RESUMEN
Objetivo: Describir y analizar desde el punto de vista clínico y epidemiológico un brote de toxiinfección alimentaria en una institución de enfermos psiquiátricos de Granada, en 2015, y examinar si el tratamiento con psicofármacos constituye un factor de riesgo para desarrollar una toxiinfección alimentaria, analizando los grados de susceptibilidad según el grupo terapéutico consumido. Método: Estudio ambispectivo de cohortes. La unidad de análisis fueron los residentes. Se realizó búsqueda activa de casos, encuesta alimentaria y búsqueda de otros riesgos, e inspección alimentaria. Se estudiaron variables de persona, lugar y tiempo. Análisis descriptivo (frecuencias absolutas y relativas), cálculo de las tasas de ataque por pabellón y por menú. Análisis bivariado (ji al cuadrado, t de Student) y riesgo relativo como medida de la fuerza de asociación. Análisis multivariado mediante regresión logística para el análisis de riesgos de la medicación. Resultados: Se contabilizaron 18 casos con diarrea sin fiebre (periodo de incubación de 6-16 horas), de carácter leve y autolimitado. Las manifestaciones clínicas, la agrupación temporal de casos y las características de los alimentos ingeridos centraron la sospecha en una toxina bacteriana. A igualdad en el resto de variables, los grupos terapéuticos N03AF y N03AG confirieron mayor riesgo de enfermar (odds ratio [OR]: 8,626; intervalo de confianza del 95% [IC95%]: 2,050-36,308; p=0,003; y OR: 14,516; IC95%: 3,155-66,784; p=0,001, respectivamente). Conclusión: La disminución del tránsito intestinal causada por la administración de antiepilépticos puede aumentar el tiempo de exposición de la mucosa intestinal a la toxina, aumentando el riesgo de enfermar y de padecer complicaciones. Debe realizarse un esfuerzo higiénico suplementario en este tipo de instituciones para prevenir estas afecciones
Objective: To describe and analyse from a clinical and epidemiological point of view, a food borne outbreak in a psychiatric institution in Granada, in 2015, and to examine whether treatment with psychoactive drugs constitutes a risk factor for the development of a food borne disease, analysing the degree of susceptibility according to the therapeutic group consumed. Method: Ambispective cohort study. Residents were the unit of analysis. Our group carried out an active case search and a food survey. A search for other risks was developed as well as a food inspection. Location, time and individual variables were studied. A descriptive analysis was conducted (absolute and relative frequencies). Calculation of attack rates by building and by menu was made. Bi-variant analysis (Chi-square test, t-Student test) and relative risk were used as a measure of strength of association. For risk analysis of medication, a multivariate analysis using logistic regression was carried out. Results: 18 cases with diarrhoea without fever were found (incubation period from 6 to 16hours). Cases were mild and self-limiting. The clinical manifestations, the temporal grouping of cases and the characteristics of the ingested foods, focussed suspicion on a bacterial toxin. Being equal in the rest of variables, the N03AF, and N03AG therapeutic groups confer greater risk of disease (odds ratio [OR]: 8.626; 95% confidence interval [95%CI]: 2.050-36.308; p=0.003; and OR: 14.516; 95%CI: 3.155-66.784; p=0.001, respectively). Conclusion: Decreased intestinal transit, caused by the administration of anticonvulsants, may increase exposure time of the intestinal mucosa to the toxin, increasing the risk of disease and suffering from complications. An additional hygienic effort should be made in this type of institution to prevent these pathologies
Asunto(s)
Humanos , Masculino , Femenino , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Psicotrópicos/uso terapéutico , Trastornos Mentales/complicaciones , Enfermedades Transmitidas por los Alimentos/complicaciones , Infecciones por Clostridium/complicaciones , Anticonvulsivantes/uso terapéutico , Trastornos Mentales/tratamiento farmacológico , Contaminación de Alimentos/análisis , Hospitales Psiquiátricos/estadística & datos numéricos , Clostridium perfringens/aislamiento & purificación , Factores de RiesgoRESUMEN
OBJECTIVE: To describe and analyse from a clinical and epidemiological point of view, a food borne outbreak in a psychiatric institution in Granada, in 2015, and to examine whether treatment with psychoactive drugs constitutes a risk factor for the development of a food borne disease, analysing the degree of susceptibility according to the therapeutic group consumed. METHOD: Ambispective cohort study. Residents were the unit of analysis. Our group carried out an active case search and a food survey. A search for other risks was developed as well as a food inspection. Location, time and individual variables were studied. A descriptive analysis was conducted (absolute and relative frequencies). Calculation of attack rates by building and by menu was made. Bi-variant analysis (Chi-square test, t-Student test) and relative risk were used as a measure of strength of association. For risk analysis of medication, a multivariate analysis using logistic regression was carried out. RESULTS: 18 cases with diarrhoea without fever were found (incubation period from 6 to 16hours). Cases were mild and self-limiting. The clinical manifestations, the temporal grouping of cases and the characteristics of the ingested foods, focussed suspicion on a bacterial toxin. Being equal in the rest of variables, the N03AF, and N03AG therapeutic groups confer greater risk of disease (odds ratio [OR]: 8.626; 95% confidence interval [95%CI]: 2.050-36.308; p=0.003; and OR: 14.516; 95%CI: 3.155-66.784; p=0.001, respectively). CONCLUSION: Decreased intestinal transit, caused by the administration of anticonvulsants, may increase exposure time of the intestinal mucosa to the toxin, increasing the risk of disease and suffering from complications. An additional hygienic effort should be made in this type of institution to prevent these pathologies.
