Biomedical subjects

E Theodorsson

Publications and source records attributed to E Theodorsson.

At least 127 records · Page 7Linked to original sources

PubMed1995

Release of somatostatin, neurotensin and vasoactive intestinal peptide upon inhibition of gastric acid secretion by duodenal acid and hyperosmolal solutions in the conscious rat.

The inhibitory effect of duodenal exposure to acid and hyperosmolal solutions on pentagastrin-stimulated gastric acid secretion was studied in conscious rats equipped with chronic gastric fistula and duodenal Thiry-Vella loop. The loop was challenged with saline, HCl or hyperosmolal polyethylene glycol. Gastric acid secretion was measured in samples from the gastric fistula. Gut peptide concentrations were measured in duodenal perfusates collected each 30 min, and in plasma samples collected both during stimulated acid secretion alone, and at the end of experiments in combination with luminal challenges of the loops. During pentagastrin-stimulated gastric acid secretion, luminal perfusion of the duodenal loop with acid caused inhibition of acid secretion (P < 0.001) and a prominent release of somatostatin both to the lumen (P < 0.001) and to the circulation (P < 0.05). Also, neurotensin (P < 0.01) and vasoactive intestinal peptide (P < 0.01) were released to the lumen, but not to the circulation. Upon perfusion of the duodenal loop with hyperosmolal polyethylene glycol, acid secretion was inhibited (P < 0.05) and somatostatin alone was released to the luminal side (P < 0.01). In conclusion, duodenal exposure to acid inhibits pentagastrin-stimulated gastric acid secretion and releases SOM to the circulation that may directly inhibit acid secretion. Concomitantly, somatostatin (SOM), neurotensin and vasoactive intestinal peptide are released to the lumen. Duodenal exposure to hyperosmolal polyethylene glycol inhibits acid secretion with a luminal release of SOM only. Thus, luminal acid and hyperosmolal solutions inhibit gastric acid secretion by separate mechanisms. After acid or hyperosmolal challenge, the release of SOM to the circulation indicates gastric acid inhibition in an endocrine manner, while a luminal release of gut peptides indicates a local peptide overflow that might be of importance via paracrine regulatory mechanisms in the intact animal.

Animals↗

PubMed1995

Immunoreactive tachykinins in 24-h collections of urine from patients with carcinoid tumours: characterization and correlation with plasma concentrations.

Tachykinins are a family of peptides that may be present in and secreted from carcinoid tumours of mid-gut origin. They are likely to play a role in the pathogenesis of, e.g. the flush, dyspnoea and valvular heart disease seen in the carcinoid syndrome. Since tachykinins are secreted from the tumour into the circulation in bursts, coinciding with flushing attacks, and have short half-lives, we anticipated that analysis of 24-h urine excretion of immunoreactive tachykinin metabolites might prove to be a more sensitive and stable parameter for monitoring than tachykinin-like immunoreactivity in plasma. The study included 48 patients hospitalized for treatment of advanced carcinoid tumours and 32 healthy controls. The urine excretion of tachykinin-like immunoreactive metabolites in the carcinoid patients (median 27.5 pmol 24 h-1, interquartile range (IQR) 8.5-51.0 pmol 24 h-1) was significantly (p<0.001) higher than that in the 32 healthy subjects (median 3.0 pmol 24 h-1, IQR 0.9-4.20 pmol 24 h-1). Of the patients, 38 (79%) had elevated 24-h urine excretion of tachykinin-like immunoreactive metabolites while 31 (64%) had elevated plasma concentrations of tachykinin-like immunoreactive metabolites. Of the patients, 27 (56%) had elevated concentrations of tachykinin-like immunoreactive metabolites both in plasma and urine, 12 (25%) had elevated concentrations only in urine excretion, 3 (6%) had elevated concentrations of only plasma tachykinin-like immunoreactive metabolites and 7 (14%) had elevation of neither plasma nor urine concentrations. Analysis by means of different column chromatographic techniques indicated that the immunoreactive material was heterogeneous, with some components co-eluting with oxidized neurokinin A (NKA) and neuropeptide K (NPK). The urine tachykinin-like immunoreactivity correlates well with that of plasma, but is a slightly more sensitive indicator of elevated tachykinin-like immunoreactivity, probably since levels of urine tachykinin-like immunoreactive metabolites reflect the overall amount of the latter secreted into the circulation during 24 h.

