Molecular Human Reproduction, Vol. 7, No. 1, 43-47,
January 2001
© 2001 European Society of Human Reproduction and Embryology
Ovary and oogenesis |
Dual effects of nitric oxide in functional and regressing rat corpus luteum
Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Serrano 669, 1414 Buenos Aires, Argentina
Abstract
The present study investigated the effect of nitric oxide (NO) on the lifespan of the corpus luteum (CL). Using a competitive nitric oxide synthase (NOS) inhibitor, L-nitro arginine methyl ester (L-NAME, 600 µmol/l), and a long-life NO donor, diethyl-aminetriamine (DETA-NONOate, 10–8, 10– 6 or 10– 4 mol/l), we found that in ovaries from rats at the mid stage of CL development, endogenous NO increased both glutathione (GSH) and progesterone production. However, during prostaglandin F2
(PGF2)-induced luteolysis NO acted as an intermediary molecule in the inhibitory effect of PGF2, on GSH content. This was supported by the fact that in-vivo PGF2 treatment enhanced nitric oxide synthase (NOS) activity. These results indicate that the NO could act with a dual action (protective or pro-oxidant) in CL development.
corpus luteum/glutathione/luteolysis/nitric oxide/prostaglandin
Introduction
Luteal regression or luteolysis is an example of a decrease in cell function, which is a normal and necessary event in the mammalian reproductive cycle. This mechanism is widely studied for its implication in early pregnancy dysfunction. Corpus luteum (CL) involution has been related to an increased generation of reactive oxygen species (ROS), e.g. O2- and H2O2 by the intact ovary (Behrman and Preston, 1989
; Riley and Behrman, 1991; Sawada and Carlson, 1991). One consequence of the production of free radicals in ovarian tissue is lipid peroxidation (Kappus, 1985), which occurs within the plasma membrane of luteal cells and may be associated with the observed loss of gonadotrophin receptors, diminished cyclic AMP formation and, therefore, with a decrease in steroidogenic ability of the CL during involution (Auletta and Flint, 1988; Wang et al., 1991). Protection against ROS in cells is provided by enzymes (superoxide dismutase, catalase and gluthation peroxidase), metabolites, e.g. glutathione (GSH) or antioxidant vitamins (Aten et al., 1992), and has been suggested to be endocrine-regulated (Laloraya et al., 1988; Aten et al., 1992; Sugino et al., 1993, 1998, 1999).
Nitric oxide (NO) has been shown to participate in numerous physiological processes which are essential for maintaining homeostasis (Ignarro, 1990; Moncada et al., 1991). Some evidence supports the involvement of NO in ovarian physiology; nitrates are secreted from mammalian ovarian dispersates (Ellman et al., 1993), NO synthase (NOS) has been located in granulosa cells by immunocytochemistry (Zackrisson et al., 1996), NOS inhibitors block human chorionic gonadotrophin (HCG)-induced ovulation in the rat (Shukovski and Tsafiri, 1994), endogenously produced NO and NO-releasing agents have been shown to inhibit steroidogenesis in granulosa and luteal cells in both rat and human (Van Voorhis et al., 1994; Olson et al., 1996). Recently, the opposite action of the NOS substrate, L-arginine, and HCG on human CL viability (Vega et al., 2000) has been described. Some authors have pointed out that NO augments oxidative stress-mediated toxicity, yet in some cases, NO has been shown to protect cells from the cytotoxicity of oxidants (Hogg et al., 1995; Wink et al., 1995).
GSH is a tripeptide thiol present in animal and plant cells. It participates in many cellular functions, including DNA and protein synthesis, regulation of enzyme activity, both interand intracellular transport, and acts as a major antioxidant in cellular protection (Deneke and Fanburg, 1989).
The relationship between GSH and toxicity mediated by NO has been investigated by other authors. NO has been shown to react with intracellular GSH to form S-nitrosoglutathione (Clancy et al., 1994); NO induces oxidative stress and gluthatione metabolism in rodent and human cells (Luperchio et al., 1996), regulates GSH synthesis in bovine aortic endothelial cells (Moellering et al., 1999) and stimulates cystein (limiting factor in GSH synthesis) uptake by bovine endothelial cells (Li et al., 1999).
