PubMed Health⌕ Search

Biomedical subjects

J F Rehfeld

Publications and source records attributed to J F Rehfeld.

At least 109 records · Page 6Linked to original sources
PubMed1997

Feedback regulation of pancreatic exocrine secretion in minipigs.

BACKGROUND: The mechanism behind the possible feedback regulation of pancreatic exocrine secretion is not well understood. METHODS: Thirteen minipigs were prepared with fistulas to the pancreatic duct and the duodenum. Peripheral venous blood was obtained for determination of secretin and cholecystokinin (CCK) levels. Four different experiments were performed: 1) diversion and reinfusion of pancreatic juice; 2) intraduodenal infusion of NaHCO3 solution, with the same volume, bicarbonate concentration, and osmolality as the collected pancreatic secretion, and reinfusion of pancreatic juice; 3) reinfusion of pancreatic secretion for 1 h before and 2 h after a meal; and 4) diversion of pancreatic secretion and intraduodenal infusion of NaHCO33 solutions before and after a meal. RESULTS: Reinfusing pancreatic juice significantly decreased pancreatic juice volume and bicarbonate output and slightly decreased the level of secretin in plasma. Alternating infusions of substitute NaHCO3 and pancreatic juice did not change pancreatic output of bicarbonate and protein, nor did it change the CCK and secretin levels in plasma. Replacing pancreatic juice with intraduodenal NaHCO3 infusions during a meal did not significantly modify the pancreatic secretion of bicarbonate and protein or the hormonal levels in blood. CONCLUSIONS: A negative feedback regulation of pancreatic exocrine secretion is present in starved minipigs. Duodenal acidity and plasma levels of secretin semm to be of importance, whereas duodenal enzyme activity and the level of CCK in plasma probably are not. A postprandial negative feedback regulation through duodenal enzymatic activity and release of CCK into blood could not be shown.

Animals↗
PubMed1997

A double-blind placebo-controlled study on the effects of omeprazole on gut hormone secretion and gastric emptying rate.

BACKGROUND: The present study was designed to investigate whether an effect of omeprazole on gastric emptying is related to changes in the secretion of selected gut hormones. METHODS: The studies were performed in healthy men after 10 days' treatment with 40 mg omeprazole daily/placebo. Food ingestion took place in a duodenal phase, I and the meal consisted of an omelette labelled with technetium Tc 99m, followed by 150 ml water labelled with indium In 111. Plasma concentrations of gastrin, cholecystokinin (CCK), and motilin were measured. RESULTS: Pretreatment with omeprazole reduced gastric emptying rates. This applied to all variables and was most pronounced with regard to amounts of solid (median (95% confidence interval)) emptied at 180 min (71% (48 - 86) for omeprazole versus 96% (87 - 100) for placebo; P < 0.01). All median values of plasma gastrin concentrations from the omeprazole series were higher than the corresponding values from the placebo series, and omeprazole induced a tenfold increase in incremental integrated area (IIA, pmol/l x 180 min) of the gastrin concentration curve (5250 (2570 - 9680) versus 575 (240 - 1485); P < 0.01). New findings include a lower postprandial secretion of CCK in the omeprazole series, and consequently, a difference in total integrated area (TIA, pmol/l x 180 min) (88 (21 - 147) versus 217 (104 - 267); P < 0.05) and IIA (pmol/l x 180 min) (52 (2 - 142) versus 165 (104 - 195); P < 0.05), respectively; a difference in IIA-30 (pmol/l x 30 min) of plasma motilin concentrations (270 (140 - 595) (omeprazole) versus 460 (285 - 655); P < 0.05); and a direct relationship between the amounts of liquid emptied at 30 min and the corresponding TIA-30 of plasma motilin in the omeprazole (Rs = 0.677; P < 0.05) and the placebo series (Rs = 0.767; P < 0.05). CONCLUSION: Pretreatment with 40 mg omeprazole daily decreases the gastric emptying rates and has a substantial influence on the secretion of gastrin, motilin, and CCK. The finding of an omeprazole-induced decrease in CCK release may have clinical implications. Further investigation into the possible effect of proton-pump inhibitors on biliary tract motility and cholesterol solubilization in gallbladder bile is warranted.