Asunto(s)
Toxinas Bacterianas/toxicidad , Brotes de Enfermedades , Enfermedades Transmitidas por los Alimentos/epidemiología , Enfermedades Transmitidas por los Alimentos/etiología , Psicotrópicos/efectos adversos , Adolescente , Adulto , Anciano , Niño , Estudios de Cohortes , Femenino , Hospitales Psiquiátricos , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Estudios Retrospectivos , España/epidemiología , Adulto JovenRESUMEN
Community-associated Clostridium difficile infection (CA-CDI) now accounts for approximately 50% of CDI cases in central Minnesota; animals and meat products are potential sources. From November 2011 to July 2013, we cultured retail meat products and fecal samples from food-producing and companion animals in central Minnesota for C. difficile by using standard methods. The resulting 51 C. difficile isolates, plus 30 archived local veterinary C. difficile isolates and 208 human CA-CDI case isolates from central Minnesota (from 2012) from the Minnesota Department of Health, were characterized molecularly, and source groups were compared using discriminant analysis. C. difficile was recovered from 0 (0%) of 342 retail meat samples and 51 (9%) of 559 animal fecal samples. Overall, the 81 animal source isolates and 208 human source isolates were highly diverse genetically. Molecular traits segregated extensively in relation to animal versus human origin. Discriminant analysis classified 95% of isolates correctly by source group; only five (2.5%) human source isolates were classified as animal source. These data do not support meat products or food-producing and companion animals as important sources of CA-CDI in the central Minnesota study region.
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Clostridioides difficile/aislamiento & purificación , Infecciones por Clostridium , Ganado/microbiología , Carne/microbiología , Mascotas/microbiología , Animales , Clostridioides difficile/clasificación , Infecciones por Clostridium/epidemiología , Infecciones por Clostridium/veterinaria , Heces/microbiología , Humanos , Minnesota/epidemiología , PrevalenciaRESUMEN
PURPOSE: There is a widening range of antidiabetic medications available; however changes in consumption patterns remain poorly documented. The aim of this study is to analyze the evolution of consumption of antidiabetic medications during the period 2001-2014 in an Andalusian region. METHODS: All antidiabetic medicines on the market were selected for analysis. Consumption data were obtained for the 15-year period and were expressed in defined daily doses (DDD) per 1000 inhabitants per day (DHD). RESULTS: During the study period consumption of insulins grew only a 2.2%, from 17.9 DHD to 18.3 DHD, while oral agents increased a 27.6%, from 41.3 DHD to 52.7 DHD. Consumption of sulfonylureas was gradually reduced from 30.1 DHD to 16.4 DHD but metformin (alone) usage increased from 4.3 DHD to 23.7 DHD, and was the most consumed agent in 2014. A rise in consumption of dipeptidyl peptidase-4 inhibitors and "other hypoglycemic agents" was also noticed. Overall expenditure in antidiabetic medications increased notably from 4.5 in 2001 to 14.4 million euros in 2014. CONCLUSION: We highlight the market uptake of antidiabetic drugs commercialized during the last decade; despite further exploration is needed to clarify the cost-benefit ratio of these new antidiabetic medicines.
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Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Pautas de la Práctica en Medicina/tendencias , Comercio/economía , Comercio/tendencias , Análisis Costo-Beneficio , Bases de Datos Factuales , Diabetes Mellitus Tipo 1/economía , Diabetes Mellitus Tipo 2/economía , Costos de los Medicamentos/tendencias , Prescripciones de Medicamentos , Revisión de la Utilización de Medicamentos , Gastos en Salud/tendencias , Humanos , Hipoglucemiantes/economía , Pautas de la Práctica en Medicina/economía , Estudios Retrospectivos , España , Factores de TiempoRESUMEN
PURPOSE: The objective of this study was to measure the impact of an intervention on the prescription habits of general practitioners (GPs) in order to improve the quality of zolpidem prescriptions in patients aged 75 or older. METHODS: A prospective multicentric non-randomized trial was performed in the Metropolitan Granada Primary Healthcare Area (Andalusian Public Healthcare Service, Spain), which serves a total population of approximately 675,000 inhabitants. All health centers volunteering to participate in the trial were included. The intervention consisted of training sessions, individualized feedback, clinical information, and financial incentives. A daily dose over 5 mg was considered non-safe. Reduction in non-safe prescriptions of zolpidem in the elderly population became a quality prescribing indicator in a pay-for-performance scheme. RESULTS: Statistically significant differences versus baseline were found between the intervention and control groups in mean zolpidem prescription prevalence (28.5 vs. 37.5, respectively; p = 0.008) and mean non-safe zolpidem prescription prevalence (16.5 vs. 34.2, respectively; p < 0.001). At the end of the study period, the total number of non-safe prescriptions was 1309, 35% lower versus baseline, with a significant difference of p < 0.001; the number in the intervention (510 vs. 1118; p < 0.001) and control (799 vs. 893; p = 0.0064) groups was also significantly lower, with a significantly greater percentage reduction in the intervention group (54.4 vs. 10.5%, p < 0.001). CONCLUSION: The quality prescribing indicator in our area was improved by the intervention developed. Further studies that include an intervention group of GPs who receive no financial incentive are required to evaluate the relative importance of an economic reward in achieving this improvement.
