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H T Debas

Publications and source records attributed to H T Debas.

At least 37 records · Page 2Linked to original sources
PubMed1993

Tachykinins mediate contraction of the human lower esophageal sphincter in vitro via activation of NK2 receptors.

The contractile response to natural tachykinins and selective peptide agonists for tachykinin receptors was studied in strips of circular smooth muscle of human lower esophageal sphincter in vitro. The effects of phosphoramidon, which inhibits neutral endopeptidase (EC.3.4.24.11) and of the non-peptide compounds, SR 48968 and CP-96,345, which selectively block NK1 and NK2 receptors, respectively, were also investigated. Substance P, neurokinin A and neurokinin B produced a concentration-dependent contractile response. The rank order of potency was neurokinin A > neurokinin B > substance P. Phosphoramidon (1 microM) potentiated the response to substance P without changing the order of potency of natural tachykinins. The NK2-selective agonist, ([ beta Ala8]neurokinin A-(4-10)), produced a concentration-dependent contraction. The NK1 ([Sar9,Met(O2)11]substance P, 1 microM) and NK3 ([MePhe7]neurokinin B, 1 microM) selective agonists, however, did not exert any contractile effect. The selective NK2 antagonist, SR 48968, potently inhibited in a concentration-dependent (10 nM-1 microM) manner the response to neurokinin A, without affecting the response to carbachol. The selective NK1 antagonist, CP-96,345 (1 microM), did not affect the response to neurokinin A. These results indicate that tachykinins contract the circular muscle of human lower esophageal sphincter, and that this effect is mediated by NK2 receptor stimulation. Moreover, a phosphoramidon-sensitive mechanism plays a role in the regulation of the response to substance P.

Benzamides↗
PubMed1993

Vagal stimulation of rat exocrine pancreatic secretion occurs via multiple mediators.

BACKGROUND: The vagus nerve contains cholinergic and noncholinergic neurons that interact with peptidergic neurons of the enteric nervous system, which stain immunohistochemically for cholecystokinin, vasoactive intestinal polypeptide, and gastrin-releasing peptide. METHODS: The role of these pancreatic exocrine secretagogues during electrical vagal stimulation was studied using specific inhibitors in urethane-anesthetized rats. RESULTS: The pancreatic secretory response to vagal stimulation was blocked significantly by each of the following: the ganglionic blocker hexamethonium (100% inhibition); the muscarinic, cholinergic blocker atropine (85% inhibition); the specific cholecystokinin A-receptor antagonist L-364,718 (84% inhibition); a gastrin-releasing peptide-receptor blocker (91% inhibition); and a vasoactive intestinal polypeptide polyclonal antibody (89% inhibition). The response was not altered by a monoclonal antibody to somatostatin. A subthreshold dose of cholecystokinin octapeptide augmented the response to electrical vagal stimulation. CONCLUSIONS: Suppression of tonic somatostatin release is not the final common event. The findings that subthreshold cholecystokinin augments vagal stimulation, together with marked inhibition by each antagonist used, are consistent with the hypothesis that potentiating interactions among several agonists mediate the vagal response in anesthetized rats. However, this study does not exclude acetylcholine as the final common mediator. Studies in conscious animals are needed to determine the physiological significance of these observations.

Animals↗
PubMed1993

Tachykinins contract the circular muscle of the human esophageal body in vitro via NK2 receptors.

BACKGROUND: The action of tachykinins in the circular muscle of the human esophageal body is not known. The present study aimed to determine the response to tachykinins and the receptor type mediating this response. METHODS: Specimen were obtained from organ donors or patients undergoing esophagectomy for cancer, and isometric tension in response to tachykinins was measured. RESULTS: Substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) evoked a concentration-dependent contraction with the following order of potency: NKA > NKB > SP. The neutral endopeptidase inhibitor, phosphoramidon, increased only the response to SP. [beta Ala8]NKA(4-10), a selective agonist of the NK2 receptor, produced a concentration-dependent contraction, whereas [Sar9,Met(O2)11]SP and [MePhe7]NKB, selective agonists of NK1 and NK3 receptors, respectively, had no effect. Contraction evoked by NKA was inhibited by the nonpeptide NK2 antagonist SR 48968 but not by the nonpeptide NK1 receptor antagonist CP-96,345, tetrodotoxin, or atropine. SR 48968 did not affect the response to carbachol. CONCLUSIONS: Tachykinins contract the circular muscle of human esophageal body by activation of NK2 receptors without involvement of neural mechanisms. Response to SP is modulated by a phosphoramidon-sensitive enzymatic activity.

