestinal motor disorders is complicated by the large variety of drug targets and their interactions, the complex relation between contractile patterns and propulsion and the occurrence of regional and species differences. A number of drug classes are discussed: cholinergic agonists/antagonists, dopamine-antagonists, calcium-entry blockers and spasmolytics, serotonin-5-HT4-agonists, cholecystokinin-antagonists, motilin-agonists, 5-HT3-antagonists, opiate agonists, and laxatives. The number of drug classes is increasing rapidly allowing a more specific treatment for the large number of gastrointestinal disorders related to disturbed motility. An interesting new development is the search for compounds interfering with transmitters of the non-adrenergic non-cholinergic nerves of the enteric nervous system a.o. nitric oxide (NO).

Prokinetic benzamides (e.g., cisapride) enhance gastrointestinal motility and transit. In vitro studies on the guinea pig ileum suggest that their effect is mediated via serotonergic 5-hydroxytryptamine (5-HT4) receptors, resulting in a facilitation of cholinergic neurotransmission. However, most in vivo studies have been performed on the canine stomach. Therefore, our aim was to determine whether the findings obtained on the guinea pig ileum can be extrapolated to another species and another organ. Does a benzamide facilitate cholinergic neutrotransmission on strips of the canine stomach in vitro? If so, does the benzamide exert its effect via a serotonergic 5-HT4 mechanism? Longitudinal muscle strips with adhering myenteric plexus were isolated from the canine stomach and were electrically stimulated at submaximal frequencies resulting in a mean contractile response of 16 +/- 7% of the response to methacholine (10(-6) M). Atropine and tetrodotoxin (both 3 x 10(-7) M) abolished the contractile responses, whereas hexamethonium (10(-4) M) had no effect. Cisapride (3 x 10(-7) M) enhanced the contractile responses from 14 to 70% (59 +/- 5% increase). 5-HT (3 x 10(-7) M) similarly enhanced the responses from 12 to 72% (58 +/- 5% increase). Cisapride induced a sustained enhancement throughout the duration of the experiment; in contrast, the effect of 5-HT subsided in about 90 min. Single-concentration administration of cisapride (10(-8)-10(-6) M) and 5-HT (10(-9)-3 x 10(-7) M) resulted in EC50 values of 1.0 (0.8-1.4) x 10(-7) M for cisapride and 1.3 (0.8-2.1) x 10(-8) M for 5-HT. Methiothepin and methysergide (both 3 x 10(-7) M; 5-HT1-receptor antagonists), ketanserin and LY 53857 (both 3 x 10(-7) M; 5-HT2-receptor antagonists), granisetron (3 x 10(-7) M; 5-HT3-receptor antagonist) or ICS 205-930 (3 x 10(-7) M; 5-HT3-receptor antagonist and in addition 5-HT4-receptor antagonist at 3 x 10(-6) M) did not reduce the responses to both cisapride and 5-HT. 1-(1-Naphthalenyl)piperazine (10(-6) M; 5-HT-receptor antagonist in the rat gastric fundus) significantly reduced the increase by 5-HT (24 +/- 7%; 7-31%) but had no effect on the cisapride (3 x 10(-7) M)-induced increase (69 +/- 4%; 8-77%).(ABSTRACT TRUNCATED AT 400 WORDS)

The synthesis of benzamides derived from 1-substituted-3-methoxy or 3-hydroxy-4-piperidinamine resulted in the selection of a substituted benzamide, cisapride, which displays potent gastrokinetic properties. Pharmacological studies showed that cisapride improves both motility and transit of the oesophagus, the stomach, the small and large intestines. Moreover it markedly improves gastropyloroduodenal coordination. The gastrokinetic effects of cisapride are largely due to an enhanced release of acetylcholine from cholinergic nerves in the myenteric plexus (plexus of Auerbach) along the digestive tract. This explains why the therapeutic efficacy of cisapride reaches from the oesophagus into the large intestine.