Asunto(s)
Hipnóticos y Sedantes/uso terapéutico , Atención Primaria de Salud , Piridinas/uso terapéutico , Anciano , Humanos , Estudios Prospectivos , ZolpidemRESUMEN
Vascular aging is characterized by up-regulation of NADPH oxidase, oxidative stress and endothelial dysfunction. Previous studies demonstrate that the activity of the evolutionarily conserved NAD(+)-dependent deacetylase SIRT1 declines with age and that pharmacological activators of SIRT1 confer significant anti-aging cardiovascular effects. To determine whether dysregulation of SIRT1 promotes NADPH oxidase-dependent production of reactive oxygen species (ROS) and impairs endothelial function we assessed the effects of three structurally different inhibitors of SIRT1 (nicotinamide, sirtinol, EX527) in aorta segments isolated from young Wistar rats. Inhibition of SIRT1 induced endothelial dysfunction, as shown by the significantly reduced relaxation to the endothelium-dependent vasodilators acetylcholine and the calcium ionophore A23187. Endothelial dysfunction induced by SIRT1 inhibition was prevented by treatment of the vessels with the NADPH oxidase inhibitor apocynin or superoxide dismutase. Inhibition of SIRT1 significantly increased vascular superoxide production, enhanced NADPH oxidase activity, and mRNA expression of its subunits p22(phox) and NOX4, which were prevented by resveratrol. Peroxisome proliferator-activated receptor-α (PPARα) activation mimicked the effects of resveratrol while PPARα inhibition prevented the effects of this SIRT1 activator. SIRT1 co-precipitated with PPARα and nicotinamide increased the acetylation of the PPARα coactivator PGC-1α, which was suppressed by resveratrol. In conclusion, impaired activity of SIRT1 induces endothelial dysfunction and up-regulates NADPH oxidase-derived ROS production in the vascular wall, mimicking the vascular aging phenotype. Moreover, a new mechanism for controlling endothelial function after SIRT1 activation involves a decreased PGC-1α acetylation and the subsequent PPARα activation, resulting in both decreased NADPH oxidase-driven ROS production and NO inactivation.
Asunto(s)
Aorta Torácica/fisiología , Endotelio Vascular/fisiología , NADPH Oxidasas/metabolismo , Sirtuina 1/fisiología , Acetilación , Envejecimiento/metabolismo , Animales , Aorta Torácica/efectos de los fármacos , Caveolinas/metabolismo , GMP Cíclico/fisiología , Endotelio Vascular/efectos de los fármacos , Activación Enzimática , Técnicas In Vitro , Masculino , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa de Tipo III/metabolismo , PPAR alfa/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Proteínas de Unión al ARN/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Resveratrol , Transducción de Señal , Sirtuina 1/antagonistas & inhibidores , Estilbenos/farmacología , Factores de Transcripción/metabolismo , Vasodilatación , Vasodilatadores/farmacologíaRESUMEN
Flavanol-rich diets have been reported to exert beneficial effects in preventing cardiovascular diseases, such as hypertension. We studied the effects of chronic treatment with epicatechin on blood pressure, endothelial function, and oxidative status in deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Rats were treated for 5 weeks with (-)-epicatechin at 2 or 10 mg kg(-1)day(-1). The high dose of epicatechin prevented both the increase in systolic blood pressure and the proteinuria induced by DOCA-salt. Plasma endothelin-1 and malondialdehyde levels and urinary iso-prostaglandin F(2α) excretion were increased in animals of the DOCA-salt group and reduced by the epicatechin 10 mg kg(-1) treatment. Aortic superoxide levels were enhanced in the DOCA-salt group and abolished by both doses of epicatechin. However, only epicatechin at 10 mg kg(-1) reduced the rise in aortic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and p47(phox) and p22(phox) gene overexpression found in DOCA-salt animals. Epicatechin increased the transcription of nuclear factor-E2-related factor-2 (Nrf2) and Nrf2 target genes in aortas from control rats. Epicatechin also improved the impaired endothelium-dependent relaxation response to acetylcholine and increased the phosphorylation of both Akt and eNOS in aortic rings. In conclusion, epicatechin prevents hypertension, proteinuria, and vascular dysfunction. Epicatechin also induced a reduction in ET-1 release, systemic and vascular oxidative stress, and inhibition of NADPH oxidase activity.