Antibodies↗

PubMed1995

Ambulatory 24-hour blood pressure and peptide balance in hemodialysis patients.

Blood pressure regulation during intermittent hemodialysis treatment involves many different mechanisms. Eight normotensive patients without antihypertensive drugs on intermittent hemodialysis treatment, mean age 50 years, were studied with 24-hour blood pressure measurements. Atrial natriuretic peptide (ANP) and neuropeptide Y (NPY) were determined concomitantly. Eight control individuals matched for age and sex were investigated in the same way. A significant increase of both systolic and diastolic blood pressure, heart rate and pathological circadian rhythm was seen among the dialysis patients. High levels of ANP were found before and after dialysis. NPY showed steady state levels through the 24 hours and did not differ between the two groups. Overhydration is a probable cause of the disturbed blood pressure regulation and increased ANP-values.

Adult↗

PubMed1995

Neuropeptides in the arthritic TMJ and symptoms and signs from the stomatognathic system with special consideration to rheumatoid arthritis.

The contribution of the nervous system to the pathophysiology of rheumatoid arthritis has been proposed to be mediated by certain neuropeptides. Neuropeptide Y, calcitonin gene-related peptide, substance P, and neurokinin A are considered modulators of inflammatory joint disease. Parameters of pain, as well as occlusal signs of tissue destruction from the arthritic TMJ and the corresponding neuropeptide concentrations in TMJ synovial fluid, were investigated in patients with various inflammatory joint diseases. The patients with rheumatoid arthritis were also examined in a separate diagnostic group. Visual analog scale, palpatory tenderness, maximal voluntary mouth opening, and anterior open bite were correlated to neuropeptide-like immunoreactivities of the above four neuropeptides. It was found that high concentrations of calcitonin gene-related peptide and neuropeptide Y in TMJ fluid are associated with pain, impairment of mandibular mobility, and occlusal signs of TMJ destruction in patients with rheumatoid arthritis. The results indicated neuropeptide involvement in rheumatoid arthritis, proposing a potentiation of the symptoms and signs by the inflammatory action of calcitonin gene-related peptide and neuropeptide Y.

Adult↗

PubMed1994

Effects of electro-acupuncture and physical exercise on regional concentrations of neuropeptides in rat brain.

The effects of single or repeated treatments with manual acupuncture (ACU), electro-acupuncture (ELACU) or physical exercise on neuropeptide Y (NPY), neurokinin A (NKA), substance P (SP), galanin (GAL) and vasoactive intestinal peptide (VIP)-like immunoreactivity (-LI) in different regions of the rat brain were studied. Initially the effect of microwave irradiation (MWI) was compared to decapitation on the recovery of neuropeptides, and significantly higher concentrations of SP-LI, NKA-LI and NPY-LI were found in the hippocampus, occipital cortex, pituitary and striatum following MWI. Repeated ELACU treatments significantly increased SP-LI, NKA-LI and NPY-LI in the hippocampus and NPY-LI in the occipital cortex. No changes were found in animals receiving ACU or performing physical exercise.

Acupuncture Therapy↗

PubMed1994

Increased concentration of calcitonin gene-related peptide in cerebrospinal fluid of depressed patients. A possible trait marker of major depressive disorder.

