Biomedical subjects
Publications and source records attributed to M Delvaux.
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BACKGROUND/AIMS: Galanin induces a contraction or a relaxation of digestive smooth muscle. Receptors mediating these effects have not been pharmacologically characterized. The aim of the study was to evaluate properties of two specific galanin antagonists M15 and M35 on galanin effects on muscle cells. METHODS: Isolated muscle cells were obtained separately from circular and longitudinal layers of guinea pig and dog ileums. Contraction was expressed as percentage decrease in cell length from control. RESULTS: Galanin induced a contraction of cells from guinea pig circular layer (50% effective concentration [EC50], 80 pmol/L) and dog longitudinal layer (EC50, 100 pmol/L). The antagonists inhibited galanin-induced contraction. The most potent was M15 (50% inhibitory concentration [IC50], 80 pmol/L in guinea pig; 90 pmol/L in dog) which was > M35 (IC50, 4 nmol/L in guinea pig; 1 nmol/L in dog). In dog circular layer, galanin inhibited cholecystokinin-induced contraction by relaxing the cells (EC50, 3 pmol/L). The antagonists inhibited this relaxation. The most potent was M35 (IC50, 60 pmol/L) which was > M15 (IC50, 900 pmol/L). CONCLUSIONS: Galanin antagonists M15 and M35 inhibit the contraction and the relaxation induced by galanin with different potency, suggesting the presence of distinct galanin receptors in gastrointestinal tract that each mediates a specific effect.
BACKGROUND/AIMS: Platelet-activating factor (PAF) is involved in the pathophysiology of motility changes induced by intestinal inflammation. The aim of this study was to evaluate a possible desensitization of PAF receptors in guinea pig intestinal smooth muscle cells after experimental inflammation induced by trinitrobenzenesulfonic acid (TNB). METHODS: Saline or TNB (80 mg/kg) was injected in the intestinal lumen, and the animals were killed 6 days later. Smooth muscle cells from the circular layer were isolated, and cell contraction induced by PAF was measured. RESULTS: In cells from saline-treated animals, PAF induced a maximal cell contraction at 10 nmol/L and half-maximal contraction (EC50) was 9 +/- 0.2 pmol/L. After TNB injection, the maximal contraction induced by PAF was observed at 1000 nmol/L and EC50 was 300 +/- 70 pmol/L, indicating a 2 logmol/L right shift of the concentration-response curve of PAF. When animals were treated with the PAF antagonist, 20 mg/kg BN52021, or with 2 mg/kg indomethacin for the 6 days after TNB instillation, the right-sided shift of the concentration-response curve of PAF did not occur. CONCLUSIONS: Desensitization of PAF receptors occurring in intestinal smooth muscle cells after TNB instillation could be mediated in vivo by PAF itself via a prostaglandin-dependent pathway.
AIM: To evaluate the effects of various doses of lintopride, a new 5HT-4 antagonist with moderate 5HT-3 antagonist properties, on oesophageal body and lower oesophageal sphincter (LOS) motility in humans. METHODS: Eight healthy male volunteers, mean age 22 (19-28) years, without any history of digestive disease or chest pain, were randomized to three doses of lintopride (0.1, 0.3 and 0.5 mg/kg i.v.) and a placebo at 1-week intervals in a double-blind, crossover study. Oesophageal motility was recorded continuously for 4 h after each dose, using perfused catheters inserted at the level of the LOS and in the body of the oesophagus, at 5, 10 and 15 cm from the LOS. Peristalsis was studied during 10 wet swallows, at 30-min intervals (T0-T240 min). RESULTS: The LOS basal pressure (23.3 +/- 2.0 cmH2O; mean +/- s.d.) remained stable after dosing with placebo to T240. After lintopride, LOS basal pressure increased significantly vs. placebo (AUC comparison: 0.1 mg/kg, P = 0.036; 0.3 mg/kg, P = 0.027; 0.5 mg/kg, P = 0.052). In contrast, the duration and extent of LOS relaxation after swallowing was not affected by any of the three doses of lintopride. The amplitude of peristaltic waves in the oesophagus increased significantly at T30 after lintopride 0.3 mg/kg (34.5 cmH2O, P = 0.020) and 0.5 mg/kg (32.5 cmH2O, P = 0.027), at T60 after 0.3 mg/kg (48.8 cmH2O, P = 0.0009) and 0.5 mg/kg (29.1 cmH2O, P = 0.029) and at T90 after 0.3 mg/kg (34.5 cmH2O, P = 0.0018). CONCLUSIONS: Lintopride significantly increased the LOS basal tone without affecting LOS physiological relaxation after swallowing. Peristaltic waves were also enhanced by lintopride.
