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General Physiology and Biophysics

Volume 30, 2011, No. 4


  The role of PPAR in myocardial response to ischemia in normal and diseased heart
Tana Ravingerova 1), Adriana Adameova, Slavka Carnicka, Martina Nemcekova, Tara Kelly, Jana Matejikova, Eleftheria Galatou, Eleftheria Barlaka, Antigone Lazou

1)Institute for Heart Research, Slovak Academy of Sciences, Centre of Excellence NOREG SAS, Bratislava, Slovak Republic.

Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors, belong to the nuclear hormone receptor superfamily regulating expression of genes involved in different aspects of lipid metabolism, inflammation and cardiac energy production. Activation of PPAR-α isoform by its natural ligands, fatty acids (FA) and eicosanoids, promotes mitochondrial FA oxidation as the primary ATP-generating pathway. On the other hand, PPAR-γ regulates lipid anabolism or storage, while, until recently, the function of PPAR-β/δ has been less explored. Under conditions associated with acute or chronic oxygen deprivation, PPAR-α modulates expression of genes that determine substrate switch (FA vs. glucose) aimed at maintenance of basic cardiac function. Although PPAR-α and PPAR-γ synthetic agonists, hypolipidemic and antidiabetic drugs, have been reported to protect the heart against ischemia/reperfusion injury, it is still a matter of debate whether PPAR activation plays a beneficial or detrimental role in myocardial response to ischemia, in particular, in pathological conditions. This article reviews some findings demonstrating the impact of PPAR activation on cardiac resistance to ischemia in normal and pathologically altered heart. Specifically, it addresses the issue of susceptibility to ischemia in the diabetic myocardium, with particular regards to the role of PPAR. Finally, involvement of PPAR in the mechanisms of lipid-independent cardioprotective effects of some hypolipidemic drugs is also discussed.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 329-341.

  Substituted derivatives of indole acetic acid as aldose reductase inhibitors with antioxidant activity: structure-activity relationship
Maria Juskova 1), Magdalena Majekova, Vassilis Demopoulos, Milan Stefek

1)Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Dubravska cesta 9, 841 04 Bratislava, Slovak Republic.

Although multiple biochemical pathways are likely to be responsible for the pathogenesis of diabetic complications, substantial evidence suggests a key role for the polyol pathway and oxidative stress initiated by hyperglycemia. Thus aldose reductase, the first enzyme of the polyol pathway, has been identified as a potential target of pharmacological intervention to prevent diabetic complications. Aldose reductase inhibitors endowed with antioxidant activity would be dually beneficial. The aim of the study was to evaluate the structure-activity relationship of commercially available indole derivatives supported by the molecular modeling of their interaction with the enzyme aldose reductase from the viewpoint of the inhibitory effect on the enzyme and their antioxidant activity. The partially purified aldose reductase was prepared from rabbit eye lenses. In vitro inhibiton of the aldose reductase was determined by a conventional method. Antioxidant action of the compounds was documented in a DPPH test. Marked differences were recorded in the aldose reductase inhibition activities of 1- and 3-indole acetic acid derivatives. The interaction energies of the inhibitor vs. enzyme-NADP+ complexes, calculated by computer aided molecular modeling, were in agreement with the higher inhibitory efficacy of 1-indole acetic acid in contrast with 3-indole acetic acid. The more efficient 1-indole acetic acid was proved to create stronger electrostatic interaction with NADP+. However, the order of the antioxidant activities of the compounds studied was not in agreement with that of the inhibitory efficacies.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 342-349.

  Nicotine reduces mortality of developing rats exposed to high-altitude hypoxia and partially suppresses the duration of cortical epileptic afterdischarges
Vladimír Riljak 1), Dana Maresova, Jaroslav Pokorny

1)Institute of Physiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.