In previous studies of the mechanism of CL regression, we reported that oxytocin increased ovarian PGF2 production during the late phase of pseudopregnancy in rats (Motta et al., 1996). This action was mediated by enhancing ovarian NOS activity (Motta et al., 1997). We also found that during the luteolytic process, endogenous NO increased PGF2 synthesis (Motta and Gimeno, 1997). By means of intrabursa ovarian sac treatment with two competitive NOS inhibitors and a NO generator, we demonstrated that NO produced locally had an antisteroidogenic effect, diminishing serum progesterone concentrations and increasing ovarian PGF2 production (Motta et al., 1999). However, at the mid stage of CL development, ovarian NOS activity was unexpectedly found to be higher than during regression (Motta and Gimeno, 1997), concomitant with the highest ovarian GSH content at this stage (unpublished data).
Taken together, we decided to study the possible relationship between NO and ovarian GSH at the mid stage of CL development. We have proposed that, in ovarian tissue (with functional CLs), high concentrations of locally produced NO could be regulating GSH synthesis. In addition, we studied the role of NO during luteolysis induced by PGF2, and its effect on ovarian GSH production.
Materials and methods
Animals
The animal model used was the same as that described previously (Lahav et al., 1989). Briefly, immature (28–30 days) female rats of the Wistar strain were given 15 IU/rat of pregnant mare's serum gonadotrophin (PMSG; Sigma Chemical Co, St Louis, MO, USA). We considered day 0 of pseudopregnancy to be 48 h post-injection. This procedure induced formation of CL that remained functional for 9 ± 1 days (as determined by progesterone radioimmunoassay). The rats were housed under conditions of controlled temperature (22°C) and illumination (14 h light:10 h dark, lights on at 05:00) and allowed free access to Purina rat chow and water ad libitum. Animals were anaesthetized with ether and killed by cervical dislocation. As in previous studies (Motta et al., 1996), ovarian tissues from rats at the mid stage of CL development (day 5 of pseudopregnancy, with highest serum progesterone concentrations) were used.
Experimental protocol
PGF2 -induced luteolysis
For PGF2-induced luteolysis, the experimental protocol used was the same (dose and time) as that described previously (Motta et al., 1999). Rats were injected i.p. with 3 mg/kg body weight of a synthetic PGF2 (ILIREN, Hoerscht Vet) in 0.5 ml of saline solution. After 2 h, animals were anaesthetized with ether and killed by cervical dislocation. Ovaries were rapidly removed for culture assays or held on ice and frozen until determination of NOS activity.
Ovarian cultures
Removal of ovarian tissue was performed as previously described (Dunnam et al., 1999). Ovarian tissues were removed and cut into quarters. They were then randomly and evenly distributed at four explants per well in a 24-well culture plate (Nunc multidish, USA) for 18 h in an incubator with a humidified chamber and 5% carbon dioxide at 37°C. Separate aliquots of culture media were collected for GSH and progesterone determination.
GSH determination
The GSH assay was carried out as described previously (Tietze, 1969). Briefly, ovarian tissues were incubated in Krebs Ringer phosphate buffer for 1 h in a Dubnoff metabolic shaker under an atmosphere of 5% CO2 in 95% O2 at 37°C. At the end of the incubation period, tissues were removed and media collected for GSH determination. In treated samples a competitive NOS inhibitor, L-nitro-arginine methyl ester (L-NAME, 600 µmol/l) was added to the incubation media. We have previously found that 600 µmol/l of L-NAME (EC50) inhibits NOS activity in ovarian tissue (Motta and Gimeno, 1997). Samples were then incubated with NADPH, glutathione reductase (GR) and Ellman's reagent (a sulphydryl reagent: 5,5'dithiobis-2-nitrobenzoic acid) yielding a chromophoric product with a molar absorption at 412 nm. Results are expressed as µmol GSH/g ovarian tissue.
Determination of progesterone
Incubation medium for hormone analysis was collected and frozen until progesterone concentrations were determined by radioimmunoassay. The progesterone antiserum was provided by Dr G.D.Niswender (Colorado State University, Fort Collins, CL, USA) with cross-reactivities <2.0% for 20 -dihydro-progesterone and deoxycorticosterone and 1.0% for other steroids normally in the serum. Results were expressed as pg/mg tissue.
