[New knowledge of the cause of diabetes?].
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Diabetes Mellitus, Type 2↗
Biomedical subjects
E Eldrup
Publications and source records attributed to E Eldrup.
Evaluation of plasma 3,4-dihydroxyphenylacetic acid (DOPAC) and plasma 3,4-dihydroxyphenylalanine (DOPA) as tumor markers in children with neuroblastoma.
Catecholamines and their metabolites are important in the diagnosis of neuroblastoma (NB). Plasma (p-) levels of 3,4-dihydroxyphenylalanine (DOPA) are increased in most NB, probably reflecting decreased DOPA decarboxylase activity. Urine (u-) homovanillic acid (HVA), a DOPA and dopamine (DA) metabolite. is also increased in most NB. DOPAC (3,4-dihydroxyphenylacetic acid) is an important metabolite of DA in tissues with monoamine oxidase (MAO) activity. Because MAO is expressed in NB tumor cells, we studied the importance of measuring p-DOPAC and p-DOPA as compared to u-HVA and u-vanillylmandelic acid (VMA) in the diagnosis and follow-up of NB. DOPAC, DOPA, dopamine, noradrenaline, adrenaline, VMA and HVA were measured by reverse-phase HPLC with electrochemical detection in 106 children (28 with NB (13 newly diagnosed), 25 with other solid tumors, 28 hospitalized for nonneoplastic diseases, and 25 healthy children). P-DOPAC or p-DOPA concentrations were above the upper normal range in 92% of untreated NB patients, as were u-HVA or u-VMA levels. None of these tumor markers was correlated to tumor stage or survival. P-DOPA but not p-DOPAC was correlated to age in NB children. Increased values of p-DOPAC and p-DOPA were found in one patient surviving NB for 10 years. Plasma DOPAC concentrations were decreased in children hospitalized for non-NB diseases, probably reflecting reduced food intake. Plasma analyses of DOPA and DOPAC seem to be useful alternatives in the diagnosis and follow-up of NB if urine sampling is to be avoided. Plasma DOPAC may be an index of nutritional status in various diseases.
3,4-Dihydroxyphenylacetic Acid↗
DOPA, dopamine, and DOPAC concentrations in the rat gastrointestinal tract decrease during fasting.
The aim of the present study was to test the hypothesis that 3, 4-dihydroxyphenylalanine (DOPA) and dopamine (DA) in the gastrointestinal tract are to a large extent of exogenous origin and derived from food. Tissue concentrations of norepinephrine (NE), epinephrine (Epi), DA, DOPA, and 3,4-dihydroxyphenylacetic acid (DOPAC), as measured by reverse-phase HPLC with electrochemical detection, were studied in fed and 4-day-fasted Wistar rats as well as in sympathectomized and adrenodemedullated rats. Sympathectomy and adrenal demedullectomy decreased tissue concentrations of NE and Epi, respectively, but had no effect on the level of tissue DOPA. Large amounts of DOPA and DA were present in the gastrointestinal tract. Fasting decreased DOPA and DA in the stomach and DOPA concentrations in the quadriceps muscle but no concentrations in other organs. DOPAC in the heart decreased both in response to sympathectomy and to fasting, whereas DOPAC decreased in plasma after fasting and in skeletal muscle after sympathectomy. We conclude that the food content of DOPA and DA is of major importance for the metabolism of DA and, thus, for the dopamine-sulfate content in the gastrointestinal tract and in plasma. The decrease in muscle DOPA after fasting may be explained by less insulin being available during fasting for stimulation of DOPA uptake in the muscle depot. DOPAC in the organism seems to be of a dual origin, derived partly from DA in the food and partly from DA synthesized in sympathetic nerves.
3,4-Dihydroxyphenylacetic Acid↗
[Dipyridamole plus acetylsalicylic acid--who is to be trusted?].
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Aspirin↗
Origin and significance of plasma dihydroxyphenylalanine.
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Animals↗
Effects of ordinary meals on plasma concentrations of 3,4-dihydroxyphenylalanine, dopamine sulphate and 3,4-dihydroxyphenylacetic acid.
