Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracts of rat anterior and intermediate-posterior pituitary were fractionated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and assayed for immunoactive ACTH and endorphin. In both lobes the major forms of immunoactive ACTH have apparent molecular weights of 31,000 (31K), 20--21K, 14K, and 4.5K, and the major forms of immunoactive endorphin have apparent molecular weights of 31K (coincident with the peak of immunoactive ACTH), 13K (a betaLPH-like peptide), and 3.5K (a beta-endorphin-like peptide). However, the quantitative distribution of immunoactivity among the various forms differs greatly between the lobes. Assays using an extreme COOH-terminal ACTH antiserum indicate that the 31K ACTH/endorphin molecule in rat anterior and intermediate pituitary is similar to the pro-ACTH/endorphin molecule from mouse pituitary tumor cells. A radioimmunoassay that is specific for the NH2-terminal non-ACTH, nonendorphin segment (referred to as 16K fragment) of the mouse pro-ACTH/endorphin molecule was used to assay extracts of rat pituitary. In addition to detecting material at 31K and 20--21K, the 16K fragment radioimmunoassay detects significant amounts of cross-reactive material with an apparent molecular weight of 16K in extracts of both lobes. This result also suggests that the structure and processing of the rat 31K ACTH/endorphin molecule is similar to that of mouse tumor cell pro-ACTH/endorphin. Cell suspensions were prepared from the anterior and intermediate lobes of the rat pituitary and maintained in culture for a 24-h period. The isolated cells from both lobes incorporate [3H] phenylalanine into immunoprecipitable ACTH- and endorphin-containing molecules. By sequential immunoprecipitation with ACTH and endorphin antisera, it is possible to demonstrate directly that a single molecule (31K ACTH/endorphin) has antigenic determinants for both ACTH and endorphin. Significant amounts of 31K ACTH/endorphin are released into the culture medium by isolated anterior lobe and intermediate lobe cells. The isolated intermediate lobe cells synthesize and secrete relatively large amounts of a beta-endorphin-like molecule; the isolated anterior lobe cells secrete significant amounts of both a betaLPH-like molecule and a beta-endorphin-like molecule. These same quantitative differences between anterior and intermediate lobe tissue were observed in immunoassays of extracts of the separated lobes and probably reflect differences in the processing of the common precursor. The isolated anterior lobe cells can be stimulated to release increased amounts of immunoprecipitable ACTH and endorphin by incubation with a cyclic AMP analog and a phosphodiesterase inhibitor.
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PMID:Existence of a common precursor to ACTH and endorphin in the anterior and intermediate lobes of the rat pituitary. 8 77

Isolated fat cells from rat epididymal adipose tissue were incubated with various lipolytic hormones in the absence and presence of the alpha-adrenergic blocking agent phentolamine. Lipolysis, stimulated by noradrenaline, isoproterenol, or ACTH, was inhibited dose-dependently by phentolamine. At concentrations of phentolamine where lipolysis was already inhibited, phentolamine had a biphasic effect on hormone-stimulated formation of cAMP. Low concentrations of phentolamine enhanced cAMP formation, while high concentrations inhibited cAMP. The additional increase of cAMP formation by phentolamine was only seen with maximally effective concentrations of noradrenaline, isoproterenol, and ACTH. Half-maximally effective concentrations were invariably inhibited by phentolamine. The activity of noradrenaline-stimulated adenylate cyclase of fat-cell plasma membranes was inhibited by phentolamine, whereas cAMP phosphodiesterase activity was unaffected.
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PMID:Biphasic effect of the alpha-adrenolytic phentolamine on hormone-stimulated formation of cyclic adenosine-3',5'-monophosphate in isolated fat cells of rats. 16 51

1. The effect of salmon gonadotropin(s) (SG) on cyclic AMP (cAMP) levels in immature trout gonadal tissue of both sexes was measured by radioimmunoassay. 2. A dose-response line was obtained to SG in gonads of both male and female trout. 3. As little as 0.45 SG units (1 SG unit = 1 mug NIH-LH-S18 in the chick bioassay) significantly increased cAMP formation in the presence of 8 mM theophylline; mammalian LH, FSH, LTH, ACTH, TSH and HCG were inactive. 4. The assay for SG was investigated with respect to time of incubation and two phosphodiesterase inhibitors; some conditions for the cAMP radioimmunoassay (cAMP-RIA) were compared.
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PMID:Fish gonadotropin(s). I. Bioassay of salmon gonadotropin(s) in vitro with immature trout gonads. 17 55