NOS activity
NOS activity in ovarian homogenate was determined by monitoring the formation of L-[ 14C] citrulline from L-[14C] arginine as described previously (Salter et al., 1991). Briefly, the frozen tissue was homogenized at 0°C in three volumes of 50 mmol/l HEPES, 1 mmol/l DL-dithiothreitol, 1 mmol/l NADPH (pH 7.5) and L-valine (50 mmol/l). Samples were incubated at 37°C for 15 min with 10 µmol/l [14C] arginine (0.3 µCi; 1 Ci = 37 GBq). The samples were then applied to 1 ml DOWEX AG50W-X8 (Na+ form; Biorad, USA) resin. The radioactivity was measured by liquid scintillation counting. Results were expressed as pmol/g/min.
Statistical analysis
Statistical analyses was carried out using the Instat program (GraphPAD software, San Diego, CA, USA). Analysis of variance and Student–Newman–Keuls tests were used for comparisons between value of groups. P < 0.05 was considered to be significant.
Results
NO produced by ovarian tissue enhances ovarian glutathione concentrations
We incubated ovaries from rats at the mid stage of pseudopregnancy (day 5) with the competitive NOS inhibitor, L-NAME. L-NAME significantly inhibited total GSH production (Figure 1a). In contrast, a long half-life NO donor (DETA-NONOate) significantly enhanced ovarian GSH concentrations only at 10–6 mol/l (Figure 1b). There was no effect at higher or lower doses.
|
NO produced by ovarian tissue enhances ovarian progesterone concentrations
The inhibition of endogenous NO production by 600 µmol/l of L-NAME significantly diminished progesterone production in ovarian tissue from rats at the mid stage of CL development (Figure 2a
). The NO donor, DETA-NONOate at 10–4 and 10 –6 mol/l, significantly enhanced ovarian progesterone production after 18 h of treatment. At the lowest dose of DETA-NONOate used (10–8 mol/l), no effect on ovarian progesterone production was observed.
|
PGF2
diminishes glutathione produced by ovarian tissue: NO as a possible intermediary metaboliteAs previously described (Motta et al., 1999
), we induced luteolysis with a synthetic PGF2. After this procedure GSH production was diminished compared with that in controls (Figure 3). When L-NAME was added during the incubation period, PGF2-induced inhibition of ovarian GSH production was completely abolished (Figure 3).
|
PGF2
induces luteolysis by increasing NOS activityIn order to know whether NO could be an intermediary in the action of PGF2
on GSH depletion during induced luteolysis, we determined NOS activity in ovarian homogenates from rats injected with PGF2 2 h before the determination of NOS activity. As shown in Figure 4, NOS activity was significantly enhanced by the in-vivo PGF2 treatment.
|
Discussion
When first discovered, NO was first considered to be a relaxation molecule (Ignarro et al., 1990; Moncada et al., 1991). Following this, many studies were conducted to investigate the role of NO in the oxidative stress, both in pathological and physiological events (Shukovski and Tsafiri, 1994; Van Voorhis et al., 1994; Motta et al., 1996, 1997). However, the formation of NO can lead to the production of reactive nitrogen oxide species (RNOS) (Wink et al., 1996). Like ROS, these NO-derived reactive intermediate species can result in damage to specific cellular targets, which leads to speculation that NO may have a significant role in various pathological conditions (Gross and Wolin, 1995; Wink et al., 1996). Recently, this radical gas has been shown to participate in numerous physiological processes which are essential for maintaining homeostasis (Ignarro, 1990; Moncada et al., 1991). Recent reports (Wink et al., 1995; Hogg et al., 1995) have pointed out that NO could protect cells from oxidants. Apparently, the toxic or protective effect of NO appears to be determined by intracellular redox status, as shown in rat oligodendrocytes (Rosenberg et al., 1999).
Taken together, and in view of the fact that we found diminished NOS activity with the age of the CL (Motta et al., 1997), the present study was performed in order to investigate the possible protective function of endogenous ovarian NO in the early stage of CL development and to compare this role with its role during luteolysis.