Cerebrospinal fluid (CSF) was collected under controlled conditions from subjects suffering from major depression (n = 63) or schizophrenia (n = 28) and from healthy controls (n = 20). Following Sep-pak extraction, calcitonin gene-related peptide immunoreactivity (CGRP-LI) was determined by radioimmunoassay in sample aliquots. CGRP-LI concentrations in CSF were increased in the depressed patients compared to the schizophrenic and control subjects (P < 0.001). No CGRP-LI differences were found between the latter two groups. CGRP-LI did not correlate to any of the technical (e.g. storage conditions) or patient (demographic, biochemical, or clinical) variables investigated. In view of the CGRP's discrete distribution and specific effects in brain and the above results, we hypothesize that increased CSF CGRP-LI might be a trait marker of major depression. Regardless of the mechanisms (altered synthesis/release/metabolism in brain or changed fate in CSF) leading to elevated CSF CGRP-LI, the identification of a possible disease trait marker should contribute to the early diagnosis of major depression and identification of family members at risk and may help in differential diagnosis in other disorders with affective symptomatology.

Adult↗

PubMed1994

The effect of a single intraperitoneal dose of hrIL-1 alpha on substance P-, neurokinin A-, calcitonin gene-related peptide- and neuropeptide Y-like immunoreactivity in cerebrospinal fluid, plasma and knee joint synovial fluid in the rat.

Substance P (SP)-, neurokinin A (NKA)-, calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-like immunoreactivity (-LI) was studied in rats' cerebrospinal fluid (CSF), plasma and synovial fluid (SF) from both knee joints at 2 and 24 h following an intraperitoneal administration of 0.05 ml human recombinant interleukin-1 alpha (i.p. hrIL-1 alpha) or saline. Increased or decreased levels of SP-, NKA and CGRP-LI were detected in CSF and plasma, whereas NPY-LI was unaffected. In SF only CGRP-LI increased bilaterally. There was a correlation in CGRP-LI content between plasma and CSF following i.p. hrIL-1 alpha but not between plasma and SF or CSF and SF. It can be concluded that (1) i.p. hrIL-1 alpha activates somatosensory afferents thereby increasing SP- and CGRP-LI content in CSF and plasma and NKA-LI in CSF; 2) i.p. hrIL-1 alpha induces a bilateral increase of CGRP-LI in SF which is not mediated through systemic circulation and is possibly a part of the general host defensive reaction.

Animals↗

PubMed1994

Multiple molecular forms of tachykinins in rat spinal cord: a study comparing different extraction methods.

Various procedures for extraction at acid, neutral and alkaline pH were compared with regard to the yield of different tachykinins and tachykinin-like substances from rat spinal cord. Reverse phase high performance liquid chromatography (RP-HPLC) and radioimmunoassay with various C-terminally directed tachykinin antisera and a newly developed N-terminally directed substance P (SP)-antiserum (SPN 1) were used. Antiserum SPN 1 fully reacts with SP-analogues modified at the C-terminal end (SP free acid and SP-Gly-Lys) and also (77%) with SP(1-9) but not with C-terminal SP-fragments lacking 2 or more N-terminal amino acids. The highest levels of SP-like immunoreactivity (LI) and neurokinin A (NKA)-LI were measured after combined water and acetic acid extraction procedures. Also when measuring cholecystokinin-like immunoreactivity the highest level was obtained following this extraction procedure. RP-HPLC revealed a major component of SP-LI at the position of synthetic SP irrespectively of the extraction method and if the C- or N-terminally directed antiserum was used. Neutral water extracts contained a late eluting component detected with the C-terminally, but not with the N-terminally, directed antiserum. Acid and alkaline extracts, in contrast, contained components which could be detected with the N-terminally, but not with the C-terminally, directed SP-antiserum. Immunoreactive components eluting at the position of NKA and NKB were found in all types of extracts with NKA-, kassinin- and eledoisin-antisera. The NKB- and neuropeptide K (NPK)-components were more prominent in acid than in neutral and alkaline extracts. In conclusion, the present results indicate that rat spinal cord may contain molecular forms of tachykinin-like immunoreactivity in addition to those previously described and illustrate the importance of the choice of extraction method in immunochemical studies. Combined extraction in water and acetic acid appears to be a suitable method when the content of peptides with different chemical properties are to be measured in a tissue sample.

