Pius Hildebrand

ROLE OF CHOLECYSTOKININ IN REGULATION OF GASTROINTESTINAL MOTOR FUNCTIONS

By means of loxiglumide, a potent and highly specific antagonist for cholecystokinin (CCK), the effects of blocking CCK receptors on gastrointestinal motility were investigated in a placebo-controlled study in healthy young men (aged 21-39, mean 24 years). Gallbladder contraction stimulated by ingestion of a liquid test meal was completely abolished by oral administration of loxiglumide 30 min before the test meal. Gastric emptying of radio-opaque markers ingested with the test meal was significantly accelerated by loxiglumide (area under the curve [markers x h] 33.3 [SEM 3.8] vs 17.9 [2.7] after placebo). No effect of loxiglumide was found on small-bowel transit time, but 7 days treatment with oral loxiglumide (800 mg three times daily) significantly shortened colonic transit time (29.4 [4.1] h after placebo, 15.0 [3.4] h after loxiglumide). It is concluded that CCK is an important mediator of meal-induced gallbladder contraction and is involved in the regulation of gastrointestinal motility in man.

Hydrolysis of dietary fat by pancreatic lipase stimulates cholecystokinin release

BACKGROUND & AIMSnThe hypothesis that cholecystokinin release requires adequate dietary fat digestion in the small intestine was investigated in 10 healthy volunteers, and the consequences of reduced fat hydrolysis on pancreaticobiliary secretions were assessed.nnnMETHODSnFat hydrolysis was inhibited by intraduodenal perfusion of tetrahydrolipstatin, an irreversible lipase inhibitor. An oil emulsion containing 0, 30, 60, or 120 mg tetrahydrolipstatin was perfused. After a 40-minute basal period, a test meal was eaten to stimulate cholecystokinin release and pancreaticobiliary responses.nnnRESULTSnIn the control without tetrahydrolipstatin, lipase output increased threefold with meal ingestion and remained doubled for 4 hours. At the ligament of Treitz, free fatty acid concentration averaged 60% of total fatty acids. Increasing doses of tetrahydrolipstatin induced a dose-dependent inhibition of duodenal lipase activity (P < 0.01); 120 mg tetrahydrolipstatin eliminated the postprandial lipase peak activity, free fatty acid levels decreased to < 5% of total fatty acids, and plasma cholecystokinin levels were suppressed by 77% (P < 0.01). Amylase and trypsin outputs were reduced by 77% and 59%, respectively, and bilirubin secretion was virtually abolished (P < 0.01).nnnCONCLUSIONSnThese findings show that tetrahydrolipstatin prevents triglyceride hydrolysis and that plasma cholecystokinin release, gallbladder emptying, and pancreatic enzyme secretion require adequate triglyceride digestion. These data also support the concept of negative feedback regulation of cholecystokinin secretion.

Effect of intravenous human gastrin-releasing peptide on food intake in humans

BACKGROUND/AIMSnBombesin and gastrin-releasing peptide (GRP) are closely related peptides. Both have been proposed to serve as a satiety signal in animals.nnnMETHODSnTo explore further the role of GRP in humans, its effects on satiety and eating behavior were investigated by infusion of GRP into healthy men at three dosages (10, 40, and 160 pmol/kg per hour) and compared with saline infusions.nnnRESULTSnGRP produced a significant reduction in calorie intake (P < 0.05) but only a 19% (nonsignificant) reduction in food intake. Fluid ingestion was not affected by GRP. No overt side effects were produced by GRP, but subjects experienced d less hunger and early fullness in the premeal period during GRP infusion but not when receiving saline (P < 0.05-0.01).nnnCONCLUSIONSnThis study shows that intravenous infusions of GRP can decrease spontaneous food intake at concentrations that produce physiological effects, such as stimulation of acid or pancreatic secretion or gallbladder contraction. The data imply that GRP-like peptides can act as satiety signals in humans, confirming data previously reported in animals.

