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Biomedical subjects

J Weidenfeld

Publications and source records attributed to J Weidenfeld.

18 recordsLinked to original sources
PubMed1992

Corticosterone implants in the paraventricular nucleus inhibit ACTH and corticosterone responses and the release of corticotropin-releasing factor following neural stimuli.

Experiments were conducted on the possible role of corticosterone (CS), at the level of the paraventricular nucleus of the hypothalamus (PVN) and dorsal hippocampus (D.HIPP), in the negative feedback effects following neural stimuli. In rats with bilateral PVN cholesterol (CHO) implants, acoustic and photic stimuli caused a significant rise in serum CS and ACTH and depletion of median eminence (ME) CRF-41 content. CS PVN implants have prevented the rise in serum CS, ACTH and ME CRF-41 depletion. Bilateral CHO or CS implants in the D.HIPP did not modify the responses of the hypothalamo-pituitary-adrenal axis to the above neural stimuli. In PVN CS-implanted rats, i.v. injection of CRF-41 increased serum CS similar to that observed in PVN CHO-implanted animals. These data are discussed in view of previous experiments on corticosteroid implants in the brain. It is concluded that CS PVN implants, by acting possibly via type II hypothalamic receptors, have prevented the release of ME CRF-41 following neural stimuli and consequently the secretion of ACTH and CS.

Acoustic Stimulation↗
PubMed1992

Glucocorticoid regulation of eicosanoid production by glial cells under basal and stimulated conditions.

We measured the production of two eicosanoids, prostaglandin E2 and thromboxane-B2, by rat glial cell cultures under basal conditions, following stimulation with phorbol-12-myristate-13-acetate and the bacterial endotoxin lipopolysaccharide, and following treatment with synthetic glucocorticoids. Stimulation of rat glial cells in culture with either phorbol-12-myristate-13-acetate or lipopolysaccharide caused a 1.5-5.0-fold increase in prostaglandin E2 production, but did not affect thromboxane production. Pretreatment of the cultures with dexamethasone markedly inhibited the stimulated production of prostaglandin E2 but had only a modest effect on basal production. Dexamethasone did not affect the activity of the enzyme protein kinase C, a putative regulator of eicosanoid synthesis. Our findings show that glucocorticoids have the potential to modulate central nervous system eicosanoid production particularly under conditions of stimulated production, such as inflammatory and demyelinating disorders. This mechanism may explain, at least in part, the therapeutic benefit of glucocorticoids in patients with multiple sclerosis.

Animals↗
PubMed1992

Eicosanoids content in small intestinal mucosa of children with celiac disease.

Celiac disease (CD) is characterized by diarrhea, growth retardation, and weight loss in genetically susceptible subjects on a gluten-containing diet. The exact pathogenesis of CD is still obscure, but it is considered to be immunologically mediated. We have previously shown elevated prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) content in small intestinal mucosa obtained from active celiac children. In the present study, we found significantly elevated PGE2, leukotriene B4 (LTB4), and leukotrienes C4, D4, and E4 (LTC4D4E4) content in small bowel mucosa from children suffering from CD on a gluten-containing diet in comparison to control subjects. PGE2 was 25,278 +/- 7,761 vs. 4,478 +/- 426 pg/mg of protein (mean +/- SEM), respectively. LTB4 was 8,807 +/- 3,706 vs. 403 +/- 63 pg/mg of protein (mean +/- SEM), respectively. LTC4D4E4 was 15,369 +/- 4,085 vs. 2,998 +/- 279 pg/mg of protein (mean +/- SEM), respectively. We conclude that the elevated content of arachidonic acid metabolic products via cyclooxygenase and lipoxygenase pathways may contribute to the diarrhea and may be involved in the pathogenesis of mucosal injury.

Adolescent↗
PubMed1992

Eicosanoids in hypoxic insult to neonatal rabbit bowel.

