Effect Of Metopirone Research Articles

Effects of metopirone on urinary excretion of adrenaline, noradrenaline and vanylmandelic acid in different physiological conditions. The possible role of adrenal cortex in catecholamine degradation.

Effects of metopirone on urinary excretion of adrenaline, noradrenaline and vanylmandelic acid in different physiological conditions. The possible role of adrenal cortex in catecholamine degradation.

The influence of adrenalectomy on α-adrenoceptor responses in rat cerebral cortex slices

Experiments were undertaken to examine the effect of depletion of adrenal steroids on neurotransmitter-stimulated cAMP accumulation in rat cerebral cortex slices. Long-term depletion due to bilateral adrenalectomy (ADX) and short term depletion due to the steroid synthesis inhibitor metopirone (MET) caused a significant increase in α1-adrenoceptor-mediated potentiation of β-adrenoceptor-stimulated cAMP accumulation. The effect of MET was prevented by corticosterone treatment. This effect of ADX was selective in that there was no change in α1-adrenoceptor-mediated inositol phosphate accumulation. In addition, ADX had no effect on potentiation of isoprenaline-stimulated cAMP by either the GABAB agonist baclofen or the phorbol ester, 4β-phorbol dibutyrate. However, 2-chloroadenosine-stimulated cAMP accumulation was significantly reduced in ADX rats.

Changes in plasma cortisol during acute cold exposure in euthermic European hedgehogs: thermoregulatory role of the hypothalamo-pituitary-adrenal axis

During acute cold exposure regulatory heat production of European hedgehogs was significantly increased with a simultaneous rise in the plasma cortisol level. Soon after cold exposure, at the time when standard metabolic rate was measured, the plasma cortisol level was reduced again. This finding indicates a highly reactive hypothalamo-pituitary-adrenal axis in euthermic hedgehogs exposed to a cold environment. Two effects of the adrenocorticostatic agent metopirone ditartrate were observed: (1) A metopirone-induced increase in nonshivering thermogenesis (NST) starting 18 min after application, reaching a maximum after 43 min and disappearing after 90 min (Fig. 1, Table 1). Simultaneously a profound long lasting hyperglycemia was observed (Fig. 2). (2) In contrast to untreated hedgehogs, animals which were given metopirone did not show an increase in the plasma cortisol level, when exposed to cold within 2 to 3 h (Fig. 6). When animals were pretreated with dexamethasone the metopirone-induced NST was suppressed, indicating that the effect of metopirone is mediated by the hypothalamo-pituitary-adrenal system (Fig. 4). The effect of metopirone at doses used in this study was reversible. It is suggested that a combined action of corticosteroids and catecholamines is involved in the control of regulatory heat production.

Effect of metopirone on the secretory response of the testis to human chorionic gonadotrophin.

Effect of metopirone on the secretory response of the testis to human chorionic gonadotrophin.

Effect of metopirone on the synthesis of lung surfactant in does and fetal rabbits.

The possible role of endogenous corticosteroids in the induction of synthesis of lung surfactant in both maternal and fetal rabbits was investigated. Metopirone (SU 4885), which specifically inhibits B hydroxylation in the adrenal gland, thus preventing endogenous cortisol production was used in this study. Pregnant rabbits received one of four treatment regimens: saline, metopirone, cortisone or metopirone plus steroid for 6 days before delivery. Studies of the lungs of the adult rabbits revealed that lung weights and percent dry weight were not influenced by drug injection. However, lung DNA content (mg/g) in the metopirone-treated group was higher than the control group, indicating an increase in cell number. Compared to the saline-treated group there was a significant decrease in lung phospholipid content in the other three groups (p smaller than 0.005). A decrease in lung lecithin and phosphatidylethanolamine was also noted in these three groups indicating that the inhibition was in the early steps of biosynthesis of lung lecithin. The specific activity of 14C-labelled palmitate in lung lecithin was not altered by drug treatment indicating that saturated fatty acid incorporation into lung lecithin is not influenced by metopirone, steroid or a combination of both drugs. Quasi-static deflation pressure-volume characteristics of the lung were also similar in all groups. However, lungs of animals receiving both metopirone and steroid had a small but statistically significant decrease in minimum surface tension (p smaller than 0.05). The change in surface tension did not correlate with a change in lung retractive forces or with lung lipid content and was, therefore, of dubious biological significance. Metopirone administration to pregnant rabbits did not alter surface active properties in the fetus from the 26th to the 29th day of gestation when compared to control fetuses. At day 30-31 gestation the offsprings of metopirone-treated rabbits had lung total phospholipid and lecithin contents, and deflation pressure-volume curves similar to control group, but minimum surface tension of minced lung extracts were high in about 60% of the fetal lungs studied (p smaller than 0.05). These results suggest that endogenous steroid production may play a significant role in the maturation of the fetal lung.

