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T L Peeters

Publications and source records attributed to T L Peeters.

At least 19 recordsLinked to original sources
PubMed1995

Transduction mechanism of motilin and motilides in rabbit duodenal smooth muscle.

The present study was undertaken to explore motilin's transduction pathway in the rabbit. Guanine nucleotides inhibited 125I-motilin binding in rabbit antral tissue and increased the dissociation of motilin from its receptor. Motilin, the motilin agonist erythromycin A enol ether (EM-201) and carbachol (taken as control) increased the production of inositol phosphates in rabbit duodenal smooth muscle strips labeled with myo-[2-3H]inositol. The effect of carbachol was blocked by atropine. Dose-response curves revealed that 50% of this effect was obtained with 3.9 nM motilin, 170 nM EM-201, 0.54 microM carbachol. Chromatographic separation of the inositol phosphate metabolites showed significant increases in the levels of [3H]inositol bisphosphate and of [3H]inositol trisphosphate. The three substances were without effect upon the metabolism of cAMP, nor did they modulate the rise in cAMP induced by GTP. We propose that motilin's transduction pathway uses a G protein that causes an increase in inositol trisphosphate which is rapidly metabolized, and which may release calcium from intracellular stores.

Adenylyl Cyclases↗
PubMed1995

Effect of octreotide on fasting gall bladder emptying, antroduodenal motility, and motilin release in acromegaly.

Subcutaneous octreotide (Sandostatin) injections lead to gall stone formation in 13-50% of acromegaly patients during one year of therapy. This study explored the effects of octreotide on interdigestive gall bladder emptying, antroduodenal motility, and motilin release. Ambulatory antroduodenal manometry was performed in six acromegaly patients before and after two months of octreotide therapy (100 micrograms thrice daily, subcutaneously). Ultrasonographic gall bladder volume measurements and plasma motilin concentrations were obtained during two migrating motor complex (MMC) cycles. Before octreotide treatment, nine of 26 phase III activities started in the antrum and 17 of 26 in the duodenum whereas during treatment 47 of 48 of phase III activity started in the duodenum (p < 0.05). Before treatment, interdigestive gall bladder emptying (mean (SEM) 39.9 (4.0)% of maximal fasting volume) and plasma motilin peaks preceded antral phase III but not duodenal phase III. During octreotide therapy no significant motilin fluctuation or gall bladder emptying was seen. Fasting gall bladder volume increased from 40.9 (9.1) ml before to 68.0 (14.8) ml (p < 0.05) during octreotide treatment. In conclusion, two months' treatment with octreotide increases the number of duodenal phase III like activity and virtually abolishes antral phase III, plasma motilin peaks, and interdigestive gall bladder emptying. These effects might contribute to the high risk of gall stone formation during longterm octreotide treatment.

Acromegaly↗
PubMed1994

Induction of secondary structure in the peptide hormone motilin by interaction with phospholipid vesicles.

Motilin is an intestinal peptide hormone that binds to a membrane bound receptor located in the gut tissue. Circular dichroism (CD) was used to study the interaction between either porcine or rabbit motilin or a 1-16 fragment of porcine motilin, with model systems of lipid membranes: sodium dodecyl sulphate (SDS), 1,2-dioleoyl-sn-glycero-3-phosphoglycerol (DOPG) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). The CD measurements show significant induction of secondary structure in both motilins and the fragment when negatively charged vesicles (DOPG) or negatively charged micelles (SDS) were present. In contrast, neutral DOPC vesicles did not induce any change in the secondary structure compared to water, in which a random-like secondary structure dominates. The induced secondary structure in the presence of DOPG vesicles is very close to that induced by a mixed aqueous solution containing 30% hexafluoroisopropanol, in which previous NMR-studies have resulted in a three-dimensional solution structure of porcine motilin. In both porcine and rabbit motilin the alpha-helix content is about 50%. This is in agreement with the presence of an amphipathic helix in the C-terminal half of motilin interacting with phospholipid membranes. The interaction appears to be mainly electrostatic in nature, and does not induce any significant alterations in the vesicle, as monitored by EPR studies of spin labels located at the fifth carbon atom of the backbone in a stearic acid molecule. In the 1-16 fragment the alpha-helical content induced by DOPG and SDS is only about 20%.

Amino Acid Sequence↗
PubMed1994

The motilin antagonist ANQ-11125 blocks motilide-induced contractions in vitro in the rabbit.

