Consequences of lipopolysaccharide and n-3 polyunsaturated fatty acid administration on aortic function of spontaneously hypertensive rats.

The aim of the work was to study the delayed effect of lipopolysaccharide (LPS) administration on endothelial function of the aorta of rats with genetic hypertension. Further, the possibility to ameliorate LPS-induced changes by n-3 polyunsaturated fatty acids (n-3 PUFA) was tested. Rats received a bolus of 1 mg/kg LPS i.p.; n-3 PUFA were administered in the dose of 30 mg/kg daily for 10 days p.o.. Ten days after receiving of LPS, the body weight gain of rats was statistically lower compared to control rats (p < 0.05). n-3 PUFA administration to LPS rats had no effect on this parameter. The TBARS and NAGA concentrations in plasma were significantly increased in the LPS group (p < 0.05) and n-3 PUFA administration returned them to control values. In functional studies, phenylephrine (PE, 1 µmol/l) evoked contraction of aortas which was not statistically different among experimental groups. However, endothelium-dependent relaxation was depressed in the LPS group (p < 0.05) and n-3 PUFA slightly recovered it to control values. In conclusion, oxidative stress seems to be responsible for aortic endothelial dysfunction detected 10 days after administration of LPS to rats. n-3 PUFA slightly improved the function of the endothelium injured by LPS, probably thanks to their antioxidant properties. Prolonged administration of higher doses of n-3 PUFA should defend the vascular endothelium against detrimental effect of bacterial inflammation.

Monotherapy of experimental metabolic syndrome: I. Efficacy and safety.

Elevated plasma cholesterol, especially low density lipoprotein (LDL) cholesterol, is one of the major risk factors for atherosclerosis and coronary heart disease. Hereditary hypertriglyceridemic rats (hHTG) were developed as a new inbred model for the study of relationships between blood pressure and metabolic abnormalities. The aim of this work was to determine the cholesterol-lowering and antioxidant effects of the novel pyridoindol derivative SMe1EC2, compared to the cholesterol-lowering drug atorvastatin, in rats fed either standard or high-fat and high-cholesterol diet (HFC; 1% cholesterol and 7.5% lard fat). Male hHTG rats fed HFC (HTG+HFC) were administered with SMe1EC2 or atorvastatin (both 50 mg/kg/day p.o.) for 4 weeks. Physiological status of animals was monitored by the measurement of preprandial glucose levels and blood pressure. Lipid profile was characterized by the serum levels of total cholesterol (TC), HDL-, LDL-cholesterol and triglycerides (TRG). The concentration of thiobarbituric acid reactive substances (TBARS) was evaluated in the kidney, liver and serum. Further, the assessment of pro-inflammatory cytokines TNF-α, IL-1 and IL-6 in the serum was completed. Feeding the animals with HFC diet resulted in increased serum levels of TC, LDL and TRG. SMe1EC2 ameliorated serum levels of LDL in hHTG rats, both on standard and HFC diet. These effects were comparable with those of the standard hypolipidemicum atorvastatin. SMe1EC2 lowered blood pressure, tissue TBARS concentrations and serum IL-1 levels of HTG+HFC rats. Beneficial effects together with very good toxicity profile predestinate SMe1EC2 to be promising agent for further surveys related to metabolic syndrome features.

The effect of omega- 3 polyunsaturated fatty acids on endothelial tight junction occludin expression in rat aorta during lipopolysaccharide-induced inflammation.

OBJECTIVES: Occludin is essential for proper assembly of tight junctions (TJs) which regulate paracellular endothelial permeability. Omega-3 polyunsaturated fatty acids (Ω-3 PUFA) protect endothelial barrier function against injury. MATERIALS AND METHODS: We examined anti-inflammatory effect of Ω-3 PUFA intake (30 mg/kg/day for 10 days) on expression and location of occludin in the aorta of adult Wistar rats after a single dose of bacterial lipopolysaccharide (LPS, Escherichia coli, 1 mg/kg). The ultrastructure of TJs after LPS administration was also investigated. We measured plasma levels of C-reactive protein (CRP), Malondialdehyde (MDA) and CD68 expression and determined the total activity of NO synthase (NOS) in the aortic tissue. RESULTS: LPS induced a significant decrease of occludin expression accompanied by structural alterations of TJs. Levels of CRP, MDA, CD68 and NOS activity were elevated after LPS injection compared to controls indicating presence of moderate inflammation. Ω-3 PUFA supplementation did not affect occludin expression in treated inflammatory group. However they reduced CRP and MDA concentration and CD68 expression, but conversely, they increased NOS activity compared to inflammatory group. CONCLUSION: Our results indicate that a single dose of LPS could have a long-term impact on occludin expression and thus contribute to endothelial barrier dysfunction. 10-day administration of Ω-3 PUFA had partial anti-inflammatory effects on health of rats without any effect on occludin expression.

