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)

The effects of human chorionic gonadotropin (HCG), forskolin, cyclic nucleotides, the phosphodiesterase inhibitors IBMX and theophylline, cyanoketone, and cycloheximide on the production of estradiol-17 beta by isolated ovarian follicles of vitellogenic goldfish (Carassius auratus) were examined using 18-hr incubations. HCG and all test agents which are known to increase intracellular concentrations of cAMP significantly stimulated the production of estradiol-17 beta. However, dibutyryl cGMP was unable to stimulate estradiol-17 beta production at any concentration used (1-10 mM). Cyanoketone at a concentration of 1 micrograms/ml completely blocked forskolin-induced estradiol-17 beta production. Even in the presence of cyanoketone, however, forskolin stimulated conversion of exogenous testosterone to estradiol-17 beta in a dose-dependent manner, suggesting the involvement of an adenylate-cyclase system in the induction of aromatase activation by vitellogenic follicles of goldfish. Cycloheximide also completely abolished HCG-induced estradiol-17 beta production when this inhibitor was added within the first 1 hr after the addition of HCG. These results provide evidence that the stimulation of estradiol-17 beta by goldfish vitellogenic follicles in response to HCG is dependent upon the synthesis of new protein.
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PMID:The in vitro effects of cyclic nucleotides, cyanoketone, and cycloheximide on the production of estradiol-17 beta by vitellogenic ovarian follicles of goldfish (Carassius auratus). 242 92

Vanadate, a normal constituent of cells, has been reported to affect a variety of enzymes involved in phosphate transfer; the findings regarding adenylate cycle vary with the tissue and experimental system. In the corpus luteum, cyclic AMP (cAMP) stimulates steroidogenesis; and prostaglandin F2 alpha, which induces luteal regression, inhibits luteinizing hormone (LH)-induced cAMP accumulation. We examined the influence of orthovanadate on cAMP concentration in isolated corpora lutea from pseudopregnant rats. With 2 mM vanadate, basal cAMP level was unaffected, but LH-induced cAMP accumulation was inhibited by 45-68%. Lower doses of vanadate (0.2-1 mM) were almost as effective. When added simultaneously with LH, vanadate was inhibitory within 25 min, but no inhibition occurred when vanadate was added for 30 min to tissue pretreated with LH for 60 min. The decrease in cAMP accumulation was observed also when corpora lutea were exposed to vanadate in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.5 mM), indicating that vanadate inhibits cAMP synthesis. Vanadate may increase cytosolic calcium by inhibiting ion pumps in cell membranes. Thus, we examined the effect of vanadate in corpora lutea incubated in calcium-depleted medium and found that vanadate still inhibited cAMP formation. Vanadyl sulfate (0.4 and 2 mM) reduced the LH-induced cAMP accumulation as effectively as vanadate. Thus, the use of vanadate as a tool for exploring physiological regulators of luteal adenylate cyclase should be considered.
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PMID:Inhibition by vanadate of cyclic AMP production in rat corpora lutea incubated in vitro. 243 73

The adenylate-cyclase activator forskolin, the guanylate-cyclase stimulator sodium nitroprusside, the phosphodiesterase inhibitor Ro 15-2041, different Ca-entry blockers, as well as various vasodilators, and the atrial natriuretic peptide were tested for antiplatelet activity. Thrombin, vasopressin, ADP, arachidonic acid, and the dihydropyridine Ca agonist CGP 28392 were used as platelet activators. The physiological and biochemical parameters of platelet function studied included shape-change reaction, intracellular free-Ca modulation, and cyclic nucleotide formation. When inhibition of the shape-change response occurred, it was accompanied by inhibition of the increase in intracellular free Ca. Furthermore, the results suggest a possible intracellular site of action of Ca entry blockers in platelets, and confirm the importance of modulation of cyclic nucleotides in the regulation of platelet function, regardless of the mechanism of platelet activation. Additional antiplatelet activity of antihypertensive agents may have a beneficial effect in reducing the associated risk of thrombo-embolic complications in essential hypertension.
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PMID:Vasodilating agents and platelet function: intracellular free calcium concentration, cyclic nucleotides, and shape-change response. 243 9