Studies on the physiological role of motilin, and more recently, on the relationship between motilin and erythromycin A, have been hampered by the lack of antagonists. We now have discovered such a compound. ANQ-11125 displaces motilin bound to an homogenate of rabbit antral smooth muscle tissue. The dissociation constant (pKd) was 8.16 +/- 0.10. However, ANQ-11125 did not induce contractions of segments of rabbit duodenum, except at high concentrations. In the presence of 1 microM ANQ-11125 the dose response curves of erythromycin-A, De(N-methyl)-N-ethyl-8,9 anhydroerythromycin A 6,9-hemiacetal and motilin were shifted about one log unit to the right, but the responses to ACh and Substance P were unaffected. Schild-analysis showed the competitive nature of the interaction and allowed the calculation of the pA2: 7.03 +/- 0.05 (motilin curves) and 7.55 +/- 0.06 (EM-523 curves). This is the first report of a motilin antagonist. Its properties definitively prove that motilides are motilin agonists.

Animals↗
PubMed1994

Motilin receptor: a model for development of prokinetics.

Erythromycin and related macrolides act as smooth muscle and neural receptors to contract rabbit duodenum and induce phase III migrating motor complex (MMC) activity in intact dogs. A recently developed motilin antagonist confirms that motility effects of erythromycin are mediated by motilin receptors. Despite species, organ, and tissue heterogeneity of motilin receptors, binding experiments with rodent antral smooth muscle tissue provide a good model for the development of this new class of prokinetics.

Animals↗
PubMed1993

Purification and amino acid sequence of motilin from cat small intestine.

Motilin was isolated from cat small intestine by a series of chromatographic steps. Using a radioreceptor assay, based upon binding of iodinated porcine motilin to rabbit antral smooth muscle membranes, it was shown that cat duodenal mucosa contains about 495 ng/g tissue, the jejunal mucosa 161 ng/g tissue and the ileal mucosa 95 ng/g tissue motilin. The duodenal mucosa was extracted with 6% acetic acid and concentrated on a cation exchange Whatman CM-52 gel. After lyophilization the material was further purified by gel filtration (Sephadex G-50), followed by reverse phase (C18), cation exchange HPLC (Mono S) and three runs on a reverse phase HPLC (Nucleosil 300-5C18) column. The UV absorbance and the radioreceptor assay were used to monitor the purification. After Mono S chromatography two forms of motilin were detected. The major peak corresponded to a 22 amino acid peptide, which differed only from canine motilin at position 12, where Lys is replaced by Arg. The smaller peak probably corresponds to a deamidated form of this peptide. The sequence homology between cat and porcine/human motilin or cat and rabbit motilin is 81.8% and 72.7%, respectively. The conservation of the first six amino acids in all five species studied is striking, confirming that the biological activity of the peptide resides in the N-terminal part.

Amino Acid Sequence↗
PubMed1993

Erythromycin effects on gastric emptying, antral motility and plasma motilin and pancreatic polypeptide concentrations in anorexia nervosa.

In primary anorexia nervosa, gastric motility is often impaired and ensuing symptoms further discourage eating. Prokinetic agents have been shown to accelerate gastric emptying in affected patients. This study investigated whether emptying of a radiolabelled semisolid 1168 kJ meal and antral contractility were enhanced by intravenous erythromycin. Eight women and two men with anorexia nervosa (21-46 years, 50-75% of ideal body weight) received 200 mg erythromycin or placebo under crossover double blind conditions. Gastric emptying and antral contractility were recorded scintigraphically for 90 minutes. In addition, plasma motilin and pancreatic polypeptide concentrations were determined. With placebo, antral contractions were of regular 3 cycles/minute frequency. With erythromycin, less frequent and partly arrhythmic long duration contractions set in and emptying was accelerated: after 90 minutes, the activity remaining in the stomach was markedly less than with placebo in all patients (Sign test, p < 0.002). Basal motilin and pancreatic polypeptide concentrations were normal and showed a normal response to the meal in all patients. Motilin concentrations decreased slightly more and pancreatic polypeptide concentrations increased markedly more with erythromycin than with placebo, possibly because the meal reached the intestine earlier. In conclusion, erythromycin accelerated emptying markedly and in most patients induced an antral motor activity characterised by long duration contractions occurring at often irregular intervals.

Adult↗
PubMed1992

Somatostatin 28 and coupling of human interdigestive intestinal motility and pancreatic secretion.