In the present study, we found that NO produced by ovarian tissue at the mid stage of CL development increases GSH production, as demonstrated by the fact that the specific NOS inhibitor diminished, while a long half-life NO donor increased GSH concentrations. This latter effect was observed at 10–6 mol/l concentration of DETA-NONOate, while lower and higher doses had no effect. The failure of the higher dose (10–4 mol/l) to stimulate GSH production could be the result of down-regulation on the NOS activity by a direct effect of NO (Rengasamy and Johns, 1993). We believe that, in the early stage of CL development, the chronic exposure of endogenous NO could be responsible for the increase in the ovarian GSH production. In the past, other authors have investigated the relationship between GSH and NO involved in a protective role, in different systems. Rosenberg et al. demonstrated that NO donors with longer half-lives were required for a protective effect in rat oligodendrocytes in culture (Rosenberg et al., 1999), while short-lived NO donors produced a cytotoxic effect depleting GSH content. These apparently controversial results could be explained by the fact that an acute exposure of cells to NO donors would lead to depletion of GSH, whereas chronic exposure would result in a progressive increase in cytosolic GSH (Li et al., 1999; Moellering et al., 1999; Rosenberg et al., 1999). In spite of diverse mechanisms being proposed (NO increasing cystine uptake, NO inducing 
-glutamylcysteine synthetase and -glutamyl transpeptidase), the activation of a crucial protective factor or inactivation of a crucial death factor in the setting of oxidative stress is still unknown.
Using L-NAME to inhibit endogenous NO and a long half-life NO donor (DETA-NONOate), we found that NO increased progesterone production. This result is in agreement with that of Dong et al. who demonstrated that NO reversed prostaglandin inhibition in ovarian progesterone secretion in rats (Dong et al., 1999). However, in contrast, a previous study using rat ovarian tissue during the late stage of CL development, demonstrated that in-vivo NO generator treatment (sodium nitroprusside) diminished serum concentrations of progesterone (Motta et al., 1999). Those results led us to conclude that NO can have opposing actions, depending on the stage of CL development. As in the GSH determination experiments, there appears to be a dose-dependent relationship between DETA NONOate and progesterone since 10–6 and 10–4 mol/l increased (while 10–8 mol/l had no effect on) ovarian progesterone production.
As NO was able to increase progesterone production and ovarian GSH content (an antioxidant metabolite) we could assume a protective role for NO at the mid stage of CL development. Recently, a dual response to NO in the functional and regressing human CL has been proposed (Friden et al., 2000). These authors demonstrated that a NO donor (spermine NONOate) significantly decreased the production of progesterone in human CL cells of the late, but not the mid, luteal phase. In addition, these authors found that NO increased concentrations of both PGF2 and PGE during the late luteal phase.
We also focused our study on the role of NO during luteolysis in order to compare the effect with the above-mentioned protective action. In previous reports, we had found that during CL demise, PGF2 and NO were related by a positive feedback pathway leading to higher concentrations of lipid peroxidation (Motta et al., 1996) concomitantly with a diminution in the progesterone concentrations (Motta et al., 1999). In this study, we demonstrated that PGF2 diminishes GSH content, and that this may be mediated by NO. The fact that PGF2-treatment increased NOS activity also suggests that this action could be NO-dependent. In agreement with our previous report (Motta et al., 1999), this confirms that as in spontaneous luteolysis, the PGF2 and NO/NOS system could be related during PGF2-induced luteolysis.
In summary, we propose that during early stages of CL development, a chronic production of NO by ovarian tissue could lead to an increase in the GSH content in a protective role. On the contrary, during luteolysis, the highest and pulsatile ovarian PGF2 secretion and acute NO production (Motta et al., 1996) would lead to an impairment in GSH production within the ovary. These results correlate well with previous findings that, during CL demise, PGF2 (via NO) enhances lipid peroxidation (Motta et al., 2000). It is important to point out that the GSH metabolite is considered to be an important factor in the prevention of lipid peroxidation. To clarify the exact mechanism of NO regulation of ovarian GSH synthesis and its importance in oxidative stress is a motivation to further pursue the target(s) of NO activity to better understand the mechanism of CL regression.
Acknowledgments
These studies were supported by Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET, PIP 4076) and by Laboratorios Bagó, Argentina. The authors thank María Inés Casella and Ramona Morales for their technical support.
