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Biochemical and Biophysical Research... Nov 1994While studying the structure-activity characteristics of motilin with motilin synthetic analogues, two compounds, motilin 1-12 [CH2 NH]3-4 and motilin 1-12 [CH2...
While studying the structure-activity characteristics of motilin with motilin synthetic analogues, two compounds, motilin 1-12 [CH2 NH]3-4 and motilin 1-12 [CH2 NH]10-11, showed high affinity for the motilin receptor combined to a weak contractile activity. The following data suggest that motilin 1-12 [CH2 NH]10-11 is a potent motilin receptor antagonist. It showed a high affinity for the motilin receptor present on membranes of rabbit antrum (pIC50: 8.24 +/- 0.08 for the analogue vs 8.96 +/- 0.02 for the native peptide). When tested in vitro on strips of rabbit duodenum, the dose-response curve to motilin 1-22 was displaced to the right with motilin 1-12 [CH2 NH]10-11 (pIC50: 8.91 +/- 0.06 in presence of saline versus 7.19 +/- 0.40 with the analogue). However, when injected i.v. in dogs, motilin 1-12 [CH2 NH]10-11 was undetectable in the peripheral blood, suggesting enzymatic degradation precluding its use in vivo.
Topics: Animals; Biological Availability; Dogs; Duodenum; Motilin; Muscle Contraction; Rabbits; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide
PubMed: 7999063
DOI: 10.1006/bbrc.1994.2686 -
Life Sciences Jun 1984Although peripheral actions have been shown for the brain-gut peptide, motilin, its localization in the CNS of mammals suggests some physiological role at this site. In...
Although peripheral actions have been shown for the brain-gut peptide, motilin, its localization in the CNS of mammals suggests some physiological role at this site. In the present experiments intracerebroventricular or intrathecal, but not peripheral, administrations of motilin produced a dose-related and naloxone reversible inhibition of the micturition reflex. Cross-tolerance was demonstrated between motilin and morphine in this respect. These data suggest a physiological role for motilin within CNS to alter urinary bladder motility, possibly through an enkephalinergic or naloxone-sensitive link.
Topics: Animals; Central Nervous System; Dose-Response Relationship, Drug; Drug Tolerance; Female; Gastrointestinal Hormones; Injections, Intraventricular; Injections, Spinal; Morphine; Motilin; Muscle Contraction; Naloxone; Rats; Rats, Inbred Strains; Urinary Bladder
PubMed: 6547500
DOI: 10.1016/0024-3205(84)90043-2 -
Regulatory Peptides Aug 1997To characterize the motilin receptors present in the chicken, the effects of chicken motilin (Phe-Val-Pro-Phe-Phe-Thr-Gln-Ser-Asp-Ile-Gln-Lys-Met-Gln-Glu-Lys-Glu-Arg... (Comparative Study)
Comparative Study
To characterize the motilin receptors present in the chicken, the effects of chicken motilin (Phe-Val-Pro-Phe-Phe-Thr-Gln-Ser-Asp-Ile-Gln-Lys-Met-Gln-Glu-Lys-Glu-Arg -Asn-Lys-Gly-Gln), Leu13 porcine motilin, canine motilin and three erythromycin derivatives (EMA, EM523, GM611) on the contractility of the chicken gastrointestinal (GI) smooth muscles were investigated in vitro and compared with those in the rabbit duodenum. In the proventriculus longitudinal and circular muscle layers, chicken motilin (3 nM-1 microM) caused an atropine- and a tetrodotoxin-sensitive contraction (EC50 = 39-49 nM), and potentiated the EFS-induced contraction without affecting the responsiveness of acetylcholine. EM523 and GM611 (3-100 microM) contracted the proventriculus longitudinal muscle, and the maximum amplitudes of contraction were about 60% of that induced by chicken motilin. Chicken motilin (0.1 nM-100 nM) also caused contraction of the ileum (EC50 = 7 nM) through direct action on the smooth muscle cells. On the other hand, erythromycin derivatives showed only a weak contractile efficacy (about 20% of the maximum response of chicken motilin) even at high concentrations (10-100 microM). The rank order of potency in the ileum was chicken motilin > canine motilin > or = Leu13 porcine motilin > > GM611 > or = EM523 > or = EMA. GM109 slightly inhibited the ideal contractions induced by Leu13 porcine motilin at 100 microM (pA2 = 3.86). In the rabbit duodenum, chicken motilin was a full agonist with the same intrinsic activity as Leu13 porcine motilin, canine motilin and the erythromycin derivatives. However, the rank order of potency (Leu13 porcine motilin > or = canine motilin > chicken motilin > GM611 > or = EM523 > EMA) was different from that in the chicken ileum. In conclusion, chicken motilin causes an excitatory response in the chicken GI tract through activation of neural (proventriculus) and smooth muscle motilin receptors (ileum). The motilin receptor present in the ileum is different from that demonstrated in the rabbit intestine, because of a different rank order of motilin peptides in producing the contraction, low contracting activity of erythromycin derivatives and low antagonistic efficacy of GM109. Different pharmacological characteristics of the mechanical response induced by motilin peptides and erythromycin derivatives between the proventriculus and the ileum are discussed.