To determine the effects of small increases in somatostatin 28 plasma concentrations on human interdigestive gastrointestinal motility and pancreatic secretion, six fasting volunteers were intubated with gastroduodenal multilumen tubes and motility and pancreatic enzyme secretion were measured. Subjects received intravenous NaCl and somatostatin 28 at 11 and 44 pmol.kg-1.h-1 for 120 minutes or at least one interdigestive cycle. The two doses increased plasma somatostatin 28 levels within the physiological or into the supraphysiological range, respectively. Somatostatin 28 at 11 and 44 pmol.kg-1.h-1 decreased the length of the interdigestive motility cycle by 50% and 67% compared with controls, respectively (both P less than 0.002). Propagation velocity of the migrating motor complex (P less than 0.01) and plasma motilin were decreased (P less than 0.01). The smaller and larger dose decreased pancreatic enzyme outputs by 50% and 65%, respectively (P less than 0.005), but with the smaller dose, phase III-associated enzyme outputs were greater than phase I outputs. These findings suggest that small changes in somatostatin 28 plasma concentrations modulate human interdigestive motility and pancreatic enzyme output while coupling of motor and secretory events is preserved.

Adult↗
PubMed1992

Erythromycin accelerates gastric emptying by inducing antral contractions and improved gastroduodenal coordination.

Erythromycin has been shown to act as a motilin agonist by binding to motilin receptors on gastrointestinal smooth muscle and to improve the severely impaired gastric emptying in patients with diabetic gastroparesis. To elucidate the motor pattern that accounts for this accelerated emptying, the effect of 200 mg erythromycin vs. placebo on postprandial motility of the stomach and the upper small intestine was examined in 13 normal subjects. Erythromycin significantly increased the amplitude of the antral contractions during the 2-hour postprandial study period (maximal difference in mean amplitude of distal antral contractions between erythromycin and placebo recorded from 80 to 90 minutes after meal: 123 +/- 17 vs. 44 +/- 12 mm Hg; P less than 0.005). The total number of antral contractions was not affected, but the contractions could be recorded manometrically higher up in the stomach after erythromycin than after placebo (9-12 vs. 3-6 cm above the pylorus). Antroduodenal coordination was significantly improved during the first postprandial hour, and the first normal phase 3 of the migrating motor complex, indicating the reappearance of fasting motility, occurred earlier after erythromycin than after placebo (128.3 +/- 14.3 vs. 173.4 +/- 16.1 minutes; P less than 0.05). These changes in postprandial motility induced by erythromycin may well account for its accelerating effect on gastric emptying.

Adult↗
PubMed1992

Effect of motilin on gastric emptying in patients with diabetic gastroparesis.

Erythromycin markedly accelerates gastric emptying, possibly because it acts as a motilin agonist. In the present study, the effect of an equipotent dose of motilin was tested. In six patients with severe diabetic gastroparesis, gastric emptying of liquids and solids was examined scintigraphically after motilin or placebo in a double-blind crossover study. Motilin (10 pmol.kg-1.min-1) or saline was infused over a 90-minute period starting 5 minutes before breakfast. Motilin markedly accelerated emptying. For liquids, the half-emptying time was reduced from 51 +/- 6 to 22 +/- 11 minutes (P less than 0.01) and for solids from 111 +/- 4 to 51 +/- 12 minutes (P less than 0.01). The mean increase in plasma motilin levels was 1315 +/- 342 pg/mL, corresponding to an effective infusion rate of about 4 pmol.kg-1.min-1. In the control experiments, basal motilin levels (173 +/- 17 pg/mL) were within the normal range but increased steadily postprandially, reaching 321 +/- 25 pg/mL at the end of the study period, probably reflecting gastric distension. The postprandial increase in pancreatic polypeptide level was blunted compared with accepted normal values but was more pronounced during motilin infusion, i.e., 650 +/- 217 vs. 279 +/- 66 pg/mL (P less than 0.01), probably because of the improved emptying. Our data show that motilin accelerates gastric emptying in diabetic gastroparesis and support the hypothesis that erythromycin's effect is mediated through motilin receptors.

Diabetic Neuropathies↗
PubMed1991

Effect of erythromycin and of octreotide on motilin receptor density in the rabbit.