Adolescent↗
PubMed1993

Initiation of gastrin expression during the development of the mouse pancreas.

Gastrin expression occurs in the pancreas in only two situations: (1) in cases of gastrinoma and (2) in the embryonic/fetal pancreas. The initiation of gastrin expression in the embryonic pancreas may be recapitulated during gastrinoma tumorigenesis. For this reason, we have tried to identify the point of onset of gastrin expression in the developing pancreas. Previously, determining the point of onset for genes in embryonic tissues has been difficult because of low expression levels and small tissue samples. Using the sensitive polymerase chain reaction assay, we were able to determine, with a sensitivity of 10 molecules of mRNA, the earliest expression of gastrin in the developing pancreas. This expression occurred at 30 somites, or at a gestation of 9.5 to 10 days.

Animals↗
PubMed1993

Clinical and functional characterization of high gastroesophageal reflux.

In 70 consecutive patients with symptoms of gastroesophageal reflux (GER), we studied lower esophageal sphincter (LES) and upper esophageal sphincter (UES) pressures, esophageal peristalsis, and esophageal acid exposure 5 and 20 cm above the LES. Based on the percentage of time the pH was below 4 in the proximal esophagus, the patients were divided into 2 groups: (1) group A, less than 3%, 48 patients; (2) group B, greater than 3%, 22 patients. LES was weaker (13.5 +/- 6.0 mm Hg in group A versus 7.8 +/- 4.6 mm Hg in group B) and shorter (2.2 +/- 0.7 cm in group A versus 1.5 +/- 0.5 cm in group B) in group B patients. Group B patients also had lower amplitude of peristalsis in the proximal (59.2 +/- 17.6 mm Hg in group A versus 42.4 +/- 18 mm Hg in group B) and distal esophagus (89.7 +/- 25.2 mm Hg in group A versus 54.7 +/- 27.9 mm Hg in group B) and lower UES pressures (73.7 +/- 30.7 mm Hg in group A versus 54.7 +/- 29.3 mm Hg in group B). Forty-one percent of group B patients had pulmonary aspiration, whereas only 2% of the patients in group A experienced pulmonary aspiration. These data show that, in a subgroup of patients with symptoms of GER, the upper esophagus is exposed to acid for more than 3% of the time. Patients with high GER differ clinically and pathophysiologically from those in whom reflux is limited to the distal part of the esophagus: those with high GER have a panesophageal motor dysfunction and a high risk of aspiration.

Esophagitis, Peptic↗
PubMed1993

Somatostatin analogue therapy in functioning neuroendocrine gut tumors.

The purpose of the workshop was to critically evaluate the use of octreotide in the management of important surgical and gastroenterological conditions. The topics covered included: (1) management of functioning gut neuroendocrine tumors, (2) new approaches to localize these tumors, (3) the place of octreotide in the treatment of variceal bleedings, and (4) the use of octreotide in postoperative conditions. Octreotide therapy has been shown to be effective in the carcinoid syndrome, in which symptom control is achieved in 85% of patients, and reduction in 5-HIAA in 60%. Although tumor regression is rarely seen, prolongation of survival probably occurs. Control of diarrhea has been achieved in 84% of patients with VIPoma treated with octreotide. Similarly, octreotide has been found to provide effective control of the necrolytic, migratory dermatitis seen in glucagonoma. By contrast, insulinomas are more resistant to somatostatin agonist therapy. In the Zollinger-Ellison syndrome, octreotide is effective in alleviating symptoms and in reducing serum gastrin levels. However, its use in this syndrome has been superceded by omeprazole. Radioiodine-labelled octreotide has been very effective in in vivo imaging of neuroendocrine tumors in the abdomen, and is now considered the best available technique for localizing these tumors preoperatively. Intraoperative localization with a hand-held gamma camera is being developed. There is an exciting future possibility to use the technique to deliver therapy to tumors. Octreotide therapy has been shown to be at least as effective as and without the adverse hemodynamic effects of Pitressin in control of variceal hemorrhage. It should be regarded as one of several modalities of therapy in the condition.(ABSTRACT TRUNCATED AT 250 WORDS)

Apudoma↗
PubMed1992

Selective release of somatostatin by calcitonin gene-related peptide and influence on pancreatic secretion.