A fully automated system to quantify different parameters of gastrointestinal motility and gastroduodenal co-ordination in conscious dogs was designed and built around a personal technical computer (HP 9816). Online it performs sampling of contractions on four different sites of the digestive tract for two dogs simultaneously, data reduction, drift correction and storage of data on hard disk. Offline it performs baseline determination, peak detection, calculation of motility parameters such as amplitude and interval, plus co-ordination between gastric and duodenal motility and presentation of the results in both tabular and graphic form. To illustrate the possibilities and advantages of the computer analysis the early postprandial motor patterns for antrum, duodenum and jejunum were quantified during the first hour after administration of a small test meal.

The effects of dopamine were studied on the isolated guinea-pig stomach preparation, including the duodenal bulb. Phasic activity: intra-arterially administered dopamine (0.25 mg/l) reduced phasic activity and blocked antro-duodenal coordination. The selective dopamine-antagonist, domperidone, increased phasic amplitude and improved antro-duodenal coordination. Tonic activity: gastric relaxation induced by equi-active concentrations of dopamine (0.25 mg/l, i.a.) and noradrenaline (0.04 mg/l, i.a.) could be antagonized by domperidone and prazosin; domperidone being more effective against dopamine and prazosin against noradrenaline. Our results support the hypothesis that dopamine acts as an inhibitory neuromodulator. The actions of dopamine in decreasing spontaneous activity and in inducing relaxation could set the stage for duodenal-gastric reflux.

The efficacies of the gastrokinetic drugs domperidone, cisapride , metoclopramide and bethanechol to improve antroduodenal coordination were compared in two test systems: in vitro, the gastroduodenal preparation of the guinea-pig; in vivo, the conscious dog implanted with strain gauges on antrum and duodenum. Antroduodenal coordination could be quantified for both the in vitro and in vivo systems. Drug effects were similar for both test models. Domperidone and cisapride , and to a lesser extent metoclopramide but not bethanechol, effectively improved antroduodenal coordination indicating that both dopaminergic and cholinergic pathways modulate antroduodenal motor patterns.

Unlabelled: Domperidone (dopamine antagonist), metoclopramide and clebopride (both dopamine antagonists and stimulators of the intramural cholinergic system), and trimebutine (spasmolytic) are used in the treatment of digestive disorders such as dyspepsia or gastritis. Our aim was to compare the effects of these compounds on the isolated intact gastroduodenal preparation of the guinea pig. Domperidone (IC50 = 10(-6) M), clebopride (10(-5) M) and metoclopramide (2 X 10(-5) M) antagonized gastric relaxations induced by dopamine. In contrast with clebopride, domperidone and metoclopramide enhanced the amplitude of gastric contractions, moderately reduced contractile frequency, and enhanced antroduodenal coordination in a dose-dependent manner (EC50 for domperidone 3 X 10(-7) M, for metoclopramide 2 X 10(-5) M). Trimebutine reduced gastric spontaneous activity and antroduodenal coordination. Trimebutine had a direct relaxatory effect on gastric tone (EC50 = 4 X 10(-6) M). The mechanism of this inhibitory effect remains unknown but our data indicate that it is not mediated via dopamine or opiate receptor subtypes., Conclusion: domperidone, clebopride, metoclopramide and trimebutine exert distinct and diverse effects on the motility parameters of the gastroduodenal preparation of the guinea pig. These diverging actions may help explain the differences in patients' responsiveness to the treatment of digestive disorders such as dyspepsia or gastritis.

An intact guinea-pig gastroduodenal preparation was used to determine the mechanism by which antroduodenal coordination is inhibited by dopamine and improved by domperidone. Domperidone effectively antagonised the inhibitory effects of dopamine in a competitive way. The lack of interference of alpha 1-, alpha 2-, and beta- adrenergic antagonists on the dopaminergic modulation indicates the presence of specific dopamine receptors in the gut wall. Both tetrodotoxin and atropine, but not hexamethonium, prevented the stimulatory effects of domperidone, indicating that intact (postganglionic?) cholinergic intramural nerves were a prerequisite for detecting these effects. In the presence of tetrodotoxin, bethanechol induced coordinated motor patterns, revealing the myogenic control of antroduodenal coordination. When dopamine was tested on coordinated motor patterns as induced by the combination of bethanechol and tetrodotoxin, it no longer inhibited coordination, suggesting that the dopamine receptor is located on nervous structures. It was concluded that dopamine inhibited, and domperidone effectively improved, myogenically controlled antroduodenal coordination via specific dopamine receptors located on nervous structures in the gut wall of the guinea-pig.