Recent studies have shown that erythromycin lactobionate (EMLB) acts as a motilin agonist and is able to accelerate gastric emptying in diabetic gastroparesis. Using the rabbit as a model, we have studied the changes in motilin receptor density induced by EMLB (a motilin agonist) and octreotide (a somatostatin analogue and an inhibitor of motilin secretion). Binding studies were performed with antral smooth muscle tissue homogenates using iodinated nor-leucine13-porcine-motilin, and binding parameters were obtained from computerized fits to displacement curves. The contractile capacity towards motilin (10(-7) M) and EMLB (10(-5) M) was measured isotonically on duodenal segments and the response was expressed relative to the maximum obtained with ACh (10(-4) M). The first hours after the last i.v. administrations of EMLB (50 mg/day given on 3 consecutive days), motilin binding was completely abolished to 0.02 +/- 0.006 fmol/mg protein, compared to the control group (0.64 +/- 0.12 fmol/mg protein). The effect was dose-related: total doses of 17.5 mg, 87.5 mg, 175 mg EMLB reduced motilin binding and contractility towards motilin and EMLB to respectively 95 +/- 10, 82 +/- 5%; 36 +/- 9, 38 +/- 9%; 3 +/- 1, 24 +/- 2% of the control values. The effect was also long lasting: binding was still reduced to 60% of the control value 48 h after the highest dose. In contrast, octreotide induced a marked but short lasting upregulation. After 3 daily s.c. injections of 5 micrograms, Bmax rose to 13.6 +/- 1.9 fmol/mg protein (P less than 0.05). It was already obtained 1 h after 3 x 2.5 micrograms/24 h. The changes in receptor-density were not related to changes in affinity. We conclude that motilin receptors can be regulated by EMLB and octreotide presumably because one compound mimicks hypermotilinemia, the other one induces hypomotilinemia.

Animals↗
PubMed1991

Ca2+ dependence of motilide-induced contractions in rabbit duodenal muscle strips in vitro.

Recent studies suggested that certain erythromycin A (EM-A) derivatives are motilin receptor agonists. As proposed by Itoh they may be called "motilides". We have investigated the Ca2(+)-dependence of contractions induced by two potent motilides, ME-34 [de(N-methyl) 8,9-anhydroeryhtromycin A 6,9-hemiacetal] and EM-523 [de(N-methyl)-N-ethyl-8,9-anhydroerythromycin A 6,9-hemiacetal], in duodenal tissues and compared the results with those previously obtained with motilin. Isometric and isotonic contractile responses of isolated longitudinal muscle sheets from the rabbit duodenum were tested under normal, Ca2(+)-free and depolarizing conditions. Prior to stimulation with motilides, the maximal response to acetylcholine was recorded and all responses were always expressed as a percentage of this response. Both motilides induced contractions in normally polarized tissue, with an EC50 of 26 +/- 5 nM for ME-34 (n = 7), and 27 +/- 5 nM for EM-523 (n = 16) and maximal responses of respectively 88 +/- 4% and 80 +/- 3%. Like motilin, both compounds induced an 'extra'-contraction in depolarized tissues. The EM-523 response in 140 mM K+ under isotonic conditions was 84 +/- 3% (n = 5) at 10(-5) M, with an EC50 that was shifted to 65 +/- 18 nM. Similar figures were obtained for ME-34. When Ca2+ was added to Ca2(+)-depleted strips, half-maximal Ca2+ values (in mM) were 1.10 +/- 0.11 (n = 9) for EM-523 and 1.13 +/- 0.12 (n = 3) for ME-34, as compared with 1.12 +/- 0.13 (n = 7) for motilin and 2.8 +/- 1.1 (n = 9) for K+. Both ME-34 and EM-523 also induced a transient contraction in Ca2(+)-free solutions under isometric conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

The influence of food temperature on postprandial blood pressure reduction and its relation to substance-P in healthy elderly subjects.

Blood pressure (BP) in the elderly may decrease after a meal or oral glucose loading. The mechanism of this phenomenon is still unclear. In addition, the effect of the temperature of a meal on postprandial BP is unknown. However, it has been suggested that vasoactive gastrointestinal peptides are involved in the etiology of postprandial BP reduction. Therefore, we studied the effects of a cold and a warm glucose solution on BP, heart rate, plasma glucose, insulin, and substance-P levels in 15 healthy elderly subjects with a mean age of 74 +/- 3 (SD) years. With an interval of at least 2 days, a warm (50 degrees C) and a cold (5 degrees C) solution (75 g glucose/300 mL water) were given in random order. After the cold glucose loading mean arterial pressure increased by a maximum of 3.9 +/- 1.3 mmHg (P less than 0.01). In contrast, BP decreased after the warm solution by a maximum of 8.0 +/- 1.1 mmHg (P less than 0.001). Neither test had an influence on plasma substance-P levels. Our data suggest that postprandial blood pressure reduction in the elderly is dependent on food temperature. Substance-P does not seem to play a role in this phenomenon.

