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Biomedical subjects

W Creutzfeldt

Publications and source records attributed to W Creutzfeldt.

At least 19 recordsLinked to original sources
PubMed1992

Vasoactive intestinal polypeptide induces neurogenic contraction of guinea-pig ileum. Involvement of acetylcholine and substance P.

The effect and mode of action of vasoactive intestinal polypeptide (VIP), a peptidergic neuromodulator in the gastrointestinal nervous system, were investigated in isolated muscle strips of the guinea-pig ileum. VIP induced concentration-dependent (20 nM-1 microM) contractions of longitudinal ileal strips. TTX (1 microM), a mixture of atropine (3 microM) and spantide (30 microM), a mixture of atropine (3 microM) and omega-conotoxin GVIA (100 nM), somatostatin (60 nM) and dynorphin (100 nM) abolished the effect of VIP. In most cases a small relaxation became evident. Desensitization to substance P in the presence of atropine prevented VIP-induced contraction. A partial inhibition was observed in the presence of atropine (3 microM), spantide (30 microM), omega-conotoxin GVIA (100 nM), beta-endorphin (265 nM), met-enkephalin (1100 nM) and a mixture of spantide (30 microM) and omega-conotoxin GVIA (100 nM). The action of VIP was not significantly modified by guanethidine (3 microM) or hexamethonium (150 microM). In circular ileal strips VIP (10-300 nM) caused concentration-dependent relaxations through a direct myogenic effect. These results indicate that the VIP produced contractions of the guinea-pig ileum are exclusively neurally mediated and involve a cholinergic as well as a noncholinergic-nonadrenergic (NANC) pathway. It is concluded that besides acetylcholine (Ach) VIP releases the peptidergic transmitter substance P from postganglionic nerve fibers of myenteric plexus. Opioid peptides and somatostatin modulate the activity of cholinergic and peptidegic nerves in the guinea-pig ileum. The release of substance P appears to depend completely on N-type voltage sensitive calcium channels.

Acetylcholine↗
PubMed1992

Determination of plasma cholecystokinin (CCK) concentrations by bioassay and radioimmunoassay in man. A critical evaluation.

The present investigation was designed to perform a direct comparison of a rat pancreatic acini bioassay system and a specific CCK radioimmunoassay (antiserum G-160) for the measurement of fasting and meal-stimulated plasma CCK in the presence and absence of the CCK receptor antagonist loxiglumide. The G-160 CCK antiserum is directed against the C-terminal O-sulfated tyrosine residue of the CCK molecule which is essential for full bioactivity of CCK peptides. For plasma extraction prior to bioassay measurement, hydrophobic reverse-phase chromatography on octadecylsilane cartridges was employed and resulted in simultaneous adsorption and elution of both CCK peptides and loxiglumide with recoveries of 87.5 +/- 9% and 75.0 +/- 5.9%, respectively. In the absence of loxiglumide, fasting and meal-stimulated values for CCK-like bioactivity and CCK-immunoreactivity (IR-CCK) were nearly identical (basal values: 1-2 pmol/l; meal-stimulated plateau levels: 4-6 pmol/l). After intravenous infusion of loxiglumide (30 mg/kg/h for 10 min, 10 mg/kg/h thereafter), resulting in plasma steady state levels of 200-300 mumol/l, meal-stimulated CCK-like bioactivity was undetectable, whereas IR-CCK levels were augmented 6.5-fold. In the bioassay system, standard samples containing 50 mumol/l loxiglumide produced complete inhibition of acinar lipase release in response to 50 pmol/l synthetic CCK-8. We conclude, that postprandial circulating non-CCK-like factors do not contribute significantly to the direct receptor-mediated stimulation of exocrine pancreatic secretion. The good agreement of CCK-like bioactivity and IR-CCK levels in the absence of loxiglumide confirms the sensitive and specific recognition of bioactive CCK peptides by the G-160 antiserum and suggests that this antibody exerts binding characteristics probably similar to a pancreatic acinar receptor.

Adult↗
PubMed1992

Pituitary adenylate cyclase activating peptide, a novel VIP-like gut-brain peptide, relaxes the guinea-pig taenia caeci via apamin-sensitive potassium channels.