Gastrointestinal motor activity of the anesthetized dog was assessed by strain gage force transducers on longitudinal and transverse muscle of the gastric body and antrum, duodenum, jejunum, ileum, and colon. Dose-dependent effects of pentagastrin (1-8192 ng/kg, i.v.) were only seen on the stomach: increases in gastric body tone, antral contractile force and contractile frequency of the gastric phasic activity. Body tone and antral force were more sensitive to pentagastrin than was contractile frequency. Supra-maximal doses and repetition of the dose-response protocol gave smaller increments for body tone and antral force, while the increase in contractile frequency remained unaffected. The different responses to pentagastrin of force and frequency indicate that pentagastrin acts on 2 different receptor-effector systems.

The effects of cisapride (R 51619), a new non-dopamine-blocking gastrokinetic drug, on gastrointestinal contractility have been determined on isolated preparations of the guinea pig. On the intact gastroduodenal preparation, cisapride enhanced contractile amplitude (3.4 X 10(-7) M), improved antroduodenal coordination (EC50 = 1.9 X 10(-7) M) and antagonized gastric relaxation induced by phenylephrine, dopamine, isoproterenol, 5-hydroxytryptamine (in the presence of atropine) and periarterial nerve stimulation (IC50 range, 9.1 X 10(-7)-2.4 X 10(-6) M). Experiments with metoclopramide yielded similar results on amplitude, coordination and dopamine-induced relaxation at 5 X 10(-5), 2.2 X 10(-5) and 1.7 X 10(-5) M, respectively. On the ileum, cisapride enhanced the contractile response to electrical stimulation at low concentrations (EC50 = 9.2 X 10(-9) M) as compared with metoclopramide (EC50 = 3.3 X 10(-6) M). On this preparation, cisapride showed no direct cholinergic or nicotine-like effects and did not enhance the response to methacholine (indicative of a lack of inhibition of acetylcholinesterase-activity and of sensitization of the muscarine receptor). On the colon ascendens, cisapride induced contractions (EC50 = 3.5 X 10(-8) M) (metoclopramide, 3.5 X 10(-6) M), insensitive to atropine and only marginally inhibited by tetrodotoxin. In conclusion, cisapride effectively improves spontaneous or electrically evoked contractions of isolated preparations of the guinea pig, most likely via facilitation of the release of acetylcholine. However, the inhibition of gastric relaxation and the induction of colonic contractions in the presence of atropine indicate that, besides cholinergic neuronal pathways, other mechanisms are involved in the motor-stimulating properties of cisapride.

In vitro studies on an intact gastroduodenal preparation of the guinea-pig indicated that dopamine inhibited motor activity via a direct action on the gastrointestinal wall. Dopamine-induced relaxations were prevented by dopamine antagonists, which also exerted intrinsic stimulatory effects and improved gastroduodenal coordination. These effects were confirmed in vivo on conscious dogs. The results cannot be explained by an interaction with alpha- receptors, since alpha-adrenergic blocking concentrations of prazosin were inactive against dopamine, and dopamine-blocking concentrations of domperidone did not interfere with noradrenaline-induced relaxations. Pharmacological evidence confirmed the presence of dopamine receptors in the stomach of conscious dogs. The presence of specific dopamine receptors in the gastrointestinal tract is strongly indicated, and an important role for endogenous dopamine as an inhibitory neuromodulator of gastroduodenal motility is suggested.

In studies of gastroduodenal motility several imaging techniques and also recordings of signals of implanted transducers are used. Combination of methods and prolonged observation times produce so much information that an automatic analysis is advantageous, the more so because more complex parameters can be analysed. Using a desktop computer, it is possible to analyse long time-series of antral and duodenal signals, obtained with implanted electrodes and strain gauges. The developed program can discriminate between the signal and the majority of artefacts. An easy manual interaction on the computer display enables the operator to either accept or adjust the indicators of recognized signals. The times of occurrence and the amplitudes of the detected peaks are retained for further analysis e.g. production of histograms of interval time, amplitude, antroduodenal time lag, or calculation of coordination parameters.