Topics: Animals; Chickens; Dogs; Erythromycin; Gastrointestinal Agents; Hormones; Ileum; Motilin; Muscle Contraction; Muscle, Smooth; Proventriculus; Rabbits; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide; Swine
PubMed: 9416990
DOI: 10.1016/s0167-0115(97)01024-0 -
Digestive Diseases and Sciences Feb 1994During phases II and III of the migrating motor complex, there is an increase in plasma motilin level that is synchronous with phasic and tonic contractile activity of... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
During phases II and III of the migrating motor complex, there is an increase in plasma motilin level that is synchronous with phasic and tonic contractile activity of the lower esophageal sphincter and of the stomach. The action of motilin on human lower esophageal sphincter is proposed to be mediated by cholinergic mechanisms. Recently, it has been shown that erythromycin was a motilin agonist. This study evaluated the pharmacological effects and the mechanisms of action of intravenous erythromycin on esophageal motility in humans. Healthy volunteers were studied three times at seven-day intervals in a randomized, double-blind fashion. Subjects were first studied for 10 min before drug administration. Afterwards, they received blindly and randomly an intravenous injection of placebo or atropine (12 micrograms/kg) followed by a 20-min continuous intravenous administration of placebo or erythromycin (150 mg). The difference (delta) between lower esophageal sphincter pressure and the duration, amplitude, and velocity of peristaltic contractions during the control period and after administration of drugs was compared. Erythromycin significantly increased (P < 0.05) the lower esophageal sphincter pressure (16.8 +/- 4.7 mm Hg) compared to placebo (-0.029 +/- 1.4 mm Hg). Erythromycin significantly decreased peristaltic contraction velocity compared to placebo (P < 0.05). The effects of erythromycin on lower esophageal sphincter pressure were completely blocked by previous administration of intravenous atropine. Erythromycin increased the number of fundic contractions compared to the placebo, but this effect was not blocked by the previous administration of atropine.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adult; Cholinergic Fibers; Double-Blind Method; Erythromycin; Esophagogastric Junction; Female; Humans; Male; Manometry; Motilin; Peristalsis; Pressure
PubMed: 8313822
DOI: 10.1007/BF02090212 -
Gut Mar 1992The commonly reported gastrointestinal side effects that occur with erythromycin are related to its prokinetic action on the gut, mediated, at least in part, by its... (Review)
Review
The commonly reported gastrointestinal side effects that occur with erythromycin are related to its prokinetic action on the gut, mediated, at least in part, by its motilin receptor stimulating activity. This action may be of clinical use in conditions associated with gastrointestinal hypomotility such as diabetic gastroparesis and intestinal pseudo-obstruction, although further work needs to be done to establish the long term therapeutic uses of erythromycin in these disorders. Macrolide compounds with no antibacterial properties but which have a pronounced prokinetic action on the gut have already been synthesised and are currently being developed for future use in man. These 'motilides' should provide a useful addition to our rather limited armamentarium of effective gastrointestinal prokinetic agents.
Topics: Animals; Digestive System; Dogs; Erythromycin; Gastrointestinal Motility; Guinea Pigs; Humans; Motilin; Rabbits; Rats; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide
PubMed: 1568663
DOI: 10.1136/gut.33.3.397 -
Sheng Li Ke Xue Jin Zhan [Progress in... Oct 1992
Review
Topics: Animals; Duodenum; Erythromycin; Humans; Motilin; Muscle Contraction; Muscle, Smooth; Receptors, Gastrointestinal Hormone; Receptors, Neuropeptide
PubMed: 1302371
DOI: No ID Found -
Peptides Sep 2003Due to motilin's relation to the migrating motor complex (MMC), the physiology of motilin has been mostly studied in man and dog. The cat does not have an MMC pattern,...
Due to motilin's relation to the migrating motor complex (MMC), the physiology of motilin has been mostly studied in man and dog. The cat does not have an MMC pattern, and little is known about cat motilin. Therefore we identified the cat motilin precursor (GenBank accession no. AF127917) and developed a quantitative polymerase chain reaction (PCR) to explore its distribution in the gastrointestinal tract and in the central nervous system (CNS). The precursor is closely related to the dog precursor and consists of an open reading frame of 348bp encoding the signal peptide (25 amino acids), the motilin sequence (22 amino acids) and the motilin associated peptide (69 amino acids). One amino acid of the signal peptide was subject to gene polymorphism. Quantification of motilin messenger RNA (mRNA) was for the first time achieved. It is most abundant in the gastrointestinal tract, with the highest concentration in the duodenum, the lowest in the colon and is not detectable in the corpus. However an important expression was also observed in several regions of the CNS, except the striatum and cerebral cortex. The highest level was in the hypothalamus (although 23-fold lower than in the duodenum), the lowest level in the pons. Moderate levels were found in the thyroid. These data suggest that the physiological role of motilin may extend beyond its effect on gastrointestinal motility.