Adult↗
PubMed1997

[Anders Jahres PRIZE 1996. Current biological and clinical aspects of gastrointestinal hormones].

1996, the great Jahre Prize for medical research was shared by Professor Jens F Rehfeld of Copenhagen and Professor Mårten Wikström of Helsinki. Jens Rehfeld is one of the world's leading experts on peptide hormones and neuropeptides, and his research has contributed much to our understanding of diseases of the gastrointestinal tract and central nervous system. So many gastrointestinal hormones have now been recognised, that the alimentary canal is considered to constitute the body's largest endocrine organ. Moreover, many hormones occur in several molecular forms and are also synthesised as neurotransmitters in the brain and the peripheral nervous system, and both in classic endocrine cells and cells of the common mucosa. Finally, a number of common tumours also synthesise intestinal peptides that function as growth factors. Gastrointestinal hormones should therefore be interpreted as being intercellular regulators, that are possibly more crucially involved in cancer, diabetes and neuropsychological diseases than in disorders of gastrointestinal secretion and motility.

Awards and Prizes↗
PubMed1996

Autocrine stimulation of AR4-2J rat pancreatic tumor cell growth by glycine-extended gastrin.

Glycine-extended gastrin (gastrin-Gly) stimulates proliferation of AR4-2J pancreatic tumor cell line through a specific receptor, different from the gastrin-cholecystokinin B receptor. Our purpose was to determine whether AR4-2J cells produced gastrin-Gly and then whether the peptide was involved in an autocrine loop. First, proliferation of AR4-2J cells in serum-free medium was inhibited by a gastrin anti-sense oligodeoxynucleotide phosphorothioate and by antibodies specific for gastrin-Gly. In contrast, antibodies specific for alpha-amidated gastrin were without effect. By using RT-PCR, we have shown that AR4-2J cells expressed gastrin mRNA. The presence of gastrin-Gly, but not alpha-amidated gastrin, in serum-free media was detected by radioimmunoanalysis. Gel chromatography revealed that the predominant molecular forms secreted were glycine-extended gastrin-34 and gastrin- 17. Furthermore, epidermal growth factor (EGF), a stimulator of gastrin gene transcription, modulates gastrin-Gly secretion by AR4-2J. These data together suggest that gastrin-Gly is an autocrine growth factor for AR4-2J cells and that it participates with EGF in the regulation of AR4-2J-cell proliferation.

Amino Acid Sequence↗
PubMed1996

Molecular structure and genetic mapping of the mouse gastrin gene.

The mouse gastrin gene has three exons totalling 460 bp and a deduced preprogastrin of 101 amino acids. The sequence of murine gastrin-34 is 94% identical to rat gastrin-34 and 76% identical to human gastrin-34. At Arg79, mouse progastrin has a unique cleavage site that might allow species-specific synthesis of gastrin-13. Northern analysis and RT-PCR demonstrated that gastrin gene transcripts are abundant in mouse stomach and duodenum and present at low levels in brain, ovary and pancreas, similar to the pattern described for other mammals. The gastrin gene was mapped to the distal region of mouse chromosome 11.

Amino Acid Sequence↗
PubMed1996

Cholecystokinin peptides and receptors in the rat brain during stress.

Cholecystokinin (CCK) has been implicated in stress and anxiety disorders. We have studied the levels of different molecular forms of CCK and CCK receptor characteristics in rats kept for 1 h in individual cages and exposed to decapitation of conspecifics, and a control group which was decapitated immediately. Total CCK concentration was found to be increased in the hippocampus of stressed animals in the first experiment: this finding was not confirmed in further studies. No effect of stress was found on total CCK levels in the frontal cortex, hypothalamus, striatum, and septum. CCK-8-sulphated, CCK-8-nonsulphated, CCK-5, and CCK-4 were separated by HPLC and measured with two antibodies with different selectivity: no effect of stress was found on the levels of any of these molecular forms of CCK. Injection procedure and diazepam (5 mg/kg) administration had no effect on total CCK levels. Exposition of rats to the decapitation procedure increased [3H]-CCK-8 binding in the frontal and cerebral (whole-frontal) cortex. This effect could not be blocked by diazepam pretreatment. Injection procedure itself increased CCK receptor binding in the cerebral cortex, but the effect of this type of stress was smaller in magnitude. The upregulation of CCK receptors in stressed animals was due to the increased binding of radioligand on CCKB receptor subtype.