Calcitonin gene-related peptide is a potent inhibitor of stimulated pancreatic exocrine secretion in vivo. The mechanism of this inhibitory action was studied in dogs and rats. The questions examined were: (1) is the inhibitory action of CGRP on pancreatic secretion mediated by somatostatin? (2) is the inhibition direct, via action on acinar cells, or indirect? and (3) is a neuronal mechanism involved, and, if so, by what pathway? In dogs with chronic pancreatic fistulae, CGRP caused significant inhibition of the outputs of pancreatic protein (63-68%) and of pancreatic bicarbonate (74-89%) and a simultaneous dose-related rise (40-102 fmol/ml) in plasma somatostatin-like immunoreactivity. A similar degree of inhibition was found when exogenous somatostatin was infused to achieve similar levels of plasma somatostatin-like immunoreactivity. More direct evidence of somatostatin mediation of CGRP action was sought in conscious rats with pancreatic fistulae using a potent and specific monoclonal antibody to somatostatin. The latter studies suggest that CGRP has both a somatostatin-dependent and a somatostatin-independent mechanism of action. In isolated rat acini, CGRP did not inhibit CCK-stimulated amylase release, suggesting that its in vivo action is indirect. In the isolated vascularly perfused rat pancreas, CGRP (10(-10)-10(-7) M) inhibited in a dose-dependent manner volume and protein output stimulated by a mixture of CCK-8 and secretin. The inhibitory action of CGRP was blocked by tetrodotoxin (10(-7) M) and by atropine (10(-7) M), but not by hexamethonium (10(-7) M). We conclude that CGRP action: (1) is partly explained by release of somatostatin; (2) is indirect; (3) is neurally mediated; and (4) involves cholinergic muscarinic neurons within the pancreas.

Amylases↗
PubMed1992

Esophageal manometry and 24-hour pH monitoring in the diagnosis of pulmonary aspiration secondary to gastroesophageal reflux.

Twenty-three consecutive patients who had persistent respiratory symptoms of unexplained etiology were evaluated to determine the presence of gastroesophageal reflux (GER) and its relationship to their respiratory complaints. Lower esophageal sphincter (LES) and upper esophageal sphincter (UES) pressures and the characteristics of the peristaltic waves in the proximal and distal esophagus were determined. Esophageal acid exposure 5 cm and 20 cm above the LES was measured using a pH probe with two antimony sensors. Aspiration was diagnosed when respiratory symptoms occurred during or within 3 minutes after a reflux episode, recorded at both levels of the esophagus. Based on these criteria, 12 patients were considered nonaspirators (group A), and 11 were categorized as aspirators (group B). Aspirators had: (1) lower LES pressure (6.1 +/- 3.1 versus 12 +/- 4.8 mm Hg, p less than 0.01); (2) decreased amplitude of peristalsis in the proximal esophagus (34 +/- 16 versus 59 +/- 21 mm Hg, p less than 0.01) and distal esophagus (46 +/- 25 versus 91 +/- 28 mm Hg, p less than 0.01), and higher incidence of simultaneous, nonperistaltic waves (30% versus 4%); and (3) lower UES pressure (44 +/- 23 versus 74 +/- 38 mm Hg). Impaired peristalsis in aspirators caused a higher acid exposure (11.4% +/- 8.0% versus 1.0% +/- 0.7% of time pH less than 4, p less than 0.01) and delayed clearance (5.5 +/- 6.5 versus 0.7 +/- 0.4 min) in the proximal esophagus. Our study shows that, in patients with respiratory symptoms of unexplained etiology, esophageal manometry and 24-hour pH monitoring will identify a subgroup of true aspirators. These patients suffer from a panesophageal motor dysfunction that affects all three barriers to aspiration: the LES, the esophageal "pump mechanism," and the UES.

Adult↗
PubMed1992

Improvement in survival of mice with proximal small bowel obstruction treated with octreotide.

Small bowel obstruction is a common disorder in surgical practice. The major morbidity of bowel obstruction relates to intestinal distension and ischemia. We hypothesized that octreotide, a potent inhibitor of gut secretion, would reduce mortality in a mouse model of lethal small bowel obstruction. C57 mice were anesthetized with urethane and prepared with either proximal jejunal or distal ileal obstruction. After 8 hours, surviving mice were randomized to receive either octreotide (100 micrograms/kg) or saline subcutaneously every 8 hours. Octreotide significantly improved survival in mice with proximal obstruction by life table analysis. Mean survival increased from 31 +/- 3 to 41 +/- 4 hours. In distal obstruction, octreotide treatment resulted in a trend towards improved survival; however, this trend failed to reach statistical significance by life table analysis. The improvement in survival in this mouse model suggests that octreotide may be a valuable adjunct in the treatment of patients with small bowel obstruction.