Actions of various methylxanthines (theophylline, theobromine, caffeine) and papaverine, i.e. drugs which are known to inhibit phosphodiesterase (PDE), were studied on the basal and stimulated synthesis of corticosterone in vitro by using rat adrenal slices. When slices were incubated with methylxanthines, the synthesis of corticosterone was slightly increased. The order of potency, expressed as the efficacy (intrinsic activity) was: theophylline greater than caffeine greather than theobromine. Papaverine did not stimulate the synthesis. The synthesis stimulated by ACTH or the dibutyryl derivative of c-AMP (DBA) was reduced by all of the inhibitors of phosphodiesterase. The molar concentration of the inhibitors which reduced the stimulated steroidogenesis by 50% was lowest for papaverine, higher for theobromine and theophylline and highest for caffeine. Papaverine was active in concentrations of about 10(-5)M, while the methylxanthines were effective in concentrations of 10(-3)--10(-2)M. When the PDE-inhibitors were added to the incubate simultaneously with the stimulant (ACTH or DBA), there was a delay of 60 min before the synthesis was completely blocked. When the stimulant was added 30 min before the administration of an inhibitor, the inhibitory action was no more evident. The inhibitory action of theophylline, but not that of papaverine, was reversed by washing adrenal slices free from the inhibitor, before adding the stimulant. The type of inhibition for papaverine as well as for methylxanthines in antagonizing both the ACTH- and DBA-stimulated synthesis of corticosterone was not competitive but of a mixed type.
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PMID:Actions of various methylxanthines and papaverine on the synthesis of corticosterone in vitro. 17 Sep 47

The in vitro effects of theophylline and aminogluthetimide upon basal and ACTH stimulated cAMP, cortisol and aldosterone responses of normal human adrenocortical tissue were evaluated. Theophylline increased basal cAMP levels and cortisol output, however, basal aldosterone output was depressed. Theophylline in concert with ACTH depressed cortisol and aldosterone output. Aminogluthetimide alone did not affect basal cAMP levels, however, the normal cAMP response to ACTH was delayed in aminogluthetimide pre-treated adrenals. Aminogluthetimide also depressed basal and ACTH stimulated cortisol and aldosterone output with the latter being more sensitive. The findings indicate that both theophylline and aminogluthetimide produce effects upon the adrenal in addition to inhibition of phosphodiesterase and cholesterol side-chain cleavage, respectively. Further, theophylline depression of ACTH stimulated steroid output may be helpful in understanding the interplay between a number of factors in the control of adrenal steroid biosynthesis and release.
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PMID:In vitro effects of theophylline and aminogluthetimide upon basal and ACTH induced cAMP levels and steroid output by the normal human adrenal gland. 20 41

As compared to fatty tissue cells of animals with normal pressure, those of SHR rats were found to be characterized by a higher lipolytic response and a larger increase in the cAMP content on exposure to the effect of ACTH. As compared to the controls, adrenalectomized SHR rats had an increased basal cAMP content and an increased lipolytic response of the adipocytes following adrenaline administration. In inhibition of phosphodiesterase in the fatty cells of adrenalectomized rats with normal pressure, the cAMP content grew by 20% as compared to that in SHR rats subjected to the operation. It is suggested that the changes in intracellular distribution of calcium, shown in this model of hypertension, may be the direct cause of the altered sensitivity of the "target" cells to the effect of hormones.
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PMID:[Mechanism of the change in adipocyte sensitivity to ACTH and adrenaline in spontaneous genetic hypertesion in rats]. 21 34

The influence of behaviorally active, N-terminal fragments of ACTH on the accumulation of cAMP in rat brain investigated in broken cell preparations of subcortical tissue, in slices of neostriatum and in vivo. ACTH1--24 has a biphasic effect on the activity of adenylate cyclase in broken cell preparations of rat brain subcortical tissue: concentrations below 25 micrometer stimulated, whereas concentrations of 0.1 mM and higher inhibited adenylate cyclase activity. The magnitude of the stimulation was dependent on the concentrations of ATP and Mg2+ in the incubation medium. Structure activity studies revealed that at a concentration of 10(-4) M ACTH1--16-NH2 and ACTH4--7 also inhibited the activity of adenylate cyclase, whereas ACTH11--24, ACTH1--10, ACTH4--10, [D-Phe7]ACTH1--10 and [D-Phe7]ACTH4--10 were inactive in this respect. Addition of 0.8 mM EGTA but not of 0.25 mM Ca2+ prevented the inhibition by 10(-4) M ACTH1--24. GMP-N-P (10(-5) M), naltrexone (10(-3) M) and ergometrine (10(-3) M) did not influence the inhibitory effect. ACTH1--24 enhanced the accumulation of cAMP in slices from rat brain neostriatum in a dose-dependent manner. This effect was already maximal 7.5 min after the addition of the peptide and was potentiated by isobutylmethylxanthine, a potent inhibitor or phosphodiesterase. Intraventricular injection of 1 microgram ACTH1--16-NH2 in rats significantly elevated (+ 27%) the concentration of cAMP in the septal region 60 min after the injection of the peptide. The results are discussed in terms of a possible involvement of cAMP as a second messenger in the central nervous system for N-terminal fragments of ACTH.
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PMID:ACTH-like neurotropic peptides: possible regulators of rat brain cyclic AMP. 21 39