Animals↗

PubMed1994

Transforming growth factor-alpha and epidermal growth factor inhibit gastric acid secretion and stimulate release of somatostatin and neurotensin in the conscious rat.

The study compared inhibitory actions of transforming growth factor-alpha (TGF alpha) and epidermal growth factor (EGF) on gastric acid secretion and effects of these peptides on release of gut peptides considered important for acid inhibitory and gastrointestinal protective mechanisms. TGF alpha and EGF did not affect basal acid secretion, but inhibited pentagastrin-stimulated acid secretion in a dose-dependent manner from 0.10 to 1.7 nmol kg-1 h-1 i.v. by maximally 72% for TGF alpha (P < 0.001) and 76% for EGF (P < 0.001). At the highest doses, TGF alpha and EGF caused 194% and 698% increase of somatostatin-like immunoreactivity (SOM-LI) in plasma, respectively (each P < 0.05). Neurotensin-like immunoreactivity (NT-LI) increased 438% by EGF (P < 0.05), but the increase of 700% with TGF alpha did not reach statistical significance. The levels of vasoactive intestinal peptide-like immunoreactivity (VIP-LI) did not change. In gastric juice, SOM-LI increased 80% by TGF alpha i.v. (P < 0.05), but NT- and VIP-LI did not change. EGF i.v. had no effects on levels of SOM-, NT- or VIP-LI in luminal juice. Thus, TGF alpha and EGF inhibit acid secretion, but also promote the release of SOM and NT into the circulation and may be involved in the acid inhibitory effects of these growth factors.

Animals↗

PubMed1994

Extraction and quantitation of neuropeptides in bone by radioimmunoassay.

The feasibility of extracting and quantifying neuropeptides in bone by radioimmunoassay was investigated in a study including 60 diaphyseal rat femora. Substance P, calcitonin gene-related peptide, neuropeptide Y and vasoactive intestinal polypeptide, previously identified in bone by immunohistochemistry, were extracted from separate homogenates of bone, periosteum and bone marrow in a solution of 4% EDTA and 2 M acetic acid. Measurable amounts of all four neuropeptides in bone, periosteum and bone marrow were obtained by radioimmunoassay in a reproducible manner. The neuropeptide immunoreactivities were characterized by reverse-phase high performance liquid chromatography. Among the four neuropeptides analyzed, neuropeptide Y consistently exhibited the highest concentrations in the different tissues. Overall, cortical bone showed the lowest neuropeptide concentrations. The concentration of vasoactive intestinal polypeptide was higher in periosteum than in bone marrow, whereas that of calcitonin gene-related peptide was uniform in these tissues. The distributional differences observed in bone tissue may be explained by a variety of physiological roles attributed to neuropeptides such as regulation of nociception, vasoactivity, immune function and local bone metabolism. The described methodology offers a new means of investigating a neuropeptidergic involvement in various disorders of the skeleton.

Animals↗

PubMed1994

Substance P-, neurokinin A-, calcitonin gene-related peptide- and neuropeptide Y-like immunoreactivity (-LI) in rat knee joint synovial fluid during acute monoarthritis is not correlated with concentrations of neuropeptide-LI in cerebrospinal fluid and plasma.