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Presión Sanguínea/efectos de los fármacos , Catequina , Endotelina-1/antagonistas & inhibidores , Endotelio Vascular/efectos de los fármacos , Hipertensión/tratamiento farmacológico , NADPH Oxidasas/antagonistas & inhibidores , Proteinuria/tratamiento farmacológico , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Catequina/farmacología , Desoxicorticosterona/efectos adversos , Dinoprost/análogos & derivados , Dinoprost/orina , Endotelina-1/sangre , Endotelio Vascular/metabolismo , Hipertensión/sangre , Hipertensión/inducido químicamente , Hipertensión/complicaciones , Masculino , Malondialdehído/sangre , NADPH Oxidasas/sangre , Factor 2 Relacionado con NF-E2/agonistas , Factor 2 Relacionado con NF-E2/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Proteinuria/sangre , Proteinuria/inducido químicamente , Proteinuria/complicaciones , Ratas , Ratas Wistar , Cloruro de Sodio Dietético/efectos adversos , Superóxidos/antagonistas & inhibidores , Superóxidos/metabolismoRESUMEN
The present study analysed the effects of the flavanol (-)-epicatechin in rats after chronic inhibition of NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME), at doses equivalent to those achieved in the studies involving human subjects. Wistar rats were randomly divided into four groups: (1) control-vehicle, (2) L-NAME, (3) L-NAME-epicatechin 2 (L-NAME-Epi 2) and (4) L-NAME-epicatechin 10 (L-NAME-Epi 10). Rats were daily given by oral administration for 4 weeks: vehicle, (-)-epicatechin 2 or 10 mg/kg. Animals in the L-NAME groups daily received L-NAME 75 mg/100 ml in drinking-water. The evolution in systolic blood pressure and heart rate, and morphological and plasma variables, proteinuria, vascular superoxide, reactivity and protein expression at the end of the experiment were analysed. Chronic (-)-epicatechin treatment did not modify the development of hypertension and only weakly affected the endothelial dysfunction induced by L-NAME but prevented the cardiac hypertrophy, the renal parenchyma and vascular lesions and proteinuria, and blunted the prostanoid-mediated enhanced endothelium-dependent vasoconstrictor responses and the cyclo-oxygenase-2 and endothelial NO synthase (eNOS) up-regulation. Furthermore, (-)-epicatechin also increased Akt and eNOS phosphorylation and prevented the L-NAME-induced increase in systemic (plasma malonyldialdehyde and urinary 8-iso-PGF2α) and vascular (dihydroethidium staining, NADPH oxidase activity and p22phox up-regulation) oxidative stress, proinflammatory status (intercellular adhesion molecule-1, IL-1ß and TNFα up-regulation) and extracellular-signal-regulated kinase 1/2 phosphorylation. The present study shows for the first time that chronic oral administration of (-)-epicatechin does not improve hypertension but reduced pro-atherogenic pathways such as oxidative stress and proinflammatory status of the vascular wall induced by blockade of NO production.
Asunto(s)
Catequina/uso terapéutico , Endotelio Vascular/efectos de los fármacos , Inflamación/tratamiento farmacológico , Óxido Nítrico/deficiencia , Estrés Oxidativo/efectos de los fármacos , Fitoterapia , Enfermedades Vasculares/tratamiento farmacológico , Animales , Aterosclerosis/prevención & control , Presión Sanguínea/efectos de los fármacos , Catequina/administración & dosificación , Catequina/farmacología , Ciclooxigenasa 2/sangre , Endotelio Vascular/fisiopatología , Hipertensión , Hipertrofia , Mediadores de Inflamación/sangre , Riñón/efectos de los fármacos , Riñón/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Miocardio/patología , NG-Nitroarginina Metil Éster , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Fosforilación , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Prostaglandinas/metabolismo , Proteinuria/tratamiento farmacológico , Ratas , Ratas Wistar , Regulación hacia Arriba , Enfermedades Vasculares/metabolismo , Enfermedades Vasculares/patología , Enfermedades Vasculares/fisiopatología , Vasoconstricción/efectos de los fármacosRESUMEN
Activation of nuclear hormone receptor peroxisome proliferator-activated receptor ß/δ (PPARß) has been shown to improve insulin resistance and plasma high-density lipoprotein levels, but nothing is known about its effects in genetic hypertension. We studied whether the PPARß agonist GW0742 might exert antihypertensive effects in spontaneously hypertensive rats (SHRs). The rats were divided into 4 groups, Wistar Kyoto rat-control, Wistar Kyoto rat-treated (GW0742, 5 mg · kg(-1) · day(-1) by oral gavage), SHR-control, and SHR-treated, and followed for 5 weeks. GW0742 induced a progressive reduction in systolic arterial blood pressure and heart rate in SHRs and reduced the mesenteric arterial remodeling, the increased aortic vasoconstriction to angiotensin II, and the endothelial dysfunction characteristic of SHRs. These effects were accompanied by a significant increase in endothelial NO synthase activity attributed to upregulated endothelial NO synthase and downregulated caveolin 1 protein expression. Moreover, GW0742 inhibited vascular superoxide production, downregulated p22(phox) and p47(phox) proteins, decreased both basal and angiotensin II-stimulated NADPH oxidase activity, inhibited extracellular-regulated kinase 1/2 activation, and reduced the expression of the proinflammatory and proatherogenic genes, interleukin 1ß, interleukin 6, or intercellular adhesion molecule 1. None of these effects were observed in Wistar Kyoto rats. PPARß activation, both in vitro and in vivo, increased the expression of the regulators of G protein-coupled signaling proteins RGS4 and RGS5, which negatively modulated the vascular actions of angiotensin II. PPARß activation exerted antihypertensive effects, restored the vascular structure and function, and reduced the oxidative, proinflammatory, and proatherogenic status of SHRs. We propose PPARß as a new therapeutic target in hypertension.