The responses of the cyclic AMP-generation system and corticosteroids biosynthesis to ACTH and angiotensin II and cholesterol and other lipid contents in adrenal tissues were estimated in the in vitro experiments in 3 cases of Cushing's syndrome due to ACTH-responsive and unresponsive adenomas, one case of Cushing's disease (diffuse hyperplasia), one case of primary aldosteronism and one normal subject. The responses of cAMP accumulation and corticosteroids production to ACTH in in vitro studies were quite in good agreement with the in vivo responses of plasma cortisol by ACTH infusion test. The adenylate cyclase activity decreased and the phosphodiesterase activity increased in the case of hyperplasia and in one case of ACTH-responsive adenoma, whereas the basal cyclic AMP content was slightly more in ACTH-responsive adenoma and maximal in hyperplasia compared with that of the normal adrenal tissue. The characteristic features observed in ACTH-unresponsive adenoma were the largest amount of the basal corticosteroids production and esterified cholesterol content, and the lowest content cAMP. These results indicate that there was not always the consistent correlation between the cAMP-generation system, corticosteroids and aldosterone production, and conversion of cholesterol to pregnenolone by the stimulation of ACTH and angiotensin II in adrenal tumors.
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PMID:Comparative study of cyclic AMP-generation system, steroid biosynthesis and lipid metabolism in vitro in ACTH responsive and unresponsive adrenal tumors. 22 40

The decline of the ACTH-stimulated cGMP to the basal level in isolated adrenocortical carcinoma cells was inhibited by cyclic phosphodiesterase inhibitors. Time-course experiments showed that the ACTH-induced level of cGMP preceded the activation of phosphodiesterase. Cells incubated with increasing concentrations of exogenous cGMP responded with a corresponding increase in the cGMP-phosphodiesterase activity. cAMP was 100-fold less effective than cGMP in the activation of cGMP-phosphodiesterase, indicating the nucleotide specificity of enzyme activation. The activation of cGMP-phosphodiesterase by ACTH-induced cGMP or exogenous cGMP was rapid. In contrast to these observations, there was no activation of cAMP-phosphodiesterase by exogenous cAMP or cGMP. These results indicate that one mechanism by which isolated adrenocortical carcinoma cells regulate the ACTH-induced increase in cGMP is the cyclic nucleotide control of the activity of its phosphodiesterase, thereby regulating cGMP degradation.
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PMID:Stimulation of guanosine 3',5'-monophosphate-phosphodiesterase activity by adrenocorticotropic hormone-activated increase of guanosine 3',5'-monophosphate in isolated adrenocortical carcinoma cells. 22 58

Non-nucleated red blood cells from rats contain adenyl cyclase, the activity of which is predominantly localized in the reticulocytes. Basal enzyme activities in membrane preparations from reticulocyte-rich blood (pretreatment of rats with acetyl-phenylhydrazide: about 60% reticuloytes) are about 5 times higher than in preparations from reticulocyte-poor blood (untreated animals: 2-3% reticulocytes). The enzyme activities are stimulated 10-fold by sodium fluoride (10(-2)M) and 6 to 8-fold by isoprenaline (10(-4)M). Adenyl cyclase activities in membrane preparations from reticulocyte-rich and reticulocyte-poor blood can be ascribed to identical enzymes since identical apparent Km (ATP; 3 times 10(-4)M, Ka (isoprenaline; 3 times 10(-6)M) and Ki (propranolol vs. isoprenaline; 3 times 10(-7)M) values were obtained in both preparations. Besides NaF, only phenylethanolamine derivatives with beta-adrenergic receptor stimulant properties were effective as stimulators of adenyl cyclase activity. The affinities (apparent Ka values) of the investigated compounds decreased in the order isoprenaline--hexoprenaline--fenoterol--salbutamol--adrenaline--terbutalin--noradrenaline--phenylephrine. For maximal intrinsic activity, the catechol structure was essential; the relative intrinsic activities of resorcinol derivatives did not exceed 0.6. The isoprenaline-stimulated adenyl cyclase activities in erythrocyte membrane preparations were competitively inhibited by beta-adrenergic blocking drugs, the affinities (apparent Ki values) decreasing in the order prindolol--penbutolol--propranolol--practolol. The dextrorotatory enantiomers of penbutolol and propranolol were 1/100 to 1/200 as active as the resp. levorotatory enantiomers. From experiments with alpha-adrenergic agonists (e.g. phenylephrine) and antagonists (e.g. phentolamine), it is concluded that alpha-adrenergic receptors do not interfere with the beta-adrenergically-mediated cAMP formation in these particular membranes. A variety of hormones and drugs known to stimulate denyl cyclase activities in various tissues, e. g. ACTH, glucagon, STH, erythropoietin, prostaglandin E1 etc. did not affect adenyl cyclase activity in reticulocyte-rich erythrocyte membrane preparations. In contrast to adenyl cyclase activity, phosphodiesterase activities in erythrocyte membrane and cytoplasmic fractions were only twice as high in reticulocyte-rich as in reticulocyte-poor preparations. From the experiments described, it is obvious that the adenyl cyclase of the rat reticulocyte is subject to monovalent-hormonal, i.e. beta-sympathomimetic stimulation. Moreover, the premature red blood cell provides a useful model for quantitative studies of the interaction of drugs with the beta-adrenergic receptor.
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PMID:The beta-adrenergic receptor-adenyl-cyclase system of rat reticulocytes: effects of adrenergic stimulants and inhibitors. 24 Jan 35


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