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Investigación
 
LINEA de INVESTIGACION

La diabetes es una enfermedad metabólica que se caracteriza por la presencia de hiperglucemia secundaria a un déficit en la secreción de insulina, a una disminución en su acción o a ambos factores. La presencia de hiperglucemia crónica se asocia con daño en diferentes órganos (ojos, riñones, nervios, corazón, vasos sanguíneos) y distintos mecanismos patogénicos se han vinculado con la producción de las complicaciones de la enfermedad. La principal causa de muerte en los pacientes con diabetes (Tipo I y II) se debe a la patología vascular que comprende a la microangiopatía y macroangiopatía diabéticas. Hipótesis recientes adjudican un papel fundamental en el desarrollo de estas lesiones a la disfunción endotelial. Si bien esta alteración obedece a múltiples factores, en estos últimos años se ha comenzado a prestar atención al papel del estrés oxidativo en su patogenia, y a los efectos del tratamiento antioxidante en la prevención de la evolución de las complicaciones vasculares. En nuestro laboratorio se encuentran en desarrollo diversos estudios experimentales en varios modelos de diabetes, con la finalidad de evaluar el papel de sustancias de probado efecto antioxidante sobre la respuesta vascular “in vitro” alterada que se observa en esos animales.


Publicaciones recientes

Obesity (Silver Spring). 2009 Oct;17(10):1866-71..
Effect of a high-fat diet on 24-hour pattern of circulating adipocytokines in rats.
Cano P, Cardinali DP, Ríos-Lugo MJ, Fernández-Mateos MP, Reyes Toso CF, Esquifino AI.
Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Madrid, Spain. Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Argentine.

We have shown a significant disruption of 24-h pattern of plasma pituitary, adrenal, and gonadal hormones in high-fat-fed rats. Our objective was to assess the effect of a high-fat diet (35% fat) on mean levels and 24-h pattern of several adipocytokines in rats. A normal diet-fed rats (4% fat) were used as controls. When body weight of high-fat-fed rats attained values about 25% higher than controls (after 66 days of treatment), the animals were killed at six different time intervals throughout a 24-h cycle. Plasma concentrations of insulin, adiponectin, interleukin (IL)-1, leptin, ghrelin, plasminogen activator inhibitor-1 (PAI-1), and monocyte chemoattractant protein-1 (MCP-1) were measured in a multianalyte profiling by using the Luminex-100 system. Tumor necrosis factor alpha (TNFalpha) and IL-6 were measured by enzyme-linked immunosorbent assay. A significant hyperglycemia developed in high-fat-fed rats, together with a significant increase in plasma insulin. Mean levels of plasma adiponectin, IL-1, IL-6, TNFalpha, and leptin augmented, and ghrelin decreased, in high-fat-fed rats. The normal daily pattern of plasma insulin, adiponectin, IL-1, IL-6, TNFalpha, leptin, ghrelin, and MCP-1 became disrupted in high-fat-fed rats. The results indicate that a high-fat diet may bring about signs of insulin resistance and mild inflammation in rats, together with the disruption in daily variations of circulating insulin and ghrelin, and of several adipocytokines including leptin, adiponectin, IL-1, IL-6, TNFalpha, and MCP-1.

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Endocrine. 2008 Apr;33(2):118-25.
Effect of a high-fat diet on 24-h pattern of circulating levels of prolactin, luteinizing hormone, testosterone, corticosterone, thyroid-stimulating hormone and glucose, and pineal melatonin content, in rats.
Cano P, Jiménez-Ortega V, Larrad A, Reyes Toso CF, Cardinali DP, Esquifino AI.
Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, Madrid, 28040, Spain; Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Argentine.

