Adenosine Differentially Amplifies Luteinizing Hormone- over Follicle-Stimulating Hormone-Mediated Effects in Acute Cultures of Rat Granulosa Cells*

Ohkawa, Reiko; Polan, Mary Lake; Behrman, Harold R.

doi:10.1210/endo-117-1-248

Cited by 16 publications

(7 citation statements)

References 16 publications

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“…Thus, the inhibitory effect of H 2 O 2 on FSH action was not due to depletion of ATP. Depletion of ATP reduces gonadotropic hormone action in ovarian cells (34,36). Thus, in subsequent studies, to evaluate the antigonadotropic actions of peroxide the cells were pretreated with 3-ABA to prevent depletion of ATP.…”

Section: Resultsmentioning

confidence: 99%

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Antigonadotropic and Antisteroidogenic Actions of Peroxide in Rat Granulosa Cells*

1990

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Reactive oxygen species are produced in the ovary. In luteal cells, peroxide abruptly inhibits LH-sensitive cAMP and progesterone production, and may serve a role as a mediator of luteolysis by such mechanisms. The objective of the present studies was to evaluate the acute actions of peroxide in rat granulosa cells. Peroxide at concentrations in the low micromolar range produced a marked and dose-dependent inhibition of FSH-sensitive cAMP accumulation and progesterone production, and depleted cell levels of ATP within 1 min. Longer treatment with peroxide (60 min) caused complete abrogation of the actions of FSH. Peroxide-induced depletion of ATP was prevented by 3-aminobenzamide, an inhibitor of DNA repair, but maintenance of cell levels of ATP did not prevent the anti-FSH effects of peroxide. Peroxide also abrogated cAMP accumulation and progesterone production in response to LH in granulosa cells. Unlike that seen with LH, inhibition of FSH-sensitive cyclic AMP accumulation by peroxide was partially reversed with isobutylmethyl xanthine, an inhibitor of cyclic AMP phosphodiesterase. Although peroxide inhibited cAMP accumulation in response to cholera toxin, it did not inhibit this same response to forskolin, which indicates that peroxide may interfere with G-protein-dependent activation of adenylate cyclase. Peroxide inhibited steroidogenesis in response to cholera toxin, forskolin, and 8-bromo-cAMP. The marked inhibitory actions of peroxide on gonadotropic hormone action and steroidogenesis in granulosa cells raise the possibility that peroxide may mediate events associated with loss of follicular function.

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Section: Resultsmentioning

confidence: 99%

“…The cells were enzymatically dispersed and granulosa cells were enriched over a discontinuous density gradient (Percoll, Pharmacia, Uppsala, Sweden), as previously described (34). Granulosa cells were recovered predominantly from the 45% (1.058 g/ml) layer.…”

Section: Animals and Preparation Of Granulosa Cellsmentioning

confidence: 99%

Antigonadotropic and Antisteroidogenic Actions of Peroxide in Rat Granulosa Cells*

1990

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“…metabolism of adenosine may not be required to maintain oocytes in meiotic arrest. Nevertheless, when mouse oocytes and oocyte-cumulus cell complexes are cultured in medium containing adenosine, the nucleoside is rapidly metabolized to phosphorylated derivatives [Heller and Schultz, 1980;Downs et al, 19861. In addition, ATP levels in granulosa and luteal cells are elevated in response to adenosine, presumably via phosphorylation of adenosine [Brennan et al, 1983;Ohkawa et al, 1985;Billig and Rosberg, 19861. These latter data suggest that adenosine could also serve as a precursor for cAMP synthesis.…”

Section: Discussionmentioning

confidence: 99%

Maintenance of meiotic arrest in mouse oocytes by purines: Modulation of cAMP levels and cAMP phosphodiesterase activity