We used our recently reported stable, transformed human renal carcinoma cell line as a model system to study the role of 3',5'-adenosine monophosphate (cAMP) in erythropoietin secretion. The erythropoietin produced by these cells is both biologically active and immunologically cross-reactive with purified native human hormone in our radioimmunoassay. Erythropoietin release by these renal carcinoma cells appears to be stimulated by cAMP as well as by the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (MIX). The response to cAMP involves a rapid and enhanced release of hormone, which occurred within 30 minutes of exposure of the cells to the effector and continued for at least 4 hours. Intracellular erythropoietin was higher in the control cultures than in the cells treated with cAMP, suggesting that cAMP stimulates the release of a storage pool of hormone. The ability of cAMP and MIX to elicit the release of erythropoietin suggests that a cAMP-mediated mechanism is involved in the release of this hormone.
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PMID:Stimulation by cAMP of erythropoietin secretion by an established human renal carcinoma cell line. 243 40

1. The effect of intracellular perfusion with cyclic AMP and cyclic GMP on Ca2+ current (ICa) was studied in single cells isolated from frog ventricle using the whole-cell patch-clamp technique and a perfused pipette. 2. Intracellular perfusion with cyclic GMP (0.1-20 microM) had no effect on the basal ICa. However, when ICa was increased by isoprenaline or by intracellular perfusion with cyclic AMP, perfusion with cyclic GMP (20 microM) reduced ICa by an average of 67%. The effect of cyclic GMP on ICa elevated by cyclic AMP was reversible. A half-maximal effect of cyclic GMP was observed at 0.6 microM. Cyclic GMP had no significant effect on the shape of the ICa current-voltage relationship. 3. The effect of cyclic GMP was specific to the 3',5' form; 2',3'-cyclic GMP had no effect. 4. The effect of cyclic GMP was apparently not mediated by stimulation of cyclic-GMP-dependent protein kinase because 8-bromo-cyclic GMP, a very potent activator of the protein kinase, was without effect. 5. Cyclic GMP had no effect on ICa elevated by the non-hydrolysable 8-bromo-cyclic AMP. The effect of cyclic GMP on cyclic-AMP-elevated ICa was partially blocked by the phosphodiesterase inhibitor, methylisobutylxanthine. Thus, it was hypothesized that the effect of cyclic GMP was mediated by hydrolysis of cyclic AMP as a result of a stimulation of a cyclic nucleotide phosphodiesterase by cyclic GMP. 6. The dose-response curve for cyclic AMP on ICa was well fitted by the Michaelis equation with a K50 (i.e. concentration of cyclic AMP at which response is 50% of the maximum) of 0.7 microM and a maximal 11-fold stimulation of ICa. Cyclic GMP shifted the curve one log unit to the right and decreased the maximal stimulation to 8.6-fold. Thus, the effect of cyclic GMP appeared uncompetitive. 7. The products of cyclic AMP and cyclic GMP hydrolysis, 5'-AMP and 5'-GMP, had no effect on ICa. Furthermore, strong buffering of intracellular pH did not reduce the effect of cyclic GMP. 8. It is proposed that cyclic-GMP-stimulation of a cyclic nucleotide phosphodiesterase may be one of several mechanisms by which acetylcholine regulates ICa.
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PMID:Cyclic guanosine 3',5'-monophosphate regulates the calcium current in single cells from frog ventricle. 244 83

We have shown in the companion paper that somatotrophs dispersed from streptozotocin diabetic rats exhibit altered sensitivity to the natural hypothalamic controlling hormones, growth hormone releasing factor and somatostatin. We have further studied the effects on growth hormone release from dispersed adenohypophysial cells of normal and streptozotocin diabetic rats of stimulation by compounds that increase cyclic 3',5'-adenosine monophosphate formation or inhibit its breakdown and of a phorbol ester. The cells of the diabetic rats had no change in sensitivity in response to either cholera toxin or forskolin. A phosphodiesterase inhibitor caused an equal GH release from cells of both diabetic and normal animals after 60 min of incubation. There was no change in sensitivity of the cells of diabetic animals or in the maximal response of these cells to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate when compared with normal cells. A low calcium medium that blocked growth hormone releasing factor stimulated growth hormone release from normal rat cells also blocked it from the cells of the diabetic rats. These results suggest that the defect in response of the somatotrophs of diabetic animals is specific and only occurs with the hypothalamic hormones and not with other secretagogues.
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PMID:Altered release of growth hormone from dispersed adenohypophysial cells of streptozotocin diabetic rats. II. Effects of a phorbol ester and secretagogues which increase cyclic AMP. 248 23