Twenty-Year History of the Organization of the International Interdisciplinary Toxicological Conferences TOXCON.

This is an overview and assessment of the value of the International Interdisciplinary Toxicological Conferences TOXCON, which have been organized reciprocally in Slovakia and the Czech Republic since 1996. Characterization of the individual annual conferences and the results of mutual cooperation between the Slovak Toxicology Society (SETOX) and the Toxicological Section of the Czech Society for Experimental and Clinical Pharmacology and Toxicology of the Czech Medical Association of J. E. Purkyne (TS CSEKFT CLS JEP) are presented. Moreover, cooperation and common efforts to promote toxicology as a modern interdisciplinary subject with toxicological organizations from the Visegrad Group (V4) and within the Federation of European Societies of Toxicology EUROTOX are also highlighted.

Progressive increase of lysosomal enzyme activities in hippocampus associated with reduction of population spike in a rat model of neurodegeneration.

OBJECTIVES: Extensive effort has been made to identify early markers of neurodegeneration as late stages have no chance of treatment. Recently, many experimental models have been used to study hallmarks of neuronal injury. One of them is the model of trimethyltin (TMT)-induced damage associated with cognitive decline, thus called a model of Alzheimer-like disease. OBJECTIVE AND METHODS: Our aim was to study neuronal transmission in hippocampal slices of male Wistar rats affected with a single dose of TMT (7.5 mg/kg, i.p.) during the first three weeks of its action. The monitored time periods after TMT administration were days 1-3; 8-10 and 15-17. At the same time periods, right hippocampi were collected for determination of changes in specific activities of two lysosomal enzymes. Electrophysiological measurements were based on stimulation of Schäffer collaterals and registration of evoked responses in the stratum pyramidale and the stratum radiatum at the CA3-CA1 synapse. Specific activities of N-acetyl-ß-D-glucosaminidase (NAGA) and cathepsin D (Cat D) were determined spectrophotometrically. RESULTS: During three weeks after i.p. TMT administration to rats, we found a time-dependent reduction of postsynaptic neuronal firing, expressed by diminished population spike (PoS) amplitude recorded in the stratum pyramidale accompanied with marked increase in specific activity of NAGA to respective 111%, 163% and 252% in the 1st, 2nd and 3rd week compared to unaffected rats. In the stratum radiatum, reduction of the slope of excitatory postsynaptic potential was not time-dependent but almost constantly reduced from the 1st to 3rd week after TMT administration (55-60%) compared to control rats. Specific activity of lysosomal enzyme Cat D was significantly increased in the 3rd week after TMT administration. CONCLUSION: This work demonstrates a time-dependent reduction of somatic response in the hippocampus of TMT affected rats during the first three weeks. This reduction of neuronal firing was later accompanied with increase of specific activity of NAGA and Cat D, supporting evidence that lysosomal dysfunction may be one of the primary contributors to TMT-induced neurodegeneration.

Rosmarinic acid mitigates signs of systemic oxidative stress in streptozotocin-induced diabetes in rats.

The aim of the work was to study the effect of rosmarinic acid (RA) on markers of oxidative stress in rats with diabetes. Diabetes was induced by streptozotocin (STZ), RA was administered orally for ten weeks. Water consumption was measured daily. Ten weeks after the first RA administration, urine was collected over 15 hours. N-acetyl-ß-D-glucosaminidase (NAGA) activity, levels of thiobarbituric acid reactive substances (TBARS) and glutathione (GSH) were determined in the pancreas, kidney, and plasma. RA administration to diabetic rats ameliorated markers of oxidative stress, as well as water consumption and urination. We assume that RA may mitigate STZ-induced diabetic manifestations by protecting rat tissues against damaging effect of free radicals.