Animals↗
PubMed1992

Effects of cholecystokinin and gastrin antagonists on pancreatic exocrine secretion stimulated by gastrin-releasing peptide.

The effects of a specific cholecystokinin (CCK) receptor antagonist (L364,718) and a gastrin receptor antagonist (L365,260) on gastrin-releasing peptide-10 (GRP-10)-stimulated pancreatic secretion were investigated in the anesthetized rat. GRP-10 stimulated pancreatic exocrine secretion in a dose-dependent manner. A dose of 1.0 nmol/kg/h elicited a significant increase in pancreatic protein output. L364,718 (2.0 mg/kg/h), at a dose that completely inhibited the stimulatory effect of exogenous CCK-8 (3.0 nmol/kg/h) on pancreatic secretion, did not suppress the excitatory effect of GRP-10. L365,260 (5.0 mg/kg/h), at a dose that completely inhibited the stimulatory effect of exogenous gastrin (20 micrograms/kg/h) on gastric acid secretion, did not suppress the excitatory effect of GRP-10 either. We concluded that CCK or gastrin do not mediate the excitatory mechanism of bombesin/GRP on pancreatic secretion. Since CCK and gastrin are the most probable candidates for excitatory mediator of bombesin/GRP, these results support the hypothesis that bombesin/GRP directly stimulates the exocrine pancreas in the rat.

Animals↗
PubMed1992

Intestinal acid inhibits gastric acid secretion by neural and hormonal mechanisms in rats.

To determine the relative contributions of neural reflexes and intestinal hormones to the inhibition of gastric acid secretion by intestinal acidification, rats with an extrinsically denervated, transplanted segment of jejunum, and those with an innervated segment of jejunum, were studied. Postoperatively, meal-stimulated gastric acid secretion was measured. When the acid secretory response to intragastric liver extract reached a plateau, graded concentrations of hydrochloric acid or saline were instilled into the jejunal segments. Gastric acid secretion was inhibited by intrajejunal acid (pH 2.5) by 79% in the innervated rats and by 64% in the transplanted group. Thus at a pH of 2.5 there was a 15% greater maximum inhibition of plateau acid response in the innervated rats than in the transplanted rats, presumably because of the extrinsic neural contribution. To examine the hormonal mediators, the effects of a somatostatin monoclonal antibody and a CCK-A receptor antagonist (L 364718) on acid-induced inhibition of gastric acid secretion were studied in transplanted rats. Treatment with a somatostatin monoclonal antibody or with L 364718 reduced the acid-induced (pH 2.5) inhibition of gastric acid secretion by 93 and 27%, respectively. Jejunal acidification inhibits gastric acid secretion in the rat by both neural and hormonal mechanisms. The hormonal mechanism is mediated by somatostatin and CCK.

Acids↗
PubMed1992

Surgical management of peptic ulcer disease.

Since the advent of H2-receptor antagonists, elective ulcer surgery is rare. The need for operation for complications of peptic ulcer disease, however, remains unchanged. Highly selective vagotomy is the elective operation of choice for duodenal ulcer worldwide. It has few side effects and a mortality that approaches 0%. Unfortunately, ulcers recur in 10% to 15% of patients, a much higher recurrence rate than that seen with vagotomy and antrectomy (less than 1%). The latter operation, however, is associated with significant side effects, such as dumping syndrome and diarrhea, and a higher operative mortality. The elective operation of choice for gastric ulcer is antrectomy. Recent prospective trials show that highly selective vagotomy should be performed routinely at the time of closure of perforated duodenal ulcer. Neither morbidity nor mortality is increased with the procedure, and the 40% to 60% ulcer recurrence rate with closure alone is reduced to 2% to 8%.

Emergencies↗
PubMed1991

Control of dumping symptoms by somatostatin analogue in patients after gastric surgery.

Octreotide acetate is a long-acting analogue of the naturally occurring inhibitory gastrointestinal peptide, somatostatin. We tested the efficacy of octreotide in controlling the symptoms of dumping syndrome in response to a provocative meal in a randomized, double-blinded, crossover trial in nine severely affected patients. Pretreatment with octreotide acetate (100 micrograms injected subcutaneously) reduced postprandial dumping symptoms from a mean +/- SEM score of 15.7 +/- 1.6 (placebo treatment day) to 4.6 +/- 1.7. With placebo treatment, all nine patients became symptomatic in response to the meal, whereas with octreotide treatment, symptoms occurred in only two of nine patients. Similarly, all placebo-treated patients showed a postprandial increase in pulse rate to a mean +/- SEM of 105 +/- 6 beats per minute, whereas only one of nine octreotide-treated patients showed an increase in pulse rate (mean +/- SEM, 80 +/- 3 beats per minute). These differences were also statistically significant. While no significant changes were observed in postprandial hematocrit values or osmolality between placebo and octreotide treatments, octreotide prevented hypoglycemia in four affected patients and significantly inhibited insulin release. We conclude that octreotide is a useful tool in the treatment of patients with severe, refractory dumping syndrome.

