Antifungal activity of terpenes isolated from the Brazilian Caatinga: a review.

Terpenoids, also named terpenes or isoprenoids, are a family of natural products found in all living organisms. Many plants produce terpenoids as secondary metabolites, and these make up a large part of essential oils. One of most important characteristic is that the compounds are volatile, have odor and can be used in a variety of applications in different industrial segments and traditional medicine. Brazil has a rich and diverse flora that can be used as a source of research for obtaining new molecules. Within the Brazilian flora, it is worth mentioning the Caatinga as an exclusively Brazilian biome where plants adapt to a specific series of weather conditions and therefore become a great storehouse of the terpenoid compounds to be described herein. Fungal infections have become increasingly common, and a great demand for new agents with low toxicity and side effects has thus emerged. Scientists must search for new molecules exhibiting antifungal activity to develop new drugs. This review aims to analyze scientific data from the principal published studies describing the use of terpenes and their biological applications as antifungals.

Early ovarian follicular development in prepubertal Wistar rats acutely exposed to androgens.

Androgens may directly modulate early ovarian follicular development in preantral stages and androgen excess before puberty may disrupt this physiological process. Therefore, the aim of this study was to investigate the dynamics of follicular morphology and circulating androgen and estradiol levels in prepubertal Wistar rats acutely exposed to androgens. Prepubertal female Wistar rats were distributed into three groups: control, equine chorionic gonadotropin (eCG) intervention and eCG plus dehydroepiandrosterone (DHEA) intervention (eCG+DHEA). Serum DHEA, testosterone and estradiol levels were determined, and ovarian morphology and morphometry were assessed. The eCG+DHEA group presented increased serum estradiol and testosterone levels as compared with the control group (P<0.01), and higher serum DHEA concentration v. the eCG-only and control groups (P<0.01). In addition, the eCG+DHEA group had a higher number of, and larger-sized, primary and secondary follicles as compared with the control group (P<0.05). The eCG group presented intermediate values for number and size of primary and secondary follicles, without significant differences as compared with the other two groups. The number of antral follicles was higher in the eCG+DHEA and eCG groups v. controls (P<0.05). The number of primordial, atretic and cystic follicles were similar in all groups. In conclusion, the present experimental model using an acute eCG+DHEA intervention was useful to investigate events involved in initial follicular development under hyperandrogenic conditions, and could provide a reliable tool to study defective follicular development with possible deleterious reproductive consequences later in life.

Adolescence and polycystic ovary syndrome: current concepts on diagnosis and treatment.

BACKGROUND: Adolescence is a time characterised by changes in reproductive hormones and menstrual patterns, which makes it difficult to diagnose polycystic ovary syndrome (PCOS) in this population. The diagnosis of PCOS has a great physical and psychosocial impact on the young person. Despite the importance of a diagnosis of PCOS at adolescence, data available are limited. AIMS: This review focuses on analysing markers of PCOS diagnosis and possible treatments in adolescence. RESULTS: Although, during adolescence, diagnosis criteria of PCOS overlap with physiological changes including clinical manifestations of hyperandrogenism (acne and hirsutism), oligo/amenorrhoea, anovulation and ovarian microcysts, there is agreement that irregular menses and hyperandrogenaemia should be used to diagnose PCOS in this population. Moreover, considering that PCOS phenotype could change through the reproductive age and that adolescents display heterogeneous ovarian morphology, it has been proposed that diagnosis of PCOS should be confirmed after the age of 18. The first-line treatment for menstrual irregularity and hirsutism are oral contraceptive pills (OCPs) and for obesity and metabolic abnormalities are lifestyle changes. Insulin-sensitizer drugs, such as metformin, may be added to the treatment in the presence of metabolic alterations. Antiandrogen drugs may also be associated for treating moderate to severe hirsutism. During adolescence, physiological changes overlap with signs and symptoms of PCOS; thus the diagnosis criteria should be carefully considered. Regarding the treatment of adolescents with PCOS, non-pharmacological interventions include lifestyle changes. Pharmacological treatments comprise OCPs, antiandrogens and metformin, used isolated or combined. CONCLUSIONS: During adolescence, physiological changes overlap with signs and symptoms of PCOS; thus the diagnosis criteria should be carefully considered. Regarding the treatment of adolescents with PCOS, non-pharmacological interventions include lifestyle changes. Pharmacological treatments comprise OCPs, antiandrogens and metformin, used isolated or combined.

