RESUMEN
Nitric oxide (NO) is produced by several cell types and has effects both detrimental and beneficial to the host. Sepsis and septic shock are conditions in which NO plays a central role in physiopathology. Stressful circumstances such as pathogens, toxins, and trauma elicit a wide variety of physiological changes. Steroid hormones and notably glucocorticoids are one of the main players in this orchestrated response. Although steroids have been used for sepsis some decades ago, their use in this condition was practically banned for several years following studies showing that high glucocorticoid doses were harmful to the host. Recently, the subject has been raised again since some studies demonstrated that adrenal insufficiency may happen in sepsis and that low dose/long-term regimen with cortisol may be beneficial to sepsis and septic shock. However, there are great gaps in our knowledge regarding the role played by steroids in sepsis, as well as the contribution of NO. In the present review, we will attempt to highlight the relationship among NO, sepsis and steroids, mainly glucocorticoids. A second purpose is to raise some unanswered questions that may provide better therapeutic alternatives to treat sepsis and septic shock.
Asunto(s)
Óxido Nítrico/metabolismo , Sepsis/metabolismo , Esteroides/metabolismo , Insuficiencia Suprarrenal/metabolismo , Animales , Antiinflamatorios/farmacología , Glucocorticoides/metabolismo , Humanos , Inflamación , Mineralocorticoides/metabolismo , Modelos Biológicos , Modelos Teóricos , Sistema Hipófiso-SuprarrenalRESUMEN
We investigated the role of soluble guanylate cyclase in lipopolysaccharide-induced hyporesponsiveness to phenylephrine. The effects of phenylephrine on the blood pressure of female Wistar rats were evaluated at 2, 8, and 24 h after lipopolysaccharide injection (12.5 mg/kg i.p.). Vasoconstrictive responses to phenylephrine were reduced 40 to 50% in all time periods. Methylene blue, a soluble guanylate cyclase inhibitor (15 micromol/kg i.v.) restored the reactivity to phenylephrine in animals injected with lipopolysaccharide 2 and 24 h earlier. However, it failed to do so in animals injected with lipopolysaccharide 8 h earlier. Incubation with sodium nitroprusside (SNP) increased lung and aorta cGMP levels in control animals and in tissues of rats treated with lipopolysaccharide 24 h earlier. However, SNP failed to increase tissue cGMP in rats injected 8 h earlier. Lipopolysaccharide reduced the vasodilatory response to NO donors 8 h after injection. This effect and the decreased lung cGMP accumulation in response to SNP were reversed by an NO synthase blocker. Guanylate cyclase protein levels were lower than controls in lungs harvested from rats injected 8 h earlier and were back to normal values in lungs of rats injected 24 h earlier with lipopolysaccharide. Thus, data indicate that there is a temporal window of 8 h after lipopolysaccharide injection in which soluble guanylate cyclase is not functional and that this loss of function is NO-dependent. Thus, the putative use of soluble guanylate cyclase inhibitors in the treatment of endotoxemia may be beneficial mainly at early stages of this condition.
Asunto(s)
Endotoxemia/enzimología , Inhibidores Enzimáticos/farmacología , Guanilato Ciclasa/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Vasoconstrictores/farmacología , Animales , Aorta/efectos de los fármacos , Aorta/enzimología , Presión Sanguínea/efectos de los fármacos , GMP Cíclico/metabolismo , Endotoxemia/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Femenino , Lipopolisacáridos/farmacología , Pulmón/efectos de los fármacos , Pulmón/enzimología , Azul de Metileno/farmacología , NG-Nitroarginina Metil Éster/farmacología , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Nitroprusiato/farmacología , Fenilefrina/farmacología , Ratas , Ratas Wistar , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/uso terapéutico , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
In chronically inflamed animals, adrenal hormones exert a positive control on the secretion of melatonin by the pineal gland. In this paper, the mechanism of corticosterone as a modulator of melatonin and N-acetylserotonin (NAS) was determined. Rat pineal glands in culture, stimulated for 5 hr with noradrenaline (10 nm), were previously incubated with corticosterone (1.0 nm-1.0 microm) for 48 hr in the presence or absence of the glucocorticoid receptor (GR) antagonist, mifepristone (1.0 microm), the proteasome inhibitor, N-acetyl-leucinyl-leucinyl-norleucinal-H (ALLN, 12.5 microm) or the antagonist of the nuclear factor kappa B (NFkappaB), pyrrolidinedithiocarbamate (PDTC, 12.5 microm). Corticosterone potentiated noradrenaline-induced melatonin and NAS production in a bell-shaped manner. The increase in NAS (12.9 +/- 2.7, n=6 versus 34.3 +/- 8.3 ng per pineal) and melatonin (16.3 +/- 2.0, n=6 versus 44.3 +/- 12.9 ng per pineal) content induced by 1 microm corticosterone was blocked by mifepristone, and mimicked by ALLN and PDTC. The presence of GRs was shown by [3H]-dexamethasone binding (0.30 +/- 0.09 pmol/mg protein) and corticosterone inhibition of NFkappaB nuclear translocation was demonstrated by electromobility shift assay. Therefore, corticosterone potentiates noradrenaline-induced melatonin and NAS production through GR inhibition of NFkappaB nuclear translocation. To the best of our knowledge, this is the first time that this relevant pathway for passive and acquired immune response is shown to modulate melatonin production in pineal gland.