Pyridoindole antioxidant-induced preservation of rat hippocampal pyramidal cell number linked with reduction of oxidative stress yet without influence on cognitive deterioration in Alzheimer-like neurodegeneration.

BACKGROUND: The idea of antioxidant therapy attenuating Alzheimer disease (AD) neuropathology starts to be attractive. Animal models are often used in these studies. An AD-like model of trimethyltin (TMT)-induced neurodegeneration, targeting the hippocampus, involves neuronal cell death and cognitive impairment. OBJECTIVES: Effect of the pyridoindole SMe1EC2 (3×50 mg/kg) and vitamin C (3×50mg/kg) was analyzed in the model of TMT-induced (8 mg/kg) neurodegeneration. METHODS: The study was focused on the effect of the antioxidants tested on learning performance in the Morris water maze (MWM) on days 21-25 after TMT administration, on biochemical variables - malondyaldehyde (MDA) and lysosomal enzyme NAGA in brain cortex and blood serum, and on pyramidal cell number in the CA1 area of the hippocampus on day 31 after TMT administration in adult male Wistar rats (n=32). RESULTS: Critical deterioration of learning performance was observed due to the TMT administration in the MWM. Further, apparent reduction of pyramidal cell number to 21% in the CA1 area of the hippocampus, increased MDA and NAGA activity in serum and increased NAGA activity in the cortex were determined contrary to controls. In serum, an increase of MDA level was prevented by both antioxidants tested without any effect on NAGA activity. SMe1EC2 apparently preserved pyramidal cell viability in the CA1 area. Both substances tested failed to ameliorate the detrimental effect of TMT on spatial memory. CONCLUSION: The biochemical and morphometrical findings suggest that reduction of oxidative stress may play a role in AD-like neurodegeneration. Different doses and timing of SMe1EC2 administration might bring improvement in next learning performance.

Assessment of antioxidative, chelating, and DNA-protective effects of selected essential oil components (eugenol, carvacrol, thymol, borneol, eucalyptol) of plants and intact Rosmarinus officinalis oil.

Selected components of plant essential oils and intact Rosmarinus officinalis oil (RO) were investigated for their antioxidant, iron-chelating, and DNA-protective effects. Antioxidant activities were assessed using four different techniques. DNA-protective effects on human hepatoma HepG2 cells and plasmid DNA were evaluated with the help of the comet assay and the DNA topology test, respectively. It was observed that whereas eugenol, carvacrol, and thymol showed high antioxidative effectiveness in all assays used, RO manifested only antiradical effect and borneol and eucalyptol did not express antioxidant activity at all. DNA-protective ability against hydrogen peroxide (H2O2)-induced DNA lesions was manifested by two antioxidants (carvacrol and thymol) and two compounds that do not show antioxidant effects (RO and borneol). Borneol was able to preserve not only DNA of HepG2 cells but also plasmid DNA against Fe(2+)-induced damage. This paper evaluates the results in the light of experiences of other scientists.

Can semi-synthetic flavonoids return old microglia to their youthful state?

A number of studies have indicated that brain inflammation may deteriorate during normal aging and that neuroinflammation is amplified in age-related neurodegenerative diseases. A pivotal role in age-related neuroinflammatory pathologies is attributed to amplified and prolonged activation of microglia. In addition, microglia from the aged brain were reported as senescent displaying many functional impairments. Flavonoids were shown to be promising molecules in modulation of neuroinflammation. Quercetin, a naturally occurring flavonoid, was proven to downregulate inflammatory genes in microglia. Synthetically modified quercetin, 3´-O-(3-chloropivaloyl)quercetin (CPQ), is assumed to posses better biological availability and enhanced antioxidant properties. In the present study, the antineuroinflammatory capacity of CPQ was assessed in BV-2 microglial cells and rat primary microglia. CPQ suppressed more efficiently than its precursor quercetin LPS-induced NO production and iNOS protein expression. However, neither of the compounds tested influenced significantly phagocytosis of BV-2 cells. In addition, CPQ showed a somewhat better suppression of PMA-induced generation of superoxide than did quercetin. Unlike quercetin, CPQ caused a decline in BV-2 microglia proliferation (without any impact on cell viability) along with interference with cell cycle progression. Both compounds tested at 10uM concentration notably enhanced viability of microglia-enriched cultures prepared from 22-month-old rat brains. This was followed by suppression of lipofuscin-like autofluorescence, improvement of lysosomal function and protection of mitochondria in the old microglia. These results can highlight the therapeutic potential of CPQ as a novel antiinflammatory drug in neurodegenerative diseases. In addition, our data suggest that both natural and semisynthetic flavonoids might protect functions of old microglia [VEGA2/0031/12,1/0076/13;APVV-0052-10;ITMS26240220040].