Novel strategies in the management of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting reproductive-aged women. PCOS has been recognized as a syndrome combining reproductive and metabolic abnormalities with lifelong health implications. Cardiometabolic alterations require regular screening and effective and targeted lifestyle advice to lose weight as well as to prevent weight gain. Pharmacological therapy includes insulin-sensitizer drugs and agents that act directly on metabolic comorbidities, such as statins and antiobesity drugs. Bariatric surgery may be an option for severely obese women with PCOS Regarding reproductive aspects, ovulation induction with antiestrogens such as clomiphene citrate or letrozole is the first-line medical treatment. Exogenous gonadotropins and in vitro fertilization (IVF) are recommended as second-line treatment for anovulatory infertility. Laparoscopic ovarian diathermy may be used in special cases and metformin is no longer recommended for ovulation induction. Combined oral contraceptives (OCs) are the first-line treatment for the management of menstrual irregularities in women not seeking pregnancy, also providing endometrial protection and contraception. Progestin-only pills or cyclical progestins are recommended for those with contraindications to OCs. Metformin is also considered a second-line choice for improving menstrual cycles in women presenting insulin-resistance and dysglicemia. Hirsutism requires cosmetic procedures and medical treatment with OCs. More severe cases may need anti-androgen drugs added to the OCs. In conclusion, strategies regarding the management of reproductive issues in PCOS encompass a tailored approach to individual needs of each patient.

Report of the international symposium: polycystic ovary syndrome: first Latin-American consensus.

During the last years, numerous consensuses have been held in different countries in order to review the data concerning diagnosis and treatment and their relationship with the ethnic origin, social status and lifestyle of women with Polycystic Ovary Syndrome (PCOS). This study describes the conclusions concerning diagnostic criteria and the appropriate treatment of women with PCOS reached during the International Symposium Polycystic Ovary Syndrome, First Latin-American Consensus held in Buenos Aires, Argentina on 4th and 5th May 2009 to be applied in South American.

Dehydroepiandrosterone to induce murine models for the study of polycystic ovary syndrome.

During the last decade a battery of animal models used for the study of polycystic ovary syndrome (PCOS) have allowed a focus on different aspects of the pathology. Since dehydroepiandrosterone (DHEA) was found to be one of the most abundant circulating androgens in women with PCOS, a rodent model showing the salient features found in women with PCOS was developed by the injection of DHEA. Although insulin-sensitizing agents, such as biguanides, are clinically used in the treatment of diabetes and PCOS, the complete understanding of their mechanisms of action remains unknown. The present review discusses the molecular mechanisms involved in the development of PCOS by using the DHEA-PCOS murine model and analyzes the role of the biguanide metformin as treatment.

Mechanisms involved in metformin action in the treatment of polycystic ovary syndrome.

The N, N' dimethyl-biguanide : Metformin is an antidiabetic drug that increases glucose utilization in insulin-sensitive tissues. As Polycystic Ovary Syndrome (PCOS) and diabetes share some altered parameters-such as abnormal glucose: insulin ratio, altered lipidic metabolism and insulin-resistance syndrome- the use of metformin has become increasingly accepted and widespread in the treatment of PCOS. Currently, metformin is used to induce ovulation and during early pregnancy in PCOS patients, however, a complete knowledge of the metformin action has not been achieved yet. This review describes beyond the classical reproductive action of metformin and explores other benefits of the drug. In addition, the present work discusses the molecular mechanisms involved further than the classical pathway that involves the AMP-activated protein kinase.

Dehydroepiandrosterone and metformin modulate progesterone-induced blocking factor (PIBF), cyclooxygenase 2 (COX2) and cytokines in early pregnant mice.

The present study examined the mechanism by which metformin (N,N'-dimethylbiguanide) prevents embryonic resorption induced in mice by dehydroepiandrosterone (DHEA). Treatment with DHEA (60mg/kg, s.c. 24 and 48h post-implantation) induces embryo resorption of early pregnant BALB/c mice while simultaneous treatment with metformin (240mg/kg, oral 24 and 48h post-implantation) prevents it. During pregnancy progesterone-induced blocking factor (PIBF) modulates prostaglandins (PGs) and cytokine production. These findings prompted us to investigate the effect of DHEA and metformin on both PIBF and cyclooxygenase 2 (COX2) expressions at the implantation sites, as well as cytokine production. PIBF and COX2 expression were detected by immunohistochemistry from DHEA and DHEA+ metformin treated 8 days-pregnant mice and serum cytokine levels of these animals were determined by ELISA. DHEA treatment both abolished PIBF expression and increased COX2 expression. Embryo resorption correlates with the lack of PIBF expression, diminished IL-6 levels and increased IL-2 concentration while metformin was able to reverse the effect of DHEA on both PIBF and COX2 expression and IL-6 levels. We concluded that hyperandrogenization induces embryo resorption in early pregnancy diminishing PIBF in implantation sites, having a pro-inflammatory effect. Metformin is able to prevent such effects.

