RESUMO
The effects of the angiotensin-converting enzyme inhibitors (ACEIs), may be partially mediated by the kinins' paracrine influence. Their actions may be exerted through nitric oxide and prostacyclin (PGI(2)) synthesis stimulation. The aim of our study was to determine whether the antihypertensive effect of Enalapril correlated with the increment in the plasmatic levels of NO and PGI(2) in essential moderate hypertensive patients. Normalization of blood pressure was observed in 20 patients, four on the 28th day, 15 on the 42th day and one on the 56th day. Enalapril-respondent subjects showed increased nitrate/nitrite levels on the 14th day (30% increment), on the 28th day (64%), on the 42th day (93.5%) and on the 56th day (96.2%) compared with basal levels, but they did not modify the circulating 6-keto PGF(1 alpha) levels. Four non-respondent patients showed a diminution in nitrate/nitrite and 6-keto PGF(1 alpha) circulating levels along the treatment. We conclude that the administration of 5-30 mg of Enalapril increases circulating NO metabolites in respondent-essential hypertensive subjects. The lack of responsiveness to the treatment may be related to the presence of risk factors such as those linked to an increase of oxidative stress. Finally, we consider that the evaluation of circulating NO may represent a predictive of the response to Enalapril in essential hypertensive patients.
Assuntos
Anti-Hipertensivos/farmacologia , Enalapril/farmacologia , Epoprostenol/sangue , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Óxido Nítrico/sangue , 6-Cetoprostaglandina F1 alfa/sangue , Adulto , Análise de Variância , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Creatinina/sangue , Enalapril/uso terapêutico , Epoprostenol/metabolismo , Feminino , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nitratos/sangue , Óxido Nítrico/metabolismo , Nitritos/sangue , Fatores de Risco , Fatores de TempoRESUMO
Lysine clonixinate (LC) is a nonsteroidal anti-inflammatory drug (NSAID) with good gastrointestinal tolerance. Treatment with LC at levels equivalent to those found in plasma following therapeutic doses resulted in significant inhibition of both cyclooxygenase 2 (COX-2) and production of 5 hydroxy-eicosatetraeonic acid (5-HETE) and slightly affected levels of cyclooxygenase 1 (COX-1) in in vitro studies carried out on human tissues. This study deals with the in vivo effect of the drug on human colon segments. Experiment 1: Five patients about to undergo hemicholectomy due to colon neoplasia were treated preoperatively with a continuous infusion of LC, to achieve a steady-state concentration between 4 and 6 mg/ml. Human colon segments from the five patients and from another five control patients receiving no treatment with [14C]-arachidonic acid were incubated. Human colon segments treated with LC showed significant inhibition of PGE2, the only prostaglandin (PG) synthesised by the tissue, as well as of 5-HETE. Experiment 2: Fifteen patients received an i.v. bolus of LC 100 mg (n1 = 5); LC 200 mg (n2 = 5) or indomethacin (INDO) 50 mg (n3 = 5). Both doses of LC showed greater inhibition of PGE2 synthesis than the INDO bolus. Both NSAIDs studied proved to have different effects on the production of 5-HETE; while treatment with LC elicited significant inhibition, levels with INDO remained unchanged. Western blotting analysis showed expression of both COX isoforms in colon segments, COX-2 levels being 20% higher. Both types of in vivo studies conducted continuous infusion and i.v. bolus, revealed that LC exerted significant inhibition of basal synthesis of PGE2 and 5-HETE.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Clonixina/análogos & derivados , Colo/efeitos dos fármacos , Neoplasias do Colo/enzimologia , Ácidos Hidroxieicosatetraenoicos/biossíntese , Lisina/análogos & derivados , Prostaglandina-Endoperóxido Sintases/biossíntese , Araquidonato 5-Lipoxigenase/biossíntese , Araquidonato 5-Lipoxigenase/efeitos dos fármacos , Clonixina/farmacologia , Colo/enzimologia , Ciclo-Oxigenase 1 , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/biossíntese , Humanos , Indometacina/farmacologia , Isoenzimas/metabolismo , Inibidores de Lipoxigenase/farmacologia , Lisina/farmacologia , Proteínas de Membrana , Prostaglandina-Endoperóxido Sintases/efeitos dos fármacos , Prostaglandina-Endoperóxido Sintases/metabolismoRESUMO
Little is known of the consequences of ethanol intake prior to fertilization on preimplantation embryo development. Recently we showed that chronic 10 and 5% w/v ethanol intake by young female mice reduces in vitro fertilization (IVF) rates. The purpose of the present work was to investigate whether the adverse effects of preconceptional low-dose chronic ethanol intake by sexually maturing female mice affects preimplantation embryo growth in vitro or in vivo in subsequent pregnancy. Prepubertal female mice were given 5% ethanol in their drinking water for 30 days. On day 27 and 29 of the ethanol treatment, females were superovulated. IVF-derived cultured embryos (in vitro development) or embryos obtained from oviducts and uteri (in vivo development) were evaluated. Whether analyzed on a per embryo or per dam basis, ethanol treatment was associated with a significant decrease in progression through embryo stages during the seven days of in vitro development and with an increase in morphologically abnormal embryos. Progression through embryo stages during four days of in vivo development was also inhibited by ethanol pretreatment of dams At 99 h post-hCG of in vivo development, there were fewer total, hatched, and expanded blastocysts, and a complete absence of implanting blastocysts among females treated with ethanol. In summary, low-dose chronic ethanol consumption of sexually maturing female mice prior to conception has adverse effects on preimplantation embryo development, both under in vitro and in vivo conditions, manifested as retarded development, embryo anormalities, and a reduction in expansion and hatching of the preimplantation blastocyst.
