SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Seven patients with Cushing's syndrome were treated with trilostane (WIN 24,540) 4 alpha,5-epoxy-17 beta-hydroxy-3-oxo-5 alpha-androstane-2 alpha-carbonitrile), an inhibitor of adrenal steroid biosynthesis. Trilostane treatment reduced steroid biosynthesis and it also improved biochemical manifestations of the disease in all of the patients treated. The average cortisol secretory rate decreased significantly with treatment, from 47.1 to 23.4 mg/24 h (P less than 0.005), and urinary 17-hydroxycorticosteroids decreased from 15.7 to 8.7 mg/24 h (P less than 0.01). Urinary free cortisol excretion decreased from 277 to 88 microgram/24 h (P less than 0.01), and 0800 h plasma cortisol levels declined from 25.0 to 12.0 microgram/dl (P less than 0.05). Conversely, dehydroepiandrosterone sulfate excretion in urine increased from 1.3 to 5.8 mg/24 h (P less than 0.0025) and in plasma increased from 162 mg/24 h (P less than 0.025). Plasma and urinary free dehydroepiandrosterone increased 2-fold. Urinary 17-ketosteroid excretion increased from 18 to 43 mg/24 h (P less than 0.001). A significant reduction in urinary excretion of tetrahydroaldosterone, tetrahydrodeoxycorticosterone, and 18-hydroxytetrahydrodeoxycorticosterone was observed with treatment. Inhibition of steroid biosynthesis was accompanied by a 2-fold increase in PRA and no change in serum cholesterol levels. Mean arterial blood pressure decreased with treatment from 109 to 97 mm Hg (P less than 0.005), and fasting blood sugar decreased from 117 to 98 mg/dl (P less than 0.005), accompanied by rise in plasma potassium levels from 3.8 to 4.3 milliequivalents/liter (P less than 0.025). Two patients on long term therapy also showed an improvement in clinical features of their disease. There were no significant treatment-related carcinoma, simultaneously producing both an excessive amount of cortisol and ACTH, is described. It is concluded that trilostane is an effective inhibitor of 3 beta-hydroxysteroid dehydrogenase enzyme system in human adrenal gland; it inhibits biosynthesis of cortisol and it is useful in the treatment of Cushing's syndrome.
A patient with Cushing's disease is described who underwent transsphenoidal adenomectomy of a basophilic microadenoma with a diameter of 3 mm. In a piece of surrounding normal pituitary tissue removed at operation, multiple small nests of adenomatous basophilic cells were found both in the adeno- and neurohypophysis. No clinical improvement was observed. Cortisol secretory rate, plasma ACTH, the absent response of plasma cortisol to insulin-induced hypoglycemia, and the responses of plasma cortisol to lysine vasopressin and TRH remained unchanged. The observations in this patient point to the presence of multiple ACTH-secreting adenomatous cell nests and microadenomas throughout pituitary gland and bring back into view the concept of primary stimulation of hypothalamic corticotropin-releasing factor as the primary derangement in some patients with Cushing's disease.
Dispersed parathyroid cells were employed to study calcium-regulated parathyroid hormone (PTH) release in severe secondary hyperparathyroidism due to chronic renal insufficiency. Cell preparations were obtained from 16 parathyroid glands of 6 patients undergoing subtotal parathyroidectomy for parathyroid bone disease and/or hypercalcemia. The effects of increasing ambient calcium concentration on immunoreactive PTH release in vitro were assessed and compared with results observed in cells prepared from 7 adenomas and 6 normal parathyroid glands. There was no difference in maximal PTH release for the 3 types of tissue (mean +/- SEM, 8.48 +/- 1.9 , 8.1 +/- 3, and 10.1 +/- 0.78 ng/10(5) cells. h respectively). In 14 of 16 hyperplastic glands, 6 of 7 adenomas, and all of the normal glands, PTH release was inhibited more than 50% by 2-3 mM calcium (suppressible glands). Of the normal glands, half of the maximal inhibition of PTH release (the set-point) occurred at less than 1.03 mM calcium in 5 of 6 cases. In 12 of 14 suppressible hyperplastic glands and all of the 6 suppressible adenomas, on the other hand, the set-point was 1.03 mM or higher (p less than 0.01 and P less than 0.002, respectively). Thus, in severe secondary parathyroid hyperplasia due to chronic renal insufficiency, there is frequently an increase in the set-point for calcium without a change in the maximal secretory rate per cell. Abnormal calcium-regulated PTH release at the cellular level, therefore, is not limited to parathyroid neoplasia (i.e. adenoma or primary hyperplasia), but may occur in secondary hyperplasia as well.