Topics: Amino Acid Sequence; Animals; Brain Chemistry; Cats; Gastrointestinal Tract; Gene Expression Profiling; Humans; Molecular Sequence Data; Motilin; Phylogeny; Protein Precursors; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Sequence Alignment
PubMed: 14706554
DOI: 10.1016/j.peptides.2003.09.005 -
General and Comparative Endocrinology Jul 2016Motilin, a peptide hormone produced in the upper intestinal mucosa, plays an important role in the regulation of gastrointestinal (GI) motility. In the present study, we...
Motilin, a peptide hormone produced in the upper intestinal mucosa, plays an important role in the regulation of gastrointestinal (GI) motility. In the present study, we first determined the cDNA and amino acid sequences of motilin in the Japanese quail and studied the distribution of motilin-producing cells in the gastrointestinal tract. We also examined the motilin-induced contractile properties of quail GI tracts using an in vitro organ bath, and then elucidated the mechanisms of motilin-induced contraction in the proventriculus and duodenum of the quail. Mature quail motilin was composed of 22 amino acid residues, which showed high homology with chicken (95.4%), human (72.7%), and dog (72.7%) motilin. Immunohistochemical analysis showed that motilin-immunopositive cells were present in the mucosal layer of the duodenum (23.4±4.6cells/mm(2)), jejunum (15.2±0.8cells/mm(2)), and ileum (2.5±0.7cells/mm(2)), but were not observed in the crop, proventriculus, and colon. In the organ bath study, chicken motilin induced dose-dependent contraction in the proventriculus and small intestine. On the other hand, chicken ghrelin had no effect on contraction in the GI tract. Motilin-induced contraction in the duodenum was not inhibited by atropine, hexamethonium, ritanserin, ondansetron, or tetrodotoxin. However, motilin-induced contractions in the proventriculus were significantly inhibited by atropine and tetrodotoxin. These results suggest that motilin is the major stimulant of GI contraction in quail, as it is in mammals and the site of action of motilin is different between small intestine and proventriculus.
Topics: Animals; Cloning, Molecular; Coturnix; Duodenum; Gastrointestinal Motility; Gastrointestinal Tract; Ghrelin; Ileum; Motilin; Muscle Contraction; Proventriculus; Sequence Homology
PubMed: 27179882
DOI: 10.1016/j.ygcen.2016.05.017 -
Methods in Enzymology 1982
Topics: Animals; Chloramines; Chromatography, Affinity; Dogs; Duodenum; Gastrointestinal Hormones; Gastrointestinal Motility; Guinea Pigs; Humans; Motilin; Rabbits; Radioimmunoassay; Tosyl Compounds
PubMed: 7115542
DOI: 10.1016/0076-6879(82)84028-7 -
Motilin and OHM-11526 activate a calcium current in human and canine jejunal circular smooth muscle.The American Journal of Physiology Aug 1997Motilin is a potent agonist for gastrointestinal smooth muscle contraction and has been proposed to regulate the onset of phase III of the migrating motor complex in...
Motilin is a potent agonist for gastrointestinal smooth muscle contraction and has been proposed to regulate the onset of phase III of the migrating motor complex in dogs and humans. The effects of motilin and OHM-11526, a motilin antagonist in rabbit smooth muscle strips, were examined in isolated canine and human jejunal circular smooth muscle cells using whole cell patch-clamp techniques with Ba2+ as the charge carrier. Effects of both drugs on inward current through L-type Ca2+ channels (ICaL) in both canine and human cells were first observed at 10(-3) M. At 10(-6) M, motilin increased ICaL in canine and human jejunal circular smooth muscle cells by 43 +/- 20 and 45 +/- 11%, respectively, and OHM-11526 increased ICaL by 54 +/- 8 and 54 +/- 14%, respectively. The increase in inward current was blocked by nifedipine and by guanosine 5'-O-(2-thiodiphosphate) but not by pertussis toxin. Washout of both drugs resulted in a further increase in ICaL. These data suggest that both motilin and OHM-11526 activate and ICaL in human and canine jejunal circular smooth muscle cells through a G protein-coupled mechanism.
Topics: Animals; Calcium; Cell Separation; Dogs; Electric Conductivity; Humans; Jejunum; Motilin; Muscle, Smooth; Patch-Clamp Techniques
PubMed: 9277420
DOI: 10.1152/ajpgi.1997.273.2.G404