The effects of cAMP on Mauthner (M-) cell excitatory and inhibitory responses were studied in vivo. Cyclic AMP was iontophoresed into the M-cell lateral dendrite, after which we monitored the changes in cellular responsiveness to stimulation of 2 classes of identified presynaptic cells: (1) excitatory fibers from the posterior branch of the ipsilateral eighth cranial nerve and (2) inhibitory interneurons activated by the M-cell collateral and commissural networks. We found that postsynaptic injections of cAMP increased the magnitudes of the electrically and chemically mediated EPSPs from the eighth nerve and enhanced M-cell inhibitory responses as well. Furthermore, cAMP augmented paired-pulse facilitation of both types of excitatory potentials. No effects on input conductance, resting membrane potential, or presynaptic spike width were observed. All effects were mimicked by aminophylline, a cAMP-dependent phosphodiesterase inhibitor but not by 5'-AMP, the cAMP breakdown product. These results provide evidence for second-messenger modulation in vivo of electrotonic and chemical synaptic potentials at mixed synapses. In addition, they provide the first evidence for cAMP modification of a glycinergic receptor-channel complex. Preliminary results from some of these experiments have been reported previously (Wolszon and Faber, 1986).
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PMID:The effects of postsynaptic levels of cyclic AMP on excitatory and inhibitory responses of an identified central neuron. 253 81

1. The effects of forskolin, a direct activator of adenylate cyclase and sodium nitroprusside, a direct activator of guanylate cyclase, were studied on rabbit isolated ear arteries preconstricted with 80 mM potassium. 2. Bolus injection of these two compounds resulted in vasodilatation. They had similar potencies in this tissue but forskolin had a significantly longer duration of action than sodium nitroprusside. 3. In the same tissue, perfusion with isobutylmethylxanthine (IBMX), a non-selective phosphodiesterase (PDE) inhibitor, or zaprinast, selective for the PDE primarily responsible for the metabolism of guanosine 3':5'-cyclic monophosphate (cyclic GMP), resulted in vasodilatation. However, SK&F 94120 selective for cyclic AMP-PDE (PDE III), primarily responsible for the metabolism of adenosine 3':5'-cyclic monophosphate (cyclic AMP), resulted in vasodilatation only at very high concentrations. The rank order of potency for the compounds was IBMX greater than zaprinast greater than SK&F 94120. 4. The effects of these three PDE inhibitors were studied on the vasoconstriction produced by perivascular sympathetic nerve stimulation in the absence of raised potassium. IBMX and zaprinast, caused a reduction in the response at 50 Hz stimulation frequency and a shift in the frequency-response curve to the right. SK&F 94120 did not displace the frequency-response curve but did reduce the response at 50 Hz. The same order of potency for the inhibition of the vasoconstrictor responses to perivascular sympathetic nerve stimulation was found as for vasodilatation i.e. IBMX greater than zaprinast greater than SK&F 94120. 5. These results indicate that in the same tissue direct activation of adenylate and guanylate cyclase results in vasodilatation. Non-specific PDE and cyclic GMP-PDE inhibition also resulted in vasodilatation and inhibition of vasoconstrictor responses to sympathetic nerve stimulation. However a selective cyclic AMP-PDE (PDE III) inhibitor did not result in vasodilatation, except at very high concentrations, or inhibit sympathetic vasoconstrictor responses except to reduce the response at 50Hz stimulation. These findings provide further support for the ability of PDE inhibitors to be tissue selective.
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PMID:A comparison of vasodilator activity of agents activating cyclic nucleotides with those inhibiting their metabolism in rabbit isolated ear artery. 254 50