Blood Glucose↗
PubMed1991

Neuroendocrine design of the gut.

The enteric nervous system (ENS) can be thought of as the third component of the autonomic nervous system. It is a vast network of neurons widely dispersed throughout the gut. The ENS is a dominant regulator of gut function through the action of peptide and non-peptide neurotransmitters. The most intensively studied roles of the ENS have been the regulation of secretory processes, such as gastric acid secretion, and motility. It is clear, however, that the ENS plays a broader role in the regulation of other gut functions, including mucosal defense, the gut immune response, and sphincter function. Alterations in the regulation of gut function by the ENS are likely or suspected in a number of conditions, including achalasia, Hirschsprung's disease, inflammatory bowel disease, Chagas' disease, chronic intestinal pseudoobstruction, biliary dyskinesia, tachygastria, and irritable bowel syndrome. Improved knowledge of the pathophysiology of these troublesome conditions makes effective therapy more likely in the future.

Digestive System↗
PubMed1991

Neural and hormonal mechanisms mediate the enterogastric reflex: a study in intestinal transplants in rats.

To determine the relative contributions of neural reflexes and intestinal hormones to the inhibition of gastric acid secretion by intestinal fat, rats with an extrinsically denervated, transplanted segment of jejunum and those with an innervated segment of jejunum were studied. Postoperatively, meal-stimulated gastric acid secretion was measured by extragastric titration. When secretion reached a plateau, graded doses of oleic acid or saline were instilled into the jejunal segments. In both groups, acid secretion was inhibited by intrajejunal fat but not saline. At doses of 0.4 and 0.08 mmol oleic acid, there was a 25% and 17% greater maximal inhibition of plateau acid response in the innervated rats than in the transplanted rats, presumably because of the neural contribution. To examine the hormonal mediators, the effects of a somatostatin monoclonal antibody and a cholecystokinin A receptor antagonist (L-364,718) on fat-induced inhibition of gastric acid secretion were studied in transplanted rats. Treatment of the patients with transplants with a somatostatin monoclonal antibody (2.18 mg IV) or L-364,718 (1 mg/kg IV) reduced the fat-induced inhibition of acid secretion by 95% and 28%, respectively. In conclusion, both neural and hormonal mechanisms mediate fat-induced inhibition of gastric acid secretion, with the hormonal mechanism predominating. Somatostatin, and to a lesser extent cholecystokinin, contribute to the hormonal mechanism.

Abdomen↗
PubMed1991

Calcitonin gene-related peptide inhibits exocrine secretion from the rat pancreas by a neurally mediated mechanism.

The mechanism by which calcitonin gene-related peptide (CGRP) inhibits exocrine secretion from the rat pancreas was examined in the isolated, vascularly perfused pancreas and in vitro using freshly isolated pancreatic acini. CGRP (10(-10)-10(-7) M) inhibited the volume and protein output from the perfused pancreas, stimulated by a mixture of the cholecystokinin octapeptide CCK8 (10(-10) M) and secretin (10(-8) M). The inhibition by CGRP was dose related and maximal at 10(-8) M (P less than 0.05). CGRP (10(-8) M) failed to inhibit amylase secretion from isolated pancreatic acini, stimulated by graded concentrations of CCK8 (10(-13)-10(-8) M). This implies an indirect mechanism of inhibition. The mechanism of inhibition was investigated in the isolated, vascularly perfused pancreas using tetrodotoxin, atropine and hexamethonium (all 10(-7) M). Tetrodotoxin and atropine but not hexamethonium prevented the inhibition of volume and protein secretion by CGRP (10(-8) M) (P less than 0.05). Tetrodotoxin, atropine and hexamethonium were without effect on exocrine secretion stimulated by CCK8 and secretin (controls). These results indicate that CGRP inhibits pancreatic exocrine secretion by an indirect, neurally mediated mechanism involving cholinergic-muscarinic transmission.

Animals↗