Asunto(s)
Modelos Animales de Enfermedad , Hipertensión/prevención & control , Hipertensión/fisiopatología , PPAR-beta/fisiología , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Caveolina 1/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Proteínas de Unión al GTP/metabolismo , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hipertensión/metabolismo , Masculino , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , PPAR-beta/agonistas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Endogámicas SHR , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Tiazoles/farmacologíaRESUMEN
We hypothesized that perinatal inhibition of soluble epoxide hydrolase (SEH), which metabolizes epoxyeicosatrienoic acids in the arachidonic acid (AA) cascade, with an orally active SEH inhibitor, 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), would persistently reduce blood pressure (BP) in adult SHR despite discontinuation of AUDA at 4 wk of age. Renal cytoplasmic epoxide hydrolase-2 (Ephx2) gene expression was enhanced in SHR vs. WKY from 2 days to 24 wk. Effects of perinatal treatment with AUDA, supplied to SHR dams until 4 wk after birth, on BP in female and male offspring and renal oxylipin metabolome in female offspring were observed and contrasted to female SHR for direct effects of AUDA (8-12 wk). Briefly, inhibition of SEH was effective in persistently reducing BP in female SHR when applied during the perinatal phase. This was accompanied by marked increases in major renal AA epoxides and decreases in renal lipoxygenase products of AA. Early inhibition of SEH induced a delayed increase in renal 5-HETE at 24 wk, in contrast to a decrease at 2 wk. Inhibition of SEH in female SHR from 8 to 12 wk did not reduce BP but caused profound decreases in renal 15(S)-HETrE, LTB4, TBX2, 5-HETE, and 20-HETE and increases in TriHOMEs. In male SHR, BP reduction after perinatal AUDA was transient. Thus, Ephx2 transcription and SEH activity in early life may initiate mechanisms that eventually contribute to high BP in adult female SHR. However, programmed BP-lowering effects of perinatal SEH inhibition in female SHR cannot be simply explained by persistent reduction in renal SEH activity but rather by more complex and temporally dynamic interactions between the renal SEH, lipoxygenase, and cyclooxygenase pathways.
Asunto(s)
Adamantano/análogos & derivados , Epóxido Hidrolasas/antagonistas & inhibidores , Epóxido Hidrolasas/fisiología , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Ácidos Láuricos , Factores de Edad , Animales , Inhibidores Enzimáticos , Epóxido Hidrolasas/genética , Epóxido Hidrolasas/metabolismo , Femenino , Edad Gestacional , Hipertensión/patología , Masculino , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/fisiología , SolubilidadRESUMEN
RWPs (red wine polyphenols) exert antihypertensive effects and improve endothelial function by reducing the plasma levels of ET-1 (endothelin-1) and the subsequent vascular production of O(2)(â¢-) (superoxide anion). Our present study was designed to evaluate whether RWPs act directly in the vascular wall improving endothelial dysfunction and O(2)(â¢-) production induced by ET-1 and to analyse the compounds responsible for these protective effects. We incubated rat isolated aortic rings in the presence or absence of ET-1 (10 nM) and RWPs (10(-4) to 10(-2) g/l) or catechin (0.2 µM), epicatechin (10 µM) and resveratrol (0.1 µM). ET-1 reduced the relaxant responses to acetylcholine, increased intracellular O(2)(â¢-) production, NADPH oxidase activity and protein expression of NADPH oxidase subunit p47phox. All these changes were prevented by RWPs. The preventive effects of RWPs were unaffected by co-incubation with either ICI-182780, an ER (oestrogen receptor) antagonist, or GW9662, a PPARγ (peroxisome-proliferator-activated receptor γ) antagonist. RWPs inhibited the phosphorylation of the mitogen-activated protein kinase, ERK1/2 (extracellular signal-regulated kinase 1/2), a key regulator of p47phox expression in response to ET-1. When the isolated polyphenols were tested, at the concentrations found in 10(-2) g/l RWPs, only epicatechin prevented endothelial dysfunction and all biochemical changes induced by ET-1 in the vascular wall. Taken together, these results indicate that RWPs prevent ET-1-induced vascular O(2)(â¢-) production by reducing overexpression of p47phox and the subsequent increased NADPH oxidase activity, leading to improvement in endothelial function. The effects of RWPs appear to be independent of ER and PPARγ activation and are related to ERK1/2 inhibition.
