Inhibition of advanced glycation endproduct formation by acetaldehyde: role in the cardioprotective effect of ethanol.
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Epidemiological studies suggest that there is a beneficial effect of moderate ethanol consumption on the incidence of cardiovascular disease. Ethanol is metabolized to acetaldehyde, a two-carbon carbonyl compound that can react with nucleophiles to form covalent addition products. We have identified a biochemical modification produced by the reaction of acetaldehyde with protein-bound Amadori products. Amadori products typically arise from the nonenzymatic addition of reducing sugars (such as glucose) to protein amino groups and are the precursors to irreversibly bound, crosslinking moieties called advanced glycation endproducts, or AGEs. AGEs accumulate over time on plasma lipoproteins and vascular wall components and play an important role in the development of diabetes- and age-related cardiovascular disease. The attachment of acetaldehyde to a model Amadori product produces a chemically stabilized complex that cannot rearrange and progress to AGE formation. We tested the role of this reaction in preventing AGE formation in vivo by administering ethanol to diabetic rats, which normally exhibit increased AGE formation and high circulating levels of the hemoglobin Amadori product, HbA1c, and the hemoglobin AGE product, Hb-AGE. In this model study, diabetic rats fed an ethanol diet for 4 weeks showed a 52% decrease in Hb-AGE when compared with diabetic controls (P < 0.001). Circulating levels of HbA1c were unaffected by ethanol, pointing to the specificity of the acetaldehyde reaction for the post-Amadori, advanced glycation process. These data suggest a possible mechanism for the so-called "French paradox," (the cardioprotection conferred by moderate ethanol ingestion) and may offer new strategies for inhibiting advanced glycation. (+info)
N-Methyl-D-aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain.
(66/41636)
Morbidity and mortality from head trauma is highest among children. No animal model mimicking traumatic brain injury in children has yet been established, and the mechanisms of neuronal degeneration after traumatic injury to the developing brain are not understood. In infant rats subjected to percussion head trauma, two types of brain damage could be characterized. The first type or primary damage evolved within 4 hr and occurred by an excitotoxic mechanism. The second type or secondary damage evolved within 6-24 hr and occurred by an apoptotic mechanism. Primary damage remained localized to the parietal cortex at the site of impact. Secondary damage affected distant sites such as the cingulate/retrosplenial cortex, subiculum, frontal cortex, thalamus and striatum. Secondary apoptotic damage was more severe than primary excitotoxic damage. Morphometric analysis demonstrated that the N-methyl-D-aspartate receptor antagonists 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonate and dizocilpine protected against primary excitotoxic damage but increased severity of secondary apoptotic damage. 2-Sulfo-alpha-phenyl-N-tert-butyl-nitrone, a free radical scavenger, did not affect primary excitotoxic damage but mitigated apoptotic damage. These observations demonstrate that apoptosis and not excitotoxicity determine neuropathologic outcome after traumatic injury to the developing brain. Whereas free radical scavengers may prove useful in therapy of head trauma in children, N-methyl-D-aspartate antagonists should be avoided because of their propensity to increase severity of apoptotic damage. (+info)
A new model rat with acute bronchiolitis and its application to research on the toxicology of inhaled particulate matter.
(67/41636)
The aim of the present study was to establish a useful animal model that simulates humans sensitive to inhaled particulate matter (PM). We have developed a new rat model of acute bronchiolitis (Br) by exposing animals to NiCl2 (Ni) aerosols for five days. Three days following the Ni exposure, the animals developed signs of tachypnea, mucous hypersecretion, and bronchiolar inflammation which seemed to progress quickly during the fourth to fifth day. They recovered from lesions after four weeks in clean air. To assess the sensitivity of the Br rats to inhaled particles, two kinds of PM of respirable size were tested with doses similar to or a little higher to the recommended threshold limit values (TLVs) for the working environment in Japan. Titanium dioxide (TiO2 = Ti) was chosen as an inert and insoluble particles and vanadium pentoxide (V2O5 = V), as a representative soluble and toxic airborne material. The Br rats exposed to either Ti or V were compared the pathological changes in the lungs and the clearance of particles to those in normal control or Br rats kept in clean air. The following significant differences were observed in Br rats: 1. delayed recovery from pre-existing lesions or exacerbated inflammation, 2. reductions in deposition and clearance rate of inhaled particles with the progress of lesions. The present results suggest that Br rats are more susceptible to inhaled particles than control rats. Therefore, concentrations of particulate matter lower than the TLVs for Japan, which have no harmful effects on normal lungs, may not always be safe in the case of pre-existing lung inflammation. (+info)
A clearance model of inhaled man-made fibers in rat lungs.
(68/41636)
A clearance model of inhaled man-made fibers (MMFs) was developed, and the calculated fiber numbers and dimensions were compared with the experimental ones using a glass fiber (GF), ceramic fiber (RF1) and two potassium octatitanate whiskers (PT1, TW). If the translocation rate by macrophages is constant and the effect of dissolution and disintegration can be ignored, the fiber number is expected to decrease exponentially with time. In the experimental study, however, the fiber number did not always decrease exponentially. In the case of RF1, the fiber number decreased almost exponentially and the diameter decreased linearly with the time. The clearance rate constant of GF during 3 to 6 months after the end of one-month exposure was greater than that during 1 to 3 months. On the contrary, the clearance rate constants of PT1 and TW during 1 to 6 months were greater than next six months. The diameter and the length of GF did not change significantly. The fiber length of PT1 tends to become longer with time although the diameter did not change significantly. Our theoretical model gives a satisfactory fit to these experimental results. (+info)
Altered vascular reactivity following partial nephrectomy in the rat: a possible mechanism of the blood-pressure-lowering effect of heparin.