Assuntos
Anormalidades Induzidas por Medicamentos , Consumo de Bebidas Alcoólicas/efeitos adversos , Blastocisto/efeitos dos fármacos , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Etanol/toxicidade , Maturidade Sexual/efeitos dos fármacos , Animais , Etanol/administração & dosagem , Feminino , Fertilização in vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Técnicas de Cultura de Órgãos , Gravidez , Maturidade Sexual/fisiologiaRESUMO
Lysine clonixinate (LC) is a nonsteroidal anti-inflammatory drug (NSAID) with good gastrointestinal tolerance. Treatment with LC at levels equivalent to those found in plasma following therapeutic doses resulted in significant inhibition of both cyclooxygenase 2 (COX-2) and production of 5 hydroxy-eicosatetraeonic acid (5-HETE) and slightly affected levels of cyclooxygenase 1 (COX-1) in in vitro studies carried out on human tissues. This study deals with the in vivo effect of the drug on human colon segments. Experiment 1: Five patients about to undergo hemicholectomy due to colon neoplasia were treated preoperatively with a continuous infusion of LC, to achieve a steady-state concentration between 4 and 6 mg/ml. Human colon segments from the five patients and from another five control patients receiving no treatment with [14C]-arachidonic acid were incubated. Human colon segments treated with LC showed significant inhibition of PGE2, the only prostaglandin (PG) synthesised by the tissue, as well as of 5-HETE. Experiment 2: Fifteen patients received an i.v. bolus of LC 100 mg (n1 = 5); LC 200 mg (n2 = 5) or indomethacin (INDO) 50 mg (n3 = 5). Both doses of LC showed greater inhibition of PGE2 synthesis than the INDO bolus. Both NSAIDs studied proved to have different effects on the production of 5-HETE; while treatment with LC elicited significant inhibition, levels with INDO remained unchanged. Western blotting analysis showed expression of both COX isoforms in colon segments, COX-2 levels being 20
higher. Both types of in vivo studies conducted continuous infusion and i.v. bolus, revealed that LC exerted significant inhibition of basal synthesis of PGE2 and 5-HETE.
RESUMO
Although many studies have explored the effects of acute or chronic ethanol exposure during the postimplantation period on embryo/fetal development, few reports have described the ethanol effects on preimplantation embryo development. Little is known about the effects of ethanol consumption prior to gestation on embryo growth. Recently, we have shown that chronic moderate ethanol intake by prepubertal female mice reduces the ovulatory response and impairs in vitro fertilization and in vitro embryo preimplantation development. The purpose of the present work was to evaluate the effects of preconceptional chronic moderate ethanol ingestion on preimplantation embryo morphology and differentiation, the timing of cleavage and embryo growth in vivo, and to determine the time pattern in which alterations appear. Prepubertal female mice were treated with 10% (w/v) ethanol for 30 days prior to conception. After inducing ovulation on day 27 and 29 of the ethanol treatment, females were mated with control males and the day of presence of vaginal plug was day 1. On day 1, a decreased percentage of normal fertilized oocytes, elevated parthenogenetic oocyte activation and unfertilized eggs with abnormal metaphase II were found in ethanol-treated, compared to control females. On day 2, while any differences in the total percentage of 2-cell embryos were observed, the treated females had a significantly higher percentage of morphologically abnormal embryos, compared to control females. On day 3, the preconceptional consumption of ethanol produced significantly reduced percentages of compacted morulae and an increased percentage of uncompacted morulae. The total percentage of morulae in the treated females was lower than in controls. On day 4, ethanol-treated females showed significantly decreased percentages of hatched attached blastocysts and increased early blastocyst and morula percentages, compared to controls. Thus, preconceptional chronic moderate ethanol ingestion by prepubertal female mice produced retarded development, impaired blastocyst hatching, abnormal embryo morphology and embryo loss by fragmentation due to alterations induced in the female gamete.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Implantação do Embrião/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Desenvolvimento Embrionário , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Etanol/farmacologia , Fertilização/efeitos dos fármacos , Animais , Doença Crônica , Esquema de Medicação , Etanol/administração & dosagem , Etanol/sangue , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Oócitos/efeitos dos fármacos , Ovulação/efeitos dos fármacos , Gravidez , Fatores de TempoRESUMO
