RESUMEN
Acyl-coenzyme A: cholesterol O-acyltransferase (ACAT) catalyzes the formation of cholesterol/fatty acyl-coenzyme A esters. Accumulation of cholesterol esters leads to pathological changes connected with atherosclerosis. We have evaluated effects of a newly synthesized ACAT inhibitor, 1-(2,6-diisopropyl-phenyl)-3-[4-(4'-nitrophenylthio)phenyl] urea (VULM 1457), on serum lipid (cholesterol and triglycerides) levels and velocity of red blood cells (RBC) in non-diabetic and diabetic hamsters fed on high cholesterol-lipid (HCHL) diet during 3 months. The VULM 1457 effects on the paw microcirculation were assessed using capillary microscopy by measuring (RBC) velocity in vivo. Hamsters fed on HCHL diet became hypercholesterolemic with a dramatic increase in serum lipids accompanied with significantly decreased RBC velocity. Diabetic hamsters fed on HCHL diet had further increased serum lipids with reduction of RBC velocity. The VULM 1457 inhibitor lowered cholesterol levels in both non-diabetic and diabetic hamsters fed on HCHL diet. The greater VULM 1457 effect was shown in diabetic hamsters fed on HCHL diet where VULM 1457 expressed hypotriglycerides effects, too. An improved RBC velocity-pronounced effect was observed in diabetic hamsters fed on HCHL diet treated with VULM 1457. These results suggest that the ACAT inhibitor, VULM 1457, is a prospective hypolipidemic and anti-atherogenic drug which treats diabetes.
Asunto(s)
Colesterol/sangre , Clofibrato/análogos & derivados , Diabetes Mellitus/metabolismo , Grasas de la Dieta/farmacología , Eritrocitos/efectos de los fármacos , Lípidos/sangre , Esterol O-Aciltransferasa/antagonistas & inhibidores , Animales , Velocidad del Flujo Sanguíneo/efectos de los fármacos , Glucemia/análisis , Colesterol/análisis , Colesterol/metabolismo , Colesterol en la Dieta/farmacología , Clofibrato/farmacología , Cricetinae , Diabetes Mellitus/fisiopatología , Dieta , Eritrocitos/fisiología , Masculino , Esterol O-Aciltransferasa/metabolismo , Triglicéridos/análisis , Triglicéridos/sangreRESUMEN
In this study we investigated functional changes in the femoral artery and ultrastructural alterations in mesenteric vessels and capillaries in the rat model of multiple low dose streptozotocin (STZ)-induced diabetes. Participation of oxidative stress in this model of diabetes was established by studying the effect of the pyridoindole antioxidant stobadine (STB) on diabetes-induced impairment. Experimental diabetes was induced by i.v. bolus of STZ (20 mg/kg) given for three consecutive days to male rats. At the 12(th) week following STZ administration, the animals revealed typical signs of diabetes, such as polyphagia, polydypsia and polyuria. There was no weight gain in the diabetic groups throughout the experiment. No exitus occurred in any group. Diabetes was characterised with high levels of plasma glucose, no significant changes in lipid metabolism, decreased serum levels of glutathione, increased serum levels of the lysosomal enzyme N-acetyl-beta-D-glucosaminidase (NAGA), injured endothelial relaxant capacity of the femoral artery and alterations in ultrastructure of mesenteric arteries and capillaries. Antioxidant STB in the dose of 25 mg/kg body weight i.p. (5 times per week) did not influence glucose levels, however, it mitigated biochemical, functional and ultrastructural changes induced by diabetes, suggesting a role of reactive oxygen species in diabetes-induced tissue damage.