Dehydroepiandrosterone and metformin regulate proliferation of murine T lymphocytes.

The aim of the present study was to assess the effect of dehydroepiandrosterone (DHEA: 10 microM) and metformin (10 microM and 100 microM) in regulating proliferation of cultured T lymphocytes. T cells were isolated from lymph nodes of prepuberal BALB/c mice. We found that DHEA, metformin and DHEA + metformin added to the incubation media diminished proliferation of T cells. The inhibition by DHEA was higher than that produced by metformin, while the combined treatment showed a synergistic action that allowed us to speculate distinct regulatory pathways. This was supported later by other findings in which the addition of DHEA to the incubation media did not modify T lymphocyte viability, while treatment with metformin and DHEA + metformin diminished cellular viability and increased both early and late apoptosis. Moreover, DHEA diminished the content of the anti-oxidant molecule glutathione (GSH), whereas M and DHEA + metformin increased GSH levels and diminished lipid peroxidation. We conclude that DHEA and metformin diminish proliferation of T cells through different pathways and that not only the increase, but also the decrease of oxidative stress inhibited proliferation of T cells, i.e. a minimal status of oxidative stress, is necessary to trigger cellular response.

The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice.

The aim of this study was to investigate the mechanisms by which N,N'-dimethylbiguanide metformin (50 mg/100 g body weight (BW) in 0.05 ml of water, given orally with a cannula) prevents the ovarian disorders provoked by the hyperandrogenization with dehydroepiandrosterone (DHEA) in prepuberal BALB/c mice. The injection of DHEA (6 mg/100 g BW in 0.1 ml of oil) for 20 consecutive days re-creates a mouse model that resembles some aspects of the human polycystic ovary syndrome (PCOS). The treatment with DHEA increased ovarian oxidative stress because it enhanced lipid peroxidation (LPO) and diminished both catalase (CAT) activity and glutathione (GSH) content. Therefore, the treatment with DHEA diminished both ovarian nitric oxide synthase (NOS) activity and prostaglandin E (PGE) production. When metformin was administered together with DHEA, the ovarian GSH content, NOS activity and PGE production did not differ when compared with controls. However, metformin was not able to prevent the effect of DHEA on ovarian LPO or CAT activity. Finally, DHEA increased the ovarian protein expressions of inducible NOS (iNOS), inducible cyclooxygenase (COX2) and the phosphorylated AMP-dependent kinase alpha (AMPK-alpha) (Thr172). Metformin administered together with DHEA was able to prevent the increase of ovarian iNOS and COX2 expressions and to enhance the activation of phosphorylated AMPK-alpha expression.

Metformin prevents embryonic resorption induced by hyperandrogenisation with dehydroepiandrosterone in mice.

The present study examined the mechanism by which metformin prevents dehydroepiandrosterone (DHEA)-induced embryonic resorption in mice. Treatment with DHEA (6 mg/100 g bodyweight, 24 and 48 h post implantation) induced 88 +/- 1 % embryonic resorption and the diminution of both serum oestradiol (E) and progesterone (P) levels. However, when metformin (50 mg/kg bodyweight) was given together with DHEA, embryo resorption (43 +/- 3% v. 35 +/- 5% in controls) and both serum E and P levels were not significantly different from controls. Glucose and insulin levels were increased in the DHEA-treated mice but when metformin was administered together with DHEA these parameters were similar to control values. Treatment with DHEA increased ovarian oxidative stress and diminished uterine nitric oxide synthase (NOS) activity; however, when metformin was administered together with DHEA, both ovarian oxidative stress and uterine NOS activity were not different from controls. Metformin treatment did not modify the percentage of CD4(+) and CD8(+) T cells from both axillar and retroperitoneal lymph nodes but prevented the increase of serum tumour necrosis factor +/- produced in DHEA-treated mice. These results show that metformin acts in DHEA-induced embryonic resorption in mice by modulating endocrine parameters, ovarian oxidative stress and uterine NOS activity.