Nitric oxide (NO) is synthesized by the rat ovary and a role in the follicular development, the ovulation, and the luteal formation has been postulated. The aims this study were to determine the activity of nitric oxide synthase (NOs) enzyme during the ovulatory process and to demonstrate the existence of a relationship between the ovarian NO production and the synthesis of prostaglandins (PGs) involved in the follicular rupture. Prepuberal rats treated with PMSG/hCG to induce ovulation were used. The NOs activity, measured by [(14)C]citrulline formation, showed an increase after PMSG administration and reached a maximum at 10 h after hCG injection. NOs activity remained high up to 24 h post ovulation. At 10 h after the hCG injection, the activity of Ca(2+)-dependent NOs (constitutive NOs) was similar to that seen at 0 h, and the activity of Ca(2+)-independent NOs (inducible NOs) increased from 14.4 to 51% of total activity. The in vitro ovarian production of PGE and PGF(2alpha) was inhibited by L-NAME and stimulated by 3-morpho-linosydnonimine (SIN-1), a NO donor. The in vivo production of ovarian prostaglandins was also inhibited by the intrabursal administration of two NOs inhibitors, N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA). Our results suggest that the inducible NOs (iNOs) is the main isoform involved in the ovulatory process and that the NO produced stimulates the synthesis of both PGE and PGF(2alpha) from the cyclooxygenase pathway, to enhance the process of follicle rupture.
Assuntos
Dinoprosta/biossíntese , Óxido Nítrico Sintase/fisiologia , Óxido Nítrico/fisiologia , Ovário/enzimologia , Ovulação/fisiologia , Prostaglandinas E/biossíntese , Animais , Gonadotropina Coriônica/farmacologia , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Feminino , Gonadotropinas Equinas/farmacologia , Molsidomina/análogos & derivados , Molsidomina/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II , Óxido Nítrico Sintase Tipo III , Indução da Ovulação , Prostaglandina-Endoperóxido Sintases/metabolismo , Ratos , Ratos Wistar , ômega-N-Metilarginina/farmacologiaRESUMO
The susceptibility of preimplantation stages of embryo development to preconceptional alcohol ingestion by females has had little investigation. We have recently shown that chronic 10% (w/v) ethanol intake by young female mice reduces the ovulatory response and impairs the quality of the oocytes. The aim of this study was to investigate the effects of 10% ethanol administration for 30 days on immature female mice on the day of in-vitro fertilization (day 1) and on preimplantation embryo development. Female mice were ovulated on days 27 and 29 of ethanol treatment and in-vitro fertilization was performed 16 h post-human chorionic gonadotrophin administration (day 30). The oocytes from the ethanol-treated females inseminated with spermatozoa from control males, showed a significantly higher percentage of parthenogenetic activation compared to the control females. An increased percentage of fragmented oocytes was found after insemination, compared to control females. When the embryos were cultured, the percentage of 2-cell (day 2), 4-cell (day 3) embryos, and compacted morulae (day 4) was significantly reduced in treated females, compared to control females. On day 5, we found a highly significant decreased percentage of early and expanded blastocysts in the ethanol-treated females. The percentage of hatching and hatched (extruded) blastocysts was also reduced significantly in treated females at days 6 and 7 (blastocyst stages). An increased percentage of morphologically abnormal embryos was found on days 5 and 6 in ethanol-treated females compared with controls. We conclude that chronic moderate ethanol ingestion by young female mice results in decreased fertilization, embryo growth retardation, cleavage arrest, and abnormal embryo development in vitro.