1. Plasma concentrations of 3,4-dihydroxyphenylalanine (DOPA), dopamine sulphate (DA-S), and 3,4-dihydroxyphenylacetic acid (DOPAC) in humans have been claimed to be indexes of sympathetic nervous activity, but the source and significance of plasma DOPA, DOPAC and DA-S have not been completely elucidated. 2. The effects of ordinary meals on plasma concentrations of total dopamine, mainly DA-S, DOPAC and DOPA were studied in seven healthy subjects. Venous blood was collected every hour for 25 h, while subjects were either fasting or received three meals at 9.00 hours, 13.00 hours and 18.00 hours. Catecholamines and metabolites were determined by reverse-phase HPLC with electrochemical detection. Neutral amino acids were measured by ion-exchange chromatography with photometric detection. 3. The food contained relatively little DOPA as compared with phenylalanine, tyrosine, isoleucine and tryptophan. The content of DA and DA-S varied considerably, with the greatest amount in the evening meal of open sandwiches. 4. Plasma DOPA decreased significantly after the meals at 13.00 hours and 18.00 hours, whereas concentrations of the other amino acids increased as expected. 5. Plasma DA-S increased significantly after meals and especially after the evening meal. Increments in DA-S above basal values after a meal were closely related to the content of DOPA+DA+DA-S in the meal. Plasma DOPAC increased significantly after the evening meal. 6. The decrease in plasma DOPA observed after a meal was probably due to uptake of DOPA by muscle tissue. Changes in plasma DA-S and DOPAC during this 25-h study reflected to a large extent the content of DOPA, DA and DA-S in the meals.
3,4-Dihydroxyphenylacetic Acid↗
beta-cell function and glucose and lipid oxidation in Graves' disease.
OBJECTIVE: Abnormal glucose metabolism with impaired glucose tolerance has been documented in patients with thyrotoxicosis but the pathogenesis is not fully understood. Therefore, the aim of the present study was to study the beta-cell function and the meal induced oxidative glucose and lipid metabolism in patients with thyrotoxicosis. DESIGN: After an overnight fast the impact of hyperthyroidism on standard mixed meal induced glucose oxidation, lipid oxidation and beta-cell function was studied. PATIENTS: Nine untreated patients with Graves' disease were compared to 9 age and weight matched healthy controls. MEASUREMENTS: Glucose and lipid oxidation were studied by indirect calorimetry before and after the meal. The insulin secretion rate was calculated by the 'combined model' approach, after which the insulin secretion rates and the ambient glucose levels were cross-correlated. The slope of these regression lines was used as a measure of beta-cell sensitivity to glucose and denotes the insulin secretory capacity. beta-Cell function was further evaluated by measurement of proinsulin and its conversion intermediates. Glucoregulatory hormones were also measured. The findings were correlated to the thyroid hormone levels. RESULTS: Fasting blood glucose and post-prandial glucose response were increased in patients (P < 0.01). The hyperthyroid patients displayed a 'dual' beta-cell defect: (a) inability to increase the insulin response appropriately to hyperglycaemia and (b) increased proinsulin levels both in the fasting state and in response to a meal. Indirect calorimetry showed increased lipid oxidation in the fasting state and at the end of the meal (P < 0.01). No difference in glucose oxidation was demonstrated in the fasting state but the post-prandial glucose oxidation was enhanced in the patients (P < 0.01). The adrenaline response was normal, whereas the noradrenaline response was impaired or absent in the patients. The thyroid hormone levels were significantly correlated to fasting levels of blood glucose, insulin, free fatty acids and lipid oxidation, but not to fasting C-peptide, glucose oxidation or catecholamines. CONCLUSIONS: Untreated Graves' disease was associated with glucose intolerance due to quantitative as well as qualitative beta-cell defects. The lipid oxidation was increased in the fasting state and at the end of the meal; after the meal the increase in glucose oxidation was more pronounced in the patients. Thyroid hormones thus increased the oxidation but not by an increase in catecholamines. Indeed, the post-prandial sympathetic response was blunted.