Notes
1 To whom correspondence should be addressed. E-mail: amotta{at}sion.com 
References
Aten, R. F., Duarte, K.M. and Behrman, H.R. (1992) Regulation of ovarian antioixdant vitamins reduced glutathione and lipid peroxidation by luteinizing hormone and prostaglandin F2 alpha. Biol. Reprod., 46, 401–407.[Abstract]
Auletta, F.J. and Flint, P.F. (1988) Mechanism controlling corpus luteum function in sheep, cows, nonhuman primates, and women, specially in relation to the time of luteolysis. Endocr. Rev., 9, 88–105.[ISI][Medline]
Behrman, H.R. and Preston, S.L. (1989) Luteolytic actions of peroxide in rat ovarian cells. Endocrinology, 124, 2895–2900.[Abstract]
Clancy, R.M., Levartovsky, D., Leszczynska-Piziak, J. et al. (1994) Nitric oxide reacts with intracellular glutathione and activates the hexose monophosphate shunt in human neutrophiles: evidence for S-nitrosoglutathione as a bioactive intermediary. Proc. Natl Acad. Sci. USA, 91, 3680–3684.
Deneke S. M., Fanburg, B.L. (1989) Regulation of cellular glutaathione. Am. J. Physiol., 257, 163–173.
Dong, Y.L., Gangula, P.R.R., Fang L. and Yallampalli, Ch. (1999) Nitric oxide reverses prostaglandin-induced inhibition in ovarian progesterone secretion in rats. Hum. Reprod., 14, 27–32.
Dunnam, R.C., Hill, M. J., Lawson, M. D. and Dunbar, J. C. (1999) Ovarian hormone secretory response to gonatropins and nitric oxide following chronic nitric oxide deficency in the rat. Biol. of Reprod., 60, 959–963.
Ellman, C., Corbett, J.A., Misko, T.P. et al. (1993) Nitric oxide mediates interleukin-1ß enhances cellular cytotoxicity. A potential role for nitric oxide in the ovulatory process. J. Clin. Invest., 92, 3053–3056.
Friden, B.E., Runesson, E., Hahlin, M. and Brannstrom. (2000) Evidence for nitric oxide as a luteolytic factor in the human corpus luteum. Mol. Hum. Reprod., 6, 397–403.
Gross, S.S. and Wolin, M.S. (1995) Nitric oxide: pathophysiological mechanism. Ann. Rev. Physiol., 57, 737–769.[ISI][Medline]
Hogg, N., Struck, A., Gross, S.P. et al. (1995) Inhibition of macrophage-dependent low density lipoprotein oxidation by nitric oxide donors. J. Lipid Res., 36, 1756–1762.[Abstract]
Ignarro, L.J. (1990) Biosynthesis and metabolism of endothelium-derived nitric oxide. Ann. Rev. Pharmacol. Toxicol., 30, 535–539.[ISI][Medline]
Kappus, H. (1985) Lipidic peroxidation: Mechanisms, analysis, enzymology and biological relevance. In Sies, H, (ed. ), Oxidative Stress 1985. Academic Press, London, UK, pp. 273–310.
Lahav, M., Davis, J.S. and Rennert, H. (1979) Mechanism of the luteolytic action of prostaglandin F2 alpha in the rat. J. Reprod. Fertil., 37 (Suppl), 233–240.
Laloraya, M., Kumar, G.P. and Laloraya, M.M. (1988) Changes in the concentrations of superoxide anion radical and superoxide dismutase during the estrous cycle of Rattus norvegicas and induction of superoxide dismutase in rat ovary by lutropin. Biochem. Biophys Res. Commun., 187, 146–153.
Li, H., Marshall, Z.M. and Whorton, A.R. (1999) Stimulation of cysteine uptake by nitric oxide: regulation of endothelial cell glutathione concentrations. Cell,. Physiol., 276, C803–C811.