Assuntos
Blastocisto/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Desenvolvimento Embrionário e Fetal , Etanol/administração & dosagem , Animais , Cromatografia Gasosa/métodos , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Etanol/análise , Feminino , Fertilização in vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Fatores de TempoRESUMO
Embryo prostaglandin (PG) synthesis plays a role in the modulation of embryo metabolism and viability, and in the beginning of the implantation. The effects of ethanol consumption seem to be mediated at least in part by PGs. Increased PG production of postimplantation embryos is associated with retardation and abnormalities in the gestational period. The aim of this study was to find out the effects of low chronic ethanol ingestion by mice, previous to pregnancy, on the PGE released by in vitro and in vivo derived embryos. Immature females or adult males were treated with 5% ethanol for 30 days. After fertilization and mating, two-cell embryos, morulae and blastocysts were collected. The PGE synthesis and release were measured by radioimmunoassay. PGE production by in vitro derived two-cell embryos from ethanol-treated females was lower than in the control group (P < 0.01). Also, PGE production was reduced when two-cell embryos came from ethanol-treated males (P < 0.01). There were no differences in PGE synthesis by in vitro derived morulae and blastocysts in these groups. Two-cell embryos derived from mating produced lower quantities of PGE when they came from ethanol-treated females mated with control males, as compared to the control group. PGE release by in vivo derived blastocysts from ethanol-treated females was reduced significantly, as compared to the control group (P < 0.01). We conclude that a low concentration of ethanol administered chronically to immature females reduces PGE synthesis and release by two-cell embryos from culture in vitro, and by embryos of days 2 and 4 from in vivo development.
Assuntos
Depressores do Sistema Nervoso Central/farmacologia , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Etanol/farmacologia , Prostaglandinas E/biossíntese , Animais , Blastômeros/efeitos dos fármacos , Blastômeros/metabolismo , Técnicas de Cultura , Desenvolvimento Embrionário , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Gravidez , Prostaglandinas E/metabolismoRESUMO
Previously, we demonstrated the presence of a nitric oxide (NO) prostaglandin (PG) pathway in myometrial cells obtained from uterine rat tissue. This pathway was modulated by estrogen and one possible function could be to modulate uterine relaxation. In the present study, we investigated the role of progesterone in the regulation of NO synthesis and the uterotonic PGE production by myometrial cells from uterine rat tissue. We worked with two groups of rats: (i) ovariectomizcd (OV) rats, without influence of sex hormones and (ii) OV rats injected with progesterone (4 mg) s.c. Myometrial uterine cells were obtained by a selective enzymatic digestion. In the incubation medium of these cells, nitrite concentration (as a measure of NO production) and PGE production were evaluated. To ensure a specific response, a competitive NOs inhibitor, N(G)-monomethyl-L-arginine; L-NMMA (300 microM) was used. We found that at 48 h of the incubation period, cells obtained from progesterone-primed uterine tissue presented an increase in the nitrite concentration concomitant with a decrease in the PGE production. When L-NMMA was added to the cells, nitrite production and PGE synthesis returned to control values. The fact that this effect had not been observed in the group of cells obtained from OV rats suggests that progesterone was responsible for it. These data provide strong evidence that in spite of the fact that estrogen and progesterone modulate the NO-PG pathway in the uterine rat tissue, the two hormones have opposite effects.
Assuntos
Músculo Liso/fisiologia , Miométrio/fisiologia , Óxido Nítrico/fisiologia , Progesterona/fisiologia , Prostaglandinas E/fisiologia , Animais , Feminino , Óxido Nítrico/antagonistas & inibidores , Nitritos/metabolismo , Prostaglandinas E/biossíntese , Ratos , Fatores de Tempo , ômega-N-Metilarginina/farmacologiaRESUMO
Little is known about the effects of low chronic alcohol intake on fertility, particularly in females. Recently, we have shown that chronic 10% (w/v) ethanol treatment affects in-vitro fertilization of mouse female gamete. The aim of this study was to solve questions concerning the lowest dose and duration of ethanol treatment required to alter the fertility of immature and adult female and adult male mouse. Mice were treated with 5% and 2.5% (w/v) ethanol in drinking water for 4 weeks. The in-vitro fertilization rates were significantly decreased with the 5% ethanol when oocytes from prepubertal and pubertal ethanol-treated females were inseminated with spermatozoa from adult control males. The in-vitro fertilization rates were not diminished when oocytes from control females were inseminated with spermatozoa from adult ethanol-treated males. Haploid oocytes were increased when oocytes came from immature females treated with ethanol. The in-vitro fertilization rates were not decreased in adult treated females. The in-vivo fertilization rates were not modified when prepubertal ethanol-treated females were mated with adult control males. Fragmented oocytes, in the in-vitro fertilization experiments, were significantly increased when they came from prepubertal and adult treated females inseminated with ethanol-treated males. These results show that there is a threshold of the ethanol dose to produce an effect. Chronic low ethanol ingestion by immature female mice has a deleterious effect on their in-vitro fertilization. Furthermore, acute ethanol ingestion by adult females during the induction of ovulation resulted in high parthenogenetic activation and fragmentation of mouse oocytes.