Circadian rhythmicity is affected in obese subjects. This article analyzes the effect of a high-fat diet (35% fat) on 24-h changes circulating prolactin, luteinizing hormone (LH), testosterone, corticosterone, thyroid-stimulating hormone (TSH) and glucose, and pineal melatonin content, in rats. When body weight of rats reached the values of morbid obesity, the animals were sacrificed at six different time intervals throughout a 24-h cycle, together with age-matched controls fed a normal diet (4% fat). Plasma hormone levels were measured by specific radioimmunoassays and glucose concentration by an automated glucose oxidase method. In rats under a high-fat diet, a significant disruption of the 24-h pattern of plasma TSH, LH, and testosterone and a slight disruption of prolactin rhythm were found. Additionally, high-fat fed rats showed significantly lower total values of plasma TSH and testosterone and absence of correlation between testosterone and circulating LH levels. Plasma corticosterone levels increased significantly in high-fat fed rats and their 24-h variation became blunted. In obese animals, a significant hyperglycemia developed, individual plasma glucose values correlating with circulating corticosterone in high-fat fed rats only. The amplitude of the nocturnal pineal melatonin peak decreased significantly in high-fat fed rats. The results underlie the significant effects that obesity has on circadian organization of hormone secretion.
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Life Sci. 2007 Oct 27;81(19-20):1467-72.
Antioxidants restore aortic ring relaxation in pancreatectomized rats.
Reyes-Toso CF, Linares LM, Witriw A, Vázquez MB, Ricci CR, Cardinali DP.
Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Piso 7, 1121 Buenos Aires, Argentina. creyesto@fmed.uba.ar

Vascular response was assessed in rats made diabetic by subtotal pancreatectomy (PPx). Adult male Wistar rats submitted to PPx eight weeks earlier, and exhibiting altered levels of fasting glucose and an abnormal tolerance glucose test, were used. Sham-operated laparotomized rats were employed as controls. Dose-response curves for acetylcholine-induced, endothelium-related relaxation of aortic rings (after previous exposure to phenylephrine) were conducted in a high glucose solution (44 mmol/L). PPx decreased significantly acetylcholine-induced relaxation only in the presence of a high glucose solution (p<0.00001). Tiron, superoxide dismutase (SOD) or melatonin restored altered aortic relaxation. Melatonin, SOD or Tiron were equally effective in restoring the impaired sodium nitroprusside-induced vasorelaxation in endothelium-denuded aortic rings of PPx rats. The results support the evidence about the ability of antioxidants to restore altered vascular reactivity of aortic rings in PPx rats, probably through the scavenging

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Exp Gerontol. 2007 Apr;42(4):337-42.
Effect of melatonin on vascular responses in aortic rings of aging rats.
Reyes-Toso CF, Obaya-Naredo D, Ricci CR, Planells FM, Pinto JE, Linares LM, Cardinali DP.
Department of Physiology, Faculty of Medicine, University of Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina. creyesto@fmed.uba.ar

In old animals a marked reduction in endothelium-dependent relaxation occurs. Since there is evidence that the endothelial dysfunction associated with aging may be partly related to the local formation of reactive oxygen species, the purpose of this study was to examine the effect of the natural antioxidant melatonin (10(-5)mol/l) on in vitro contractility of aged aortic rings under conditions of increased oxidative stress (40 m mol/l glucose concentration in medium). Experiments were carried out in 18-20 months old, Wistar male rats, using adult (6-7 months old) animals as controls. A higher plasma lipid peroxidation was found in aged rats as compared to the younger ones. In a first experiment, dose-response curves for acetylcholine-induced relaxation of aortic rings were conducted. Analyzed as a main factor in a factorial ANOVA, age decreased and melatonin augmented the relaxing response to acetylcholine. melatonin's restoring effect on aortic ring relaxation was found in aged aortic rings only and was more pronounced in the presence of a high glucose medium. In a second experiment, the effect of melatonin on the contractility response to phenylephrine of intact or endothelium-denuded aortic rings obtained from aged or control rats was examined in normal or high glucose medium. A main factor analysis in the factorial ANOVA indicated that age and operation augmented, and melatonin decreased, aortic ring contractility response to phenylephrine. Melatonin's restoring effect on aortic contractility was seen in aged aortic rings. The effect of age or a high glucose medium on phenylephrine-induced contractility was more pronounced in the absence of an intact endothelium. Aging did not affect the relaxant response of intact or endothelium-denuded rings to sodium nitroprusside. The results support the improvement by melatonin of vascular response in aging rats, presumably via its antioxidant activity.

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Endocrine. 2006 Dec; 30(3):269-78.
Effect of ethanol on 24-h hormonal changes in prolactin release mechanisms in growing male rats.
Jiménez-Ortega V, Cardinali DP, Cano P, Fernández-Mateos P, Reyes-Toso C, Esquifino AI.

Departamento de Bioquímica y Biología Molecular III, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain; Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Argentine.