Adult↗
CSF and plasma concentrations of free norepinephrine, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), 3,4-dihydroxyphenylalanine (DOPA), and epinephrine in Parkinson's disease.
OBJECTIVE: To investigate endogenous cerebrospinal fluid catecholamines in Parkinson's disease. MATERIAL AND METHODS: Basal concentrations of free norepinephrine (NE), dopamine (DA), epinephrine (E), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylalanine (DOPA) in cerebrospinal fluid (csf) and plasma were measured using reverse-phase HPLC with electrochemical detection in 16 patients with Parkinson's disease and 21 control patients with low back pain. RESULTS: Parkinsonian patients had significantly decreased values of csf NE and DOPAC, the strong relationship between plasma and csf NE was disrupted and neither was there any age related increase of plasma NE. In l-DOPA treated patients plasma DA and DOPA concentrations were raised and csf DOPAC values were inversely related to severity of disease (Hoehn and Yahr score). Csf E concentrations were also reduced in parkinsonian patients whereas csf DA concentrations were unchanged. Csf DOPA concentrations were insignificantly decreased in parkinsonian patients. CONCLUSIONS: These results point towards a diffuse neuronal dysfunction in Parkinson's disease and indicate that lumbar csf NE and csf DOPAC are of central nervous origin.
3,4-Dihydroxyphenylacetic Acid↗
Increase in plasma 3,4-dihydroxyphenylalanine (DOPA) appearance rate after inhibition of DOPA decarboxylase in humans.
Concentrations of DOPA in plasma are relatively high as compared to norepinephrine. The significance of plasma DOPA has not been elucidated. One would expect that substantial amounts of DOPA are derived from sympathetic nerves. There appears, however, neither to be a depot of DOPA in nerves nor is there a close correlation between plasma DOPA and sympathetic activity. The aim of the present study was to obtain further information about plasma DOPA by studying DOPA kinetics in healthy humans both with and without inhibition of DOPA decarboxylase by benserazide. Plasma DOPA and other catecholamines were measured by reverse-phase HPLC with electrochemical detection and DOPA clearance and appearance rate were studied using infusion of 3H-DOPA. The plasma clearance of DOPA was 1.02 1 min-1. Approximately 20% of this value could be explained by DOPA being decarboxylated in the kidneys and excreted as dopamine. The DOPA appearance rate was 1.13 micrograms min-1 and the extremities accounted for approximately 1/5 of this value. After inhibition of DOPA decarboxylase by benserazide the DOPA appearance rate increased 7-fold, whereas the DOPA clearance only decreased slightly and insignificantly. These findings are probably explained by two factors: (1) There is normally a large production of DOPA in some tissues from which DOPA spillover into plasma only occurs to a minor extent and tracer DOPA only mixes with this compartments to a small degree; (2) These compartments are permeable to benserazide, which blocks the decarboxylation of DOPA, which then leaves the tissues and spillover to plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dihydroxyphenylacetic Acid↗
Venous plasma noradrenaline increases with age: correlation to total blood volume and long-term smoking habits.
Venous plasma noradrenaline (NA), cardiac index, total blood volume, and other haemodynamic parameters were measured in 12 young (median age of 29, range 21-37 years) and 10 elderly (median age of 68, range 55-85 years) healthy male subjects in the resting supine and sitting positions. Cardiac index was equal in the two groups and did not correlate to plasma NA. Plasma NA was significantly elevated in the elderly subjects in the sitting position (2.47 +/- 0.28 vs. 1.80 +/- 0.13 nmol l-1, P = 0.038). Elevated plasma NA levels were confined to elderly long-term smokers. Sitting plasma NA was significantly correlated to total blood volume corrected for body weight, r = -0.720, P = 0.0002, but with no difference in blood volume between smokers and non-smokers. It is concluded, that long-term smoking may result in elevated plasma NA levels seen in elderly subjects. It is suggested, that this is a compensatory mechanism to vascular dilation induced by chronic smoking.
3,4-Dihydroxyphenylacetic Acid↗
Pulsatile gonadotropin secretion and basal prolactin levels during dopamine D-1 receptor stimulation in normal women.