Luperchio, S., Tamir, S. and Tannenbaum, S.R. (1996) NO-induced oxidative stress and glutathione metabolism in rodent and human cells. Free Radical Biol. Med. ., 21, 513–519.[ISI][Medline]
Moellering, D., McAndrew, J., Patel, R.P. et al. (1999) The induction of GSH synthesis by nanomolar concentrations of NO in endothelial cells: a role for gamma-glutamylcysteine synthase and gamma- glutamyl transpeptidase. FEBS Letts., 448, 292–296.[ISI][Medline]
Moncada, S., Palmer, R.M.J. and Higgs, E.A. (1991) Nitric oxide physiology, pathophysiology and pharmacology. Pharmacol. Rev., 43, 109–112.[ISI][Medline]
Motta, A.B. and Gimeno, M.A.F. (1997) Nitric oxide participates in the corpus luteum regression in ovaries isolated from pseudopregnant rats. Can. J. Physiol. Pharmacol., 75, 1335–1339.[ISI][Medline]
Motta, A.B., Franchi, A.M., Faletti, A. and Gimeno, M.A.F. (1996) Effect of an oxytocin receptor antagonist on ovarian and uterine synthesis and release of prostaglandin F2 alpha in pseudopregnant rats. Prost. Leukotr. Essential Fatty Acids, 54, 95–100.
Motta, A.B., Franchi, A.M. and Gimeno, M.A.F. (1997) Role of nitric oxide on uterine and ovarian prostaglandin synthesis during luteolysis in the rat. Prost. Leukotr. Essential Fatty Acids, 56, 265–269.
Motta, A.B., Estevez, A. and Gimeno, M.A.F. (1999) The involvement of nitric oxide in corpus luteum regression in the rat: feedback mechanism between prostaglandin F2 alpha and nitric oxide. Mol. Hum Reprod., 5, 1011–1016.
Motta, A.B., Estevez, A., Franchi, A.M. et al. (2000) Regulation of lipid peroxidation by nitric oxide and PGF2 during luteal regression in rats. Reproduction, in press.
Olson, L.M., Jones-Burton, C.M. and Jablonka-Shariff, A. (1996) Nitric oxide decreases estradiol synthesis in rat luteal cells in vitro: possible role for nitric oxide in functional luteal regression. Endocrinology, 137, 3531–3539.[Abstract]
Rengasamy, A. and Johns, R. (1993) Regulation of nitric oxide synthase by nitric oxide. Mol. Pharmacol., 44, 124–128.[Abstract]
Riley, J.C.M. and Behrman, H.R. (1991). In vivo generation of hydrogen peroxide in the rat corpus luteum during luteolysis. Endocrinology, 128, 1749–1753.[Abstract]
Rosenberg, P.A., Li, Y., Ali, S. et al. (1999) Intracellular redox state determines whether nitric oxide is toxic or protective to rat oligodendrocyte in culture. J. Neurochem, 73, 476–484.[ISI][Medline]
Salter, M., Knowles, R. G. and Moncada, S. (1991) Widespread tissue distribution, species distribution and changes in activity of Ca2+-dependent and Ca2+-independent nitric oxide synthases FEBS Lett., 291, 145–149.[ISI][Medline]
Sawada, M. and Carlson, J.C (1991) Studies on the mechanism controlling generation of superoxide radical in luteinized rat ovaries during regression. Endocrinology, 135, 1645–1650.[Abstract]
Shukovski, L. and Tsafiri, A. (1994) The involvement of nitric oxide in the ovulatory process in the rat. Endocrinology, 135, 2287–2290.[Abstract]
Sugino, N., Nakamura, Y., Okuno, N. et al. (1993) Effects of ovarian ischemia–reperfusion on luteal function in pregnant rats. Biol. Reprod., 49, 354–358.[Abstract]
Sugino, N., Hirosawa-Takamori, M., Zhong, L. et al. (1998) Hormonal regulation of copper-zinc superoxide dismutase and manganese superoxide dismutase messenger ribonucleic acid in the rat corpus luteum: induction by prolactin and placental lactogens. Biol. Reprod., 59, 599–605.
Sugino, N., Takiguchi, S., Kashida, S. et al. (1999) Suppression of intracellular superoxide dismutase activity by antisense oligonucleotides causes inhibition of luteal cells. Biol. Reprod., 61, 1133–1138.
Tietze, F. (1969) Enzymatic method for quantitative determination of nanogram amounts of total and oxidized glutathione. Anal. Biochem., 27, 502–522.[ISI][Medline]
Vega, M., Urrutia, L., Iniguez, G. et al. (2000) Nitric oxide induces apoptosis in the human corpus luteum in vitro. Mol. Hum. Reprod., 6, 681–687.