Prostaglandin E2 (PGE2) and iloprost induced a concentration-dependent contraction of smooth muscle cells isolated from the circular layer of guinea-pig ileum. PGE2- and iloprost-induced contractions were inhibited by the selective EP1-receptor antagonist, SC19220 (1-acetyl-2-(8-chloro-10, 11-dihydrodibenz (b,f) (1,4) oxazepine-10-carbonyl)-hydrazine), indicating the involvement of the EP1 subtype of the PGE2 receptor. When cells were incubated for 10 min in the presence of strontium (4 mM L-1), an inhibitor of the release of Ca2+ from intracellular store, the contractile effect of PGE2 and iloprost was inhibited. In contrast, incubation of cells in Ca/2+)-free medium, Ca(2+)-free medium plus EGTA, or in the presence of nifedipine, an organic Ca(2+)-channel blocker, did not alter the PGE2- and iloprost-induced contraction. These observations suggest that the myogenic effect of PGE2 and iloprost on intestinal smooth muscle is dependent on the release of intracellular calcium.
The usefulness and accuracy rate of endoscopic ultrasonography (EUS) in the diagnosis of chronic pancreatitis (CP) were prospectively evaluated in 81 patients with suspected pancreatic disease. All underwent EUS, abdominal ultrasonography (AUS), and computed tomography (CT), and endoscopic retrograde cholangiopancreatography (ERCP) was performed in 55 of the cases. The diagnosis of CP was established in 44 patients (CP group) including 24 with a calcified form. No pancreatic disease was observed in 18 patients (control group), and 19 patients had a pancreatic tumor. In the CP group AUS was less accurate than EUS in visualizing the pancreas, performances of CT scan being identical to EUS in this respect. A good correlation was observed between EUS and ERCP for visualization and measurement of the Wirsung duct. The most significant changes observed by EUS in the CP group were dilatation of the main pancreatic duct, heterogeneous echogenicity of the pancreatic parenchyma, and cysts < 20 mm in size even in noncalcified CP or with normal pancreatograms. Sensitivity of EUS for diagnosis of CP was 88% (AUS, 58%; ERCP, 74%; CT scan, 75%), the specificity being 100% for ERCP and EUS, 95% for CT scan, and 75% for AUS. The good performances of EUS allow early diagnosis of CP in symptomatic patients since heterogeneous echogenicity of the pancreatic parenchyma seems to be almost specifically associated with the disease.
Smooth muscle strips and isolated muscle cells from the circular layer of dog colon, were used to study the effect of prostaglandin E2 (PGE2) and their analogs acting at EP receptors: Iloprost (IP/EP1), butaprost (EP2) and enprostil (EP3) and SC19220 (antagonist EP1) to characterize the EP-receptors involved in the control of muscle function. In strips treated with tetrodotoxin, only enprostil provoked a concentration-dependent contraction. The concentration of enprostil inducing a half maximal contraction (EC50) was 400 nM and the maximal effect was obtained at 1 microM. PGE2, butaprost and iloprost induced a dose-dependent relaxation, with an EC50 of 200, 80 and 200 nM, respectively. The maximal relaxation was obtained at 1 microM for all these agents. When the EP1 antagonist, SC19220 (10 microM), was added 20 min before PGE2 or their analogs, their respective concentration-response curves were not affected. In isolated cells, PGE2 and enprostil induced a cell contraction in a concentration-dependent manner, whereas iloprost and butaprost had no effect by themselves. The maximal contraction was 241.1 +/- 1.7% at 10 nM PGE2 and 22.5 +/- 1.6% at 10 nM enprostil. EC50 of PGE2 and enprostil was 40 pM. SC 19220, at concentrations ranging from 1 pM to 0.1 microM, failed to inhibit the contraction induced by either PGE2 or enprostil. When cells were preincubated for 1 min with butaprost or iloprost at concentrations ranging from 1 pM to 1 microM, the contraction induced by CCK8 (10nM) was inhibited in a concentration-dependent matter.(ABSTRACT TRUNCATED AT 250 WORDS)