Asunto(s)
Aorta/efectos de los fármacos , Endotelina-1/antagonistas & inhibidores , Endotelio Vascular/efectos de los fármacos , Flavonoides/farmacología , Fenoles/farmacología , Vino/análisis , Animales , Antihipertensivos/farmacología , Aorta/enzimología , Aorta/fisiopatología , Endotelina-1/farmacología , Endotelio Vascular/enzimología , Endotelio Vascular/fisiopatología , Masculino , NADPH Oxidasas/metabolismo , NADPH Oxidasas/fisiología , Óxido Nítrico/metabolismo , Oxígeno/metabolismo , Polifenoles , Ratas , Ratas Wistar , Técnicas de Cultivo de Tejidos , Vasoconstricción/efectos de los fármacosRESUMEN
ET-1 induces vascular O(2)(*-) production via activation of NADPH oxidase. We have investigated whether c-Src and MAPKs activation are involved in ET-1-induced vascular oxidative response. At 2 h, ET-1 induced an increase in NADPH oxidase-driven O(2)(*-) production in rat isolated aortic rings, which was completely suppressed in PP2 (c-Src inhibitor)-pretreated rings, whereas PP3 (inactive analogue of PP2) was without effect. ET-1 increased the levels of phospho-c-Src, the active form of c-Src, and the phosphorylation of cortactin, a Src-specific substrate. Both c-Src and cortactin phosphorylation induced by ET-1 were prevented by PP2. The increased expression of p47(phox), the main cytosolic subunit of NADPH oxidase, induced by ET-1 was also prevented by PP2. The increased vascular O(2)(*-) production and p47(phox) up-regulation induced by ET-1 was only inhibited in aortic rings coincubated with the ERK1/2 inhibitor, PD98059; being without effects both the p38 MAPK inhibitor, SB203580, and JNK inhibitor, SP600125. Aortic rings incubation with ET-1 increased the phosphorylation of ERK1/2. This effect was suppressed by coincubation with PP2 showing that this event is down-stream of c-Src activation. In conclusion, ET-1 induces NADPH oxidase-driven O(2)(*-) generation through increase of p47(phox) protein expression. The signalling pathway for this effect involves c-Src activation and ERK1/2 phosphorylation.
Asunto(s)
Aorta Torácica/enzimología , Endotelina-1/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Superóxidos/metabolismo , Animales , Aorta Torácica/efectos de los fármacos , Proteína Tirosina Quinasa CSK , Cortactina/metabolismo , Activación Enzimática , Regulación Enzimológica de la Expresión Génica , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Fosforilación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Ratas , Ratas Wistar , Transducción de Señal , Factores de Tiempo , Familia-src QuinasasRESUMEN
Peroxisome proliferator-activated receptor beta/delta (PPAR-beta) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily that regulates the transcription of many target genes. More recently, acute, nongenomic effects of PPAR-beta agonists have also been described. In the present study, we hypothesized that PPAR-beta agonists might exert acute nongenomic effects on vascular tone. Here, we report that the structurally unrelated PPAR-beta ligands [4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]phenoxy]acetic acid (L-165041) and 4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl] methyl]thio]-2-methylphenoxy]acetic acid (GW0742) induced vascular relaxation in phenylephrine-precontracted endothelium-intact rat aortic rings, which was significantly inhibited by endothelial denudation or nitric-oxide synthase (NOS) inhibition with N(G)-nitro-l-arginine methylester. These relaxant effects reached steady state within 15 min. The relaxation induced by L-165041 and GW0742 in aortic rings precontracted with the thromboxane A(2) analog 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha (U-46619) was unaffected either by removal of extracellular calcium or by incubation with calcium-free solution containing the intracellular calcium chelator 1,2-bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetra(acetoxymethyl) ester. However, the phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY-294002) inhibited the endothelium-dependent relaxant responses induced by both PPAR-beta agonists. Blockade of PPAR-beta with 3-[[[2-methoxy-4-(phenylamino)phenyl]amino]sulfonyl]-2-thiophenecarboxylic acid methyl ester (GSK0660) also partially inhibited these relaxant responses, although PPAR-gamma blockade with 2-chloro-5-nitro-N-phenylbenzamide (GW9662) had no effect. In human umbilical vein endothelial cells, L-165041 and GW0742 increased nitric oxide (NO) production and Akt and endothelial NOS (eNOS) phosphorylation, which were sensitive to PI3K inhibition and PPAR-beta blockade. In conclusion, the PPAR-beta agonists acutely caused vasodilatation, which was partially dependent on endothelial-derived NO. The eNOS activation is calcium-independent and seems to be related to activation of the PI3K-Akt-eNOS pathway.