Efficacy of quercetin derivatives in prevention of ulcerative colitis in rats.

Reactive oxygen species has been implicated to contribute significantly to tissue injury associated with ulcerative colitis. Thus compounds with antioxidant properties could be potential therapeutic agents in this disease. Flavonoid compounds are known to possess antioxidative and antiinflammatory properties. Two derivatives of the flavonoid quercetin (Q), chloronaphthoquinone quercetin (CNC) and monochloropivaloyl quercetin (MCP), showed improved antioxidant properties and moreover, they efficiently inhibited aldose reductase activity in vitro. The aim of the work was to test the potential efficacy of quercetin and these synthetic derivatives in vivo in prevention of intestinal inflammation during ulcerative colitis in rats. Colitis was induced by intracolonic administration of acetic acid (4% solution). The control group received the same volume of saline. The vehicle dimethyl sulfoxide (DMSO) and the drugs Q, CNC or MCP were administered orally two hours and then one hour before the acetic acid or saline instillation. After 48 hours, the animals were sacrificed and the colon was weighed, measured and scored for visible damage. Acetic acid triggered an intense inflammatory response of the colon, characterised by haemorrhage, ulceration and bowel wall thickening. From the drugs tested, only CNC (2 × 50 mg/kg) effectively depressed inflammatory damage of the colon. The mechanism of this beneficial effect remains to be elucidated.

Supplementation with n-3 polyunsaturated fatty acids to lipopolysaccharide-induced rats improved inflammation and functional properties of renal Na,K-ATPase.

Measurements of enzyme kinetics of renal Na, K-ATPase were used for characterization of ATP- and Na⁺-binding sites in rats that were subjected to 10 days of moderate inflammation that was induced by a single dose of Escherichia coli lipopolysaccharides (LPSs) at a dose of 1 mg kg⁻¹ body weight. We hypothesized that LPSs might initiate a malfunction of renal Na, K-ATPase, which is a key enzyme involved in regulation of sodium homeostasis in the organism. We also investigated the potential effect that fish oil (FO) has in the prevention of Na, K-ATPase alterations by administering FO daily at a dose of 30 mg kg⁻¹. Alone, LPS elevated the level of C-reactive protein by more than 500% and free radicals by 36% in plasma, as indicated by an increased level of malondialdehyde. The Na, K-ATPase was slightly altered in the vicinity of the ATP-binding site as suggested by the 9% increase of the concentration of ATP necessary for half-maximal activation of the enzyme, thus indicating a deteriorated binding of ATP as a consequence of inflammation. Daily supplementation of FO partly attenuated LPS-induced injury, as observed by a significant decrease in the plasma levels of C-reactive protein and free radicals, hence maintaining the activity of renal Na, K-ATPase to the level of healthy control animals. In conclusion, our findings showed that FO prevented an excessive malondialdehyde production in LPS-treated animals and stabilized renal Na, K-ATPase.

Comparison of biological processes induced in HepG2 cells by tert-butyl hydroperoxide (t-BHP) and hydroperoxide (H2O2): The influence of carvacrol.