We employed a computer program to curve-fit data relating PTH release in vitro to the extracellular calcium concentration in parathyroid cells prepared from normal bovine and human as well as pathological human parathyroid tissue. In bovine cells and 82% of human cell preparations in which PTH release was more than 50% suppressible by high calcium concentrations, the data were successfully fitted to symmetrical sigmoidal curves. Such curves were defined by four parameters [A = maximum PTH release, B = slope of the curve at the setpoint, C = set-point (calcium concentration causing half-maximal inhibition of secretion), and D = minimum PTH release]. There was excellent agreement between the predicted values for these parameters and those we have obtained previously using visual fits. We also generated theoretical curves with the program to assess the possible contribution of changes in parameters A through D to hypersecretion of PTH in hyperparathyroidism. These analyses suggested that changes in maximal PTH secretion, slope of the curve, set-point, and maximal suppressibility of PTH release all might contribute to hormonal hypersecretion. On a quantitative basis, however, changes in the set-point produced the largest alteration in secretory rate for a given change in the value of a parameter. These results provide a mathematical model for the relationship between PTH release and the extracellular calcium concentration. Moreover, they provide a means of analyzing theoretically the contribution of various qualitative changes in this relationship to states of hypo- and hypersecretion of PTH.
To investigate the pulsatile nature of PRL release in the physiologically hyperprolactinemic postpartum period, we sampled blood at 10-min intervals for 24 h in each of 6 healthy lactating women at both 3 weeks and 3 months postpartum. The subsequent immunoactive PRL time series were subjected to episodic peak detection (Cluster analysis) and multiple parameter deconvolution analysis. The 24-h mean serum PRL concentrations were significantly higher at 3 weeks than at 3 months postpartum; viz. 113 +/- 12 vs. 66 +/- 15 micrograms/L (P = 0.003). Assessment of episodic PRL pulsatility revealed significantly higher maximal PRL peak heights (296 +/- 63 vs. 141 +/- 44 micrograms/L), fractional peak heights (863 +/- 150 vs. 374 +/- 58%), incremental peak amplitudes (250 +/- 60 vs. 96 +/- 3 micrograms/L), and peak areas (13 +/- 3 vs. 4 +/- 1 mg/L.min) in the earlier postpartum period. In contrast, PRL peak frequencies and interpulse intervals were not different in the early and late postpartum sessions. Deconvolution analysis revealed that the mean mass of PRL secretory bursts was significantly greater at 3 weeks (182 +/- 4.1 micrograms/L) than 3 months (15 +/- 1.6 micrograms/L). There were no changes in the calculated half-life of endogenous PRL viz. 29 +/- 2.5 min (3 weeks) vs. 26 +/- 3.0 min (3 months). We conclude that physiological postpartum hyperprolactinemia is achieved by selectively altering the endogenous secretory rate in each PRL release episode, with no change in the number of bursts of PRL discharged or the PRL half-life.
To investigate the mechanisms responsible for the postpartum suppression of reproductive function, LH and PRL levels were determined at 10-min intervals for 8 h in 10 lactating women, in 10 nonlactating women treated with bromocriptine, and in 5 nonpuerperal women. The lactating women were studied on postpartum day 7 (n = 5) or between days 28 and 35 (n = 5). All nonlactating women were studied on day 7. Five of them were treated with the opioid antagonist naltrexone to evaluate the role of endogenous opioids. By using a specific LH assay which does not cross-react with hCG, we were able to measure pulsatile LH secretion in the early puerperium for the first time. On day 7, LH levels were below the detection limit in both lactating and nonlactating women, hence no pulses could be detected. Chronic opioid blockade in bromocriptine-treated non-lactating women did not result in increased LH levels. Pulsatile LH secretion was present between days 28 and 35 of lactation, although pulse amplitude (P less than 0.05) and mean LH level (P less than 0.05) were lower than in nonpuerperal women. Mean LH in lactating women was negatively correlated with mean PRL (-0.87, P less than 0.05). Deconvolution analysis of the PRL responses to suckling revealed that PRL was secreted in distinct bursts, separated by intervals of secretory quiescence. Mean duration of PRL bursts was 40 +/- 4 min and the maximum secretory rate was reached around the end of suckling. We conclude that pulsatile LH secretion is completely suppressed during early lactation and partially suppressed during late lactation. Because the duration of suckling was similar, the relatively strong suppression during the early puerperium must be due to additional inhibitory factors. It has been suggested that endogenous opioids are involved in this process, but our results in puerperal women do not support this hypothesis.