The effect of the specific dopamine D-1 receptor agonist Fenoldopam on pulsatile gonadotropin secretion and prolactin (PRL) secretion was investigated in normal women. The gonadotropin response to subsequent gonadotropin-releasing-hormone (GnRH) administration was also studied. Eight women received 8-hour infusions of either Fenoldopam (0.5 microgram/kg per minute) (Smith Kline and French, Harrow, United Kingdom) or placebo. After 7 hours of infusion, GnRH was given intravenously. The luteinizing hormone (LH) response to GnRH was significantly higher during Fenoldopam compared with placebo (LH; 13.1 +/- 9.0 versus 9.4 +/- 4.3 IU/L). Basal LH levels, pulse amplitude, and pulse frequency during Fenoldopam infusion were not different from placebo. Prolactin levels increased significantly during Fenoldopam (24 +/- 2 micrograms/L) compared with placebo (16 +/- 2). The results suggest that D-1 receptor stimulation does not affect pulsatile gonadotropin secretion but increases the pituitary responsiveness to GnRH. Additionally, dopamine and Fenoldopam have opposite effects on PRL secretion, the latter increasing PRL levels.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Monocyte chemotactic activity in sera after hypnotically induced emotional states.
In a number of studies it has been shown that psychological factors in general and specifically emotional factors can be correlated to changes in immunological function and defence mechanisms. Although the mediating pathways between the central nervous system and the immune system still remain unclear, it is known that some of the 'classical stress hormones' such as cortisol and catecholamines have modulatory effects on different immunological parameters. In this investigation we wished to study the effect of brief hypnotically induced emotional states on monocyte chemotaxis and endocrinological parameters. Eleven highly hypnotically susceptible volunteers were, while in a deep trance, given suggestions to re-experience earlier life experiences involving intense anger and depression in random order. Before concluding hypnosis subjects were given suggestions to re-experience a feeling of happiness and well-being. Monocyte chemotactic activity in sera and serum levels of cortisol, as well as venous plasma levels of the catecholamines epinephrine, norepinephrine, DOPA and DOPAC, were measured before hypnosis, after each emotional state and immediately after hypnosis. The results showed a significant differences (P less than 0.02) in chemotactic activity between the angry and the depressed emotional states, the depressed state exhibiting a decreased chemotactic index compared with the angry state. Chemotactic index after the happy relaxed emotional state also showed a significant (P less than 0.01) increase compared with both chemotactic index before hypnosis and chemotactic activity after the angry and depressed state. Though there were significant differences between emotions and between emotions and the before-hypnosis-condition, no clear-cut significant differences between the emotional states of anger and depression could be detected for serum cortisol levels and catecholamine plasma levels. Significant positive correlations (P less than 0.01) for differences in chemotactic activity and differences in plasma DOPA levels between emotional states was found. When investigated in vitro, DOPA did not in itself exhibit monocyte chemotactic properties. No other significant correlations between differences in chemotactic activity and other endocrinological parameters could be detected. Soluble interleukin-2 receptors in serum were also measured. No significant differences were found.
Anger↗
The relationship between age and venous plasma concentrations of noradrenaline, catecholamine metabolites, DOPA and neuropeptide Y-like immunoreactivity in normal human subjects.
Forearm venous plasma concentrations of noradrenaline (NA), catecholamine metabolites (dihydroxyphenylglycol (DHPG), dihydroxyphenylacetic acid (DOPAC], dihydroxyphenylalanine (DOPA) and neuropeptide Y-like immunoreactivity (NPY-LI) were studied in 22 men aged 20 to 81 years in the supine position and after 30 min of standing posture. Venous plasma NA, DHPG and NPY-LI increased significantly in the standing position, whereas venous plasma DOPAC and venous plasma DOPA remained unchanged. Increments in venous plasma NA and DHPG upon standing up, as well as venous plasma NA in the standing-up position, increased significantly with age. The ratio between increments in venous plasma DHPG and venous plasma NA did not change with age. Venous plasma NPY-LI and venous plasma DOPA did not change with age, whereas venous plasma DOPAC decreased significantly. Changes in venous plasma NPY-LI were negatively correlated with changes in pulse pressure. These results confirm previous studies that sympathetic activity increases with age. The unchanged ratio between increments in venous plasma DHPG and venous plasma NA suggests that intra-neuronal deamination of recaptured NA is unchanged in the elderly. The lower basal venous plasma DOPAC concentration may suggest a reduced basal intraneuronal synthesis of NA in old age.