Eicosanoids, derivatives of arachidonic acid, play a role in several inflammatory diseases of the bowel. To determine whether prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and leukotriene C4D4E4 (LTC4D4E4), have a role in hypoxic insult to the intestine, we examined the levels of these mediators in a hypoxic neonatal rabbit model. One group of animals underwent hypoxic insult postnatally, the second group did not undergo hypoxia and served as a control. The levels of PGE2, LTB4, and LTC4D4E4 were determined by radioimmunoassay. PGE2 in the hypoxic group was 1,779 +/- 142 pg/mg protein (mean +/- SD) as opposed to 2,380 +/- 197 pg/mg protein in the control group (p less than 0.02). LTB4 level was 5,446 +/- 3,492 pg/mg protein in the hypoxic rabbits and 3,362 +/- 2,570 pg/mg protein in the control group (p less than 0.03). There was no statistically significant difference in the level of LTC4D4E4 between the two groups. Our study shows that hypoxia shifts the arachidonic acid metabolism toward enhanced lipoxygenase activity with a resultant increase in LTB4 levels and a concomitant decrease in cyclooxygenase activity with reduced PGE2 levels in the bowel. The shift in the balance between these eicosanoids may play a role in the pathogenesis of ischemic-hypoxic bowel diseases by enhancing the inflammatory response in the intestine, and simultaneously, diminishing cytoprotection.

Animals↗
PubMed1992

Role of the central adrenergic system in the regulation of prostaglandin biosynthesis in rat brain.

The role of endogenous catecholamines in the regulation of brain prostaglandin (PG) synthesis was studied in the rat. Male rats were injected in the brain lateral ventricle or in the ventral noradrenergic bundle with either the catecholaminergic neurotoxin 6-hydroxydopamine or vehicle. Other groups of rats were injected intraperitoneally with the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine, or with the inhibitor of dopamine-beta-hydroxylase, FLA-63. All these drugs produced a significant depletion of norepinephrine (NE) content in the cortex and hypothalamus. The rats that had lower levels of NE exhibited reduced capacity to synthesize PGE2 but not thromboxane B2 and 6-keto-PGE1 alpha in the cortex and hypothalamus. However, induced production of PG, stimulated by the bacterial endotoxin lipopolysaccharide (LPS), remained unchanged, namely, a similar (2- to 2.5-fold) increase of PG synthesis was noted in control and in NE-depleted rats. We suggest that the regulation of PG synthesis under basal condition requires intact adrenergic input, whereas LPS-induced production of PG is independent of the adrenergic innervation.

6-Ketoprostaglandin F1 alpha↗
PubMed1991

Effect of 6-hydroxydopamine and 5,7-dihydroxytryptamine on tissue uptake and cell nuclear retention of corticosterone in the rat hypothalamus.

Previous studies have shown that norepinephrine and serotonin can modulate the glucocorticoid (GC) binding capacity in the hippocampus. The aim of the present study was to evaluate the role of these neurotransmitters in regulating GC receptors in the hypothalamus. Injection of the neurotoxin 6-hydroxydopamine (6-OHDA) into the ventral noradrenergic bundle (VNAB) and 5,7-dihydroxytryptamine (5,7-DHT) into the raphe nuclei caused a marked depletion in norepinephrine and serotonin, respectively, in the paraventricular nucleus (PVN) and mediobasal hypothalamus (MBH). The injection of these neurotoxins did not change the basal levels of ACTH and corticosterone. Injection of 6-OHDA into the VNAB caused a significant reduction in the cell nuclear binding of corticosterone in the PVN but not in the MBH. Conversely, injection of 5,7-DHT into the raphe nuclei caused a significant reduction in cell nuclear binding of corticosterone in the MBH but did not affect binding in the PVN. These results demonstrate that at least part of the nuclear corticosteroid receptors in the PVN and MBH are differentially regulated by the noradrenergic and serotonergic systems.

5,7-Dihydroxytryptamine↗
PubMed1991

Effect of hypothalamic norepinephrine depletion on median eminence CRF-41 content and serum ACTH in control and adrenalectomized rats.

