RESUMEN
The effects of chronic blockade of vasopressin type 1a receptors (V1aR) and the additive effects of a type 2 receptor (V2R) antagonist on the treatment of hypertension-induced heart failure and renal injury remain to be unknown. In this study, Dahl salt-sensitive hypertensive rats were chronically treated with a vehicle (CONT), a V1aR antagonist (OPC21268; OPC), a V2R antagonist (tolvaptan; TOLV), or a combination of OPC21268 and tolvaptan (OPC/TOLV) from the pre-hypertrophic stage (6 weeks). No treatment altered blood pressure during the study. Significant improvements were seen in median survival for the OPC and TOLV, and the OPC/TOLV showed a further improvement in Kaplan-Meier analysis. Echocardiography showed suppressed left ventricular hypertrophy in the OPC and OPC/TOLV at 11 weeks with improved function in all treatment groups by 17 weeks. In all treatment groups, improvements were seen in the following: myocardial histological changes, creatinine clearance, urinary albumin excretion, and renal histopathologic damage. Also, key mRNA levels were suppressed (eg, endothelin-1 and collagen). In conclusion, chronic V1aR blockade ameliorated disease progression in this rat model, with additive benefits from the combination of V1aR and V2R antagonists. It was associated with protection of both myocardial and renal damage, independent of blood pressure.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Benzazepinas/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Hipertensión/complicaciones , Enfermedades Renales/prevención & control , Piperidinas/farmacología , Quinolonas/farmacología , Receptores de Vasopresinas/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada , Fibrosis , Regulación de la Expresión Génica , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Hemodinámica/efectos de los fármacos , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/metabolismo , Hipertrofia Ventricular Izquierda/prevención & control , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/etiología , Enfermedades Renales/genética , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Masculino , Ratas Endogámicas Dahl , Receptores de Vasopresinas/metabolismo , Factores de Tiempo , Tolvaptán , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacosRESUMEN
Although hyperlipidemia, high blood pressure, and diabetes increase the risk of arteriosclerosis, it is not clear whether hyperuricemia increases the risk of arteriosclerosis or not. We examined the effects of uric acid and curative drugs for hyperuricemia on atherosclerosis-susceptible C57BL/6J apolipoprotein E-deficient (apoE(-/-)) mice. Male apoE(-/-) mice (age: 6 weeks) were fed a normal diet (normal diet group) or a uric acid-enriched diet. Mice fed the uric acid-enriched diet were divided into three groups and administered a drinking vehicle (high uric acid diet group), allopurinol (20 mg·kg(-1)·d(-1)), or benzbromarone (20 mg·kg(-1)·d(-1)) for 10 weeks. Serum uric acid concentrations were higher in the high uric acid diet group than in the normal diet group, and concentrations in the allopurinol and benzbromarone groups were lower than in the high uric acid diet group. Serum total cholesterol and triglyceride levels were lower in the allopurinol group than in the high uric acid diet group. Oxidative stress was lower in the benzbromarone group than in the high uric acid diet group. Atherosclerotic lesion areas were smaller in the allopurinol and benzbromarone groups than in the high uric acid diet group. Thus, hyperuricemia may not be an independent risk factor for arteriosclerosis; however, the administration of allopurinol and benzbromarone prevented the development of atherosclerosis in apoE(-/-) mice fed a uric acid-enriched diet. The anti-atherosclerotic effect was in part due to lower total cholesterol and oxidative stress in the serum. Other possible mechanisms underlying this effect should be investigated.