In a recent study we have shown a bilateral release of substance P (SP)-, neurokinin A (NKA)-, calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-like immunoreactivity (-LI) in rat synovial fluid during acute monoarthritis. In order to elucidate the mechanisms underlying these phenomena, we examined the correlation between neuropeptide-LI in rat cerebrospinal fluid (CSF) and synovial fluid and between plasma and synovial fluid following the intra-articular injection of equal volumes (0.05 ml) of either Freund's adjuvans, carrageenan 2%, substance P 10(-5) M or human recombinant interleukin-1 alpha. Control rats were given saline intra-articularly. CSF, plasma and synovial fluid from the knee joints were obtained at 2, 6 and 24 h after injection and were analysed by specific radioimmunoassays. The intra-articular injection of pro-inflammatory substances induced changes in neuropeptide-LI in synovial fluid, CSF and plasma. However, there was no correlation between neuropeptide-LI in synovial fluid and plasma or between synovial fluid and CSF. The results of the present study does not support the hypothesis that the bilateral changes in neuropeptide-LI in synovial fluid were due to a release of neuropeptides from the inflamed joint into the systemic circulation. However, in carrageenan induced inflammation there was a tendency towards a correlation in SP-LI between CSF and synovial fluid suggesting that central neurogenic mechanisms should be studied in order to explain the bilateral changes seen.

Acute Disease↗

PubMed1994

VIP-antiserum inhibits fluid secretion by the inflamed gallbladder mucosa.

The inflammatory fluid secretion by the gallbladder mucosa in experimental cholecystitis is induced by an increased prostaglandin formation and is mediated by intramural nerves. In the present study the effect of VIP-antiserum on the inflammatory fluid secretion in the gallbladder was tested in a validated experimental model in cats. The animals were studied in acute experiments 6 weeks after a procedure when the cystic duct was tied and gallstones were implanted in the gallbladder. During basal conditions there was a continuous secretion of fluid into the lumen of the inflamed gallbladder averaging 0.43 +/- 0.18 ml/h. Injection of VIP antiserum, obtained from immunized rabbits and diluted with saline 1:10 in a bolus of 4 ml into the coeliac artery reversed this secretion into an absorption of 1.72 +/- 0.44 ml h-1 (P < 0.001). VIP-antiserum did not affect the fluid adsorption in control animals with an intact gallbladder and injection of control serum from rabbits not immunized to VIP did not affect fluid secretion in the inflamed gallbladders. The results support the idea that the inflammatory fluid secretion in the gallbladder mucosa is mediated by VIP-ergic nerve fibres.

Animals↗

PubMed1994

HCl-stimulated duodenal HCO3- secretion in conscious rat. Interactions among VIP, nicotinic receptor mechanisms, and prostaglandins.

Using an isolated loop of the proximal duodenum of conscious rats, the role of vasoactive intestinal peptide (VIP) in the duodenal HCO3- response to HCl was examined, especially interactions with participating cholinoceptor mechanisms and prostaglandins. A 5-min perfusion with 150 mmol/liter HCl increased luminal VIP during 3 hr, with a peak output during and immediately after the acid challenge. The HCl-stimulated output was unaffected by atropine and hexamethonium, but was augmented by indomethacin from 13.6 (9.5-17.8) to 39 (20-85) fmol/cm/min. The HCO3- secretion in response to graded doses of intravenous VIP (0.00625-6 nmol/kg/30 min) was dose-dependent to maximally 33.5 +/- 10.5 mumol/cm/hr. The HCO3- secretion during a single intravenous infusion of VIP (12 nmol/kg/hr), 13.9 +/- 4.2 mumol/cm/hr, was unchanged by atropine, reduced to 10.0 +/- 3.5 mumol/cm/hr by hexamethonium, and augmented to 18.9 +/- 4.7 mumol/cm/hr by indomethacin. Exogenous VIP did not change the basal luminal output of PGE2; neither did exogenous PGE2 nor indomethacin affect the basal luminal output of VIP. HCl-induced increases in luminal outputs of VIP, substance P, and neurokinin A (the two latter with unknown roles) were differentially affected by atropine, hexamethonium, and indomethacin, indicating that the acid challenge released the peptides through controlled mechanisms. In conclusion, in the duodenal HCO3- response to luminal HCl, VIP may have a stimulatory role, which partially depends on nicotinic, but not on muscarinic cholinoceptor mechanisms, and which is negatively modulated by prostaglandins.