In this study we examined the role of the noradrenergic innervation of the hypothalamus on the adrenalectomy-induced changes in median eminence (ME) CRF-41 and serum ACTH. 6-Hydroxydopamine (6-OHDA), the catecholaminergic neurotoxin, or vehicle was injected into the ventral noradrenergic bundle of male rats. One week later animals underwent adrenalectomy or sham operation and were sacrificed 18 or 120 h later. In sham-operated rats 6-OHDA did not affect ME CRF-41 content or serum ACTH. In vehicle-injected adrenalectomized rats ACTH was increased approximately 3-fold at 18 h and almost 6-fold at 120 h. At 18 h CRF-41 content was markedly depleted (reduced approximately 20-fold) but by 120 h CRF-41 content had partially recovered and was about 70% of control animals. In adrenalectomized animals, 6-OHDA lesions caused a complete inhibition of the increase in serum ACTH both at 18 h and at 120 h. Pretreatment with 6-OHDA partially attenuated the drastic reduction in ME CRF-41 content following adrenalectomy at 18 h. However, at 120 h, the neurotoxin prevented the recovery of CRF-41 following adrenalectomy. These results suggest that intact norepinephrine innervation to the hypothalamus is necessary for the increased production of ACTH following adrenalectomy and that its interruption interferes with both the adrenalectomy-induced ME CRF-41 reduction and subsequent recovery.

Adrenalectomy↗
PubMed1991

Differential recovery of adrenocortical responses to neural stimuli following administration of 5,7-dihydroxytryptamine into the hypothalamus.

In view of the role of serotonin in adrenocortical regulation, the effects of depletion of hypothalamic serotonin, using localized injections of the neurotoxin 5,7-dihydroxytryptamine into the hypothalamic paraventricular nucleus, on the rise in plasma corticosterone following afferent neural stimulation, were studied. The neurotoxin caused a significant reduction (p less than 0.001) in hypothalamic serotonin content of about 50% during the first month and about 30% up to two months later. Basal and ether stress-induced rises in plasma corticosterone levels were unaffected at all times after this treatment, but responses to stimulation of the sciatic nerve were reduced for up to four weeks (p less than 0.01), recovering at later times. Responses to photic and acoustic stimuli were almost entirely prevented up to four weeks following the treatment (p less than 0.001) but showed a gradual recovery to full, or almost full, adrenocortical responses at eight weeks, following acoustic and photic stimulation respectively. These results demonstrate a differential recovery of the adrenocortical responses, following the neurotoxin injection and indicate that different neural modalities require different 5-HT concentrations in the PVN for the expression of a full adrenocortical response.

5,7-Dihydroxytryptamine↗
PubMed1991

Depletion of hypothalamic norepinephrine and serotonin enhances the dexamethasone negative feedback effect on adrenocortical secretion.

The role of norepinephrine (NE) and serotonin (5-HT) in the negative feedback effect of dexamethasone (DEX) on the adrenocortical response to ether stress was investigated. Injection of the catecholamine neurotoxin, 6-hydroxydopamine, into the ventral noradrenergic bundle or the paraventricular nucleus of the hypothalamus (PVN) which produced a very significant depletion in hypothalamic NE content enhanced the negative feedback effect of DEX. Injection of the 5-HT neurotoxin, 5,7-dihydroxytryptamine, into the raphé nuclei or PVN, which caused a depletion of hypothalamic 5-HT, produced a similar effect on the adrenocortical response to DEX. The degree of negative feedback may be viewed as a balance of neural stimulatory and glucocorticoid influences of the hypothalamus. Thus the removal of the stimulatory effects of NE and 5-HT on adrenocortical secretion, by the neurotoxic lesions, enhanced the inhibitory influence of DEX.

5,7-Dihydroxytryptamine↗
PubMed1991

Neural control of adrenocortical secretion.