Asunto(s)
Cromonas/farmacología , Endotelio Vascular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Morfolinas/farmacología , PPAR-beta/agonistas , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Proto-Oncogénicas c-akt/metabolismo , Vasodilatación/efectos de los fármacos , Anilidas/farmacología , Animales , Aorta/efectos de los fármacos , Endotelio Vascular/fisiología , Humanos , Masculino , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fenoxiacetatos/farmacología , Fosforilación/efectos de los fármacos , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Sulfonas/farmacología , Tiazoles/farmacología , Tiofenos/farmacología , Venas Umbilicales/efectos de los fármacos , Venas Umbilicales/metabolismoRESUMEN
Insulin sensitivity is partly dependent on insulin-mediated nitric oxide (NO) release and antioxidants may decrease insulin resistance by amelioring NO bioavailability. The effects of chronic therapy with the antioxidant quercetin on blood pressure, vascular function and glucose tolerance in male spontaneously hypertensive rats (SHR), a model of genetically hypertension and insulin resistance, were analyzed. Rats were divided into four groups, WKY vehicle, WKY quercetin, SHR vehicle and SHR quercetin. Animals were daily administered by gavage for four weeks: vehicle, quercetin in vehicle (10mg/kg body weight). Blood pressure was followed by tail-cuff plethysmography. Chronic quercetin treatment reduced systolic blood pressure, and significantly reduced left ventricular (-10%) and renal (-6%) hypertrophy. However, oral glucose tolerance test, homeostatic model assessment of insulin resistance, total cholesterol and triglycerides were unaffected by quercetin in both strains of rats. It also improved the blunted aortic endothelium-dependent relaxation to acetylcholine, without affecting both endothelium-dependent relaxation to insulin and endothelium-independent relaxation to sodium nitroprusside in SHR. In WKY rats, quercetin in vitro and in vivo, impaired the relaxation to insulin. Quercetin reduced both plasma malondialdehyde levels and aortic superoxide production in SHR. Furthermore, quercetin inhibited insulin-stimulated protein kinase B (Akt)- and endothelial NO synthase (eNOS) phosphorylation. In conclusion, quercetin reduced blood pressure, left ventricular and renal hypertrophy and improved NO-dependent acetylcholine relaxation. However, and despite its antioxidant effects, quercetin was unable to improve insulin sensitivity possibly through its specific interference with the insulin signalling pathway.
Asunto(s)
Hipertensión/metabolismo , Quercetina/farmacología , Administración Oral , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Línea Celular , Ayuno , Glucosa/administración & dosificación , Glucosa/farmacología , Homeostasis/efectos de los fármacos , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Técnicas In Vitro , Insulina/metabolismo , Insulina/farmacología , Resistencia a la Insulina , Masculino , Óxido Nítrico Sintasa de Tipo III/metabolismo , Oxidación-Reducción , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Quercetina/administración & dosificación , Quercetina/uso terapéutico , Ratas , Ratas Endogámicas SHR , Transducción de Señal/efectos de los fármacosRESUMEN
Epidemiological studies have reported an inverse association between dietary flavonoid intake and mortality for ischemic heart disease. Quercetin reduces blood pressure and restores endothelial dysfunction in hypertensive animals. However, quercetin (aglycone) is usually not present in plasma, but it is rapidly metabolized during absorption by methylation, glucuronidation and sulfation. We have analyzed the vasorelaxant effects and the role on NO bioavailability and endothelial function of quercetin and its conjugated metabolites (quercetin-3-glucuronide, isorhamnetin-3-glucuronide and quercetin-3'-sulfate) in rat aorta. Thoracic aortic rings isolated from Wistar rats were mounted for isometric force recording and endothelial function was tested by measuring the vasorelaxant response to acetylcholine. NADPH-enhanced O(2)(-) release was quantified in homogenates from cultured aortic smooth muscle cells using lucigenin chemiluminescence. Unlike quercetin, the conjugated metabolites had no direct vasorelaxant effect, and did not modify endothelial function or the biological activity of NO. However, all metabolites (at 10 micromol/L) prevented, at least partially, the impairment of endothelial-derived NO response under conditions of high oxidative stress induced by the SOD inhibitor DETCA. Furthermore, they protected the biological activity of exogenous NO when impaired by DETCA. Quercetin and quercetin-3'-sulfate (>or=10 micromol/L) or quercetin-3-glucuronide (100 micromol/L) inhibited NADPH oxidase-derived O(2)(-) release. Quercetin and quercetin-3-glucuronide (1 micromol/L) prevented the endothelial dysfunction induced by incubation with ET-1. These data indicate, for the first time, that the conjugated metabolites could be responsible for the in vivo protective activity of quercetin on endothelial dysfunction.