The effects of Ca and other agents on secretion of plasminogen activator (PA) and PTH have been examined and compared, using parathyroid cells obtained from the glands of chronic renal patients. During 2 weeks culture at different [Ca], the secretory rates of PA activity and PTH were parallel; steady-state secretion over 24-h periods was maximal at 0.5-0.9 mM Ca, minimal at 1.5-2.5 mM Ca, and the [Ca] at 50% suppression was 1.1 mM. At 2.5 mM Ca, two inhibitors of cellular proteolysis, 3-methyladenine and chloroquine, stimulated secretion of both PA activity and PTH. The results indicated that secretion of PA from human parathyroid cells is regulated similarly to that of PTH. The characteristics of human parathyroid PA were also examined using human parathyroid adenoma tissue. In homogenates, the highest specific activity of PA was in microsomal fractions. The Mr of PA from tissue and from culture media was 70 kilodalton by sodium dodecyl sulfate gel electrophoresis followed by zymography, or by Western blotting using antisera to human tissue PA (tPA). Enzyme activity was inhibited by incubation with antisera to tPA but not to urokinase. In contrast to bovine parathyroid cells that secrete a urokinase, human parathyroids apparently contain and secrete tPA.
To evaluate the developmental and sex-specific changes in spontaneous GH secretion in terms of both secretory rate and pulsatile pattern, we investigated 24-h GH profiles (integrated 20-min samples) in 208 healthy children (91 girls and 117 boys) of normal heights at all stages of puberty. The plasma GH concentrations were transformed to GH secretion rates by means of a deconvolution technique. In prepubertal boys and girls, the mean secretion rates were comparable (0.66 and 0.68 U/24 h), but increased during puberty differently: earlier in girls, already at stage 2, with the highest rates at stages 3 and 4 (1.70 and 1.96 U/24 h); later in boys, at stage 4 (1.66 U/24 h). In both sexes the GH secretion rate decreased to prepubertal values at stage 5. The GH secretion rate correlated negatively with weight for height expressed in SD scores only in puberty (boys, r = -0.44, P < 0.001; girls, r = -0.22; P < 0.05). The number of peaks with high amplitudes increased with the progress of puberty in both boys (stage 2) and girls (stages 3 and 4). In both prepubertal girls and boys, a marked day-night rhythm was observed, which disappeared in midpuberty in boys owing to a greater increase in peak amplitudes during the day than at night. The mean number of peaks per 24 h was unchanged in girls, but decreased in late pubertal boys. In summary, we found a sex-specific increase in the GH secretion rate during pubertal development that occurs at an earlier pubertal stage and is more pronounced in girls than in boys. There are underlying changes in the mean GH amplitudes in both boys and girls as well as an increased baseline secretion in girls. In puberty, body composition modulates the GH secretion rate in both sexes.