This paper presents comparisons of biological impacts of the oxidants H2O2 and t-BHP on human liver cells, and shows modulation of these effects by the phenolic compound carvacrol. To understand better how these oxidants exert their effect on DNA and on the activity of the enzymes superoxide dismutase (SOD) and glutathione peroxidase (GPx), we measured intracellular antioxidant glutathione (iGSH) and intracellular reactive oxidative species (iROS). DNA lesions corresponded to single-strand DNA breaks, alkali-labile lesions and formamido-pyrimidine-DNA-glycosylase (FPG)-sensitive sites. Pre-treatment of cells with carvacrol substantially decreased the number of H2O2-induced DNA lesions, but the number of t-BHP-induced DNA lesions was not reduced. Activities of both SOD and GPx were stimulated significantly by carvacrol and were reduced by the combined effect of carvacrol and oxidants. H2O2 and t-BHP alone influenced the level of antioxidant enzymes differently. While H2O2 did not markedly change the activity of SOD or GPx, lower concentrations of t-BHP stimulated activity of SOD and mainly GPx. The level of iROS was increased by both oxidants and decreased by carvacrol applied either alone or with oxidants. The level of iGSH was not influenced in any of the treatments tested. Our results show that although both oxidants induced oxidative stress and damaged cellular DNA, their influences on other molecular processes were different. The protective effect of carvacrol against DNA-damaging effects of H2O2 was unambiguous, but reduction by carvacrol of the DNA-damaging effect of t-BHP was not observed. These results suggest that the phenolic compound carvacrol contributes to the defence mechanisms of the human organism, but these beneficial effects are dependent on the origin and source of the actual oxidative stress.

Subchronic perinatal asphyxia in rats: embryo-foetal assessment of a new model of oxidative stress during critical period of development.

Approximately 3% of annual births suffer from birth asphyxia and one million of these newborns die. The aim of this study was to develop a model for studying subchronic perinatal asphyxia (SPA) in rats. Pregnant animals were exposed to 10.5% O2 during sensitive stages of brain development for 4h a day. Biochemical variables were analysed immediately and 24h after asphyxia. SPA caused significant reduction of foetal weight, produced abnormalities of distal parts of the skeleton, and anomalies in the development of brain ventricles. Time-dependent changes were observed in several parameters indicating adjustment of the developing organism to the delivery. Whereas lactate was elevated immediately after asphyxia, glucose mirrored high energy needs 24h after the insult. Immunohistochemical examination of the placentas revealed overgrowth of acidic glycoconjugates in the extracellular matrix of vascular walls in the animals exposed to asphyxia. We observed the presence of muscle fibres in chorionic plate arteries and also in intraplacental arteries. The present model proved to be useful for the study of asphyxial conditions during pregnancy. As it is non-invasive and allows to control asphyxial conditions, it appears suitable for the screening and investigation of indicators of asphyxia in the mother and foetus.

Melatonin attenuates hypertension-related proarrhythmic myocardial maladaptation of connexin-43 and propensity of the heart to lethal arrhythmias.

We hypothesized that the pineal hormone melatonin, which exhibits cardioprotective effects, might affect myocardial expression of cell-to-cell electrical coupling protein connexin-43 (Cx43) and protein kinase C (PKC) signaling, and hence, the propensity of the heart to lethal ventricular fibrillation (VF). Spontaneously hypertensive (SHR) and normotensive Wistar rats fed a standard rat chow received melatonin (40 µg/mL in drinking water during the night) for 5 weeks, and were compared with untreated rats. Melatonin significantly reduced blood pressure and normalized triglycerides in SHR, whereas it decreased body mass and adiposity in Wistar rats. Compared with healthy rats, the threshold to induce sustained VF was significantly lower in SHR (18.3 ± 2.6 compared with 29.2 ± 5 mA; p < 0.05) and increased in melatonin-treated SHR and Wistar rats to 33.0 ± 4 and 32.5 ± 4 mA. Melatonin attenuated abnormal myocardial Cx43 distribution in SHR, and upregulated Cx43 mRNA, total Cx43 protein, and its functional phosphorylated forms in SHR, and to a lesser extent, in Wistar rat hearts. Moreover, melatonin suppressed myocardial proapoptotic PKCδ expression and increased cardioprotective PKCε expression in both SHR and Wistar rats. Our findings indicate that melatonin protects against lethal arrhythmias at least in part via upregulation of myocardial Cx43 and modulation of PKC-related cardioprotective signaling.

Rosmarinic acid administration attenuates diabetes-induced vascular dysfunction of the rat aorta.