Effects of pituitary adenylate cyclase activating peptide (PACAP-(1-27)) and vasoactive intestinal polypeptide (VIP) on the guinea-pig taenia caeci were studied in the presence of guanethidine and scopolamine. Both peptides (1 nmol/1-1 mumol/l) concentration-dependently relaxed the smooth muscle of the taenia. PACAP-(1-27) and VIP were nearly equipotent. Apamin (30 nmol/l), a selective blocker of calcium-activated potassium channels, abolished the relaxation induced by PACAP-(1-27) whereas the effect of VIP remained unaffected. PACAP-(1-27) may be a candidate for the noncholinergic, non-adrenergic inhibitory neurotransmitter which induces apamin-sensitive relaxation in the intestinal tract.

Animals↗
PubMed1992

Influence of a platelet-activating factor antagonist on severe pancreatitis in two experimental models.

This study investigates the role of platelet-activating factor (PAF) in experimental pancreatitis. The concentration of PAF quantified in ascites of bile-induced pancreatitis by radioimmunoassay (RIA) ranged from 3.67 +/- 0.39 pmol/mL 2 h to 0.954 +/- 0.39 pmol/mL 10 h after injection of taurocholate. Administration of a potent PAF antagonist, WEB-2170, prior to injection of taurocholate prolonged mean survival time in rats receiving i.v. camostate and albumin (46.4 h, n = 15, vs controls 38.3 h, n = 13). However, the survival rate after 72 h was not improved. The histologically estimated severity of pancreatitis and pancreatic enzymes in blood, tissue, or ascites was not affected. WEB-2170 had no effect on survival when injected simultaneously with taurocholate into the pancreatic duct or given i.v. after induction of pancreatitis (1, 0.1, or 0.01 mg/kg WEB-2170 vs controls). Subcutaneous injection of 10 mg/kg WEB-2170 also did not improve survival in pancreatitis induced by choline-deficient, ethionine-supplemented diet in mice. It is concluded that administration of a PAF antagonist after the onset of severe experimental pancreatitis does not influence its outcome, although activation of PAF may play a role in the pathogenesis of pancreatitis.

Animals↗
PubMed1992

Mechanism of insulin resistance in CCl4-induced cirrhosis of rats.

Insulin action was studied in rats with CCl4/phenobarbital-induced cirrhosis of the liver using the euglycemic hyperinsulinemic clamp technique coupled with isotopic measurement of individual tissue glucose uptake, glycogen formation, and lipogenesis. In cirrhotic rats, dose response curves showed a reduction of insulin-stimulated total body glucose disposal of about 30%. Insulin action on tissue glucose uptake and initial phosphorylation (assessed with [3H]2-deoxyglucose) were unchanged; however, incorporation of [14C]glucose into lipids and particularly into glycogen was reduced substantially (being most pronounced in skeletal muscle and diaphragm) at maximally as well as half-maximally effective serum insulin concentrations during euglycemic clamping. At identical IV insulin infusion rates, steady-state serum insulin concentrations were elevated up to fourfold in cirrhotic animals. Antilipolytic action of insulin was unaltered. These data suggest that the principal metabolic pathway affected in insulin resistance of rats with experimental cirrhosis appeared to be insulin-stimulated glycogen formation in muscle tissues.

Adipose Tissue↗
PubMed1992

Contrasting effects of pituitary adenylate cyclase activating polypeptide (PACAP) on in vivo and in vitro prolactin and growth hormone release in male rats.

Pituitary adenylate cyclase activating polypeptide (PACAP) is produced by hypothalamic neurons which terminate within the median eminence suggesting that it may be a hypophysiotropic hormone. However, little endocrine activity has been ascribed to the peptide. Therefore we studied the effects of PACAP on prolactin (Prl) release from dispersed cultivated rat pituitary cells in vitro using conventional cultures as well as the reverse hemolytic plaque assay (RHPA). Furthermore the effects of the peptide on in vitro GH release were assessed. In addition, the activity of the peptide on in vivo release of Prl and GH was studied in hypothalamus-lesioned animals. PACAP dose dependently inhibited Prl release form dispersed pituitary cells in both, monolayer cell cultures and the RHPA, whereas GH secretion was not affected. In hypothalamus-lesioned rats which have high Prl levels due to the absence of hypothalamic dopamine, PACAP further stimulated Prl release. Serum GH increased more than 20 fold in response to the intravenous PACAP infusion. Thus in vitro (inhibition of Prl release, no effect on GH release) and in vivo (stimulation of both hormones) experiments yielded contradicting effects of PACAP on pituitary hormone release. We suggest that PACAP may stimulate the release of a paracrine, yet unknown factor which in the intact pituitary overrides the direct inhibitory action of PACAP on the lactotropes. The same or another paracrine factor may also enhance in vivo GH release. In cell culture the paracrine factor is diluted by the medium. Therefore the peptide never reaches effective concentrations which are present within the intact pituitary tissue.

