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)

Ovarian function may be modulated by cells of the immune system. We have investigated the role of neutrophils (polymorphonuclear leukocytes) on rat luteal cell function. Activated neutrophils inhibited LH-sensitive cAMP accumulation, which was dependent on neutrophil cell number. At a concentration of 10(6) neutrophils/ml and 10(5) luteal cells/ml, LH-stimulated cAMP accumulation was inhibited by 50%. The inhibitory effect of activated neutrophils was reversed by superoxide dismutase (SOD) and catalase. LH-stimulated progesterone production was also inhibited by activated neutrophils. Progesterone production by 10(5) luteal cells was inhibited approximately 20% in the presence of 10(6) activated neutrophils, and this inhibition was blocked by SOD and catalase. Conditioned medium from activated neutrophils also produced inhibitory effects on LH-stimulated cAMP accumulation and progesterone production, which could be reversed by SOD and catalase. The phosphodiesterase inhibitor isobutylmethylxanthine had no significant effect on the inhibition of cAMP accumulation by conditioned medium from activated neutrophils. Luteal cells loaded with a fluorescent indicator for determining intracellular reactive oxygen species (dichlorofluorescein diacetate) showed increased fluorescence in the presence of activated neutrophils. No increase in fluorescence occurred in the absence of neutrophils or in the presence of SOD and catalase. These studies demonstrate that reactive oxygen species produced by activated neutrophils can enter the luteal cell and cause antigonadotropic effects. Although the experimental model used in the present studies may not be truly physiological, the data demonstrate that neutrophils may play a role in functional and structural regression of the corpus luteum in the rat.
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PMID:Effects of neutrophils in rat luteal cells. 131 Feb 72

The effects of activin and inhibin on steroidogenesis in the human ovary were investigated. Granulosa cells harvested from follicles of women undergoing oocyte recovery for in vitro fertilization were maintained in culture for 4 days before treatment in serum-free medium. Human recombinant inhibin-A and activin-A at concentrations of 100 ng/mL did not affect basal progesterone secretion (P greater than 0.05). Progesterone concentrations were increased 2- to 6-fold by hCG or FSH. Activin-A inhibited the progesterone response to hCG compared with that of cells treated with hCG alone (P less than 0.01). The effect of activin-A was dose dependent and significant at 16-18 h of treatment (P less than 0.01). Inhibin-A at the same concentrations as activin-A had no effect on the progesterone responses to hCG and FSH. The hCG-induced accumulation of 20 alpha-hydroxyprogesterone was also attenuated by simultaneous activin-A treatment compared to that in cells treated with hCG alone (P less than 0.01). To investigate the mechanism of action of activin-A, cells were treated with a cAMP analog (8-bromo-cAMP) or an activator of adenylate cyclase (forskolin), with or without activin-A. Activin-A had no effect on 8-bromo-cAMP-stimulated progesterone accumulation. Likewise, forskolin-stimulated progesterone accumulation was not affected by activin-A. The hCG-induced increase in intracellular cAMP was decreased by activin-A in the presence of a phosphodiesterase inhibitor, isobutylmethylxanthine (P less than 0.01). Thus, activin-A may inhibit progesterone production by suppression of gonadotropin-induced cAMP production. These results support an autocrine role of activin-A in the steroidogenic capacity of human ovarian cells.
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PMID:Inhibition of progestin accumulation by activin-A in human granulosa cells. 132 53