Animals↗
PubMed1996

An efficient cellular system for mutational analysis of prohormone processing.

A novel system for heterologous expression of prohormones based on transient transfection of the HIT beta-cell line was established using human progastrin as a model. Progastrin was expressed at high levels compared to other gene transfer systems in endocrine cells, and the processing pattern was similar to that of normal antral gastrin cells. Thus, gastrin was partially tyrosine O-sulfated and carboxyamidated. Cell extracts contained mainly gastrin-17 and gastrin-34 and the corresponding glycine-extended forms. In contrast, the media contained more incompletely processed gastrin forms. This suggests that gastrin was directed to the regulated secretory pathway but that some progastrin products were constitutively secreted. Glucose increased both the level of gastrin gene expression and maturation to carboxyamidated peptides, indicating that glucose influences the activity of the amidation enzyme complex, peptidylglycine alpha-amidating mono-oxygenase (PAM), in insulin cells. Mutational analysis of tyrosine sulfation of gastrin demonstrated that substitution of the uncharged residue carboxy-terminal to the tyrosine with an acidic residue does not increase sulfation in contrast to previous results, where the amino-terminal residue was replaced with an acidic residue. The mutant peptides displayed sulfation-dependent processing, supporting our recent suggestion that tyrosine sulfation increases the proteolytic processing of prohormones.

Amino Acid Sequence↗
PubMed1996

Transcriptional regulation of the human cholecystokinin gene: composite action of upstream stimulatory factor, Sp1, and members of the CREB/ATF-AP-1 family of transcription factors.

We have examined cis-elements and trans-acting factors that regulate transcription of the human cholecystokinin (CCK) gene. Transient expression of CCK promoter deletion constructs in human SK-N-MC neuroblastoma cells depicted positive cis-elements between the positions -100 to -92, -84 to -74, and -58 to -37, 5' to the transcription initiation site. Correspondingly, DNase I protection analysis showed that transacting factors bound to elements within these regions. The sequences encompass a putative basic helix-loop-helix leucine zipper (bHLH-ZIP) element, an Sp1 element, and a combined cAMP- and TPA-responsive element (CRE/TRE) at positions -97 to -92, -39 to -34, and -80 to -73, respectively. Mobility and supershift assays demonstrated that upstream stimulatory factor (USF) and Sp1 bind to the former elements and competition experiments confirmed that CREB/ATF and AP-1 bind to the CRE/TRE element. Mutation of the bHLH-ZIP and CRE/TRE elements decreased the activity of the promoter by 65% and 42%, respectively. The activity of the promoter was increased six- and two-fold after stimulation with forskolin and TPA, respectively. Stimulation was eliminated after mutation of the CRE/TRE element. Co-transfection experiments with pRSV-c-jun, pSV-fos, and pRC-RSV-CREB constructs showed that jun, CREB, and AP-1 stimulate transcription. We conclude that USF, Sp1, and members of the CREB/ATF and AP-1 family of transcription factors are the major determinants of CCK gene transcription.

Base Sequence↗
PubMed1996

Pharmacokinetics and organ metabolism of carboxyamidated and glycine-extended gastrins in pigs.