Animals↗
PubMed1992

Comparison of subcutaneously administered soluble insulin and des-(B26-B30)-insulin-B25-amide in rabbit, pig and healthy man.

Subcutaneous injections of soluble human insulin and of the monomeric insulin analogue des-(B26-B30)-insulin-B25-amide were given to fasted rabbits, pigs and healthy man. The time course of blood glucose decline and the rate of appearance of the hormones in the peripheral circulation were studied for doses of 0.35 and 0.7 nmol/kg. In rabbits an identical time course with early glucose nadirs between 45 and 60 min and hormone peaks at about 20 min were observed for both hormones. Similar results were obtained for insulin and the analogue in pigs. When injected into humans, slightly earlier peaks of the analogue at 30 to 45 min were measured compared to insulin peaks at 60 min. In addition, a trend towards faster decline in blood glucose could be demonstrated after analogue injection. In contrast to monomeric insulin analogues produced by recombinant DNA technology, s.c. injections of des-(B26-B30)-insulin-B25-amide do not appear to meet mealtime insulin requirements better than soluble insulin.

Adult↗
PubMed1992

Comparison of the effect of GIP and GLP-1 (7-36amide) on insulin release from rat pancreatic islets.

After ingestion of glucose both GIP (gastric inhibitory polypeptide, glucose-dependent insulinotropic polypeptide) and GLP-1(7-36amide) (glucagon-like polypeptide-1, 7-36amide) may play a physiological role in augmenting insulin release. Their insulinotropic effect was compared in isolated rat islets after 24-h maintenance in tissue culture (11 mmol l-1 glucose). Ten islets per vial were then incubated in Krebs-Ringer-Hepes buffer for 30 min; insulin was measured radioimmunologically. Both hormones were always compared in the same experiment. At 16.7 mmol l-1 glucose both GIP and GLP-1(7-36amide) 2 x 10(-10) mol l-1 significantly increased insulin release; 10(-10) mol l-1 of either hormone had no significant effect. The response at 10(-9) and 10(-8) mol l-1 was similar for both; at 4 x 10(-10) mol l-1 GLP-1(7-36amide), however, was clearly more effective than GIP. At low glucose (2.8 or 5.0 mol l-1) no significant differences were found. A concentration of 10(-8) mol l-1 of both hormones was slightly stimulatory. At 8.3 mmol l-1 glucose, 10(-9) mol l-1 GLP-1(7-36amide) was 60% more effective than GIP (4.8 +/- 0.4 vs. 3.0 +/- 0.4, n = 13, P less than 0.005), the response to 10(-8) mol l-1 was similar. These data show comparable effects of high concentrations of GIP and GLP-1(7-36amide) on glucose-induced insulin release; at presumably physiological concentrations, however, GLP-1(7-36amide) was clearly more effective. The combination of the two peptides was not more than additive, suggesting that they act via the same final mechanism.

Animals↗
PubMed1992

Critical evaluation of the 'heated-hand-technique' for obtaining 'arterialized' venous blood: incomplete arterialization and alterations in glucagon responses.