Three phosphodiesterase (PDE) type III inhibitors were tested and found to inhibit Xenopus oocyte maturation induced by insulin with apparent IC50 values of 2.2 +/- 0.2 microM Cl-930, 25 +/- 3 microM imazodan (Cl-914), and 786 +/- 237 microM piroximone (MDL 19,205). The same rank order of potencies was observed for inhibition of insulin-like growth factor-I (IGF-I)-induced oocyte maturation, with IC50 values of 5.5 +/- 0.9 microM Cl-930, 54 +/- 4 microM imazodan, and 1190 +/- 395 microM piroximone. Oocyte maturation induced by microinjection of Ha p21ras was also inhibited by pretreatment of oocytes with Cl-930 or imazodan, with IC50 values of 4.3 +/- 1.2 and 59 +/- 4 microM, respectively. Progesterone-induced maturation was not affected by PDE III inhibitor action; and, neither type IV PDE inhibitors (Ro 20, 1724 or rolipram) nor dipyridamole (a type V PDE inhibitor) inhibited cell division induced by IGF-I or microinjected Ha p21ras. In addition, while insulin-stimulated oocyte PDE activity measured in vivo after microinjection of 200 microM [3H] cAMP was inhibited by nonselective and type III-specific drugs (with IC50 values of 4.2 +/- 1.8 microM Cl-930 and 26 +/- 6 microM imazodan), type IV and type V inhibitors did not inhibit hormone-stimulated enzyme activity. This pharmacological evidence demonstrates a necessary role for PDE III in insulin-, IGF-I-, and p21ras-induced meiotic cell division in Xenopus laevis oocytes.
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PMID:Type III phosphodiesterase plays a necessary role in the growth-promoting actions of insulin, insulin-like growth factor-I, and Ha p21ras in Xenopus laevis oocytes. 166 4

These experiments examined the influence of estradiol and progesterone given in vivo on norepinephrine (NE) regulation of cAMP synthesis in hypothalamic and preoptic area slices in vitro. Administration of progesterone to estrogen-primed female rats attenuated NE-induced slice cAMP accumulation. This hormone-dependent reduction in NE-stimulated cAMP synthesis was observed in slices incubated with TTX and in slices prepared from hypophysectomized rats, suggesting that progesterone effects on NE receptor activation of cAMP-generating systems are not secondary to the release of neurotransmitters that inhibit adenylyl cyclase or to changes in pituitary hormone secretion. Progesterone suppression of NE-induced cAMP formation could be prevented by incubating slices in the presence of a phorbol ester. In additional studies, the activity of beta-NE receptors was assessed by measuring isoproterenol (ISO)-stimulated cAMP accumulation in the presence of the phosphodiesterase inhibitor RO-20-1724, and the activity of alpha 1 receptors was evaluated by measuring phenylephrine (PHE) augmentation of the ISO response. Estradiol reduced the cAMP response to ISO in both hypothalamic and preoptic area slices, and this effect was not reversed by subsequent progesterone treatment. Estradiol also enhanced PHE augmentation of ISO-stimulated cAMP synthesis. Moreover, administration of progesterone subsequent to estradiol eliminated alpha 1-receptor augmentation of the ISO response. An alpha 1 enhancement of the ISO response is observed if the progestin receptor antagonist RU 38486 is administered before progesterone. Progesterone also abolished PHE potentiation of vasoactive intestinal polypeptide-stimulated cAMP accumulation. In contrast, neither phorbol ester nor muscarinic (carbachol) potentiation of the cAMP response to ISO was affected by progesterone. The data suggest that ovarian steroids regulate the coupling of both alpha 1 and beta receptors to the membrane effector systems that generate intracellular cAMP.
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PMID:Alpha 1-adrenoceptor augmentation of beta-stimulated cAMP formation is enhanced by estrogen and reduced by progesterone in rat hypothalamic slices. 216 57