Interleukin-1beta up-regulates nitrite production: effects on ovarian function.

We have previously reported that Interleukin-1beta (IL-1beta) affects ovarian function in the rat, modulating prostaglandin and progesterone (P) production. As IL-1beta effects were associated to nitric oxide (NO) synthesis, in the present work we have further examined the role of ovarian NOS-system, in IL-1beta antisteroidogenic action. Mid-luteal explants from rats were incubated for 4 h in the presence of IL-1beta (1-35 ng/ml)-alone or in combination with NOS-inhibitors-and then assayed for P and nitrite production. IL-1beta treatment reduced P levels in a dose-dependent manner, returning to basal levels at 35 ng/ml. This reduction in steroid synthesis was paralleled by a dose-dependent increase in nitrite levels, reaching a maximum at 25 ng/ml but without effect at 35 ng/ml. L-Arginine (1 and 2 mM) was able to mimic IL-1beta actions and the NOS blocker L-Nitro-Arginin-Methyl Ester reverted these effects. Moreover, the selective iNOS inhibitor, 1400 W, completely abolished IL-1beta antisteroidogenic effect, therefore confirming the dependence of IL-1beta action upon iNOS activation. Finally, IL-1beta did not affect eNOS expression but up-regulated iNOS mRNA and protein levels. Our results suggest an interaction between IL-1beta and the NOS-system. Thus, we may conclude that in the rat iNOS-derived NO production, induced by IL-1beta, affects ovarian P biosynthesis and hence NO may be a major effector molecule of ovarian IL-1 system.

Sequence of interleukin 1beta actions on corpus luteum regression: relationship with inducible cyclooxygenase and nitric oxide synthase expression.

Corpus luteum regression has been described in terms of: (i) functional luteolysis - a reversible decline in serum progesterone concentration; and (ii) structural luteolysis - irreversible morphological changes and tissue remodelling events within the cellular membrane. In rats, PGF(2alpha) and interleukin 1beta (IL-1beta) are involved in structural luteolysis, PGF(2alpha) by increasing ovarian lipid peroxidation, and IL-1beta by reducing progesterone and increasing PGF(2alpha) concentrations. The aim of the present report was to determine whether by an early action IL-1beta is able to regulate functional luteolysis. Thus, ovarian explants from rats at the mid-stage of corpus luteum development were incubated during short periods with either 15 or 25 ng IL-1beta ml(-1). At 15 ng ml(-1), IL-1beta inhibited progesterone after 4 and 8 h of culture without affecting PGF(2alpha) production, and a longer incubation (21 h) was needed to increase PGF(2alpha) production. In contrast, IL-1beta enhanced PGF(2alpha) concentrations at 8 h only at the higher dose (25 ng ml(-1)). The observed reduction in progesterone synthesis at the lower dose of IL-1beta before the increase in PGF(2alpha) concentrations led to the hypothesis that IL-1beta regulates functional luteolysis (progesterone diminution) before it affects structural luteolysis (PGF(2alpha) increase). The fact that the early IL-1beta action was described at 4 h but no effects on inducible nitric oxide synthase and inducible cyclooxygenase expression were found before this time led to the suggestion that these inductions were not necessary for the early IL-1beta action described.

Relationship between endothelin 1 and nitric oxide system in the corpus luteum regression.

The present study was designed to investigate the relationship between the nitric oxide (NO) system and endothelin 1 (ET-1) in the mechanism of corpus luteum (CL) development and consequently regression in rats. We first evaluated basal ET-1 levels in ovarian tissue from rats with different stages of CL development. An increased ovarian ET-1 content was found during CL regression. In a dose-department response, ET-1 decreased progesterone (P4) and increased prostaglandin (PG) PGF2alpha production. By means of a competitive nitric oxide synthase (NOS) inhibitor: L-nitro arginine methyl ester (L-NAME) and a slow NO releasing: diethyl-aminetriamine (DETA-NONOate), we demonstrated that NO system could be the intermediary in the ET-1 diminishing P4 production. The Western blot analysis revealed an increase on iNOS while eNOS protein expression was diminished. We also found a diminution of total NOS activity after ET-1 treatment. These data suggest the existence of a functional relationship between ET-1 and NOS isoforms leading the regulation of CL functionally.