We have previously reported that treatment of hen granulosa cells with the tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), or the diacylglycerol analog, 1-oleoyl-2-acetylglycerol (OAG), attenuates the steroidogenic response to luteinizing hormone (LH) at sites both prior and distal to the formation of cyclic 3',5'-adenosine monophosphate (cAMP). The present study was designed to determine the site(s) of inhibition within the steroidogenic pathway by evaluating the effects of OAG and PMA on key enzyme systems involved in hen granulosa cell steroidogenesis: adenylyl cyclase, phosphodiesterase, the cholesterol-side-chain-cleavage (CSCC) complex and 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD). The adenylyl cyclase activator, forskolin (0.1 mM), stimulated a 3.3-fold increase in granulosa cell cAMP formation, and this increase was inhibited by the presence of OAG (2.5, 25 and 63 microM) in a dose-dependent manner. By contrast, a 1.8-fold increase in cAMP accumulation induced by the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX; 1.0 mM), was not altered by OAG at any dose (2.5, 25 and 63 microM). Inclusion of 25-hydroxycholesterol (2500 ng/tube) in the incubation medium in the presence of 1.0 microM cyanoketone resulted in a 10-fold increase in pregnenolone production. Increasing concentrations of OAG (2.5, 25 and 63 microM) caused a dose-dependent suppression of the conversion of 25-hydroxycholesterol to pregnenolone. On the other hand, granulosa cells incubated with 200 ng/tube pregnenolone increased progesterone production 100-fold, but this increase was not inhibited by either PMA (3.2, 32, 8.1 and 162 nM) or OAG (2.5, 25 and 63 microM). The results indicate that activation of protein kinase C can suppress the function of at least two key enzymes involved in hen granulosa cell steroidogenesis. Inhibition of adenylyl cyclase greatly reduces the steroidogenic response of granulosa cells to endocrine factors that act via increasing levels of cAMP (i.e. LH). Furthermore, a reduction in CSCC activity limits the availability of precursor required for progesterone production. These data provide additional evidence of a role for protein kinase C in modulating ovarian function in the domestic hen.
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PMID:Mechanisms by which a phorbol ester and a diacylglycerol analog inhibit hen granulosa cell steroidogenesis. 254 39

Dipyridamole (DPM) enhanced the sensitivity of human ovarian carcinoma 2008 cells to etoposide (VP-16) producing a 5.5-fold reduction in 50% inhibitory concentration at a DPM concentration of 20 microM. This interaction was shown to be truly synergistic by isobologram and median effect analysis. DPM increased the steady-state VP-16 content of 2008 cells; a DPM concentration of 4 microM increased VP-16 content by 2-fold. DPM was 25 times less potent when cells were incubated in human plasma. In tissue culture medium 96% of the DPM was free, whereas in plasma only 15% was non-protein bound. DPM did not displace VP-16 from proteins under either condition. DPM did not increase the initial influx of VP-16 but did inhibit the initial efflux, reducing the efflux rate constant by 27%. DPM had no effect on the later stages of drug efflux, nor did it irreversibly bind VP-16 in the cell. The effect of DPM was evident within 1 min; once removed, the effect disappeared within 2 min. DPM is a potent nucleoside membrane transport inhibitor and can also inhibit cyclic AMP (cAMP) phosphodiesterase in platelets. Nitrobenzylthioinosine, another nucleoside transport inhibitor which competes for binding with DPM, did not enhance sensitivity to VP-16 or increase VP-16 cellular accumulation and did not block the effect of DPM. In 2008 cells, DPM did not increase cAMP; when cAMP was increased by incubation with dibutyryl cyclic 3':5'-AMP, there was no synergy with VP-16. The results indicate that enhanced sensitivity to VP-16 was not due to an effect of DPM on the protein binding of VP-16 or on cellular cAMP and suggest that it is not directly related to inhibition of nucleoside transport. This effect appears to be a newly identified mechanism of action for this agent.
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PMID:Dipyridamole enhancement of etoposide sensitivity. 254 35


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