Asunto(s)
Corticosterona/farmacología , Melatonina/biosíntesis , FN-kappa B/antagonistas & inhibidores , Norepinefrina/farmacología , Glándula Pineal/efectos de los fármacos , Glándula Pineal/metabolismo , Serotonina/análogos & derivados , Animales , Secuencia de Bases , ADN/genética , ADN/metabolismo , Dexametasona/metabolismo , Femenino , Antagonistas de Hormonas/farmacología , Leupeptinas/farmacología , Masculino , Mifepristona/farmacología , FN-kappa B/genética , Técnicas de Cultivo de Órganos , Pirrolidinas/farmacología , Ratas , Ratas Wistar , Receptores de Glucocorticoides/antagonistas & inhibidores , Serotonina/biosíntesis , Tiocarbamatos/farmacologíaRESUMEN
Caffeic acid and some of its derivatives such as caffeic acid phenetyl ester (CAPE) and octyl caffeate are potent antioxidants which present important anti-inflammatory actions. The present study assessed the in vitro and in vivo effects of five caffeic acid derivatives (caffeic acid methyl, ethyl, butyl, octyl and benzyl esters) and compared their actions to those of CAPE. In the model of LPS-induced nitric oxide (NO) production in RAW 264.7 macrophages, the pre-incubation of all derivatives inhibited nitrite accumulation on the supernatant of stimulated cells, with mean IC50 (microM) values of 21.0, 12.0, 8.4, 2.4, 10.7 and 4.80 for methyl, ethyl, butyl, octyl, benzyl and CAPE, respectively. The effects of caffeic acid derivatives seem to be related to the scavenging of NO, as the compounds prevented SNAP-derived nitrite accumulation and decreased iNOS expression. In addition, butyl, octyl and CAPE derivatives significantly inhibited LPS-induced iNOS expression in RAW 264.7 macrophages. Extending the in vitro results, we showed that the pre-treatment of mice with butyl, octyl and CAPE derivatives inhibited carrageenan-induced paw edema and prevented the increase in IL-1beta levels in the mouse paw by 30, 24 and 36%, respectively. Butyl, octyl and CAPE derivatives also prevented carrageenan-induced neutrophil influx in the mouse paw by 28, 49 and 31%, respectively. Present results confirm and extend literature data, showing that caffeic acid derivatives exert in vitro and in vivo anti-inflammatory actions, being their actions mediated, at least in part by the scavenging of NO and their ability to modulate iNOS expression and probably that of other inflammatory mediators.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Ácidos Cafeicos/química , Ácidos Cafeicos/farmacología , Animales , Carragenina/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Ésteres/química , Ésteres/farmacología , Extremidades/patología , Concentración 50 Inhibidora , Interleucina-1/metabolismo , Lipopolisacáridos/farmacología , Ratones , Estructura Molecular , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II , Nitritos/metabolismo , Peroxidasa/metabolismoRESUMEN
OBJECTIVE: Nitric oxide is an important participant in septic shock. For example, it causes profound vasodilation and hypotension. Despite their potent antiinflammatory properties, glucocorticoids are not routinely used in septic shock. Some studies show that antiinflammatory doses of glucocorticoids can be beneficial, but other studies do not indicate their use in this situation. We have previously shown the inhibitory effect of nitric oxide on glucocorticoid receptor binding in vitro. Nitric oxide donors decreased the binding of immunoprecipitated glucocorticoid receptor obtained from mouse L929 fibroblasts. These in vitro findings prompted us to study whether in vivo manipulations of the nitric oxide system would interfere with the glucocorticoid receptor binding. DESIGN: Prospective, experimental study. SETTING: Research laboratory at a university. SUBJECTS: Female Wistar rats. INTERVENTIONS: Injection of bacterial lipopolysaccharide, anesthesia, cardiovascular perfusion, and organ removal for biochemical assays. MEASUREMENTS AND MAIN RESULTS: Following lipopolysaccharide injection, plasma nitrate + nitrite increased and inducible nitric oxide synthase activity was stimulated in several organs, the highest rates being in the lung and spleen. If dexamethasone was injected before lipopolysaccharide, it completely blocked inducible nitric oxide synthase induction and the increase in plasma nitrate + nitrite. On the other hand, if dexamethasone was injected after lipopolysaccharide, it failed to affect both inducible nitric oxide synthase induction and increased plasma nitrate + nitrite levels. Lipopolysaccharide also caused an inhibition of glucocorticoid receptor binding in lung and spleen. Previous administration of a nitric oxide synthase inhibitor prevented both lipopolysaccharide-induced decrease in glucocorticoid receptor binding and the increase in plasma nitrate + nitrite. Injection of a nitric oxide donor into naive animals significantly decreased glucocorticoid receptor binding activity and prevented dexamethasone-induced increase in liver tyrosine aminotransferase activity. CONCLUSIONS: The results indicate that the failure of glucocorticoids to exhibit their antiinflammatory effects when administered to endotoxemic rats may be explained, at least in part, by the nitric oxide-induced inhibition of glucocorticoid receptor binding ability, thus precluding the expression of the antiinflammatory effects of both exogenous and endogenous corticosteroids.