Nicotine has been repeatedly reported as substance possessing neuroprotective properties. This study focused on the possible beneficial effects of nicotine against the high-altitude hypoxia (9000 m for one hour). 15 min prior to hypoxia exposition rats (12- and 35-day-old) were treated with nicotine. Next day electrodes have been implanted and the effects of nicotine and hypoxia (or both factors) on duration of afterdischarges (ADs) were tested. Administration of nicotine declined the hypoxia-induced mortality in 35-day-old animals. Nicotine pretreatment had no effect on ADs duration in 12-day-old pups, therefore brought about suppression of ADs in 35-day-old animals. Taken together, our data show that nicotine exhibits an anticonvulsant effect that is age-dependent. The mechanisms of nicotine neuroprotective properties include probably the influence of calcium homeostasis, increase synthesis of variety of growth factors, inhibition of the caspase cascades and antioxidant capability of nicotine.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 350-355.

  Evaluation of trace elements and oxidative stress levels in the liver and kidney of streptozotocin-induced experimental diabetic rat model
Dervis Ozcelik 1), Matem Tuncdemir, Melek Ozturk, Hafize Uzun

1)Department of Biophysics, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.

Functional and morphological consequences of ischemic lesions are partially related to the production of reactive oxygen species (ROS). The aim of the study was to create a unilateral photothrombic lesion with minimal morphological changes and minor sensorimotor and cognitive deficits and also to test whether the application of ROS scavengers after the end of induction of ischemia had improved the functional outcome. Adult Wistar male rats were randomly divided into five groups: naive control, sham operated animals, animals with induced ischemia, and two groups of animals with induced ischemia and subsequent ROS scavenger application –melatonin or tempol. The group subjected to ischemia showed a significant decline in performance in sensorimotor tests and the Morris water maze (MWM) test, compared to control animals. Tempol (50 mg/kg, i.p.) did not improve sensorimotor function and did not change spatial learning. Melatonin (100 mg/kg, i.p.), on the contrary, resulted in a significant improvement in animals’ performances. All the ischemia subjected animals had increased speed of swimming in the MWM test, compared to the control group. Our findings showed that subsequent application of ROS scavengers improve ischemia outcomes, with melatonin being more potent. Conversely, neither melatonin, nor tempol decreased swimming speed cased by ischemia.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 356-363.

  Age-dependent ultrastructural changes of coronary artery in spontaneously hypertensive rats
Martina Cebova 1), Frantisek Kristek

1)Institute of Normal and Pathological Physiology, Centre of Excelence for Cardiovascular Research, Slovak Academy of Sciences, 813 71 Bratislava, Slovak Republic.

The age-dependent differences in basic cardiovascular parameters, geometry and structure of coronary arteries between Wistar and spontaneously hypertensive rats (SHR) were evaluated. SHR of the age 3-, 9-, 17-, and 52-week and age-matched Wistar rats were used. Blood pressure (BP) was measured by the plethysmographic method. Animals were perfused with a glutaraldehyde fixative under pressure of 90 mmHg (3-week-old) and 120 mmHg (9-, 17-, 52-week-old). Coronary arteries were processed for electron microscopy. The proportions and cross sectional areas (CSA) of extracellular matrix in intima and media, endothelial and muscle cells were determined by point counting method. Cardiac hypertrophy and except of 3-week-old rats also BP increase and coronary wall hypertrophy was found in all ontogenic periods in SHR compared to Wistar rats. Arterial wall hypertrophy was evoked by increase of CSA of medial extracellular matrix and smooth muscle cells. In 52-week-old SHR, CSA of muscle cells did not differ from that in 17-week-old SHR but the CSA of intimal and medial extracellular matrix significantly increased. The CSA of endothelial cells and CSA of intimal extracellular matrix were increased only in 52-week-old SHR. The independency between BP and trophicity of individual components of the coronary wall during ontogeny of SHR was documented.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 364-372.

  Study of the effect of DNA polymorphisms in the mannose-binding lectin gene (MBL2) on disease severity in Slovak cystic fibrosis patients
Eva Tothova Tarova 1), Helena Polakova, Hana Kayserova, Peter Celec, Maria Zuzulova, Ludevit Kadasi

1)Department of Molecular Biology, Faculty of Natural Sciences, Comenius University Bratislava, Slovak Republic.