OBJECTIVES: Oxidative stress as well as inflammation processes are engaged in diabetic vascular complications. Rosmarinic acid, a natural phenol antioxidant carboxylic acid, was found to have multiple biological activity, including anti-inflammatory and antitumour effects, which are a consequence of its inhibition of the inflammatory processes and of reactive oxygen species scavenging. The aim of this work was to study effects of rosmarinic acid administration on vascular impairment induced by experimental diabetes in rats. METHODS: Diabetes was induced by streptozocin (3 × 30 mg/kg daily, i.p.) in Wistar rats. Rosmarinic acid was administered orally (50 mg/kg daily). Ten weeks after streptozocin administration, the aorta was excised for functional studies, evaluation by electron microscopy and real time PCR analysis. KEY FINDINGS: In the aorta of diabetic rats, decreased endothelium-dependent relaxation was accompanied by overexpression of interleukin-1ß, tumour necrosis factor-α, preproendothelin-1 and endothelin converting enzyme-1. Structural alterations in the endothelium, detected by electron microscopy, indicated aortic dysfunction caused by diabetes. The diabetes-induced aortic disorders were prevented by rosmarinic acid administration. CONCLUSIONS: Rosmarinic acid protected aortic endothelial function and ultrastructure against diabetes-induced damage. Both antioxidant and anti-inflammatory effects of rosmarinic acid seemed to participate in the mechanism of this protection.

Effect of prenatal administration of venlafaxine on postnatal development of rat offspring.

About 3% of pregnant women are treated with antidepressant drugs during gestation. After delivery the number of treated women increases to 5 to 7%. Most prescribed antidepressants in pregnancy are selective serotonin re-uptake inhibitors and/or serotonin and noradrenaline re-uptake inhibitors, such as fluoxetine, paroxetine, sertraline, citalopram and venlafaxine (VENF). Despite the fact that VENF has been assigned to pregnancy category C by the FDA, experimental studies with this drug are rare. The aim of this pilot study was to investigate the effect of prenatal administration of VENF on early postnatal development of rat offspring and selected biochemical variables at weaning of pups. Pregnant female Wistar rats were treated with VENF from day 15 to 20 of gestation at the doses of 7.5, 37.5 and 70 mg/kg. Females were allowed to spontaneously deliver their pups. After delivery the pups were inspected for viability, gross malformation and they were weighed on day 0, 4 and 21 post partum. On day 21 post partum, the pups were killed, brains were removed from the skulls and blood samples were collected for biochemical assay (proteins, glucose-GOD, glucose-HEX, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and total antioxidant status). The study showed that prenatal VENF administration resulted in a mild maternal intoxication manifested by decreased body weight gain of pregnant females. There was no effect of the drug tested on the body and brain weights of offspring. No obvious morphological alterations were observed in the delivered pups. Similarly, there were no changes in the selected biochemical variables determined.

Up-regulation of myocardial connexin-43 in spontaneously hypertensive rats fed red palm oil is most likely implicated in its anti-arrhythmic effects.

The purpose of this study was to test our hypothesis that red palm oil (RPO) intake may affect abnormalities of myocardial connexin-43 (Cx43) and protein kinase Cε (PKCε) signaling, and consequently the propensity of the spontaneously hypertensive rat heart (SHR) heart to arrhythmias. SHR and Wistar-Kyoto (WKY) rats fed a standard rat chow plus red palm oil (200 µL/day) for 5 weeks were compared with untreated rats. Cytosolic but not particulate PKCε expression as well as Cx43-mRNA, total Cx43 proteins, and its phoshorylated forms were increased, and disordered localization of Cx43 was attenuated in the left ventricle of RPO-fed SHR compared with untreated rats. These alterations were associated with suppression of early post-ischemic-reperfusion-related ventricular tachycardia and electrically inducible ventricular fibrillation. However, the treatment dose of RPO caused down-regulation of myocardial Cx43, but did not alter its cell membrane distribution or overall PKCε expression in WKY rats. It was, however, associated with poor arrhythmia protection, suggesting overdosing. Results indicate that SHR benefit from RPO intake, particularly because of its apparent anti-arrhythmic effects. This protection can be, in part, attributed to the preservation of cell-to-cell communication via up-regulation of myocardial Cx43, but not with PKCε activation.