This study analyzes the effect of chronic ethanol feeding on 24-h variation of hypothalamic-pituitary mechanisms involved in prolactin regulation in growing male Wistar rats. Animals were maintained under a 12:12 h light/dark photoperiod (lights off at 2000 h), and they received a liquid diet for 4 wk, starting on d 35 of life. The ethanol-fed group received a similar diet to controls except that maltose was isocalorically replaced by ethanol. Ethanol replacement provided 36% of the total caloric content of the diet. Rats were killed at six time intervals every 4 h, beginning at 0900 h. Mean concentration of serum prolactin in ethanol-fed rats was 58.7% higher than in controls. Peak circulating prolactin levels occurred at the early phase of the activity span in both groups of rats, whereas a second peak was found late in the resting phase in ethanol-fed rats only. In control rats, median eminence dopamine (DA), serotonin (5-HT), gamma-aminobutyric acid (GABA), and taurine levels exhibited two maxima, the major one preceding prolactin release and a second one during the first part of the resting phase. Median eminence DA and 5-HT turnover (as measured by 3,4-dihydroxyphenylacetic acid, DOPAC/DA, and 5-hydroxyindoleacetic acid, 5-HIAA/5-HT ratio) showed a single maximum preceding prolactin, at 0100 h. Ethanol treatment did not affect median eminence DA or 5-HT levels but it decreased significantly their turnover rate. The midday peak in DA and 5-HT levels (at 1300 h) was abolished and the night peak (at 0100 h) became spread and blunted in the ethanol-fed rats. This was accompanied with the disappearance of the 0100 h peak in DA and 5-HT turnover and the occurrence of a peak in 5-HT turnover at 1700 h. Ethanol intake suppressed the night peak in median eminence GABA and taurine (at 0100 h) as well as the midday peak of GABA. Ethanol augmented pituitary levels of DOPAC and 5-HIAA. The results indicate that chronic ethanol administration affects the mechanisms that modulate the circadian variation of prolactin release in growing male rats.
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Amino Acids. 2006 Oct;31(3):299-302.
Effect of melatonin treatment on oxygen consumption by rat liver mitochondria.
Reyes-Toso CF, Rebagliati IR, Ricci CR, Linares LM, Albornoz LE, Cardinali DP, Zaninovich A.
Departamento de Fisiología and Hospital de Clínicas, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. creyesto@fmed.uba.ar

The objective of this study was to examine the in vivo effect of melatonin on rat mitochondrial liver respiration. Two experiments were performed: For experiment 1, adult male rats received melatonin in the drinking water (16 or 50 microg/ml) or vehicle during 45 days. For experiment 2, rats received melatonin in the drinking water (50 microg/ml) for 45 days, or the same amount for 30 days followed by a 15 day-withdrawal period. At sacrifice, a liver mitochondrial fraction was prepared and oxygen consumption was measured polarographically in the presence of excess concentration of DL-3-beta-hydroxybutyrate or L-succinate. Melatonin treatment decreased Krebs' cycle substrate-induced respiration significantly at both examined doses. The stimulation of mitochondrial respiration caused by excess concentration of substrate recovered after melatonin withdrawal. Basal state 4 respiration was not modified by melatonin. Melatonin, by curtailing overstimulation of cellular respiration caused by excess Krebs' cycle substrates, can protect the mitochondria from oxidative damage.
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J Physiol Biochem. 2006 Sep;62(3):207-12.
Comparative effects of melatonin and vitamin E in restoring aortic relaxation in pancreatectomized rats.
Reyes-Toso CF, Linares LM, Albornoz LE, Obaya-Naredo D, Wallinger ML, Ricci CR, Cardinali DP
Departamento de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina. creyesto@fmed.uba.ar
In a previous study we reported the efficacy of melatonin to restore the decreased relaxation response to acetylcholine (ACh) or to sodium nitroprusside (SNP) in aortic rings of rats turned hyperglycemic by subtotal pancreatectomy. The effect was amplified by pre-incubation in a high (44 mmol/l) glucose solution, a situation that resulted in oxidative stress. We hereby compare the effect of another antioxidant, vitamin E, with that of melatonin on ACh response in intact aortic rings or on SNP response in endothelium-denuded aortic rings obtained from pancreatectomized or sham-operated rats. Dose-response curves to ACh or SNP were performed in the presence or absence of melatonin or vitamin E (10-5 mol/1) in 10 or 44 mmol/1 glucose medium. Melatonin was more effective than vitamin E in restoring ACh- or SNP-induced relaxation of aortic rings in a high glucose medium. The differences between the two antioxidants may rely on the ability of melatonin to diffuse readily into intracellular compartments.

 
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Sitio de la Facultad de Medicina