Asunto(s)
Apolipoproteínas E/metabolismo , Arteriosclerosis/etiología , Hiperuricemia/complicaciones , Hiperuricemia/tratamiento farmacológico , Ácido Úrico/efectos adversos , Envejecimiento , Alopurinol/uso terapéutico , Alimentación Animal/análisis , Animales , Apolipoproteínas E/genética , Benzbromarona/uso terapéutico , Dieta , Regulación de la Expresión Génica , Supresores de la Gota/uso terapéutico , Masculino , Ratones , Ratones Noqueados , Factores de Riesgo , Ácido Úrico/administración & dosificación , Uricosúricos/uso terapéuticoRESUMEN
BACKGROUND: The development of alcoholic liver disease is a complex process that involves both the parenchymal and non-parenchymal cells of the liver. We examined the effect of an Ecklonia cava extract on ethanol-induced liver injury. METHODS: Isolated hepatocytes and hepatic stellate cells (HSCs) were incubated with ethanol. Ecklonia cava polyphenol (ECP) was added to the cultures that had been incubated with ethanol. Male Wistar rats were fed a diet that included 0.02% or 0.2% ECP or no ECP. For a period of 3 weeks, the animals were given drinking water containing 5% ethanol and were also treated with carbon tetrachloride (CCl4) (0.1 ml/kg of body weight). RESULTS: In the cultured hepatocytes, the ECP treatment suppressed the ethanol-induced increase in cell death by maintaining intracellular glutathione (GSH) levels. In HSCs, ECP treatment suppressed the ethanol-induced increases in type I collagen and α-smooth muscle actin expression by maintaining intracellular levels of reactive oxygen species and GSH. We examined the effects of ECP on serum AST and ALT activity, as well as the progression of liver fibrosis in rats treated with ethanol and CCl4. ECP treatment suppressed plasma AST and ALT activities in the ethanol- and CCl4-treated rats. ECP treatment fully protected the rats against ethanol- and CCl4-induced liver injury. GENERAL SIGNIFICANCE: ECP may be a candidate for preventing ethanol-induced liver injury.
Asunto(s)
Depresores del Sistema Nervioso Central/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Etanol/toxicidad , Kava/química , Polifenoles/uso terapéutico , Sustancias Protectoras/uso terapéutico , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Western Blotting , Tetracloruro de Carbono/toxicidad , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Colágeno Tipo I/metabolismo , Glutatión/metabolismo , Células Estrelladas Hepáticas/citología , Células Estrelladas Hepáticas/efectos de los fármacos , Células Estrelladas Hepáticas/metabolismo , Hepatocitos/citología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Técnicas para Inmunoenzimas , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Alpinia galanga and Languas galanga, which are plants belonging to the ginger family, are frequently used for cooking, especially in Thai and Indonesian cuisine. The compound 1'-acetoxychavicol acetate (ACA), which is naturally obtained from the rhizomes and seeds of these gingers, has antioxidant and anti-inflammatory properties. We investigated the anti-obesity effects of ACA in 3T3-L1 adipocytes and in high fat diet (HFD)-induced rat models of obesity. ACA caused a significant decrease in the activity of GPDH in 3T3-L1 adipocytes without eliciting cell cytotoxicity, and it inhibited cellular lipid accumulation through the down-regulation of transcription factors such as PPARγ and C/EBPα. ACA also induced a dose-dependent phosphorylation of AMP-activated protein kinase (AMPK). In the animal model, rats fed an HFD containing 0.05% ACA gained less weight than rats fed an HFD alone. The visceral fat mass in rats fed an HFD containing 0.05% ACA tended to be lower than that in rats fed an HFD alone. Furthermore, a histological examination of livers from rats fed an HFD showed steatohepatitis. However, rats fed an HFD containing 0.05% ACA showed no histopathological changes in the liver tissue. Our results show that ACA exerts anti-obesity activities both in vitro and in vivo and suggests that ACA may have a novel preventive activity against obesity and possibly other metabolic diseases.