Teratology on the crossroads: historical aspects and modern approaches.

Teratology is the science of congenital developmental disorders (CDDs), overt or latent defects of the organism resulting from the effect of internal and external factors on developmental processes. In this article the significance and position of present-day teratology is discussed in the context of development of this branch of science and related disciplines. The authors present an updated overview of the most important milestones and stages of the development of teratology. Based on the analysis of the historical development of theses and theories that represent a decisive contribution to this field, we present a survey of the fundamental principles of experimental and clinical teratology. The aim of observing these principles is to get insight into developmental relations and to understand mechanisms of action on the level of cell populations (elementary morphogenetic processes), tissues and organs. It is important to realize that any negative intervention into the normal course of these processes, either on genetic or non-genetic basis, inevitably leads to a sequence of subsequent changes resulting in the development of congenital developmental disorders. Despite modern approaches of molecular biology and genetics, along with top diagnostic techniques, we are still not able to identify the actual cause in more than 50% of all congenital defects. One-half of the unidentified cases are referred to as "multifactorial", a term that is rather ambiguous. It either means that some of the basic principles of teratogenesis still escape our attention, or the interpretation of some of the well known principles might be misleading. A third possibility is rather pessimistic. The development of the individual is so sophisticated and dependent on a delicate network of a multitude of factors mutually affecting each other that it is extremely prone to give rise to a plethora of spontaneous errors which are unpredictable and impossible to prevent. Nevertheless, the long and complicated history of scientific endeavour has yielded considerable present-day knowledge on causes and mechanisms of CDDs, a history whose beginnings date back to antiquity.

Antioxidant SMe1EC2 may attenuate the disbalance of sodium homeostasis in the organism induced by higher intake of cholesterol.

The study was focused to the influence of higher intake of cholesterol on properties of the renal Na,K-ATPase, a key system in maintaining the homeostasis of sodium in the organism. Feeding for 4 weeks with cholesterol-enriched food for rats afflicted with hereditary hypertriglyceridemia by itself enhanced the activity of Na,K-ATPase, probably as a consequence of higher number of active enzyme molecules as suggested by 32 % increase of V (max) value. This may be hypothesized as a reason for the increased retention of sodium. Three-week-lasting treatment of animals kept on high cholesterol diet with antioxidant SMe1EC2 in a dose of 10 mg kg(-1) day(-1) normalized the function of renal Na,K-ATPase to the level comparable in hypertriglyceridemic rats fed with the standard diet. Therefore, our results suggest that the antioxidant SMe1EC2 in the applied dose seems to be effective in the attenuation of cholesterol-induced retention of sodium. Treatment for 3 weeks with Fenofibrate in a dose of 100 mg kg(-1) day(-1) reversed the function of renal Na,K-ATPase only slightly.

Sex differences in endothelial function of aged hypertriglyceridemic rats - effect of atorvastatin treatment.

The aim of the study was to test the hypothesis that the effect of atorvastatin on endothelium-dependent relaxation of the superior mesenteric artery (SMA) may differ in male vs. female aged hypertriglyceridemic rats (HTGs). Experiments were performed on 11-month-old male and female Prague hereditary HTGs. Atorvastatin (ATO) was administered p.o. in the dose of 0.30 mg/100g/day. Controls received vehiculum. After two months of ATO administration blood pressure, serum triglycerides (TG) and total cholesterol (CHOL) were determined. Endothelial function of SMA was studied in vitro using evaluation of relaxant responses of precontracted SMA to acetylcholine. The serum TG of control male HTGs were found to be statistically higher than those of female controls, while CHOL and blood pressure did not share gender differences. Responses of SMA of female control HTGs were statistically decreased compared to their male counterparts. ATO treatment induced decrease in blood pressure and TG of both males and females, yet CHOL values were reduced only in females. The protective effect of ATO on SMA endothelial function was much more pronounced in females compared to males. We conclude that vascular endothelial dysfunction of aged HTG rats is more severe and more attenuated by ATO in females compared to males. The protective effect of ATO on vascular endothelial function does not seem to depend solely on its lipid lowering action.