In order to test the degree of 'arterialization' and the occurrence of arterio- (or capillary-) venous differences in glucose concentrations for commonly used blood sampling sites (including the retrogradely cannulated dorsal hand vein with application of dry heat to this hand/arm--the 'heated-hand-technique'), oxygen partial pressure (oxygen saturation) and plasma glucose was determined in blood drawn from different venous sites before and after an oral glucose load (75 g). Experiments with and without heating (hot air 68 degrees C) were compared in nine healthy volunteers. Basal pO2 (and oxygen saturation) increased in the order cubital fossa vein less than superficial forearm vein less than dorsal hand vein. Heating raised pO2 by approximately 20 mmHg; P = 0.008) and oxygen saturation (P = 0.008-0.02) at all sites, including those on the contralateral arm. Capillary-venous glucose differences after the glucose challenge were significantly related to the sampling site (P less than 0.0001). They were reduced by approximately 50% in response to heat exposure (P = 0.008-0.011) and could be correlated to pO2-values (r = 0.92; P = 0.01). The lowest capillary-venous glucose concentration difference was measured with the 'heated-hand-technique' (0.4 +/- 0.1 mmol l-1). Heating did not alter integrated incremental glucose (capillary values), insulin, and C-peptide-responses and late, counter-regulatory responses (120-240 min after glucose) of cortisol, growth hormone, and adrenalin. However, the late glucagon response was enhanced (P = 0.011) by heating, concomitant with a significantly reduced 'reactive' decrement in glucose concentrations. In conclusion, the 'heated-hand-technique' provides blood more similar to arterial blood that can be obtained from other venous sampling sites. However, significant residual differences in pO2 and glucose concentrations remain. In addition, altered counter-regulatory hormone responses may occur with heating.

Adult↗
PubMed1992

Repeated upper gastrointestinal hemorrhage caused by metachromatic leukodystrophy of the gall bladder.

A 27-year-old man with metachromatic leukodystrophy (MLD) of the adult type had developed repeated severe gastrointestinal (GI) bleeding. During endoscopic retrograde cholangiography (ERC), hemobilia was observed on two occasions. The definite diagnosis was obtained by a biopsy specimen taken from the lumen of the gall bladder during ERC, demonstrating large masses of metachromatic material inside the gall bladder. Upon cholecystectomy, papillomatosis of the gall bladder was found virtually obliterating the lumen of the gall bladder. A blood clot was observed at the angle of the cystic duct; histologic examination revealed diffuse hemorrhage into the stroma of the gall bladder. The patient is without upper GI hemorrhage since 3 years. In patients with MLD and upper GI bleeding, one should, therefore, be aware of the gall bladder as a possible source of hemorrhage.

Adult↗
PubMed1992

Inter-relationship between serum gastrin levels, gastric mucosal histology and gastric endocrine cell growth.

The development of gastric enterochromaffin-like (ECL)-cell hyperplasia in humans may be associated with extreme hypergastrinaemia, as occurs in Zollinger-Ellison syndrome (ZES) and pernicious anaemia (type A gastritis). More recently, endocrine cell hyperplasia has been found in all forms of chronic atrophic gastritis and even in cases of focal atrophy. Serum gastrin levels, non-antral gastric endocrine (argyrophil) cell growth, and the severity and type of concomitant gastritis were monitored in 66 unoperated and 8 antrectomized patients with poorly responsive peptic ulcer or reflux oesophagitis during up to 5 years' treatment with high-dose omeprazole, 40 mg daily. A small subgroup of patients (23%) had serum gastrin concentrations of more than four times the normal upper limit. These patients also had hyperplasia of the gastric argyrophil cells. More importantly, the same subgroup of patients had high-grade (atrophic) gastritis. Micronodular hyperplasia of argyrophil cells was significantly more frequent in biopsies showing atrophic gastritis (48%) than in biopsies showing only superficial gastritis (3.6%). It is concluded that, as previously demonstrated in untreated patients with gastric ulcer, the argyrophil cell hyperplasia observed during high-dose omeprazole therapy is related to the progression of chronic atrophic gastritis rather than to serum gastrin levels.

Biopsy↗
PubMed1992

Lack of effect of synthetic human gastric inhibitory polypeptide and glucagon-like peptide 1 [7-36 amide] infused at near-physiological concentrations on pentagastrin-stimulated gastric acid secretion in normal human subjects.

Gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 [7-36 amide] (GLP-1) are glucose-dependent insulinotropic gut hormones. Under experimental conditions, both have been shown to reduce stimulated gastric acid secretion. To study their individual and combined effects on pentagastrin-stimulated (0.1 micrograms/kg/h from -90 to 120 min) gastric volume, acid and chloride output, on separate occasions, synthetic human GIP (1 pmol/kg/min) and/or GLP-1 [7-36 amide] (0.3 pmol/kg/min) or placebo (0.9% NaCl with 1% albumin) were infused intravenously (from -30 to 120 min) in 9 healthy volunteers. At 0 min, a glucose infusion was started that mimicked the glycemic profile after an oral glucose load of 50 g/400 ml and allowed for the glucose-dependent insulinotropic action of GIP and GLP-1 [7-36 amide]. Pentagastrin stimulated acid output significantly, but neither GIP nor GLP-1 [7-36 amide] either alone or in combination, reduced pentagastrin-stimulated gastric acid secretion. The circulating concentrations of GIP and GLP-1 [7-36 amide] obtained at steady state during exogenous administration of synthetic peptides were similar to or higher than those reached after oral glucose (endogenous secretion). In conclusion, (penta)gastrin-stimulated gastric acid secretion is not inhibited by physiological circulating concentrations of GIP or GLP-1 [7-36 amide]. Therefore, the insulinotropic action of these intestinal hormones is physiologically more important than their possible role as enterogastrone.