Effects of metopirone on duodenal differentiation and yolk sac retraction in chick embryos.

Effects of metopirone on duodenal differentiation and yolk sac retraction in chick embryos.

Effects of metopirone on the structure of endocrine glands in the male lizard, Cnemidophorus l. lemniscatus (L.).

Adrenals, pituitary glands, thyroids, testes and kidneys of metopirone-treated and control male lizards were studied by light microscopy. Pituitary-interrenal axis: A great hypertrophy and hyperplasia of the interrenal cells and the pituitary corticotrophs were found in the experimental group. Pituitary-thyroid axis: Metopirone-treated animals showed a moderate hypertrophy and degranulation of pituitary thyrotrophs, and signs of uneven hyperactivity of the thyroid. Pituitary-testicular axis: By effect of metopirone, a marked regression of pituitary interstitiotrophs and a virtual disappearance of the testicular interstitial gland took place. The second portion of the kidney sexual segments appeared degranulated as in castrated animals. The pituitary folliculotrophs and the seminiferous epithelium of the testis did not show alterations.

Steroids of invertebrates IV. On the optic tentacle-gonadal axis in the control of the male-phase ovotestis in the slug ( Ariolimax californicus)

The giant land slug, Ariolimax californicus, is a protandrous hermaphrodite. The role of the optic tentacles in affecting the sexual status of the ovotestis in other gastropods has been investigated ( Pelluet and Lane (1961); Pelluet (1964). The present study was undertaken to determine if the optic tentacles exert a hormonal influence upon the male phase of the ovotestis, and whether steroids are implicated in determining the presumptive capacity of the optic tentacle to influence the gonad. The experimental approach used was to follow histological changes occurring in the ovotestis of immature slugs under the following conditions: (1) optic tentacle removal and replacement therapy; (2) administration of steroids to animals with and without optic tentacles; (3) the effect of Metopirone in the presence and absence of optic tentacles. The results of these investigations strongly suggested that the optic tentacle exerts a profound influence upon the ovotestis of immature animals. Optic tentacle removal in immature slugs produced maturation of the testicular elements of the gonad within 21 days to a stage histologically comparable with that occurring normally in animals almost three times the age and body weight; precocious spermatogenesis was induced. Similar results were obtained by administering dehydroepiandrosterone and 11-ketotestosterone (presumptively identified by GLC techniques in male-phase gonads) to slugs with and without optic tentacles. Optic tentacle homogeneates apparently halted further precociously induced spermatogenesis, but may also have caused spermiation to occur. Metopirone, when administered to young males in increasing dose levels in the presence of the optic tentacles, caused progressive disorganization of spermatogenesis. Histologically, this appeared as an apparent hyperplasia of the gonial cells lining the tubule walls. No similar effects were seen in animals without optic tentacles treated with Metopirone. These results suggested that tentacular control of the male phase of the ovotestis might be limited to that portion of the gonad cycle up to the point of spermiation. Steroids appeared to influence the effect of this tentacular regulator or modifier of ovotesticular development. The evidence suggested that the male phase in A. californicus ovotestis is controlled partially by the optic tentacle.

Effect of metopirone on the rate of cortisol disappearance from plasma

Effect of metopirone on the rate of cortisol disappearance from plasma

The effects of metopirone and aldactone on the pars distalis of the pituitary, the interrenal tissue and the interstitial tissue of the testis in the common frog, Rana temporaria.

The effects of metopirone and aldactone on the histology of the pars distalis of the pituitary, the interrenal gland and the interstitial tissue of the testis were studied in male common frogs. Activation of the interrenal tissue by these substances was paralleled by a stimulation of one of the tinctorial cell types in the distal lobe namely the basophils 3 and of caudal chromophobic cells. Simultaneously a regression of the interstitium testis was observed. It is suggested that either the basophils 3 or the caudal chromophobic cells have a corticotropic function.

The Metopirone test of pituitary corticotrophin release: Evaluation of 101 tests

The ACTH secreting potential of the pituitary gland was tested, using the steroidal 11β-hydroxylase inhibitor, Metopirone ®, in eighty patients (1 gm. Metopirone orally each six hours for forty-eight hours) on 101 occasions, and the increase in 17-oxogenicsteroid (OGS) excretion was followed. Twenty-one patients had a maximum OGS response of less than 50 mg. Of these, fifteen had a history of hypopituitarism, pituitary damage or steroid suppression, and the remainder were either suffering from metastatic breast cancer or had been treated with tranquilizer drugs. All patients judged clinically to have a normal adrenal-pituitary axis had a response of between 50 and 100 mg. per day. Of the twenty-three patients who had an OGS response greater than 100 mg. per day, nine were suffering from Cushing's syndrome, four from acromegaly and five were obese. The effect of Metopirone on OGS excretion provides a clinically useful test of pituitary ACTH “reserve”. Metopirone caused increases in the excretion of 11-desoxy-OGS which were about half the OGS increases and which gave no better correlation with clinical status.