Prevalence of Helicobacter pylori infection in infants and family contacts in a poor Bangladesh community

AlthoughH. pylori is well established as an etiological agent of type B gastritis and a predisposing factor for peptic ulcer, knowledge about its transmission is unclear. In this study we examined the prevalence ofH. pylori infection in the family members of index infants infected with this organism as indicated by positive [13C]-urea breath test (UBT). We performed UBT among family members of 15 predominantly breastfed infants, eight with and seven withoutH. pylori infection. Infection rates were 82% and 91% in family contacts of the infected and noninfected infants respectively, the average infection rate being 85%, which is rated to be high. There was no difference in infection rates among the parents of the infected and noninfected infants. Fifty percent and 70% families belonging to infected and noninfected infants, respectively, were found to have all members infected withH. pylori. No evidence of sex predilection of infection was found. We conclude that in communities with high prevalence ofH. pylori infection, there is almost an equal infection rate among the family contacts of infected and noninfected infants, suggesting that environmental factors may be more important than intrafamilial transmission.

Effect of loxiglumide, a cholecystokinin antagonist, on pancreatic polypeptide release in humans

The purpose of this study was to determine the role of cholecystokinin in the regulation of postprandial pancreatic polypeptide secretion in humans. The pancreatic polypeptide responses to modified sham feeding and gastric instillation of a test meal were first compared with the response to oral ingestion of the same meal. The experiments were repeated under cholinergic (atropine) and cholecystokinin (loxiglumide) blockade. Atropine completely abolished the pancreatic polypeptide response to sham feeding and caused significant reductions after gastric and oral food intake. Loxiglumide, on the other hand, significantly reduced pancreatic polypeptide release to oral food (51% inhibition) without affecting the response to sham feeding. In separate experiments using a duodenal perfusion system, the effects of atropine and loxiglumide on intestinal phase-stimulated pancreatic polypeptide release were examined, and both cholinergic and cholecystokinin blockade induced complete suppression. It was concluded (a) that cholecystokinin is involved in postprandial pancreatic polypeptide response, especially during the intestinal phase stimulation, and (b) that the cholinergic system is crucial and superimposed on cholecystokinin in stimulating pancreatic polypeptide release.

[10] Covalent inactivation of lipases

Publisher Summary This chapter presents and discusses results chiefly concerning the covalent inhibition of gastric and pancreatic lipases. Lipolysis is catalyzed by preduodenal and pancreatic lipases. In humans, the hydrolysis of alimentary triacylglycerols begins in the stomach and is catalyzed by human gastric lipase (HGL) that is able to hydrolyze short- and long-chain triacylglycerols at comparable rates. Under acidic pH conditions, HGL has been shown to be remarkably stable and active, whereas pancreatic lipase irreversibly loses its lipolytic capacity. Achieving specific and covalent inhibition of lipolytic enzymes is a difficult task, because of nonmutually exclusive processes such as interfacial denaturation, changes in “interfacial quality,” and surface dilution phenomena. Furthermore, the interfacial enzyme binding and/or the catalytic turnover can be diversely affected by the presence of potential amphipathic inhibitors. The chapter provides selected experimental data illustrating the specific problems encountered during the covalent inhibition of digestive lipases.

Calcitonin gene-related peptides I and II and calcitonin: Distinct effects on gastric acid secretion in humans

The human calcitonin gene-related peptides I and II (CGRP I and CGRP II) are two neuropeptides that have been recognized throughout the gastrointestinal system including the stomach. The present study was undertaken to compare in healthy volunteers the effects of intravenous infusions of CGRP I and CGRP II (79 pmol/kg.h) on pentagastrin-stimulated acid secretion to those of calcitonin (88 pmol/kg.h). Calcitonin gene-related peptide I did not inhibit basal or pentagastrin-stimulated acid secretion. However, CGRP II and calcitonin inhibited pentagastrin-stimulated acid responses by 20% and 28%, respectively (p less than 0.05 and p less than 0.01), whereas basal acid output was only reduced with calcitonin (p less than 0.05). These effects were recognized with low doses of pentagastrin, and absent with high doses suggesting competitive inhibition. Furthermore, step-doses of CGRP I and CGRP II (79-320 pmol/kg.h) were given intravenously on continuous pentagastrin stimulation and compared with calcitonin (88-352 pmol/kg.h). Calcitonin gene-related peptide II and calcitonin induced a dose-dependent decrease of acid output, whereas CGRP I was ineffective. The inhibitory effects of CGRP II and calcitonin are not due to increased gastric alkaline secretion or to somatostatin release, as neither peptide stimulated gastric bicarbonate secretion or induced an increase in circulating somatostatin. In conclusion, CGRP II, unlike CGRP I, inhibits gastric acid secretion in humans. Inhibitory effects of CGRP II and of calcitonin were comparable. The results imply that CGRP I and II, at the level of the stomach, have distinct biological properties in humans.