Interleukin-1beta in the functional and structural luteolysis. Relationship with the nitric oxide system.

The aim of the present report was to investigate the in vitro effect of interleukin-1beta(IL-1beta) on corpus luteum (CL) function and some aspects of this mechanism involved. Ovarian rat dispersates from mid-luteal phase were exposed to different doses of IL-1beta (1, 10, 20 ng/ml). Meanwhile 1, 10 and 20 ng/ml of IL-1beta decreased progesterone (P4) production, only the highest doses of IL-1beta increased prostaglandin F2alpha (PGF2alpha) levels. To investigate the possible relationship between PGs production and P4 synthesis, we incubated together IL-1beta (20 ng/ml) and indomethacin (0.1 mM) a potent inhibitor of cyclooxygenase pathway. We found that P4 inhibition induced by IL-1beta was completely prevented by addition of indomethacin. On the other hand, when ovarian rat tissue were exposed at 20 ng/ml of IL-1beta (doses that affected both PGF2alpha and P4 production) the nitric oxide synthase (NOS) activity was augmented. Moreover, IL-1beta effects on PGF2alpha and P4 levels were impaired when a NOS inhibitor N(W)-nitro- L -arginine methyl ester (L-NAME, 600 microM) was added to the incubation media. These data demonstrate that: (i) at the tested doses (1-20 ng/ml), IL-1beta is involved in CL function through the diminution of P4 production of whole ovarian dispersate culture; (ii) at the highest doses assayed (20 ng/ml) IL-1beta increased PGF2alpha production; (iii) at these doses, IL-1beta decreased P4 production by means of a cyclooxygenase pathway and (iv) the NO system would be a key intermediary second messenger in the IL-1beta actions.

Regulation of lipid peroxidation by nitric oxide and PGF2alpha during luteal regression in rats.

Corpus luteum regression is related to an increased generation of reactive oxygen species. Although several studies indicate that PGF(2alpha) is involved in regression of the corpus luteum in mammalian species through an increase in reactive oxygen species, the exact mechanism remains unknown. In the present study, the relationship between nitric oxide and PGF(2alpha) in regulation of lipid peroxidation was studied. Ovarian tissue from pseudopregnant rats at mid- (day 5) or late phase or at the time of regression (day 9 of pseudopregnancy) of corpus luteum development was used. Thiobarbituric acid reactants, used as a lipid peroxidation index, were higher on day 9 of pseudopregnancy than on day 5. In contrast, glutathione content (an antioxidant metabolite) was lower on day 9 than on day 5 of pseudopregnancy. These results indicate that there was an enhanced oxidative status in ovarian tissue during luteolysis. Administration of N(omega)-nitro-L-arginine methyl ester (L-NAME: 600 micromol l(-1)), a competitive nitric oxide synthase (NOS) inhibitor, led to a decrease in basal thiobarbituric acid reactant content in ovarian tissue from rats on day 9 of pseudopregnancy only, indicating that during regression of the corpus luteum, NO could act as intermediary in ovarian lipid peroxidation. Administration of a luteolytic dose (3 microg kg(-1) body weight i.p.) of a synthetic PGF(2alpha) increased thiobarbituric acid reactant content in ovaries from rats on day 9 of pseudopregnancy. As this effect was reversed partially by L-NAME, it is proposed that during regression of corpora lutea, PGF(2alpha) and NO are involved in regulation of lipid peroxidation. As this effect was only reversed partially, it is possible that there is another mechanism involving PGF(2alpha) (but not the NO-NOS pathway) in regulation of ovarian lipid peroxidation. Furthermore, the administration of PGF(2alpha) enhanced ovarian NOS activity, whereas cyclooxygenase inhibition (by indomethacin treatment in vivo) reduced it. As western blotting of ovarian homogenates obtained from PGF(2alpha)-injected rats increased inducible NOS (iNOS) content, it is concluded that PGF(2alpha) enhances both activity and synthesis of NO in rat ovarian tissues during luteolysis. Taken together, these results indicate that in ovaries with regressing corpora lutea, both NO and PGF(2alpha) are involved in part in regulation of lipid peroxidation.

Dual effects of nitric oxide in functional and regressing rat corpus luteum.

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 micromol/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 F(2 alpha) (PGF(2 alpha))-induced luteolysis NO acted as an intermediary molecule in the inhibitory effect of PGF(2 alpha), on GSH content. This was supported by the fact that in-vivo PGF(2 alpha) 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.