We measured the concentration of progesterone and estradiol and calculated the progesterone:estradiol ratio in nonpregnant and pregnant human myometrium. Progesterone, estradiol and the progesterone:estradiol ratio were higher in pregnant than in nonpregnant myometrium. There was no difference in the concentration in the presence of labor. The progesterone:estradiol ratio showed a similar pattern. We also investigated the effect of the ovarian steroids on the activity of cyclic adenosine monophosphate-phosphodiesterase (cAMP-PDE). Progesterone in pharmacologic doses inhibited the activity of the high-affinity enzyme as much as 72% and the low-affinity form as much as 34%. High-affinity phosphodiesterase from nonpregnant myometrium was the least sensitive to inhibition, and the enzyme from pregnant myometrium obtained from laboring women was the most sensitive. Low-affinity phosphodiesterase from nonpregnant myometrium was less sensitive to inhibition than enzyme from pregnant women with or without labor. The degree of inhibition of the low-affinity enzyme in the two pregnant groups was not different. The type of inhibition was competitive in both the high- and low-affinity forms. Estradiol at similar concentrations did not have any effect on the activity of the enzyme. Progesterone in part may exert its effect on the human myometrium by its effect on cyclic adenosine monophosphate-PDE activity and the metabolism of cAMP.
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PMID:Progesterone and estradiol concentrations in nonpregnant and pregnant human myometrium. Effect of progesterone and estradiol on cyclic adenosine monophosphate-phosphodiesterase activity. 217 9

The present experiments examined the effects of progesterone on adrenergic receptor coupling to adenylate cyclase in hypothalamic and preoptic area slices by monitoring norepinephrine (NE)-stimulated increases in cAMP accumulation. Progesterone treatment of estrogen-primed rats decreased NE-induced slice cAMP accumulation. The reduced cAMP response was estrogen-dependent since it was not demonstrable in slices from rats exposed to progesterone without prior estrogen priming. Neither generalized increases in phosphodiesterase activity nor decreases in the catalytic activity of adenylate cyclase could account for the reduced ability of NE to stimulate cAMP accumulation in hypothalamic slices. Moreover, the cAMP response to two other activators of adenylate cyclase, adenosine and vasoactive intestinal peptide, was not decreased in slices from rats treated with estrogen plus progesterone. Selective adrenergic agonists and antagonists were employed to determine which adrenergic receptors mediate cAMP accumulation in progesterone-exposed slices. Slice cAMP levels were elevated by the beta receptor agonist isoproterenol but not by alpha 1 (phenylephrine) or alpha 2 (clonidine) agonists. However, clonidine potentiated the effect of isoproterenol on slice cAMP formation whereas phenylephrine did not. Likewise, NE-stimulated cAMP accumulation was completely antagonized only by a combination of both beta (propranolol) and alpha 2 (yohimbine) antagonists. The data suggest that in slices from estrogen plus progesterone-treated rats, alpha 2 receptors contribute significantly to NE stimulation of cAMP accumulation. The overall depression of the cAMP response to NE in progesterone-exposed slices may involve a decrease of alpha 1 receptor facilitation of cAMP synthesis.
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PMID:Progesterone depression of norepinephrine-stimulated cAMP accumulation in hypothalamic slices. 254 2

The diterpene, forskolin, is a potent and reversible inhibitor of progesterone-induced meiosis in Xenopus laevis oocytes (ED50 of inhibition approximately 3 microM). Forskolin alone increases cAMP concentration in oocytes, but, unlike with cholera toxin treatment, there is no lag phase, and reversibility is obtained by washing the cells. Progesterone decreases the forskolin effect on cAMP accumulation, but cAMP concentration remains above the level observed in oocytes treated with progesterone alone. The data corroborate the previously-established antagonistic effect of cAMP on progesterone-induced meiosis. Preliminary experiments in the presence of a phosphodiesterase inhibitor suggest that, as in other biological systems, forskolin is an activator of adenylate cyclase in xenopus laevis oocytes. Contrary to what is observed when forskolin is present in the incubation medium, no effect of the diterpene is recorded after its injection into oocytes, evoking a site of action at the external side of the membrane.
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PMID:Forskolin increases cAMP and inhibits progesterone induced meiosis reinitiation in Xenopus laevis oocytes. 618 Aug 91