Animals↗

PubMed1994

Microflora modulates endocrine cells in the gastrointestinal mucosa of the rat.

BACKGROUND/AIMS: Gastrointestinal peptides and biogenic monoamines participate in the regulation of gastrointestinal functions. The aim of this study was to examine the influence of the microflora on the distribution of endocrine cells and on the release of gastrointestinal peptides. METHODS: A quantitative morphological study using stereological methods was performed in gastrointestinal sections of conventional and germ-free rats. Tissue and plasma concentrations of peptides were measured. RESULTS: The total volumes of gastrin- and serotonin-immunoreactive cells were significantly increased in the gastric mucosa of germfree rats (P < 0.05), as well as the total volumes of serotonin- and motilin-immunoreactive cells in the ileum (P < 0.05) and serotonin-immunoreactive cells in the colonic mucosa (P < 0.05). The tissue concentration of somatostatin was significantly higher in the jejunum (P < 0.05) and lower in the ileum of germfree rats than in controls (P < 0.05). Plasma glucagon was significantly increased in germfree rats (P < 0.05). The total volume of the fundic mucosa was enlarged in germfree rats (P < 0.05), whereas the total volume, the mucosal thickness, and the number of crypt cells of the colonic mucosa were significantly reduced in these rats compared with controls (P < 0.05). CONCLUSIONS: Our findings suggest that the intraluminal microflora influences the release of biologically active peptides and that it participates in the regulation of gastrointestinal endocrine cells and the epithelial structure.

Animals↗

PubMed1994

Extraction of neuropeptides from joint tissue for quantitation by radioimmunoassay. A study in the rat.

The feasibility of extracting neuropeptides from rat knee joints for quantitation by radioimmunoassay was tested. The investigation, based on 25 adult Lewis rats, focused on substance P, calcitonin gene-related peptide, neuropeptide Y, and vasoactive intestinal polypeptide. The relative recovery of the peptides in different extraction media was assessed Both knee joints including the articulating epiphysis were dissected and cut into small pieces. The series was divided into five subgroups, 10 joints in each, for extraction in five different media: 1) 1 M acetic acid in 4% EDTA, 2) 2 M acetic acid in 4% EDTA, 3) neutral water in 4% EDTA, 4) 2 M acetic acid in 4% EDTA and 95% alcohol, and 5) 2 M acetic acid without EDTA. Measureable concentrations of the four neuropeptides were reproducibly assessed by RIA. Although all extraction media provided measurable concentrations, 2 M acetic acid in 4% EDTA was found to give the highest overall yield of the four neuropeptides analyzed. Reverse-phase HPLC confirmed that the immunoreactivities assessed by RIA corresponded to the four neuropeptides of interest. Experimental and clinical evidence suggest a neurogenic involvement in the pathophysiology of inflammatory joint disease, e.g., rheumatoid arthritis. The extraction procedure described offers a means of determining neuropeptide concentrations in joint tissue under normal and pathologic conditions by RIA.

Animals↗

PubMed1994

Glutamine supplementation does not prevent small bowel mucosal atrophy after total parenteral nutrition in the rat.

Glutamine supplementation to non-lipid parenteral nutrition has been demonstrated to attenuate villus atrophy and increase mucosal DNA content in the rat. This study was performed in order to determine the effects of glutamine supplementation to a balanced TPN mixture (including lipids) on epithelial cell kinetics using autoradiography. Male Sprague-Dawley rats were used. Group 1 (control) received food and an intravenous saline infusion. Group 2 received an intravenous TPN mixture including lipids but without glutamine. The same TPN mixture, glutamine replacing an isonitrogenous amount of non-essential amino acids, was given to Group 3. Animals were fed for 7 days, whereafter blood and intestinal samples were taken 1 h after injection of tritiated thymidine. Microscopy of specimens from proximal jejunum revealed a significant reduction in the number of cells in crypts and villi in both TPN groups (2 and 3) compared to orally fed animals (p < 0.001). Epithelial cell numbers were not significantly different in Group 2 and 3. Similarly, the labelling index (number of labelled cells/number of crypt cells) was not affected by glutamine administration. In plasma, glucagon concentrations in Group 2 (TPN without glutamine) seemed to decrease compared to Group 1 and 3 (p = 0.06). In this study, glutamine supplementation did not affect apithelial atrophy or cell proliferation. It is concluded, that the effects of glutamine on mucosal atrophy and renewal in jejunum may depend on the composition of the TPN mixture supplied during parenteral feeding.