(69/41636)
BACKGROUND: This study was designed to assess whether the antihypertensive effect of heparin in rats after renal mass reduction (RMR) is related to changes in nitric oxide activity, and to study in vitro the altered behaviour of resistance-sized arteries induced by chronic administration of heparin. METHODS: Male Wistar rats were assigned to one of two experimental protocols. In the first protocol, RMR rats received heparin (250 units/day s.c.) and tail systolic blood pressure (SBP) was measured weekly for 4 weeks. In a subgroup, urinary nitrate excretion (UNO3) and in vitro vascular reactivity of isolated perfused mesenteric arterial beds were measured 2 weeks after RMR. The second protocol assessed whether inhibition of NO synthesis with L-NAME (70 mg/l added to the drinking water) prevents the blood-pressure-lowering effect of heparin. RESULTS: In untreated RMR rats SBP increased from 111+/-3 mmHg to 127+/-5 mmHg at 2 weeks and 139+/-5 mmHg at 4 weeks. In contrast, in RMR rats treated with heparin, SBP was 114 +/-3 mmHg at 2 weeks and 115+/-4 mmHg at 4 weeks (P<0.05 for both). Treatment with L-NAME increased SBP both in untreated and heparin-treated RMR groups. Two weeks after nephrectomy daily urinary nitrate increased significantly more in RMR rats treated with heparin than in untreated RMR rats (22+/-2 vs 14.2+/-2.3 micromol/day, P<0.05). In vitro studies performed at 2 weeks showed that vessels of untreated RMR rats had a blunted vasodilator response to acetylcholine that was restored to levels similar to that of controls in the heparin-treated group. CONCLUSIONS: These results suggest that, in rats after renal ablation, heparin may exert its antihypertensive effect, at least in part, by affecting the altered behaviour of resistance vessels during the development phase of hypertension. Increased NO production may contribute to this effect. (+info)
Melatonin inhibits release of luteinizing hormone (LH) via decrease of [Ca2+]i and cyclic AMP.
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The role of [Ca2+]i and cAMP in transduction of the melatonin inhibitory effect on GnRH-induced LH release from neonatal rat gonadotrophs has been studied, because melatonin inhibits the increase of both intracellular messengers. Treatments increasing Ca2+ influx (S(-) Bay K8644 or KCI) or cAMP concentration (8-bromo-cAMP or 3-isobutyl-1-methylxanthine) potentiated the GnRH-induced LH release and partially diminished the inhibitory effect of melatonin. Combination of the treatments increasing cAMP and calcium concentrations blocked completely the melatonin inhibition of LH release. The combined treatment with 8-bromo-cAMP and S(-) Bay K8644 also blocked the melatonin inhibition of GnRH-induced [Ca2+]i increase in 89 % of the gonadotrophs, while any of the treatments alone blocked the melatonin effect in about 25 % of these cells. These observations suggest that a cAMP-dependent pathway is involved in regulation of Ca2+ influx by melatonin and melatonin inhibition of LH release may be mediated by the decrease of both messengers. (+info)
The influence of NO synthase inhibitor and free oxygen radicals scavenger--methylene blue--on streptozotocin-induced diabetes in rats.
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The excessive production of nitric oxide (NO) and the subsequent increase of local oxidative stress is suggested as one of the pathophysiological mechanisms of streptozotocin-induced diabetes. It was reported that the administration of NO synthase inhibitors partially attenuated the development of streptozotocin-induced diabetes and reduced hyperglycaemia. Here we have studied the influence of methylene blue, which combines the properties of NO synthase inhibitor with antioxidant effects. The experiments were performed on male rats divided into four groups: control, diabetic (single dose of 70 mg of streptozotocin/kg i.p.), methylene blue (50 mg/kg in the food) and diabetic simultaneously fed with methylene blue. After 45 days the experiments were discontinued by decapitation. Serum glycaemia, glycated haemoglobin and oxidative stress parameters (plasma malondialdehyde concentration and erythrocyte superoxide dismutase activity) were significantly higher in the diabetic group. Simultaneous methylene blue administration partially reduced glycaemia and glycated haemoglobin, but did not decrease oxidative stress. We conclude that NO synthase inhibitor methylene blue partially attenuates the development of streptozotocin-induced diabetes in male rats, but does not reduce the development of oxidative stress in the diabetic group. (+info)
Alloxan in vivo does not only exert deleterious effects on pancreatic B cells.
(72/41636)
The aim of the experiment was to investigate the mechanism of harmful alloxan action in vivo. 75 mg/kg b.w. of this diabetogenic agent were administered to fasting rats. Two minutes later the animals were decapitated. It was observed that alloxan caused a distinct rise in blood insulin and glucose levels with a concomitant drop of free fatty acids. The amount of sulfhydryl groups in the liver of alloxan-treated rats was decreased and glutathione peroxidase activity was substantially higher. These results indicate that some changes observed in alloxan-induced diabetes can not only be the consequence of B cells damage by alloxan but may also be the result of its direct influence on other tissues. It was also observed that glucose given 20 min before alloxan injection only partially protected against the deleterious effects of alloxan. (+info)