Asunto(s)
Adipocitos/efectos de los fármacos , Adipogénesis/efectos de los fármacos , Alcoholes Bencílicos/farmacología , Grasas de la Dieta/administración & dosificación , Células 3T3-L1 , Adenilato Quinasa/metabolismo , Adipocitos/metabolismo , Animales , Western Blotting , Masculino , Ratones , Fosforilación , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Although recent clinical trials have demonstrated the efficacy of the oral vasopressin (AVP) type 2 receptor (V2R) antagonist tolvaptan, its long-term effects on the myocardium and kidney in heart failure (HF) are not clear. We examined the chronic effects of tolvaptan administration on both the myocardium and kidney in a rat hypertensive HF model. METHODS AND RESULTS: Not only circulating AVP level but also myocardial AVP and V1a receptor (V1aR) expressions, renal V1aR, and V2R expressions were significantly upregulated during the transition to HF. The animals were chronically treated with low-dose or high-dose (HD) tolvaptan or vehicle from the left ventricular (LV) hypertrophic stage. Chronic tolvaptan treatment persistently increased urine volume but did not affect blood pressure. In the HD group, the animal survival significantly improved (log-rank test, P<0.01). At the HF stage, the progression of LV dysfunction was prevented and lung congestion was suppressed. Activation of atrial natriuretic peptide, endothelin-1, AVP, and V1aR mRNA levels were significantly suppressed in the LV myocardium. Meanwhile, renal histopathologic damage was ameliorated and renal function was improved in the HD group at the HF stage. Concomitantly, not only activation of aquaporin-2 but also those of V2R, V1aR, renin, and endothelin-1 in the kidney were significantly suppressed (all P<0.05). CONCLUSIONS: These results indicate that chronic tolvaptan treatment has beneficial effects by preventing not only the progression of LV dysfunction but also that of renal injury in hypertensive rats with HF. The underlying mechanism may be related to the suppression of myocardial and renal neurohumoral activation.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Benzazepinas/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Antagonistas de Hormonas/administración & dosificación , Hipertensión/tratamiento farmacológico , Enfermedades Renales/prevención & control , Disfunción Ventricular Izquierda/prevención & control , Administración Oral , Animales , Arginina Vasopresina/sangre , Biomarcadores/sangre , Biomarcadores/orina , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Esquema de Medicación , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Hipertensión/diagnóstico por imagen , Hipertensión/etiología , Hipertensión/metabolismo , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/fisiopatología , Masculino , Miocardio/metabolismo , Miocardio/patología , Péptidos Natriuréticos/sangre , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas Dahl , Receptores de Vasopresinas/genética , Receptores de Vasopresinas/metabolismo , Cloruro de Sodio Dietético , Factores de Tiempo , Tolvaptán , Ultrasonografía , Micción/efectos de los fármacos , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/metabolismo , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular Izquierda/efectos de los fármacosRESUMEN
Zinc (Zn) is an essential nutrient that is required in humans and animals for many physiological functions, including immune and antioxidant functions, growth and reproduction. The present study was conducted to examine the influence of Zn deficiency on the protective action against mild oxidative stress induced by a low dose of carbon tetrachloride (CCl(4)) in rats. Male Wistar rats were administered 125 or 250 µL/kg body weight CCl(4), which caused mild or no elevation of serum LDH, AST and ALT enzyme levels in rats fed a diet with adequate Zn. Treatment with CCl(4) (125 µL/kg) caused a significant release of these enzymes into the serum of rats fed a Zn-deficient diet but not in those given a diet with adequate Zn. Furthermore, no histological abnormalities were observed in CCl(4)-untreated rats fed either a diet with adequate Zn or a Zn-deficient diet or in CCl(4) (125 µL/kg)-treated rats fed a diet with adequate Zn. In CCl(4) (125 µL/kg)-treated rats fed a Zn-deficient diet, however, we observed associated collagen accumulation in the liver and hepatic necrosis. The degree of fibrosis was also more severe in CCl(4) (250 µL/kg)-treated rats fed a Zn-deficient diet. These results show that zinc deficiency during an oxidative stress injury negates the protective actions of certain treatments that normally block oxidative damage. The present study suggests that Zn plays an important role in regulating the antioxidative defense system under mild CCl(4) toxic conditions.