A variety of neural sensory stimuli as well as the stimulation of extrahypothalamic structures can produce an increase in ACTH and corticosterone (CS) secretion. This effect is mediated, at least partially, by corticotropin releasing factor (CRF)-41. Experiments involving stimulation, brain lesions and hypothalamic deafferentations have demonstrated that the mechanisms responsible for this activation are not uniform and the effects of the various modalities are mediated by different pathways. In addition to the anterior hypothalamic input, which plays an important role in the mediation of the adrenocortical responses, the medial forebrain bundle as well as a medial posterior hypothalamic input are also essential for the activation of the hypothalamo-pituitary-adrenocortical axis for some neural modalities. Norepinephrine (NE) seems to have a facilitatory effect on these mechanisms as depletion of hypothalamic NE blocks the rise in serum CS following both peripheral and central neural stimuli. This effect is mediated by alpha 1 and alpha 2 adrenoceptors, the role of beta receptors being unclear. NE palsy also an important role in the early and late changes of CRF-41 content in the median eminence and serum ACTH following adrenalectomy.

Adrenocorticotropic Hormone↗
PubMed1979

Prenatal diagnosis of 11beta-hydroxylase deficiency congenital adrenal hyperplasia.

To predict 11beta-hydroxylase deficiency congenital adrenal hyperplasia antenatally, studies were performed in urines and amniotic fluids from 2 pregnant women who had previously given birth to affected infants and whose present pregnancies also resulted in infants with the disease. Urinary tetrahydro-11-deoxycortisol [pregnane-3alpha, 17alpha, 21-triol-20-one (THS)] was abnormally elevated in the first, second, and third trimesters (maximal values, 3.5 and 0.9 mg/24 h, respectively) but was undetectable after delivery in these mothers, in 15 normal pregnancies (10--40 weeks of gestation), and in 6 heterozygote parents. Amniotic fluid levels of THS, tetrahydrocortisol [pregnane-3alpha, 11beta, 17alpha, 21-tetra-o1-20-one (THF)], tetrahydrocortisone [pregnane-3alpha, 17alpha, 21-triol-11, 20-dione (THE)] measured by RIA at 18 weeks of gestation in the first mother and at 40 weeks in the second revealed 12.5- and 8.4-fold increases in THS, respectively, but normal THF and THE levels compared to mean levels in normal pregnancies. The THS to THF plus THE ratio, which was constant throughout pregnancy in 125 normal women (mean +/- SD, 0.63 +/- 0.34) despite the variable levels of these metabolites, was significantly elevated in both patients (4.4 and 3.8, respectively). These studies indicate that prenatal diagnosis of 11beta-hydroxylase deficiency congenital adrenal hyperplasia based on hormonal measurements is feasible.

Adrenal Hyperplasia, Congenital↗
PubMed1978

Metabolism of diethylstilbestrol: identification of a catechol derived from dienestrol.

The enzymatic oxidation of E-3,4-bis-(p-hydroxyphenyl)-hex-3-ene (diethylstilbestrol) by either mushroom tyrosinase or rat liver microsomes in the presence of NADPH and air yields a catechol. Upon further oxidation of both compounds with periodate and condensation of the resulting o-quinones with o-phenylenediamine, phenazines are produced. The phenazines derived from the products of both the plant and animal enzyme systems are identical to the product obtained by oxidation of diethylstilbestrol with potassium nitrosodisulfonate and condensation of the o-quinone produced with o-phenylenediamine. High and low resolution mass spectra of the phenazine are consistent with its derivation from a catechol having two fewer hydrogens than diethylstilbestrol.

Animals↗
PubMed1978

11 beta-Hydroxydehydroepiandrosterone in a case of virilizing adrenal adenoma: isolation from urine and mitochondrial conversion from dehydroepiandrosterone.

11 beta-Hydroxydehydroepiandrosterone has been isolated from the urine of a 14-yr-old girl with a virilizing adrenal adenoma. Its excretion was estimated to be 0.4 mg/24 h by gas chromatography and the compound was further identified by mass spectrometry. When [7-3H]dehydroepiandrosterone was incubated with mitochondria prepared from the adenoma, approximately 10% was converted to 11 beta-hydroxydehydroepiandrosterone. The identity of the radioactive 11 beta-hydroxydehydroepiandrosterone was verified by reversed isotopic dilution, its conversion to 11 beta-hydroxyandrostenedione, and its mobility in several chromatographic systems. This is the first demonstration of an 11 beta-hydroxylase from a human source having an affinity for dehydroepiandrosterone.