Van Voorhis, B.J., Dunn, M.S., Snyder, G.D. and Weiner, C.P. (1994) Nitric oxide an autocrine regulator of human granulosa–luteal cell steroidogenensis. Endocrinology, 135, 1799–1806.[Abstract]
Wang, H.Z., Wu, Y.F., Lu, S.H. et al. (1991) The hormonal control of human luteal cells. In Hasseltine, F.P. and Findley, J.K. (eds), Growth Factor in Fertility Regulation. Cambridge University Press, New York, pp. 99–113.
Wink, D.A., Cook, J.A., Krishna, M.C. et al. (1995) Nitric oxide protects against alkyl peroxide-mediated cytotoxicity: further insights into the role nitric oxide plays in oxidative stress. Arch. Biochem. Biophys, 319, 402–407.[ISI][Medline]
Wink, D.A., Grisham, J.B., Mitchell, J.B. and Ford, P.C. (1996) Direct and indirect effects of nitric oxide in chemical reactives relevant to biology. Methods Enzymol., 268, 12–16.[ISI][Medline]
Zackrisson, U., Mikani, M., Wallin, A. et al. (1996) Cell-specific localization of nitric oxide synthases (NOS) in the rat ovary during follicular development, ovulation and luteal formation. Hum. Reprod., 12, 2667–2673.
Submitted on July 18, 2000; accepted on November 1, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. Shirasuna, S. Watanabe, T. Asahi, M. P B Wijayagunawardane, K. Sasahara, C. Jiang, M. Matsui, M. Sasaki, T. Shimizu, J. S Davis, et al. Prostaglandin F2{alpha} increases endothelial nitric oxide synthase in the periphery of the bovine corpus luteum: the possible regulation of blood flow at an early stage of luteolysis Reproduction, April 1, 2008; 135(4): 527 - 539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Stocco, C. Telleria, and G. Gibori The Molecular Control of Corpus Luteum Formation, Function, and Regression Endocr. Rev., February 1, 2007; 28(1): 117 - 149. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. V. Orozco, Z. Sosa, V. Fillipa, F. Mohamed, and A. M. Rastrilla The cholinergic influence on the mesenteric ganglion affects the liberation of ovarian steroids and nitric oxide in oestrus day rats: characterization of an ex vivo system J. Endocrinol., December 1, 2006; 191(3): 587 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lapointe, M. Roy, I. St-Pierre, S. Kimmins, D. Gauvreau, L. A. MacLaren, and J.-F. Bilodeau Hormonal and Spatial Regulation of Nitric Oxide Synthases (NOS) (Neuronal NOS, Inducible NOS, and Endothelial NOS) in the Oviducts Endocrinology, December 1, 2006; 147(12): 5600 - 5610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. T Grazul-Bilska, C. Navanukraw, M. L. Johnson, D. A Arnold, L. P Reynolds, and D. A Redmer Expression of endothelial nitric oxide synthase in the ovine ovary throughout the estrous cycle. Reproduction, October 1, 2006; 132(4): 579 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Elia, V. Sander, C.G. Luchetti, M.E. Solano, G. Di Girolamo, C. Gonzalez, and A.B. Motta The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice Mol. Hum. Reprod., August 1, 2006; 12(8): 475 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A Vonnahme, D. A Redmer, E. Borowczyk, J. J Bilski, J. S Luther, M. L. Johnson, L. P Reynolds, and A. T Grazul-Bilska Vascular composition, apoptosis, and expression of angiogenic factors in the corpus luteum during prostaglandin F2{alpha}-induced regression in sheep. Reproduction, June 1, 2006; 131(6): 1115 - 1126. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Jaroszewski, D. J. Skarzynski, R. M. Blair, and W. Hansel Influence of Nitric Oxide on the Secretory Function of the Bovine Corpus Luteum: Dependence on Cell Composition and Cell-to-Cell Communication Experimental Biology and Medicine, June 1, 2003; 228(6): 741 - 748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Tamanini, G. Basini, F. Grasselli, and M. Tirelli Nitric oxide and the ovary J Anim Sci, February 1, 2003; 81(14_suppl_2): E1 - 7. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||