The elimination of carboxyamidated gastrin-17 and its glycine-extended precursor was studied in anesthetized pigs during constant-rate infusion. Extraction of amidated gastrin-17 was recorded in the hindlimb (42%), kidney (40%), head (32%, P < 0.001), and the gut (13%, P < 0.01). Elimination was not recorded in the liver, lungs, or heart. Extraction of glycine-extended gastrin-17 was measured in the kidney (36%), hindlimb (31%, P < 0.001), head (26%), and the gut (16%, P < 0.01), but not in the liver or the lungs. Glycine-extended gastrin-17 was not processed to amidated gastrin during infusion. The half-life, metabolic clearance rate, and apparent volume of distribution for amidated gastrin-17 were 3.5 +/- 0.4 min, 15.5 +/- 1.1 ml.kg-1.min-1, and 76.5 +/- 9.9 ml/kg, respectively, and for glycine-extended gastrin-17 were 4.3 +/- 0.6 min, 17.4 +/- 0.9 ml.kg-1.min-1, and 104.7 +/- 11.9 ml/kg, respectively. We conclude that extraction of amidated and glycine-extended gastrin-17 varies in the vascular beds, with elimination mainly confined to nonorgan tissues and the kidneys.

Animals↗
PubMed1996

Metabolism and influence of glycine-extended gastrin on gastric acid secretion in man.

Glycine-extracted gastrins are the immediate precursors of the bioactive carboxyamidated gastrins. The effect on gastric acid secretion and the pharmacokinetics of glycine-extended gastrin-17 were studied in 8 normal subjects. The elimination in plasma after bolus injection was biexponential, the half-lives being 4.1 +/- 0.2 and 21.8 +/- 0.9 min, and clearance and apparent volume of distribution being 7.9 +/- 0.6 ml/kg/min and 69.5 +/- 2.7 ml/kg, respectively. Infusion of the peptide at three consecutive dose rates did not stimulate gastric acid secretion, although plasma concentrations reached supraphysiological levels. Nor did glycine-extended gastrin-17 influence submaximal acid secretion induced by amidated gastrin-17. In contrast to amidated gastrins, the concentration of glycine-extended gastrins in peripheral venous plasma did not increase significantly after a meal. The postprandial rise in amidated gastrin was unaffected by concomitant infusion of glycine-extended gastrin-17. A reduction in glycine-extended gastrin-17 concentrations in plasma during constant-rate infusion of the peptide was observed after a protein meal (p < 0.05). This reduction was reflected by an increase in glycine-extended gastrin-17 is without immediate effect on gastric output in man. The postprandial increase in clearance might be due to increased splanchnic blood flow with subsequently increased peptide elimination.

Adult↗
PubMed1996

Gallbladder emptying and cholecystokinin response to fish oil and trioleate ingestion.

The aim of the present study was to compare gallbladder emptying, gastric emptying and release of cholecystokinin (CCK), gastrin and secretin after intragastric administration of fish oil and trioleate. After intravenous injection of 99mTc-HIDA, 30 ml of a lipid labelled with 111In was administered through a gastric tube. Using dual scintigraphy with two markers, gallbladder and gastric emptying were measured simultaneously for 120 min. Plasma concentrations of gastrin, secretin and CCK, were determined throughout the period. The emptying of the gallbladder was reduced by 27% and the release of CCK by 85% after fish oil as compared with trioleate. Gastric emptying as well as the release of gastrin and secretin were similar after the two types of fat. The results suggest that the reduced gallbladder emptying after fish oil may be due to a smaller release of CCK.

Adult↗
PubMed1996

Hepatic and intestinal elimination of endogenous gastrin in pigs.

The elimination of endogenous carboxyamidated and glycine-extended gastrins in liver and gut was studied before and after feeding in 14 anesthetized pigs. Before the meal, liver and gut extractions were nonsignificant. After feeding, the release rate of amidated gastrin increased from 7.5 +/- 2.6 to 21.9 +/- 5.3 pmol/min (p < 0.02), and the liver extracted significant amounts of amidated gastrin, while the intestinal extraction remained nonsignificant. The postprandial hepatic extraction ratio increased from 0.09 +/- 0.04 to 0.18 +/- 0.04 (p < 0.01). Before feeding, the hepatic and extrahepatic clearance rates were 80.0 +/- 38.7 and 232.3 +/- 77.7 ml/min. Clearance rates after feeding were 144.8 +/- 29.5 (p < 0.01) and 326.4 +/- 75.3 ml/min (NS), respectively. Portal plasma displayed a small postprandial increase in the concentration of glycine-extended gastrin, but extraction over the liver and gut remained nonsignificant. Gel chromatography of portal plasma showed that the fraction of postprandial amidated gastrin corresponded to gastrin-17. The concentration of glycine-extended gastrin was too low for chromatographic analysis. We conclude that endogenous amidated gastrin is eliminated in the liver after feeding in pigs.