Lung infections are the leading cause of morbidity and mortality in cystic fibrosis (CF). Mannose-binding lectin (MBL) is a key factor in innate immunity. We therefore investigated whether MBL2 gene variants are associated with pulmonary function or susceptibility to Pseudomonas aeruginosa and Burkholderia cepacia infection in Slovak patients affected with CF. DNA polymorphisms in exon 1 and the promoter region were typed by single base primer extension assay in 91 patients and 100 healthy controls. The concentrations of MBL protein were determined in 34 patients by a sandwich enzyme-linked immunosorbent assay, and spirometric and microbiological data were collected from medical records. In this study we found that MBL2 genotypes were associated neither with earlier acquisition of P. aeruginosa or B. cepacia nor with reduced pulmonary function among patients. Although MBL2 genotypes were associated with the MBL2 protein serum level, results were statistically significant only for polymorphisms in exon 1, with p = 0.0008. The role of the MBL2 gene in lung disease severity in CF patients represents a very complex phenomenon where both genetic and environmental factors play an important role in addition to that of the MBL2 gene. Understanding this complexity requires further studies based on a broader scale of genetic factors involving both a whole-genome approach and a larger patient cohort.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 373-378.

  Mutation analysis of PMP22 in Slovak patients with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies
Peter Resko 1), Jan Radvansky, Zuzana Odnogova, Marian Baldovic, Gabriel Minarik, Helena Polakova, Roland Palffy, Ludevit Kadasi

1)Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovak Republic.

Charcot-Marie-Tooth disease (CMT) and related peripheral neuropathies are the most commonly inherited neurological disorders in humans, characterized by clinical and genetic heterogeneity. The most prevalent clinical entities belonging to this group of disorders are CMT type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP). CMT1A and HNPP are predominantly caused by a 1.5 Mb duplication and deletion in the chromosomal region 17p11.2, respectively, and less frequently by other mutations in the peripheral myelin protein 22 (PMP22) gene. Despite being relatively common diseases, they haven’t been previously studied in the Slovak population. Therefore, the aim of this study was to identify the spectrum and frequency of PMP22 mutations in the Slovak population by screening 119 families with CMT and 2 families with HNPP for causative mutations in this gene. The copy number determination of PMP22 resulted in the detection of CMT1A duplication in 40 families and the detection of HNPP deletion in 7 families, 6 of which were originally diagnosed as CMT. Consequent mutation screening of families without duplication or deletion using dHPLC and sequencing identified 6 single base changes (3 unpublished to date), from which only c.327C>A (Cys109X) present in one family was provably causative. These results confirm the leading role of PMP22 mutation analysis in the differential diagnosis of CMT and show that the spectrum and frequency of PMP22 mutations in the Slovak population is comparable to that seen in the global population.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 379-388.

  The effects of chronic long-term intermittent hypobaric hypoxia on blood rheology parameters
Nermin Yelmen 1), Semra Ozdemir, Ibrahim Guner, Selmin Toplan, Gulderen Sahin, Onur Yaman, Sevtap Sipahi

1)Department of Physiology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.

The effect of chronic long-term intermittent hypobaric hypoxia (CLTIHH) on blood rheology is not completely investigated. We designed this study to determine the effect of CLTIHH on blood rheology parameters. Present study was performed in 16 male Spraque-Dawley rats that divided into CLTIHH and Control groups. To obtain CLTIHH, rats were placed in a hypobaric chamber (430 mmHg; 5 hours/day, 5 days/week, 5 weeks). The control rats stayed in the same environment as the CLTIHH rats but they breathed room air. In the blood samples aspirated from the heart, hematocrit, whole blood viscosity, plasma viscosity, plasma fibrinogen concentration, erythrocyte rigidity index and oxygen delivery index were determined. The whole blood viscosity, plasma viscosity, hematocrit and fibrinogen concentration values in the CLTIHH group were found to be higher than those of the control group. However, no significant difference was found in erythrocyte rigidity index and oxygen delivery index between the groups. Our results suggested that CLTIHH elevated whole blood viscosity by increasing plasma viscosity, fibrinogen concentration and hematocrit value without effecting the erythrocyte deformability. Hence, CLTIHH that may occur in intermittent high altitude exposure and some severe obstructive sleep apnea (OSA) patients may be responsible for hemorheologic changes in those subjects.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 389-395.