Asunto(s)
Vasos Sanguíneos/efectos de los fármacos , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Animales , Antioxidantes/farmacología , Vasos Sanguíneos/patología , Vasos Sanguíneos/fisiopatología , Carbolinas/farmacología , Arteria Femoral/efectos de los fármacos , Arteria Femoral/fisiopatología , Técnicas In Vitro , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/patología , Microscopía Electrónica , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Estreptozocina/administración & dosificación , Estreptozocina/toxicidad , Vasodilatación/efectos de los fármacosRESUMEN
Consistent with the postulated role of oxidative stress in the etiology of late diabetic complications, pharmacological interventions based on biological antioxidants have been suggested. The aim of the present study was to investigate the effect of dietary supplementation with the pyridoindole antioxidant stobadine on the myocardial antioxidant status and ultrastructure of streptozotocin-diabetic rats. Diabetic male Wistar rats were fed for 32 weeks a standard diet or a diet supplemented with stobadine (0.05% w/w). Control rats received a standard diet or stobadine-supplemented diet (0.16% w/w). Plasma levels of glucose, cholesterol and triglycerides were increased significantly by diabetes. Activities of superoxide dismutase and catalase were markedly elevated in the diabetic myocardium. Myocardial levels of conjugated dienes increased after eight months of diabetes, in spite of significantly increased myocardial alpha-tocopherol and coenzyme Q9 content. The long-term treatment of diabetic animals with stobadine (i) reduced plasma cholesterol and triglyceride levels yet left the severe hyperglycemia unaffected, (ii) reduced oxidative damage of myocardial tissue as measured by conjugated dienes, (iii) reversed myocardial levels of alpha-tocopherol and coenzyme Q9 to near control values, (iv) reduced elevated activity of superoxide dismutase in the diabetic myocardium, and (v) attenuated angiopathic and atherogenic processes in the myocardium as assessed by electron microscopy examination. These results are in accordance with the postulated prooxidant role of chronic hyperglycemia and provide further evidence that development of pathological changes in diabetic myocardium is amenable to pharmacological intervention by biological antioxidants.
Asunto(s)
Antioxidantes/farmacología , Carbolinas/farmacología , Diabetes Mellitus Experimental/metabolismo , Miocardio/ultraestructura , Animales , Antiarrítmicos/farmacología , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Cardiomiopatías/prevención & control , Catalasa/metabolismo , Colesterol/sangre , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Corazón/efectos de los fármacos , Masculino , Miocardio/enzimología , Miocardio/metabolismo , Oxidación-Reducción , Distribución Aleatoria , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismo , Triglicéridos/sangre , Ubiquinona/metabolismo , Vitamina E/metabolismoRESUMEN
The aim of the present work was to test the sensitivity of young male Wistar rats, Dobrá Voda (Dv:WI) to the diabetogenic effect of streptozotocin (STZ) with regard to their health condition and mortality rates. Eight-week-old rats, weighing from 200 to 230 g, were randomised into five groups of eight animals. Streptozotocin was administered by i.v. injection in doses of 40, 50, 60 and 70 mg/kg body weight. The animals were kept on a standard diet with free access to water for 4 months. The highest STZ dose (70 mg/kg) was lethal to the animals, the doses of 50 and 60 mg/kg induced persistent hyperglycaemia with glucose levels above 20 mM. Body weights of STZ treated rats from all experimental groups were significantly lower than those of control animals. Considerable polyuria was observed in all STZ treated rats. About 40% of the STZ treated animals were found to develop overt cataract between days 90 and 100. At the end of the experiment, significant albuminuria was observed in the experimental groups administered 50 and 60 mg/kg STZ doses. We conclude that young male Wistar rats, Breeding Facility Dobrá Voda (Dv:WI), Slovakia, treated by a single i.v. STZ dose of 50 or 60 mg/kg developed a persistent disease state characterised by severe hyperglycaemia with major clinical signs of diabetes mellitus.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Estreptozocina/toxicidad , Animales , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Muerte , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Relación Dosis-Respuesta a Droga , Conducta de Ingestión de Líquido/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
The tolerance of the new calcium antagonist VULM 993 was investigated in a series of toxicological studies. The following results were obtained: the maximum tolerated oral dose in acute toxicity was 10,000 mg/kg for mice and 6600 mg/kg for rats, for venous administration it was 26.1 mg/kg in mice and 32.2 mg/kg in rats. In subacute oral toxicity test in rats, VULM 993 showed no toxic effect up to 300 mg/kg/d. The drug was not teratogenic in rats (5, 50 or 250 mg/kg/d, p.o.). VULM 993 did not show any positive response in tests for genotoxicity in vitro. Transplacental study of VULM 993 in rabbits indicated active placental barrier function in the late stage of pregnancy. The toxicological profile of VULM 993 is characterised by a high tolerance in all relevant species of experimental animals, and no biologically significant mutagenic potential was recorded.