3,4-Dihydroxyphenylacetic Acid↗
Effect of dopamine and a dopamine D-1 receptor agonist on pulsatile thyrotrophin secretion in normal women.
The inhibitory effect of a pharmacological dose of dopamine and the specific dopamine D-1 receptor agonist fenoldopam on basal and pulsatile TSH secretion was investigated in normal women. The TSH response to fenoldopam and subsequent releasing hormone administration was also studied. Six women received placebo or dopamine infusion (4.0 micrograms/kg min) for 17 h. After 9 h, blood samples were collected every 10 min between 0800 and 1600 h for measurement of TSH. Eight women received 8-h (0900-1700 h) infusions of either fenoldopam (0.5 micrograms/kg min) or placebo. After 7 h of infusion 10 micrograms TRH, 5 micrograms GnRH and 25 micrograms CRF was given i.v. Blood samples were collected every 10 min. Dopamine infusion as well as fenoldopam infusion significantly reduced both mean basal TSH secretion and TSH pulse frequency compared with corresponding control infusions (P less than 0.05). However, while the effect on TSH pulsatility was comparable (P greater than 0.05), the percentage decrease in basal TSH levels after 16 h of dopamine infusion was 51 +/- 16% (mean +/- SD) and after 7 h of fenoldopam infusion 19 +/- 12% (P less than 0.05). Neither of the drugs affected TSH pulse amplitude and fenoldopam did not influence TRH-stimulated TSH release (P greater than 0.05). The results suggest that dopamine D-1 receptors are involved in modulation of TSH pulsatility probably at the hypothalamic level. It is argued that dopaminergic inhibition of basal TSH secretion and TSH pulsatility is predominantly regulated through dopamine D-2 receptors at the pituitary level, and through D-1 receptors at the hypothalamic level, respectively.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Effect of dopamine, dopamine D-1 and D-2 receptor modulation on ACTH and cortisol levels in normal men and women.
The regulation of the hypothalamic-pituitary-adrenal axis by dopamine is not fully understood. Therefore, we have studied the effect of dopamine, metoclopramide, a D-2 receptor antagonist, and fenoldopam, a specific D-1 receptor agonist, on ACTH and cortisol levels in normal subjects. Normal women received 5-h infusions of either glucose (N = 6) or dopamine at rates of 0.04 (N = 6), 0.4 (N = 6) and 4.0 micrograms.kg-1.min-1 (N = 8). After 3 h, 10 mg metoclopramide was given iv. No intergroup differences regarding ACTH and cortisol levels were observed (p greater than 0.05). In a second study six women received dopamine (4.0 micrograms.kg-1.min-1) or glucose for 18 h. During the infusions cortisol and ACTH levels were similar on the two study days. Administration of metoclopramide (10 mg) after 17 h induced a significant increase in cortisol levels during dopamine infusion (p less than 0.05), whereas no effect was observed during placebo infusion. ACTH levels were unaffected by metoclopramide. In a third study, 9 normal women and 9 normal men received fenoldopam (0.5 micrograms.kg-1.min-) or placebo infusions for 3 h. In males, median ACTH and cortisol levels were significantly lower (p less than 0.05) during fenoldopam compared with placebo infusion. In contrast, fenoldopam did not affect ACTH and cortisol levels in normal women. The results suggest that the effect of dopamine D-1 receptor stimulation on ACTH and cortisol secretion is mainly at the hypothalamic level and that this effect is sex-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Variability in plasma oestrogen concentrations in men with a myocardial infarction.