Animals↗
PubMed1996

Influence of meal composition on postprandial peripheral plasma concentrations of vasoactive peptides in man.

In a randomized cross-over study healthy non-obese male human subjects received standardized isocaloric, isovolumetric meals consisting of either carbohydrate, protein or fat and a non-caloric control meal consisting of an equal volume of water. Peripheral venous plasma concentrations of calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and peptide YY (PYY) were measured pre- and postprandially. Plasma CGRP concentrations were lowered following the protein meal and following the fat meal, but remained unaltered after carbohydrate or water ingestion. Plasma VIP concentrations increased slightly following the carbohydrate meal and following water loading. The PYY concentrations increased after the protein and the carbohydrate meal and a slight rise was observed following fat ingestion. Water loading did not affect the plasma level of PYY. We conclude that the postprandial peripheral plasma concentrations of CGRP, VIP and PYY are dependent on the caloric meal composition. The VIP, but not the CGRP and PYY concentrations seem to be influenced by gastric distension. The physiological significance of the postprandial alterations in peripheral concentrations of these peptides is at present uncertain.

Adult↗
PubMed1996

The relationship between gut hormone secretion and gastric emptying in different phases of the migrating motor complex.

BACKGROUND: No studies are available on the relationship between the response of gut hormones and gastric emptying in different phases of the migrating motor complex. This study examined whether basal gut hormone concentrations in plasma before food ingestion are predictors of emptying characteristics and whether different hormone secretion patterns are associated with specific alterations in emptying rate. METHODS: Twelve healthy men were examined on two occasions: one with meal ingestion in phase I and the other with meal ingestion in phase II. The meal consisted of an omelette labelled with 99mTc followed by 150 ml water labelled with 111In. Plasma concentrations of gastrin, cholecystokinin, motilin, and peptide YY were measured in the fasting state, immediately after food ingestion, and at 15-min intervals in the postprandial period. RESULTS: New findings from the present study include a higher incremental integrated postprandial motilin response in phase I than in phase II (998 pmol/l*30 min (495 to 2010) versus 210 pmol/l*30 min (-270 to 2323), p < 0.05), and a linear relationship between median total integrated motilin response and solid emptying at 120 min in phase I (Rs = 0.58; p < 0.05). Furthermore, in phase I a linear relationship between total integrated area of cholecystokinin and solid emptying at 120 min was demonstrated (Rs = 0.62; p < 0.05). CONCLUSION: The findings from the present investigation have to be considered in the future design of studies that focus on postprandial release of gastrointestinal hormones. The transition from phase III to phase I is a reproducible and easily recognized pressure event. Therefore, we recommend the use of food ingestion immediately after termination of duodenal phase III.

Adult↗
PubMed1996

Disturbed motilin and cholecystokinin release in the irritable bowel syndrome.

BACKGROUND: The irritable bowel syndrome (IBS) is associated with motor abnormalities in the small intestine and colon. Neuropeptides may have an important role in initiating and regulating the intestinal motility. Motilin has been proposed to initiate the peristaltic reflex in the small intestine and cholecystokinin the gastrocolic reflex. METHODS: In 18 patients with IBS and 11 healthy control subjects plasma motilin and cholecystokinin (CCK) concentrations were measured after intraluminal stimulation of water and a fat-rich meal. RESULTS: The IBS patients had reduced motilin secretion after both water intake and the fat meal. In contrast, the fat meal elicited an exaggerated and prolonged CCK release in the IBS patients. CONCLUSIONS: Disturbed motilin and CCK release may partly be responsible for the intestinal dysmotility in the IBS patients.

Adult↗