Journal Article↗

PubMed1994

Repeated electroconvulsive stimuli: changes in neuropeptide Y, neurotensin and tachykinin concentrations in time.

1. The effects of repeated electroconvulsive stimuli (ECS) on neuropeptide Y (NPY)-, neurokinin A (NKA)-, substance P (SP)- and neurotensin (NT)- like immunoreactivity (-LI) levels in specific rat brain regions were studied in order to establish changes in peptide tissue concentrations in time after the last ECS. 2. The rats were sacrificed 15 minutes, 60 minutes, 1 day, 7 days or 15 days after the sixth sham ECS or ECS, using focused microwave irradiation. 3. Following dissection of the brains, peptides were extracted and measured in extract aliquots by radioimmunoassays. 4. ECS increased NPY-LI in both right and left hippocampus, frontal cortex and occipital cortex at 15 min, 60 min and 1 day after the treatments. Seven days following the last treatment, NPY-LI concentrations were elevated in the left hippocampus and occipital cortex but not in the corresponding right structures. Fifteen days following the last ECS treatment no changes in NPY concentrations were seen. 5. Also NKA-LI was increased in both the right and left hippocampus; the duration of changes was identical to those of NPY-LI. 6. No effects on SP- or NT-LI were found. 7. These results are in line with our hypothesis that one of the ECT's mechanisms of action might involve its effects on NPY and NKA.

Animals↗

PubMed1994

Polyamines regulate human medullary thyroid carcinoma TT-cell proliferation and secretion of calcitonin and calcitonin gene-related peptide.

The significance of polyamines for the neoplastic proliferation and secretion of calcitonin (CT) and calcitonin-gene-related peptide (CGRP) by the human medullary thyroid carcinoma TT cell line was investigated. TT cells were cultured in vitro for 6 days with or without additions of pathway inhibitors of polyamine biosynthetic enzymes. Treatment of the cells with 1 mM of the specific L-ornithine decarboxylase (ODC) inhibitor DL-alpha-difluoromethylornithine (DFMO) resulted in a 97% decrease in ODC activity, lowered contents of putrescine (96%) and spermidine (85%) and cell proliferation rates (90%) along with a compensatory 15-fold increase in S-adenosyl-L-methionine decarboxylase (SAMDC) activity. DFMO treatment also led to a decrease in cellular content of CT (33%) and CGRP (26%), while the drug enhanced secretion of CT (31%) but depressed that of CGRP (26%), and elevated the ratio of CT to CGRP secreted into the medium by 74%. Ethylglyoxal bis(guanylhydrazone) (EGBG), a SAMDC inhibitor, at 100 microM evoked a similar reduction of cell proliferation and lowered the content of spermine by 81%. Furthermore, EGBG treatment caused a 34-fold increase in ODC activity and a subsequent 35-fold build-up of putrescine, but also seemed to stabilize SAMDC as evidenced by a highly enhanced SAMDC activity (approximately 200-fold) during enzyme assays in the absence of the inhibitor. EGBG exposure resulted in an increase in cellular CT content (110%) and secretion of the hormone (82%), while not affecting CGRP content or release.2+ EGBG effects were partially counteracted by DFMO.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosylmethionine Decarboxylase↗