The effect of motilin on the regulation mechanism of intestinal motility in conscious horses.
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Laparotomy was performed on seven thoroughbreds to attach a force transducer to the proximal jejunum, distal jejunum, and ileum, as well as to the serous membrane of the cecum. Following observation of intestinal motility in conscious horses, they were intravenously injected with motilin (0.6 microgram/kg) to examine its effect on intestinal motility. Strong contractions peculiar to horses were observed in small intestine. Further, motilin caused strong contractions in the proximal jejunum. The results suggested the involvement of motilin in the regulation mechanism of intestinal motility. (+info)
Effect of motilin on the lower oesophageal sphincter.
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The effect of motilin on lower oesophageal sphincter (LES) pressure has been studied in unanesthetised specially trained dogs using an infusion manometric technique. Motilin produced significant rises in resting pressure and contractions of the LES after doses ranging from 0-009 mug/kg to 0-05 mug/kg. Doses greater than 0-05 mug/kg resulted in repetitive high amplitude contractions. Atropine 30 mug/kg completely abolished the effect of the lower doses of motilin. Higher doses of motilin in atropinised dogs still caused a small rise in baseline pressure and contractile activity still appeared. Hexamethonium 2 mg/kg resulted in both a diminished rise in LES pressure and the disappearance of contractions after motilin. Hexamethonium and atropine together completely abolished the LES response to motilin. We conclude that motilin increases LES pressure by acting on preganglionic cholinergic neurones to release acetylcholine which excites other cholinergic neurones supplying the circular muscle of the LES. (+info)
Receptor for motilin identified in the human gastrointestinal system.
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Motilin is a 22-amino acid peptide hormone expressed throughout the gastrointestinal (GI) tract of humans and other species. It affects gastric motility by stimulating interdigestive antrum and duodenal contractions. A heterotrimeric guanosine triphosphate-binding protein (G protein)-coupled receptor for motilin was isolated from human stomach, and its amino acid sequence was found to be 52 percent identical to the human receptor for growth hormone secretagogues. The macrolide antibiotic erythromycin also interacted with the cloned motilin receptor, providing a molecular basis for its effects on the human GI tract. The motilin receptor is expressed in enteric neurons of the human duodenum and colon. Development of motilin receptor agonists and antagonists may be useful in the treatment of multiple disorders of GI motility. (+info)
Differential changes in ACh-, motilin-, substance P-, and K(+)-induced contractility in rabbit colitis.
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To test the hypothesis that the changes in intestinal contractility, which accompany inflammation of the gut, are agonist specific, we compared the response of inflamed strips to substance P (SP), motilin, ACh, and K(+) as a function of time. In parallel experiments, changes in the general mechanical properties (passive tension, optimal stretch) of the colitic tissue were evaluated. Colitis was induced by trinitrobenzenesulfonic acid, and rabbits were killed after 1, 2, 3, 5, or 8 days. Passive tension was increased starting from day 2 until day 8, and maximal active tension (T(max)) was generated at less stretch from day 5. A 50% decrease in T(max) was observed for ACh and K(+) between days 2 and 3 and for motilin and SP between days 3 and 5. For all compounds, T(max) returned to normal after 8 days. The pEC(50) value (negative logarithm of the concentration that induces 50% of the maximal contractile activity) for ACh was increased from day 3 until day 8 and for SP at day 3, whereas for motilin it was decreased at day 1. The changes in passive tension and optimal stretch indicate generalized structural alterations of smooth muscle tissue. However, the different time profiles of the changes in active tension and contractile potency for different contractile agents suggest that inflammation specifically affects receptor-mediated mechanisms. (+info)
Motilin receptors in the human antrum.
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Motilin is an intestinal peptide that stimulates contraction of gut smooth muscle. The motilin receptor has not been cloned yet, but motilin-receptor agonists appear to be potent prokinetic agents for the treatment of dysmotility disorders. The aim of this study was to determine neural or muscular localization of motilin receptors in human upper gastrointestinal tract and to investigate their pharmacological characteristics. The binding of (125)I-labeled motilin to tissue membranes prepared from human stomach and duodenum was studied; rabbit tissues were used for comparison. Solutions enriched in neural synaptosomes or in smooth muscle plasma membranes were obtained. Various motilin analogs were used to displace the motilin radioligand from the various tissue membranes. The highest concentration of human motilin receptors was found in the antrum, predominantly in the neural preparation. Human motilin receptors were sensitive to the NH(2)-terminal portion of the motilin molecule, but comparison with rabbit showed that both species had specific affinities for various motilin analogs [i.e., Mot-(1-9), Mot-(1-12), Mot-(1-12) (CH(2)NH)(10-11), and erythromycin]. Motilin receptors obtained from synaptosomes or muscular plasma membranes of human antrum expressed different affinity for two motilin-receptor agonists, Mot-(1-12) and Mot-(1-12) (CH(2)NH)(10-11), suggesting that they correspond to specific receptor subtypes. We conclude that human motilin receptors are located predominantly in nerves of the antral wall, are functionally (and probably structurally) different from those found in other species such as the rabbit, and express specific functional (and probably structural) characteristics dependent on their localization on antral nerves or muscles, suggesting the existence of specific receptor subtypes, potentially of significant physiological or pharmacological relevance. (+info)
The effect of motilin agonist ABT-229 on gastro-oesophageal reflux, oesophageal motility and lower oesophageal sphincter characteristics in GERD patients.