Asunto(s)
Antioxidantes/farmacología , Endotelio Vascular/efectos de los fármacos , Glucurónidos/farmacología , Quercetina/farmacología , Sulfatos/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacología , Acetilcolina/farmacología , Animales , Antioxidantes/metabolismo , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiopatología , Biotransformación , Relación Dosis-Respuesta a Droga , Endotelina-1/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Flavonoles/farmacología , Glucurónidos/metabolismo , Técnicas In Vitro , NADPH Oxidasas/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Quercetina/análogos & derivados , Quercetina/metabolismo , Ratas , Ratas Wistar , Sulfatos/metabolismo , Superóxidos/metabolismo , Vasodilatadores/metabolismoRESUMEN
Chronic administration of the most abundant dietary flavonoid quercetin exerts antihypertensive effects and improves endothelial function. We have investigated the effects of quercetin and its methylated metabolite isorhamnetin (1-10microM) on endothelial dysfunction and superoxide (O(2*)(-)) production induced by endothelin-1 (ET-1, 10nM). ET-1 increased the contractile response induced by phenylephrine and reduced the relaxant responses to acetylcholine in phenylephrine contracted intact aorta, and these effects were prevented by co-incubation with quercetin, isorhamnetin or chelerythrine (protein kinase C (PKC) inhibitor). This endothelial dysfunction was also improved by superoxide dismutase (SOD), apocynin (NADPH oxidase inhibitor) and sepiapterin (tetrahydrobiopterin synthesis substrate). Furthermore, ET-1 increased intracellular O(2*)(-) production in all layers of the vessel, protein expression of NADPH oxidase subunit p47(phox) without affecting p22(phox) expression and lucigenin-enhanced chemiluminescence signal stimulated by calcium ionophore A23187. All these changes were prevented by both quercetin and isorhamnetin. Moreover, apocynin, endothelium denudation and N(G)-nitro-l-arginine methylester (l-NAME, nitric oxide synthase inhibitor) suppressed the ET-1-induced increase in A23187-stimulated O(2*)(-) generation. Moreover, quercetin but not isorhamnetin, inhibited the increased PKC activity induced by ET-1. Taken together these results indicate that ET-1-induced NADPH oxidase up-regulation and eNOS uncoupling via PKC leading to endothelial dysfunction and these effects were prevented by quercetin and isorhamnetin.
Asunto(s)
Endotelina-1/metabolismo , Endotelio Vascular/metabolismo , NADPH Oxidasas/fisiología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Proteína Quinasa C/metabolismo , Quercetina/farmacología , Superóxidos/metabolismo , Animales , Antihipertensivos/farmacología , Inhibidores Enzimáticos/farmacología , Flavonoles/metabolismo , Flavonoles/farmacología , Masculino , Ratas , Ratas Endogámicas SHR , Ratas WistarRESUMEN
Red wine polyphenols (RWPs) have been reported to prevent hypertension and endothelial dysfunction. Several individual RWPs exert estrogenic effects. We analyzed the possible in vivo protective effects on blood pressure and endothelial function of RWPs in female spontaneously hypertensive rats (SHR) and its relationship with ovarian function. RWPs (40 mg/kg by gavage) were orally administered for 5 weeks. Ovariectomized rats showed both increased isoprostaglandin F(2alpha) excretion and aortic superoxide production and reduced relaxant response to acetylcholine and contraction to the endothelial nitric oxide synthase (eNOS) inhibitor l-NAME measured in the aorta but similar blood pressure, as compared with sham-operated rats. Moreover, in ovariectomized rats aortic eNOS expression was unchanged, whereas caveolin-1, angiotensin II receptor (AT)-1, and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p22(phox) and p47(phox) expression was increased compared with sham-operated rats. In both ovariectomized and sham-operated SHR, RWPs reduced systolic blood pressure, urinary isoprostaglandin F(2alpha) excretion, and aortic O(2)(-) production, improving the endothelium-dependent relaxant response to acetylcholine in SHR. These changes were associated with unchanged aortic eNOS expression, whereas caveolin-1 was increased and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p22(phox) and p47(phox) expression was reduced. RWPs had no effect on the AT-1 overexpression found in ovariectomized animals. All these results suggest that a chronic treatment with RWPs reduces hypertension and vascular dysfunction through reduction in vascular oxidative stress in female SHR in a manner independent of the ovarian function.
Asunto(s)
Aorta/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Flavonoides/farmacología , Hipertensión/tratamiento farmacológico , Fenoles/farmacología , Vino , Animales , Aorta/fisiología , Presión Sanguínea/efectos de los fármacos , Peso Corporal , Caveolina 1/genética , Caveolina 1/metabolismo , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Femenino , Hipertensión/patología , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/patología , Isoprostanos/orina , Riñón/patología , NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ovariectomía , Polifenoles , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas SHR , Especies Reactivas de Oxígeno/metabolismo , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 1/metabolismoRESUMEN
Red wine polyphenols (RWPs) have been reported to exert beneficial effects in preventing cardiovascular diseases, such as hypertension. We studied the effects of chronic treatment with RWPs and apocynin, an inhibitor of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, on blood pressure, endothelial function, and oxidative status in deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Rats were administered RWPs (40 mg/kg) or apocynin (33 microg/kg) daily by gavage for 5 weeks. Plasma catechin levels were detected only after RWP treatment. RWPs and apocynin prevented both the increase in systolic blood pressure and the proteinuria induced by DOCA-salt. Plasma malonyldialdehyde levels, urinary iso-prostaglandin F(2alpha) excretion, aortic superoxide production, and aortic NADPH oxidase activity were found to be increased in animals of the DOCA group. RWP and apocynin treatments reduced these parameters in DOCA-salt rats, having no effect on control rats. However, only RWPs reduced the increase in plasma endothelin-1 (ET-1) levels and aortic p22(phox) gene overexpression found in DOCA-salt animals. RWPs and apocynin also improved the blunted endothelium-dependent relaxation response to acetylcholine in noradrenaline-precontracted aortic rings. All these results suggest that chronic treatment with RWPs prevents hypertension and vascular dysfunction. RWPs prevent vascular oxidative stress by inhibiting NADPH oxidase activity and/or by reducing ET-1 release.