Administration, Oral↗
PubMed1991

[The potentials of erythromycin derivatives in the treatment of gastrointestinal motility disorders].

In low dosages erythromycin imitates the effect of motilin on the gastrointestinal motility. In vitro experiments show that erythromycin is a motilin agonist: it displaces motilin which is bound to its receptor; it directly acts on smooth musculature and it possesses the same animal and tissue specificity. Structural changes cause adequate changes in the binding affinity and in the contractile activity. Several motilides such as erythromycin derivatives with prokinetic properties have no antibiotic activity, but they cause a distinct increase of the prokinetic activity. Motilides may be defined as a new group of prokinetic substances: the motilinomimetics. Erythromycin normalises the delayed evacuation of the stomach of solid and fluid food in diabetic, idiopathic and postvagotomy gastroparesis. For the treatment of gastrooesophageal reflux disease, gastritis, pathological overgrowth of the small intestine, hypokinesia of the gallbladder and the chronic obstipation erythromycin appears as a promising medicament. The substances with a stronger effect may become even still more useful medicaments. A better understanding of the relation between motilin and motilides may lead to new knowledge about the regulation of the gastrointestinal motility.

Biliary Tract↗
PubMed1990

Improvement of gastric emptying in diabetic gastroparesis by erythromycin. Preliminary studies.

Erythromycin mimics the effect of the gastrointestinal polypeptide motilin on gastrointestinal motility, probably by binding to motilin receptors and acting as a motilin agonist. Erythromycin may thus have clinical application in patients with disturbances of gastroduodenal motility, such as diabetic gastroparesis. To examine this possibility, we studied the effect of erythromycin on gastric emptying in 10 patients with insulin-dependent diabetes mellitus and gastroparesis. We studied the emptying of liquids and solids simultaneously on separate days after the intravenous administration of erythromycin (200 mg) or placebo, using a double-isotope technique and a double-blind, crossover design. Erythromycin shortened the prolonged gastric-emptying times for both liquids and solids to normal. For example, 120 minutes after the ingestion of a solid meal, mean (+/- SE) retention was 63 +/- 9 percent with placebo and 4 +/- 1 percent with erythromycin, as compared with 9 +/- 3 percent in 10 healthy subjects. The corresponding values 120 minutes after the ingestion of a liquid meal were 32 +/- 4, 9 +/- 3, and 4 +/- 1 percent, respectively. Gastric emptying also improved, but to a lesser degree, in the 10 patients after four weeks of treatment with oral erythromycin (250 mg three times a day). These preliminary results suggest that erythromycin may have therapeutic value in patients with severe diabetic gastroparesis.

Adult↗
PubMed1990

Dopamine interrupts gastrointestinal fed motility pattern in humans. Effect on motilin and somatostatin blood levels.

The aim of this study was to investigate the hypothesis that during the postprandial period in humans, dopamine interrupts the gastrointestinal motility pattern through a mechanism that is peptide-mediated. Fourteen normal human subjects were studied by means of intestinal manometry. After recording two consecutive migrating motor complexes a 900-kcal solid-liquid meal was given. In eight subjects 30 min after the meal, placebo or dopamine (5 micrograms/kg/min) was infused for 15 min and then the recording continued for 120 min. In the remaining six subjects dopamine was administered twice with a 90-min interval in between. In three subjects the first dopamine infusion after the meal was preceded by treatment with placebo, the second by domperidone (20 mg intravenous as bolus), in the other three subjects domperidone was given before the first dopamine infusion. Blood samples for the determination of somatostatin and motilin were drawn basally, during, and immediately after dopamine in seven subjects. The results show that dopamine interrupts the fed motility pattern, inhibiting the high antral waves, and activates a duodenal phase III of migrating motor complexes. The pretreatment with domperidone completely prevented the dopamine effect. Plasma levels of motilin increased significantly during dopamine, while somatostatin blood levels did not change. These findings support the hypothesis that a dopaminergic mechanism may modulate the cycling of duodenal motor complex in humans.

Adult↗