The effect of Metopirone (SU-4885) on the metabolism of progesterone by the perfused previable human fetus.

A previable human fetus was first perfused with Metopirone (Metyrapone, SU-4885) and then with progesterone-7-3H. The following metabolites were isolated and identified in the fetal tissues and perfusate: 11-deoxycortisol from adrenal and perfusate; deoxycorticosterone sulfate from adrenal, perfusate, and residue; 6β-hydroxyprogesterone and 20α-dihydroprogesterone from perfusate; pregnanolone from perfusate, liver, lung, intestine, and residue; 3β-hydroxy-5α-pregnan-20-one from perfusate, liver, and residue; pregnanediol from perfusate, liver, lung, intestine, and residue; pregnanediol sulfate from adrenal, perfusate, liver, and intestine; and pregnanolone sulfate from adrenal, perfusate, liver, intestine, and residue. The results obtained demonstrate that SU-4885 inhibits 11β-hydroxylation in the human fetal adrenal and alters the metabolism of progesterone in the tissues of the human fetus, but it does not affect the ability to conjugate metabolites with sulfuric acid.

The effect of metopirone and aldactone on the interrenal tissue of intact and pars distalis-ectomized common frogs, Rana temporaria.

The effects of metopirone (SU-4885) and aldactone (SC-9420) on the histology and histochemistry of the interrenal tissue of male common frogs, Rana temporaria, have been studied. From the changes in nuclear and cellular size, mitotic rate, and lipid and cholesterol content it has been concluded that in intact animals the administration of metopirone as well as of aldactone resulted in an increase of the interrenal secretory activity. The effects were very similar to that of ACTH. Ablation of the pars distalis prevented the interrenal activation by metopirone. The effect of aldactone was markedly reduced in operated frogs, but some stimulation remained. It is suggested that both substances act by way of enhancing pituitary ACTH ouput. The dependence of the secretion of corticosteroids on pituitary ACTH is discussed.

Mechanism of metopirone inhibition of a soluble adrenal steroid 11-beta-hydroxylase.

The effect of Metopirone (2-methyl-1,2-bis(3-pyridyl)-1-propanone) (Su-4885) on the 11β-hydroxylation of 11-deoxycorticosterone (DOC) and NADPH oxidation has been examined in a soluble enzyme system extracted from an acetone powder of bovine adrenal mitochondria. Addition of Metopirone in the absence of DOC stimulated the oxidation of reduced nicotinamide–adenine dinucleotide phosphate (NADPH) by the enzyme system. Under the experimental conditions employed, 11β-hydroxylation was inhibited 50% by Metopirone at a final concentration of 4.2 μmoles/l, a quantity 27 times less than that required to produce a twofold increase in NADPH oxidation in the absence of DOC. Low levels of Metopirone that effectively inhibited corticosterone formation produced a similar decrease in NADPH oxidation associated with the hydroxylation reaction, indicating the interrelationship of 11β-hydroxylation and NADPH oxidation. Evaluation of kinetic data showed that the inhibition of 11β-hydroxylation produced by Metopirone was competitive. The Kmfor the 11β-hydroxylation of DOC was 1.8 × 10−5 mole/l and the Kifor Metopirone was 3.2 × 10−7 mole/l. The ratio Km:Kiindicated that the affinity of Metopirone for the 11β-hydroxylase was 56 times greater than that of DOC.

The effects of Metopirone on glucose metabolism

The Metopirone (Metp), tested on the isolated and beating heart of Bufo vulgaris or on the homogenates of this organ revealed: (1) an excito-metabolic activity, which manifests itself in variations of the contraction force of the cardiac muscle and in the potentiation both of the temporary repolarization phenomena and of the tissue phosphorylase; (2) the tendency to favor the penetration of 2-deoxyglucose (2-DG) into myocardial cells.

Steroid metabolites from cholesterol-C14 in a patient with adrenal cancer: effects of metopirone.

The urinary steroid metabolites following the injection of C14-cholesterol before and after the administration of Metopirone to a female patient with an adrenal cancer were isolated and identified. The injected C14-cholesterol was excreted in the urine at a low but constant rate for at least 80 days following the injection of the sterol. The 11-oxygenated steroid disappeared from the urine following the administration of Metopirone; the only corticosteroid metabolites isolated from the urine were those of 11-deoxycortisol. The results of the study indicate that Metopirone inhibited 11-hydroxylation in the cancerous tissue. 6β-Hydroxyandrostenedione was also isolated; this appears to be the first description of its presence in human urine.