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To study the role of abnormal visceral perception in the pathophysiology of the irritable bowel syndrome (IBS), we evaluated colonic tone and visceral perception during intracolonic distension using a flaccid balloon connected to a computerized barostat and placed in the descending colon of IBS patients and healthy controls. In the first part of the study, basal colonic tone and response to pharmacological (neostigmine and glucagon) and physiological (1000-kcal meal) stimuli were recorded in nine IBS patients. Colonic tone increased by 72 +/- 27% after injection of neostigmine and decreased by 88 +/- 62% after glucagon. After the meal, the maximal increase in colonic tone was 76 +/- 31% with the total response to the meal lasting 109.7 +/- 32.0 min. In the second part of the study, symptomatic responses (discomfort and pain thresholds) and pressure variations were evaluated during two different methods of distension (stepwise and intermittent) in a randomized order in the nine IBS patients and six healthy controls. Each distension method was repeated twice in IBS patients to study reproducibility. In IBS patients, the mean discomfort threshold volume was 172 +/- 76 ml when using stepwise and 167 +/- 43 ml when using intermittent distension. The mean pain threshold volume was 250 +/- 25 ml when using stepwise and 211 +/- 22 ml when using intermittent distension, this difference being statistically significant (P < 0.02). Discomfort and pain threshold volumes recorded during the first session of the same distension method were not different from those recorded during the second one.(ABSTRACT TRUNCATED AT 250 WORDS)
In the present study we report the results of Nd:YAG laser treatment in 36 patients with rectal carcinoma in whom negative biopsies were obtained at the end of the treatment. The laser (100-W maximal power output) was applied through a flexible endoscope during 20- to 40-min sessions repeated every three days until the lesion was destroyed completely. Follow-up examinations, including endoscopy with biopsies, liver and endorectal ultrasonography and chest x-ray were performed every three months during the first year and thereafter once a year. Between 1980 and 1991, 272 patients were treated. All were unfit for surgery because of metastasis (78), recurrence after an other procedure (54), associated conditions, or old age (140). No circumferential tumors of any size were obliterated, but among the 139 patients presenting with a noncircumferential lesion less than 7 cm in diameter, negative biopsies were obtained after laser treatment in 36 patients (26%). Of these 36 patients, eight had been treated previously by surgery (5) or radiotherapy (3). Mean follow-up is 37 months (range 12-71). Recurrences were observed in four cases. Seven patients died during the study but only one death was related to the cancer (pelvic extension 19 months after treatment). Endorectal ultrasonography was performed prior to treatment in 15 patients and showed no invasion of the rectal wall deeper than the submucosa. After treatment, endorectal ultrasonography in 22 patients showed significant changes corresponding to cicatricial pattern in 60% of controlled patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of octreotide (1.25 micrograms/kg subcutaneously) on colonic tone and visceral perception were evaluated in 10 IBS patients, using a barostat and compared to placebo in a double-blind crossover study. Colonic sensory thresholds were also studied in healthy controls for comparison with IBS patients. Colonic tone was reflected by variations in volume of the barostat balloon. Baseline volume was 117 +/- 38 ml and was not modified by placebo (122 +/- 40 ml) or octreotide (106 +/- 42 ml). After the meal, maximal decrease in balloon volume was 75 +/- 4% following placebo (P < 0.001) beginning after 9 +/- 3 min and lasting 136 +/- 17 min. Following octreotide, the maximal decrease was 69 +/- 16% (NS vs placebo), after 10 +/- 3 min and lasting 140 +/- 22 min. In the second part, discomfort and pain thresholds were evaluated during isobaric distensions (4 mm Hg increments, 5-min duration, 5-min interval with return to pressure 0 between each). The pressure inducing discomfort was 21.2 +/- 5.9 mm Hg following placebo vs 29.6 +/- 6.6 mm Hg following octreotide (P < 0.01). The pressure inducing pain was 24.8 +/- 7.3 mm Hg following placebo vs 33.2 +/- 7.3 mm Hg following octreotide (P < 0.01). In healthy subjects, discomfort and pain were induced by colonic distensions at a mean intraballoon pressure of 32.7 +/- 5.8 mm Hg and 36.7 +/- 3.9 mm Hg, respectively. Compliance curves were not different following placebo and octreotide. Octreotide significantly increases thresholds for visceral perception in IBS patients without modifying compliance during distension nor colonic tone.