Progesterone appears to be the physiological inducer of meiosis in amphibian oocytes. In Rana pipiens, dl-propranolol mimics the action of progesterone and both agents have a common action in producing a rapid [45Ca] efflux and a fall in intracellular cAMP followed by nuclear breakdown. Comparison of the rate of hydrolysis of injected [3H]-cAMP and of the conversion of injected [3H]-ATP to [3H]-cAMP followed exposure to meiotic inducers and inhibitors indicates that adenylate cyclase and not phosphodiesterase is the rate-limiting step in regulating [cAMP]i in the oocyte. The results suggest that progesterone initiates the resumption of the meiotic divisions by down-regulation of membrane adenylate cyclase, possibly via Ca2+ release from specific membrane sites.
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PMID:Regulation of Ca2+ and cyclic AMP during the first meiotic division in amphibian oocytes by progesterone. 626 Aug 41

Progesterone depressed rapidly (50% at 1 min) and persistently cyclic AMP (cAMP) concentration that had been elevated by cholera toxin in Xenopus laevis oocytes. cAMP remained below 1 pmol per oocyte (mean basal level) for approximately 1 hr and thereafter rose to approximately 120% of control values, while germinal vesicle (nucleus) breakdown did not occur. In the absence of cholera toxin, progesterone treatment for 6 hr maintained cAMP concentration below the basal level (but not lower than 80%), and germinal vesicle breakdown occurred. Experiments in the presence of phosphodiesterase inhibitors suggested that progesterone modulates adenylate cyclase activity. The maturation promoting factor, which is formed after 3-5 hr of progesterone treatment and provokes germinal vesicle breakdown after its injection into untreated oocytes, also decreased cAMP concentration, an observation that may explain its "autoamplification." Nonsteroidal inducers of meiosis reinitiation (e.g., propranolol, methoxyverapamil, mersalyl) diminished the cholera toxin-mediated accumulation of cAMP, in contrast to compounds devoid of meiotic-inducing capacity and antagonist to progesterone action, such as gammexane (an inositol analogue) and 5'-deoxy-S-(2-methylpropyl)-5'-thioadenosine (a methylase inhibitor), that increased the nucleotide level. The fine control, suggested by the effects of small changes in cAMP levels, gives evidence of great sensitivity to a critical determinant governing meiotic cell division.
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PMID:Cyclic AMP-mediated control of meiosis: effects of progesterone, cholera toxin, and membrane-active drugs in Xenopus laevis oocytes. 627 98

Although luteinizing hormone (LH) is known to down-regulate its own receptor in several gonadal cell types, the mechanisms underlying this process are poorly understood. To elucidate these mechanisms we have examined the role of cAMP and progesterone in LH-stimulated down-regulation of the LH receptor, using cultured granulosa cells as a model. LH receptors were induced by culturing the cells with follicle-stimulating hormone for 2 days, and once induced, could be down-regulated by a brief exposure to LH. Down-regulation also occurred when cells were cultured with activators of adenylate cyclase, inhibitors of phosphodiesterase, or analogues of cAMP. Cholera toxin and N6,O2'-dibutyryladenosine 3':5'-cyclic monophosphate, like LH, decreased the number of LH receptors, without affecting affinity for 125I-human chorionic gonadotropin (hCG). The extent of receptor loss after treatment with LH plus cholera toxin was no greater than that caused by LH alone. LH, hCG, and deglycosylated hCG, which binds to the LH receptor but has little bioactivity, caused down-regulation, and their relative capacity to cause down-regulation was highly correlated with their relative capacity to stimulate cAMP production. Indirect evidence suggested that maximal down-regulation requires activation of adenylate cyclase for at least 3 h. Consistent with this idea, a 3-h exposure to dibutyryl cAMP caused near-maximal down-regulation. Progesterone secretion was enhanced by all agents that caused down-regulation of the LH receptor; however, there was little correlation between progesterone secretion and down-regulation. Furthermore, maximal down-regulation occurred when progesterone secretion was inhibited greater than 99% with cyanoketone. These data indicate that cAMP, but not progesterone, plays a central role in LH receptor down-regulation in the granulosa cell and that elevation of intracellular cAMP levels for 3 h is both necessary and sufficient to trigger maximal down-regulation.
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PMID:A central role for cyclic AMP, but not progesterone, in luteinizing hormone receptor down-regulation in the granulosa cell. 631 88


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