A physiological role for cholecystokinin as a regulator of gastrin secretion

To explore the role of cholecystokinin (CCK) in regulating gastrin secretion in humans, the effect of a CCK antagonist (loxiglumide) on meal-stimulated hormone responses was investigated. Subjects received 500 mL of a liquid test meal in the presence and absence of loxiglumide (22 mumol.kg-1.h-1). In the control experiments, both plasma gastrin and CCK levels increased postprandially. In loxiglumide-treated subjects there was a marked elevation in gastrin (area under the curve, 11,042 +/- 1493/120 min vs. 2156 +/- 281 pg/120 min) and CCK levels compared with the control experiment. These observations were confirmed in experiments with modified sham feeding and gastrin-releasing peptide stimulation in which loxiglumide pretreatment also caused a significant increase in gastrin release compared with saline (P less than 0.05). Further studies with intravenous infusion of gastrin, CCK-8, and CCK-33 with and without loxiglumide showed that the increases in CCK and gastrin during loxiglumide application cannot be explained by alterations in clearance rates. The findings of this study show that postprandial gastrin secretion is influenced by CCK and support the concept of a negative feedback control of gastrin secretion by CCK.

Human gastrin-releasing peptide : biological potency in humans

Gastrin-releasing peptide (GRP) was infused in graded doses (1-27 pmol/kg per h) to healthy human volunteers to study the effects on gastric, pancreatic and gallbladder functions as well as on gastrin, CCK and PP release. The results were compared to equimolar doses of synthetic bombesin. GRP significantly (P less than 0.05) stimulated gastric and pancreatic secretory responses, gallbladder contraction and gastro-enteropancreatic hormone release in a dose-dependent manner. GRP was found to be equipotent to bombesin with respect to gastric acid secretion, pancreatic enzyme output, gallbladder contraction and plasma hormone release. We conclude (a) that human GRP has similar biologic effects as synthetic bombesin; (b) as GRP is localized exclusively in nerve tissue and has potent effects on different organs, it is a likely candidate for peptidergic control of human gastric, pancreatic and gallbladder functions.

Helicobacter pylori Colonization in Infants and Young Children is Not Necessarily Associated with Diarrhoea

A cohort of 151 infants and young children aged 1-23 months from a poor peri-urban community of Bangladesh was studied to determine the relationship between Helicobacter pylori colonization and morbidity due to diarrhoea. A 13C urea breath test was performed to detect the presence of H. pylori. Children were followed up at home every alternate day for 6 months and diarrhoeal morbidity data were collected. Diarrhoeal morbidity was compared between H. pylori-positive and H. pylori-negative children. Sixty-eight (45 per cent) children were H. pylori positive and 83 (55 per cent) were H. pylori negative. During the first 1-month period following the breath test, three (4.4 per cent) H. pylori-positive and four (4.8 per cent) H. pylori-negative children had diarrhoea. Thirty-two (47 per cent) of the children in the positive group and 43 (52 per cent) in the negative group had one or more episodes of diarrhoea during the 6-month follow-up period. Median number of diarrhoeal episodes was 1.0 (range 1.0-4.0) in the H. pylori-positive children and 2.0 (range 1.0-5.0) in the H. pylori-negative children (p = 0.19). No significant difference was observed in the cumulative days with diarrhoea. The results of this study suggest that H. pylori colonization is not associated with diarrhoeal morbidity in infants and young children.