Smooth muscle cells isolated by enzymatic digestion were used to determine the direct effects of galanin on circular and longitudinal muscle layers from dog proximal colon and to investigate the intracellular pathways involved in these effects. Effects of galanin were compared to those observed with other contracting [cholecystokinin octapeptide (CCK8)] and relaxing [vasoactive intestinal peptide (VIP)] agents. In longitudinal cells, galanin and CCK8 induced a contraction that was maximal at 1 nM galanin and 1 nM CCK8 and was 23.9 +/- 4.5% and 23.4 +/- 3.4%, respectively, of the length of resting cells. Incubation of cells in Ca(2+)-free medium or in the presence of nifedipine caused an inhibition of galanin-induced contraction whereas it had no effect on the contraction induced by CCK8. Vasoactive intestinal peptide, forskolin, and 8 bromo cAMP inhibited CCK-induced contraction but failed to inhibit contraction induced by galanin. The contraction induced by galanin was abolished; the CCK-induced contraction was unchanged by pertussis toxin. In circular cells, CCK8 induced a contraction that was maximal at 10 nM and was 24.2 +/- 2.6%. Galanin had no effect by itself. When cells were preincubated (1 min) with galanin (10 fM-1 microM), the CCK8-induced contraction was inhibited, with a maximal effect at 10 nM galanin. Likewise, VIP inhibited the CCK8-induced contraction with a maximal effect at 1 microM. Preincubation of cells with somatostatin, N-ethylmaleimide, and (R)-p-cAMPS inhibited galanin- and VIP-induced relaxation. In conclusion, galanin induces a contraction of longitudinal smooth muscle cells that is dependent on an influx of extracellular calcium and an activation of pertussis toxin G-protein.(ABSTRACT TRUNCATED AT 250 WORDS)
PTH-related peptide (PTHrP), which shares 8 of 13 NH2-terminal residues with PTH, causes similar biological effects and interacts with the same receptor as PTH. In the gastrointestinal tract, human PTH and PTHrP-(1-34) relax rat fundic strips. However, the level of their action and the receptor involved in this effect are unknown. The aims of this study were 1) to determine the effects of human PTH-(1-34), human PTHrP-(1-34), -(1-16), and -(7-34) and vasoactive intestinal peptide (VIP) on circular isolated smooth muscle cells from guinea pig ileum; 2) to study the intracellular pathways involved in these effects; and 3) and to characterize the receptors involved by using specific antagonists. Smooth muscle cells were dispersed by enzymatic digestion. Contraction was assessed by measuring the length of 50 cells and expressed as the percent decrease in cell length from the control value. The relaxing effects of PTH, PTHrP and analogs, VIP, or antagonists were expressed as a percentage of the maximal effect observed in their absence. VIP, PTH-(1-34), and PTHrP-(1-34), -(1-16), and -(7-34) had no effect by themselves on these cells. However, when cells were contracted by the sulfated C-terminal octapeptide of cholecystokinin (10 nM), VIP, PTH-(1-34), and PTHrP(1-34) inhibited the sulfated C-terminal octapeptide of cholecystokinin-induced contraction in a concentration-dependent manner, whereas PTHrP-(1-16) and -(7-34) had no effect. The EC50 values of VIP, PTH-(1-34), and PTH-(1-34), and PTHrP-(1-34) were 7 nM, 20 pM, and 20 pM, respectively. The VIP antagonist ([D-P-Cl-Phe6,Leu17]VIP) inhibited VIP-, PTH-(1-34)-, and PTHrP(1-34)-induced relaxation, with IC50 values of 20, 500, and 400 pM, respectively. Likewise, the PTH/PTHrP antagonist [Tyr34-bovine PTH-(7-34)NH2] inhibited PTH-(1-34)-, PTHrP(1-34)-, and VIP-induced relaxation, with IC50 values of 1, 1, and 90 pM, respectively. Preincubation of cells with somatostatin, N-ethylmaleimide, and (R)-p-cyclic adenosine-3',5'-monophosphothioate inhibited the PTH-(1-34), PTHrP(1-34)-, and VIP-induced relaxation. In conclusion, human PTH and PTHrP induce a relaxation of intestinal smooth muscle by a direct myogenic effect. This effect requires the 1-34 amino acid sequence and is mediated by the activation of adenylate cyclase and protein kinase-A. Interactions among PTH, PTHrP, and VIP indicate that they may cross-react with their respective receptors.
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The aim of the present study was to evaluate the effect of in vitro preincubation with PAF of isolated smooth muscle cells from guinea pig ileum in order to assess possible PAF receptor desensitization. Cells dispersed by enzymatic digestion were preincubated with PAF for 30 min and the contractile effect of PAF was then assayed. In cells preincubated for 30 min with 10 nM PAF, the concentration inducing maximal cell contraction was 1 microM instead of 10 nM in freshly dispersed cells and the EC50 was 40 nM instead of 10 pM. This desensitization to the contractile effect of PAF was prevented when cells were preincubated for 30 min with PAF plus PAF antagonist BN52021, PGE2 antagonist SC19220, cyclooxygenase inhibitor indomethacin and the phospholipase A2 inhibitor bromophenacyl bromide. In similar experiments, no desensitization occurred for CCK8 receptors after preincubation with either PAF, PGE2 or CCK8. These results indicate that homologous desensitization of PAF receptors could occur via a PGE2-dependent pathway in intestinal smooth muscle cells from guinea pig.
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From March to October 1989, 237 French gastroenterologists included 1,301 patients referred for irritable bowel syndrome in a 9-month epidemiological survey based on questionnaires and monthly auto-evaluation. In the patient population, the high preponderance of women (sex ratio: 2.33), the high prevalence of cholecystectomy (9%), appendectomy (53%) and an association with at least one symptom of non-ulcer dyspepsia (70%) were observed. Fifty per cent of the patients completed the 9-month follow-up period; among them, 60% declared an improvement in their symptoms, but only 30% in their quality of life and independently of the clinical course. This study suggests that symptoms and quality of life in patients consulting for irritable bowel syndrome should be taken into account separately, both in daily practice and in therapeutic evaluation.