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BACKGROUND: ABT-229, a motilin agonist without antibacterial activity, has been shown to enhance both lower oesophageal sphincter pressure in cats and gastric emptying in humans. AIM: To investigate the effect of oral treatment with ABT-229 10 mg b.d., ABT-229 5 mg b. d. and cisapride 10 mg q.d.s. on gastro-oesophageal reflux, lower oesophageal sphincter pressure, transient lower oesophageal sphincter relaxations and symptoms in GERD patients. METHODS: Twenty-four GERD patients completed the study. A randomized, double-blind, placebo-controlled, three-period incomplete crossover design was used with three dosing periods of 7 days. All patients received ABT-229 10 mg b.d. and placebo during two of the three periods. In the remaining period 12 patients were given ABT-229 5 mg b.d. and 12 received cisapride 10 mg q.d.s. Ambulatory 24 h recordings of oesophageal pH and pharyngeal, oesophageal, lower oesophageal sphincter and gastric pressures were performed on day 7 using an assembly incorporating a Dent sleeve connected to a portable water-perfused manometric system. RESULTS: Oesophageal acid exposure was not affected by ABT-229 or cisapride, but the incidence of reflux episodes was reduced by cisapride. None of the drugs affected oesophageal motility, lower oesophageal sphincter pressure or the incidence of transient lower oesophageal sphincter relaxations. Both ABT-229 10 mg b.d. and cisapride reduced the severity of daytime heartburn. CONCLUSION: The value of ABT-229 in the treatment of GERD appears to be limited. (+info)
Enteric locus of action of prokinetics: ABT-229, motilin, and erythromycin.
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We investigated the in vivo and in vitro locus of actions of prokinetics: motilin, erythromycin, and ABT-229. The test substances were infused close intra-arterially in short segments of the jejunum in the intact conscious state. Each prokinetic acted on a presynaptic neuron and utilized at least one nicotinic synapse to stimulate circular muscle contractions. The final neurotransmitter at the neuroeffector junction was ACh. Motilin and erythromycin, but not ABT-229, also released nitric oxide. Each prokinetic utilized somewhat different subtypes of muscarinic, serotonergic, tachykininergic, and histaminergic receptors, except for the M(3) receptor, which was common to all of them. In contrast, none of the prokinetics stimulated contractions in mucosa-free or mucosa-attached muscle strips, or rings, even though methacholine or electrical field stimulation induced phasic contractions in all of them. The prokinetics also did not release ACh in longitudinal muscle-myenteric plexus preparations. Each prokinetic, however, decreased the length of enzymatically dispersed single cells. In conclusion, each prokinetic may act on a different subset of presynaptic neurons that converge on the postsynaptic cholinergic and nonadrenergic noncholinergic motoneurons. The presynaptic neurons may be impaired in the muscle bath environment. (+info)
Motilides accelerate regional gastrointestinal transit in the dog.
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BACKGROUND: Motilides have prokinetic effects on the upper gut during fasting, increasing the strength of antral contractions and stimulating gastroduodenal phase 3 sequences. Effects on the distal gut, and postprandially, are less well documented. AIM: To evaluate dose-response effects of motilin and erythromycin on gastric emptying, small bowel and colonic transit in the dog using a validated scintigraphic technique. METHODS: For gastric emptying and small bowel transit, 99mTc labelled beads were added to a meal of dog chow (450 kcal). Regional colonic transit was measured by 111In labelled beads placed in a capsule which dissolved and released radiation into the proximal colon. Scintiscans were taken at regular intervals and indices of whole-gut transit were calculated. Drugs were given by slow intravenous administration. RESULTS: In the doses used, motilin accelerated regional colonic transit but did not hasten gastric emptying or small bowel transit. Single or repeated doses of motilin had similar effects on colonic transit. Erythromycin accelerated gastric emptying, small bowel transit and regional colonic transit. CONCLUSIONS: Motilin receptors are apparently present in the canine small bowel and colon. Postprandially, motilides accelerate transit in the distal gut. (+info)