To evaluate spontaneous GH secretion in terms of both secretory rate and pulsatile pattern in prepubertal children born small for gestational age (SGA) and still short (below -2 SD scores) at or after 2 yr of age, 24-h GH profiles were investigated in 106 such patients (75 boys and 31 girls; mean age, 7.3 +/- 0.3 yr), 14 of whom (10 boys and 4 girls) had Silver-Russell syndrome. The 24-h secretion of GH was compared with that in 2 reference populations of prepubertal children born at an appropriate size for gestational age (AGA): 179 short healthy children (143 boys and 36 girls; mean age, 10.2 +/- 0.2 yr) and 73 children of normal stature (54 boys and 19 girls; mean age, 10.4 +/- 0.3 yr). Plasma GH concentrations from the 24-h profiles were transformed to GH secretion rates by means of a deconvolution technique. For the SGA children, the mean GH secretion rate was 0.3 U/24 h, with a positive correlation with age, whereas for the reference groups it was higher, 0.5 U/24 h for the short children (P < 0.05) and 0.7 U/24 h for the children of normal stature (P < 0.001). Interestingly, the GH secretion rate correlated positively with weight for height, expressed as the SD score, in girls born SGA (r = 0.40; P < 0.05), whereas an inverse correlation was found for the short AGA girls (r = -0.44; P < 0.05). The mean baseline GH level in the SGA children correlated negatively with age (r = -0.53; P < 0.01), with the highest values found for children younger than 6 yr of age. On the average, 8 GH peaks/24-h period were found in all groups of children, and using Fourier time-series analyses, a similar rhythmicity was found in all groups. In the SGA group, the children younger than 6 yr of age had more GH peaks with lower amplitudes than the older children. It is concluded that children born SGA and still short at or after 2 yr of age spontaneously secrete less GH than healthy children of short stature born AGA. Both of these subgroups of prepubertal short children, however, secrete less GH than children of normal height. This finding might in part explain the growth failure in SGA children. Moreover, in the youngest SGA children (2-6 yr of age) there was another pattern of GH secretion, with a high basal GH level, a low peak amplitude, and a high peak frequency.(ABSTRACT TRUNCATED AT 400 WORDS)
1. Potassium is the major cation in the secretion of the salivary glands of Calliphora and is necessary for full secretory rates. 2. Other ions (rubidium and sodium) can support secretion in the absence of potassium. 39. During stimulation with 5-HT a Nernst plot of the basal membrane potential has a slope of 53 mV for a tenfold change in external potassium concentration and the slope at rest deviates from this over the range I-20 mM external potassium. 4. Hyperpolarization of the basal membrane by 5-HT is abolished if the chloride in the bathing medium is replaced by isethionate. 5. The diuretic agent amiloride inhibits fluid secretion by a mechanism which may include a reduction in calcium entry in addition to its recognized effect on sodium permeability. 6. A model is proposed in which fluid secretion is driven by the active transport of potassium across the apical membrane with chloride following passively.
Characterization of dopamine (DA) receptor subtypes was examined on the canine exocrine pancreas using selective DA receptor agonists and antagonists in anesthetized dogs. Each drug was injected i.a. in a single bolus fashion. Graded doses of DA (0.01-3 mumol) produced dose-dependent increases in the secretory rate of pancreatic juice, with a maximum effect at approximately 1 mumol. SCH23390 (3-30 nmol), a selective D-1 DA receptor antagonist, caused a progressive parallel shift to the right in the dose-response curve for DA-induced pancreatic secretion without changes in the maximal response. However, domperidone (3 mumol), a selective D-2 DA receptor antagonist, did not antagonize the DA-induced pancreatic exocrine secretion. A Schild analysis of the data indicates that the inhibitory constant value for SCH23390 to inhibit DA-stimulated secretion was 6.9 nmol. In addition, the stimulatory effects of SKF38393 (0.1-10 mumol) and YM435 (0.3-30 nmol), selective D-1 DA receptor agonists, and LY171555 (1-10 mumol), a selective D-2 DA receptor agonist, on pancreatic secretion were demonstrated. The rank order of agonist potency was YM435 > DA > SKF38393 >> LY171555. These results suggest that DA-induced pancreatic exocrine secretion is mediated by activation of D-1 DA receptors.