Adenoma↗
PubMed1977

21-Hydroxylation of C-11-oxygenated and C-11-deoxysteroids by perfused dog adrenals.

The left adrenal of two female dogs were perfused with either 3 muCi [4-14C]cpd. S (2) and 45 muCi [1, 2-3H] 21-deoxycortisone (Dog I), or with 1 muCi [4-14C] 17-hydroxyprogesterone and 65 muCi [1,2-3H] 21-deoxycortisone (Dog II). In Dog I, 40% of the perfused 21-deoxycortisone was converted to cortisone and 23% of cpd. S was converted to cortisol. In Dog II the percent conversion of 21-deoxycortisone to cortisone and of 17- hydroxyprogesterone to cortisol was 24% and 15% respectively. The results demonstrate that the dog adrenal has the capability of hydroxylating an 11-oxygenated steroid at C-21.

Adrenal Glands↗
PubMed1977

A case of adrenogenital syndrome with aberrant 11beta-hydroxylation.

A 17 year old female patient with hypertension, amenorrhoea and hirsutism was found to have subnormal levels of plasma and urinary cortisol, significant plasma levels of Reichstein's compound S and 21-deoxycortisol, high urinary levels of THS and pregnanetriolone as well as elevated levels of plasma and urinary testosterone. Treatment with 0.5 mg/day of dexamethasone or 25 mg/day cortisone reduced her hypertension and restored her menstrual cycles, but also resulted in the development of moon face, body striae and a gain in weight. Lower doses of cortisone were without effect. The deficient cortisol production coupled with the presence of unusual intermediates such as Reichstein's compound S and 21-deoxycortisol can be explained by a shift in the substrate specificity of 11beta-hydroxylase from C-21-hydroxylated substrates (i.e. compound S) to C-21-deoxy substrates (i.e. 17-hydroxyprogesterone).

17-Ketosteroids↗
PubMed1975

Steroidogenesis in a virilizing ovarian tumour.

A metabolic study with tissue from a virilizing arrhenoblastoma, using as precursors [7-3H]pregnenolone, [7-3H]17alpha-hydroxypregnenolone,[4-14C]17alpha-hydroxyprogesterone and [4-14C]testosterone, revealed that in spite of a deficient activity of 3beta-hydroxysteroid dehydrogenase-5-isomerase the overall production of testosterone was compensated by an increased activity of a lyase converting [4-14C]17alpha-hydroxyprogesterone to testosterone (via androstenedione) and was comparable to the production obtained by normal ovarian tissue. The masculinizing effects of the tumour in vivo were most probably caused by accumulation of testosterone due to deficiencies in enzymes catabolizing testosterone to 17-ketosteroids and its aromatization to oestrogen. The unique property of the arrhenoblastoma to convert [4-14C]17alpha-hydroxyprogesterone to [4-14C]11-deoxycortisol (Reichstein's compound S) suggests an adrenal origin of the tumour which may explain its limited capacity to aromatize testosterone.

17-alpha-Hydroxypregnenolone↗
PubMed1975

The effects of HCG, indomethacin, flufenamic acid and aspirin in the immature female rat.

Immature female rats (21 to 23 days old, 35 to 45 g) were injected subcutaneously with 2-5 i. u. HCG 18 hr before autopsy. Ovaries and uteri were removed; wet weight, dry weight and uterine protein content were determined. Ovarian and uterine weights, ovarian blood volume and uterine protein content were increased after HCG treatment. When immature female rats were pretreated with indomethacin, flufenamic acid or aspirin, the ovarian effects of HCG were inhibited: only slight increases in ovarian weight and blood volume were observed. Indomethacin attenuated the increases in uterine weight, and protein content, but neither flufenamic acid nor aspirin were effective in inhibiting these responses. The possible role of prostaglandins and of oestrogen as mediators of these responses is discussed.

Animals↗