The involvement of nitric oxide in corpus luteum regression in the rat: feedback mechanism between prostaglandin F(2alpha) and nitric oxide.

In the corpus luteum (CL), prostaglandin F(2alpha) (PGF(2alpha)) is a physiological agent with luteolytic actions. Nitric oxide (NO) is a messenger molecule capable of modulating diverse pathophysiological processes. The aim of the present study was to investigate the role of ovarian NO in PGE (a luteotrophic prostanoid) and PGF(2alpha) (a luteolytic prostanoid) production and in progesterone synthesis during CL regression in the rat. To obtain a longer functional CL, we used a pseudopregnant (PSP) rat model. By means of intrabursa ovarian sac treatment of two competitive nitric oxide synthase (NOS) inhibitors, N(G)-monomethyl-L-arginine (L-NMMA, 1 mg/kg) and N(W)-nitro-L-arginine methyl ester (L-NAME; 3 mg/kg), and sodium nitroprusside (SNP, 0.05 mg/kg) as a NO generator, we found that NO, produced by the ovarian tissue during the last 2 days of CL development (days 8 and 9), increased PGF(2alpha) production in the ovary and diminished serum progesterone concentrations leading to CL involution. We also proposed a positive feedback mechanism between PGF(2alpha) and NO, to ensure luteal regression. Thus, we injected intraperitoneally a luteolytic dose (3 microg/kg) of a synthetic PGF(2alpha) during the mid and late phase of CL development. Ovarian NOS activity was evaluated. The results confirmed our hypothesis; we did not see any effect in the mid-stage of CL development, but increased ovarian NOS activity was found in PGF(2alpha)-injected late pseudopregnant rats.

Regulation of prostaglandin production by nitric oxide in rat smooth muscle myometrial cells.

Smooth muscle myometrial cells isolated by an enzymatic method from estrogenized rats were used after 7-10 days of culture. They were incubated for 24 h with two distinct competitive nitric oxide (NO) inhibitors: NG-monomethyl-L-arginine (L-NMMA: 300 microM) and L-nitro-arginine methylester (L-NAME: 600 microM, 5 mM and 10 mM). Afterwards, the supernatants were separated in order to measure nitrite production and prostaglandin PGE synthesis. In the present report, we demonstrate that myometrial cells from estrogenized rats are able to produce NO, since all the inhibitors significantly decrease the production of nitrites in the culture media. Furthermore, we report that both inhibitors inhibited PGE synthesis by myometrial cells. We also used a donor of NO in the incubation medium for 24 h, sodium nitroprusside (NP), obtaining an strong (P< 0.001) increase in both nitrite and PGE production. We conclude that myometrial cells can produce NO and that one possible role of the NO synthetized by this cells may be the modulation of PGE production.

[Role of nitric oxide in the synthesis of prostaglandin F2 alpha and progesterone during luteolysis in the rat]. / Rol del óxido nítrico en la sintesis de prostaglandina f2 alpha y progesterona durante la luteolisis en la rata.

In the corpus luteum (CL) prostaglandin F2 alpha (PGF2 alpha) is a luteolytic agent. Nitric oxide (NO) is a messenger molecule capable of modulating diverse pathophysiological processes. Many of these functions are related with the female reproductive tract. The aim of the present study was to investigate the role of ovarian NO in PGF2 alpha production arid in progesterone synthesis during CL regression in the rat. By means of the intrabursa (i.b.) ovarian sac treatment of two competitive NO inhibitors, NG-monomethyl-L-arginine (L-NMMA; 1 mg/kg); NW-Nitro-L-arginine methyl ester (L-NAME, 3 mg/kg) and sodium nitroprusside (SNP, 0.05 mg/kg) as a NO generator we found that NO, produced by the ovarian tissue during the last days (days 8 and 9) of CL development, acted by increasing PGF2 alpha production in the ovary and diminishing seric progesterone levels leading to CL involution. We also postulated a positive feedback mechanism between PGF2 alpha and NO, to ensure luteal regression. Thus, we injected intraperitoneally (i.p.) a luteolytic dose (3 micrograms/kg) of a synthetic PGF2 alpha during the mid and late phase of CL development. The ovarian activity was evaluated. The results confirmed our hypothesis; we did not see any effect in mid-stage of CL development, while at a late stage enhancement of ovarian NOs activity was observed in PGF2 alpha-infected animals.