Adult↗
PubMed1992

Role of endogenously released cholecystokinin in determining postprandial insulin levels in man: effects of loxiglumide, a specific cholecystokinin receptor antagonist.

To estimate the contribution of postprandial cholecystokinin (CCK) responses to circulating insulin concentrations and insulin secretion, a specific CCK receptor antagonist (loxiglumide; 10 mg/kg body weight/h) or saline were infused intravenously in normal volunteers, beginning 90 min before insulin secretion was stimulated on separate occasions by the intraduodenal administrations of glucose, glucose and protein, and glucose plus protein with the admixture of pancreatin. The release of CCK (radioimmunoassay) was stimulated by the protein component of the nutrients from basal 2.4 +/- 0.4 to 8.0 +/- 1.2 pmol/l. CCK plasma levels were significantly higher with loxiglumide (p < 0.05). Glucose-dependent insulinotropic polypeptide (GIP) was also released by all nutrient mixtures. Loxiglumide significantly inhibited the amount of bilirubin and pancreatic enzymes recovered from duodenal aspirates. In contrast, in none of the experiments, C-peptide increments and hence insulin secretion rates were altered by loxiglumide. With glucose and protein as intraduodenal stimulus (no pancreatin added), the plasma amino acids rose significantly less (by approximately 50% of the control experiment) and the increment in insulin (but not C-peptide) concentrations was significantly reduced by loxiglumide. This is most likely explained by a change in insulin metabolic clearance. This effect cannot be a primary action of CCK because there was no similar effect of loxiglumide with the same intraduodenal stimulus plus added pancreatin. Pancreatic enzymes reduced maldigestion secondary to loxiglumide effects on pancreatic exocrine secretion: The increment in circulating amino acid concentrations was similar with and without loxiglumide. In conclusion, CCK does not alter insulin secretion and, therefore, is not an incretin hormone in man. Blocking CCK actions on the exocrine pancreas by loxiglumide, however, can secondarily cause reductions in postprandial insulin profiles by altering insulin clearance. These changes are possibly related to reductions in circulating amino acid concentrations.

Adult↗
PubMed1992

Budd-Chiari syndrome as the primary manifestation of a fibrolamellar hepatocellular carcinoma.

An 18-year-old female patient was admitted with ascites, right upper abdominal tenderness and peripheral edema. Angiography showed complete occlusion of the vena cava inferior up to the level of the right atrium. By open heart surgery, masses of thrombotic material were pulled out of the v. cava inferior/vv. iliacae which histologically contained tumor cell populations consistent with a hepatocellular carcinoma. Celiacography showed a highly vascularized tumor in the right hepatic lobe. Histologically, it proved to be fibrolamellar subtype hepatocellular carcinoma.

Adolescent↗
PubMed1992

Entero-insular axis and diabetes mellitus.

1. The incretin effect (i.e. the difference between the insulin response after oral and i.v. glucose) is reduced in type 2 diabetes although GIP secretion is normal or exaggerated. This suggests an insensitivity of the diabetic B-cell to GIP. However, it could also indicate the lack of another not yet defined "incretin". 2. While CCK is a potent incretin in rats and dogs, physiological concentrations of this hormone do not stimulate insulin secretion in man in presence of elevated blood levels of glucose or phenylalanine in the physiological range. It also does not interact with GIP. 3. Glucagon-like peptide I (7-36) is a potent glucose-dependent stimulator of insulin secretion in animals and man. Preliminary data suggest release after oral glucose despite localization of the GLPI containing cells predominantly in the ileum and colon. More data are needed before GLPI (7-36) can be regarded as a physiological incretin and its role in type 2 diabetes assessed.

Animals↗