STUDY OBJECTIVES: Inhalation of hypertonic saline or mannitol solutions acutely increases mucociliary clearance. Because increased clearance is often coupled with increased mucus secretion, we hypothesized that hyperosmolar agents would stimulate mucus secretion. SETTING AND SUBJECTS: The isolated tracheae of healthy young adult ferrets were studied in a basic research laboratory. MEASUREMENTS AND RESULTS: We demonstrated that there was a dose-dependent increase in mucin secretion by enzyme-linked lectin assay after incubation with 1.69 g/dL (597 mOsm/L), 3.69 g/dL (1,192 mOsm/L), 5.69 g/dL (1,823 mOsm/L), and 10.69 g/dL (3,612 mOsm/L) of saline solution over Krebs-Henseleit solution control (288 mOsm/L) [p < 0.01 for 1.69 g/dL of saline solution and p < 0.0001 for others]. Mannitol solution, 15 g/dL (1,040 mOsm/L), also significantly increased mucin secretion (n = 4, p < 0.005). There was a 47% and 54% increase in secretion of the serous cell product lysozyme after exposure to 3.69 g/dL (1,192 mOsm/L) and 10.69 g/dL (3,612 mOsm/L) saline solutions, respectively (n = 5, p < 0.05). Secretion was only stimulated when the hyperosmolar exposure was on the luminal side of the epithelium. Mucin secretion was induced within minutes of 3.69 g/dL of saline solution exposure, and this increased mucin secretion quickly peaked. The ratio of mucin to lysozyme secretion was approximately 2. This ratio appeared to be independent of the osmotic concentration of the stimulus and therefore of secretory rate. CONCLUSIONS: Mucus secretion is markedly stimulated in response to hyperosmolarity. This may be a protective response. These results also suggest that the therapeutic use of hyperosmolar aerosols should be evaluated with care when used for patients with mucus hypersecretion and impaired mucus clearance.
We have studied the maturation of a glucose-responsive insulin release from fetal rat islets, and specifically investigated the impact of nutrients, alpha-adrenoceptors, imidazoline receptors, and cyclic adenosine monophosphate (cAMP). Islets were isolated from 21 -d-old fetal rats and maintained for 7 d in tissue culture at 3.3 or 11.1 mM glucose and various supplements. Culture in the presence of the nonglucidic nutrient alpha-ketoisocaproic acid (KIC), markedly enhanced both basal and stimulated insulin release from islets cultured at either low or high glucose. Additionally, KIC significantly elevated the insulin content of islets maintained in low glucose, whereas it slightly lowered it in islets cultured at high glucose. Culture with phentolamine, an antagonist of alpha-adrenergic and imidazoline receptors, markedly amplified both basal and glucose-stimulated insulin secretion when added with islets cultured in either low or high glucose. By contrast, the pure alpha2-adrenoceptor antagonist benextramine had no such effects. Addition to culture media of a membrane-permeant agonist (Sp-cAMP[S]) or antagonist (Rp-cAMP[S]) of cAMP-dependent protein kinases types I and II failed to influence basal or glucose-responsive insulin secretory rates at either glucose concentration during culture as well as islet insulin content. In conclusion, islet beta-cell differentiation and functional maturation of the stimulus-secretion coupling can be accelerated in vitro in fetal rat pancreatic tissue by nutrient stimulation, and by interference with imidazoline receptors, whereas cAMP seems virtually ineffective in this respect. These effectors may be of regulatory significance in the in vivo development of glucose-sensitive beta-cells.
Hyperleptinemia is a common feature of pregnancy in mammals. The source of increased plasma leptin is uncertain. We examined leptin secretory rates in vitro to test the hypothesis that leptin secretion is upregulated during pregnancy. Two species of insectivorous bats were examined, Myotis lucifugus and Eptesicus fuscus, because of their unique reproductive cycle. Body mass and plasma leptin significantly increased with gestation and decreased during lactation. Adiposity increased in midgestation, then decreased in late gestation and lactation and was not significantly correlated with plasma leptin in pregnant or early lactating individuals. Leptin secretion in vitro per gram of adipose tissue tended to increase with gestation but was not significantly correlated with plasma leptin in the same individuals. Leptin secretion from placentae, however, increased with gestation and was significantly correlated with plasma leptin from the same individuals. In suckling pups, plasma leptin was high shortly after birth, then decreased to low levels that were not correlated with adiposity thereafter. We conclude that in bats, the placenta is a major source of circulating leptin during pregnancy, and that adiposity and plasma leptin levels are decoupled during three different periods of intense metabolic demand (pregnancy, early lactation, and neonatal growth).
Explore the source record for details and available documents.