et al. 1989

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Hypoxanthine and adenosine are present in preparations of mouse ovarian follicular fluid, and these purines maintain mouse oocytes in meiotic arrest in vitro (Eppig et al.: Biology of Reproduction 33:1041-1049. 1985). The first hypothesis tested in this study is that purines which maintain meiotic arrest act by maintaining meiosis-arresting levels of cyclic adenosine monophosphate (cAMP) in the oocyte. Oocyte-cumulus cell complexes were incubated in control medium (no added purines), or medium containing 0.75 mM adenosine, 4 mM hypoxanthine, or both for 3 hr and the percentage of the oocytes that underwent germinal vesicle breakdown (GVB) and the cAMP content of the intact complexes and the oocytes were determined. Adenosine alone had little inhibitory effect on GVB at this time point but sustained higher levels of cAMP in the oocytes. Hypoxanthine maintained 80% of cumulus cell-enclosed oocytes in meiotic arrest and also sustained higher cAMP levels in the oocytes. The addition of adenosine to hypoxanthine-containing medium increased the percentage of oocytes maintained in meiotic arrest, and increased the amount of cAMP in the oocytes above that maintained by either hypoxanthine or adenosine alone. Neither hypoxanthine, adenosine, nor hypoxanthine plus adenosine altered the cAMP content of intact complexes when assayed after 3 hr culture. Microinjection of an inhibitor of the catalytic subunit of cAMP-dependent protein kinase induced GVB in denuded oocytes cultured in medium containing hypoxanthine. This purine, therefore, maintained meiotic arrest by sustaining elevated cAMP levels within the oocytes. The second hypothesis tested in this study is that purines maintain meiosis-arresting levels of cAMP, at least in part, by inhibiting cAMP phosphodiesterase activity. In descending order of potency, 3-isobutyl-1-methylxanthine (IBMX), guanosine, hypoxanthine, adenosine, and xanthosine inhibited cAMP phosphodiesterase in oocyte lysates. Moreover, like the potent phosphodiesterase inhibitor IBMX, hypoxanthine augmented the meiotic arrest and cAMP accumulation mediated by follicle-stimulating hormone (FSH) in intact complexes. Therefore, inhibition of oocyte phosphodiesterase appears to be one mechanism by which the purines could maintain meiosis-arresting levels of cAMP.

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“…The purine nucleoside is able to influence, by various mechanisms, intracellular cAMP levels. It interacts with specific surface receptors to stimulate or inhibit adenylate cyclase [Daly,198.51 and/or it is transported into the cell and phosphorylated to adenosine triphosphate (ATP), thereby increasing substrate availability for adenylate cyclase [Brennan et al, 1983;Ohkawa et al, 1985;Billig and Rosberg, 19861. Adenosine alone (at concentrations of up to 750 pM) does not alter the time course of spontaneous in vitro maturation by mouse oocytes, although it synergizes with hypoxanthine and dbcAMP to maintain the oocyte in the prophase stage [Eppig et al, 1985b;Downs et al, 1986;Petrungaro et al, 19861. In a preliminary report, we have shown also that adenosine prolongs the meiotic maturation delay caused by forskolin, a stimulator of adenylate cyclase activity [Salustri et al, 19861. The present study investigated the mechanism by which adenosine acts on meiotic arrest in the oocyte and whether or not the adenosine-forskolin synergism is dependent on changes in ATP content.…”

Section: Introductionmentioning

confidence: 99%

Adenosine potentiates forskolin‐induced delay of meiotic resumption by mouse denuded oocytes: Evidence for an oocyte surface site of adenosine action

Salustri¹,

Petrungaro²,

Conti³

et al. 1988

Gamete Research

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Adenosine is present in the mouse follicular fluid and has been shown to interfere with oocyte maturation in vitro. To clarify the mechanism of adenosine action on meiotic arrest, we have characterized the synergistic action of this purine with forskolin on the meiotic resumption of mouse denuded oocytes. Forskolin delays meiotic resumption by approximately 1 hour; adenosine at concentrations ranging between 30-750 microM has no significant effect. Conversely, adenosine treatment together with forskolin produces a further delay in the resumption of meiosis. This adenosine effect is dose-dependent and mimicked by adenosine analogs like N6-phenylisopropyl adenosine (PIA), 2-chloroadensoine (2-CLA), 5'-N-ethylcarboxamide (NECA). Dipyridamole, which inhibits adenosine transport, does not prevent the meiosis-arresting synergistic effect of adenosine with forskolin. Adenosine causes a 50% increase of adenosine triphosphate (ATP) content in the oocyte. However, this increase is not directly responsible for the observed delay in oocyte maturation for the following reasons: (1) the dose response of inhibition of meiotic resumption does not correlate with the doses of adenosine producing an increase in ATP; (2) dipyridamole blocks the increase in intracellular ATP, but it has no effect on the adenosine inhibition of maturation; (3) adenosine analogs inhibit oocyte maturation but do not affect intracellular ATP levels. These results suggest that the synergism of adenosine with forskolin on meiotic arrest does not require uptake of the nucleoside nor its conversion to ATP and that the adenosine effects are exerted at the level of the oocyte plasma membrane.

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Adenosine Differentially Amplifies Luteinizing Hormone- over Follicle-Stimulating Hormone-Mediated Effects in Acute Cultures of Rat Granulosa Cells*

Cited by 16 publications

References 16 publications

Antigonadotropic and Antisteroidogenic Actions of Peroxide in Rat Granulosa Cells*

Antigonadotropic and Antisteroidogenic Actions of Peroxide in Rat Granulosa Cells*

Maintenance of meiotic arrest in mouse oocytes by purines: Modulation of cAMP levels and cAMP phosphodiesterase activity

Adenosine potentiates forskolin‐induced delay of meiotic resumption by mouse denuded oocytes: Evidence for an oocyte surface site of adenosine action

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