Several studies have reported high levels of oestrogens--especially oestradiol--in plasma in men surviving an acute myocardial infarction (AMI). We have measured plasma levels of the two major oestrogens, oestrone and oestradiol, for three days during the acute AMI and at three months after discharge. Patients admitted to a coronary care unit with ischaemic heart disease without proof of an infarction and patients without evidence of heart disease served as controls. We found significantly higher oestrone levels during the acute infarction than at three months afterwards and also higher than in men without AMI. Men who died shortly after admission had grossly elevated plasma oestrone concentrations. As oestrone levels were correlated to excretion of catecholamines and cardiac enzyme levels in plasma and as circulating levels of oestrone are influenced by ACTH, the hyperoestronaemia may reflect stress-induced increased adrenocortical activity. Plasma oestradiol concentrations in men with AMI decreased significantly during the first three days after admission. In men given no medication oestradiol concentrations did not differ significantly from those in the control groups. Three months after the infarction, the median plasma oestradiol (but not oestrone) concentrations were significantly elevated, but not if only data from men given no medication were considered.
Adult↗
Possible thyrotrophs insensitivity to dopamine in hyperprolactinaemic amenorrhoeic patients.
The study assessed the sensitivity of the thyrotrophs of hyperprolactinaemic patients to a physiological dose of dopamine (DA). Eight hyperprolactinaemic amenorrhoeic patients received 4-hour infusions of either DA (0.4 micrograms/kg x min) or glucose. Twelve normal women served as controls. In normal women the mean thyrotrophin (TSH) concentration declined significantly (P less than 0.05) from 81 +/- 6.6% of basal levels during glucose infusion to 59 +/- 5.8% of basal levels during DA infusion. In contrast DA infusion to hyperprolactinaemic patients caused no significant reduction in TSH levels compared to glucose infusion (DA infusion 68 +/- 4.7% of basal levels; glucose infusion 73 +/- 4.9% of basal levels). DA infusion caused a significant reduction in serum prolactin (PRL) levels both in hyperprolactinaemic patients (P less than 0.001) and normal women (P less than 0.02), but the PRL suppression was significantly (P less than 0.05) less pronounced in the hyperprolactinaemic patients, compared to normal women. We propose that the abnormal PRL as well as TSH secretion in hyperprolactinaemic amenorrhoeic patients may be due to a common defect. Both the lactotrophs and the thyrotrophs may be relatively insensitive to dopaminergic inhibition.
Adult↗
Effect of fenoldopam, a dopamine D-1 receptor agonist, on pituitary, gonadal and thyroid hormone secretion.
The influence of fenoldopam, a dopamine (DA) D-1 receptor agonist, on basal and GnRH/TRH stimulated PRL, GH, LH, TSH, testosterone and thyroid hormone secretion was studied in nine normal men. All men received 4-h infusions of either 0.9% saline or fenoldopam at an infusion rate of 0.5 microgram/kg min, 12-16 ml/h, adjusted according to weight. After 3 h of infusion, 50 micrograms GnRH and 100 micrograms TRH was given i.v. Blood samples were collected every 15 min from 1 h before to 1 h after the infusion for a total of 6 h for measurements of PRL, LH, FSH, GH, TSH, testosterone, T4 and T3. The median PRL concentration increased significantly (P less than 0.01) to 128%, range 87-287, of preinfusion levels, compared to the decline during control infusion (85%, 78-114). Basal TSH levels declined significantly to 71% (60-91) during fenoldopam compared with 82% (65-115) during control infusion (P less than 0.05). Basal LH, FSH, GH and thyroid hormones were similar during fenoldopam and control infusions (P greater than 0.05). The LH response to GnRH/TRH was significantly (P less than 0.02) increased by fenoldopam infusion. Basal and stimulated testosterone concentration was lower during fenoldopam (P less than 0.01) infusion compared with control. Other hormones were similar after GnRH/TRH stimulation during fenoldopam and saline infusions. These results suggest that DA D-1 receptors are involved in the modulation of pituitary hormone secretion. We suggest that the effect of fenoldopam on PRL and TSH is mainly at the hypothalamic level. Regarding the effect on LH concentrations, an additional direct effect of fenoldopam on testosterone regulation can not be excluded.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