  The aqueous garlic, onion and leek extracts release nitric oxide from S-nitrosoglutathione and prolong relaxation of aortic rings
Marian Grman 1), Anton Misak, Sona Cacanyiova, Frantisek Kristek, Zuzana Tomaskova, Anna Bertova, Karol Ondrias

1)Faculty of Mathematics, Physics and Informatics, Comenius University, Bratislava, Slovak Republic.

Garlic, onion and leek have beneficial effects in treatment of numerous health disorders. The aim of the present study was to investigate underlying molecular mechanisms. To test the potency of the aqueous garlic, onion and leek extracts to release NO from GSNO we have measured NO oxidation product, NO2–, by the Griess reagent method. Further, we studied the ability of garlic extract to relax noradrenaline-precontracted rat aortic rings in the presence of GSNO and effects of garlic extract on electrical properties of rat heart intracellular chloride channels. We have observed that: i) garlic, onion and leek extracts released NO from GSNO in the order: garlic > onion > leek; ii) the ability of garlic extract to release NO was pH-dependent (8.0 > 7.4 > 6.0) and potentiated by thiols (Cys >> GSH = N-acetyl-cysteine > oxidized glutathione) at concentration 100 µmol/l; iii) the garlic extract (0.045 mg/ml) prolonged relaxation time of aortic rings induced by GSNO (50 nmol/l) and inhibited intracellular chloride channels. We suggest that NO-releasing properties of the garlic, onion and leek extracts and their interaction with Cys and GSH are involved in NO-signalling pathway which contributes to some of its numerous beneficial biological effects.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 396-402.

  T-type calcium channel blockers – new and notable
Ľubica Lacinová 1)

1)Institute of Molecular Physiology and Genetics, Centre of Excellence for Cardiovascular Research, Slovak Academy of Sciences, Bratislava, Slovak Republic.

Since cloning of the T-type or CaV3.n calcium channel family in 1998–1999 much progress was made in investigation of their regulation. Most effective metal CaV3 channel blockers are trivalent cations from lanthanide group together with transition metals La3+ and Y3+. Divalent cations Zn2+, Cu2+ and Ni2+ inhibit CaV3.2 channels more efficiently than CaV3.1 and CaV3.3 channels via second high-affinity binding site including histidine H191 specific for the CaV3.2 channel. Dihydropyridines and phenylalkylamines in addition to block of L-type calcium channel can inhibit CaV3 channels in clinically relevant concentration.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 403-409.

  Investigation of a weak magnetic field effect on the in vitro catalytic activity of adenosine deaminase and xanthine oxidase
Kadir Batcioglu 1), Metin Dogan, Ayse Uyumlu, Basri Satilmis, Nevzat Bayri, Selcuk Atalay, Hakan Demirtas

1)Department of Biochemistry, Faculty of Pharmacy, University of Inonu, Malatya, Turkey.

The effect of a weak magnetic field (MF) on adenosine deaminase (ADA) and xanthine oxidase (XOD) activities have been investigated. A 50 Hz uniform MF was generated, and the magnitude of the field was kept constant at 5.8 mT. The changes in ADA activity over time were significantly different in and out of the MF; MF caused a steeper decline in ADA activity compared to the situation when no MF is present. In addition, MF caused a significant increase in XOD activity. There were no significant time-related changes for either enzyme in the absence of the MF. We suggest that a weak MF affects enzymatic systems.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 410-414.

  Extremely low frequency magnetic field induces oxidative stress in mouse cerebellum
Li Chu 1), Jong Lee, Yun Nam, Yu Lee, Won-Hee Park, Byung-Cheon Lee, Daejin Kim, Yoon Chung, Ji Jeong

1)Department of Pharmacology and Research Institute for Translational System Biomics, College of Medicine, Chung-Ang University, 221 Heukseok-Dong, Dongjak-Gu, Seoul 156-756, South Korea.

We have investigated whether extremely low frequency magnetic field (ELF-MF) induces lipid peroxidation and reactive oxygen species in mouse cerebellum. After exposure to 60 Hz ELF-MF at 2.3 mT intensity for 3 hours, there was a significant increase in malondialdehyde level and hydroxyl radical. ELF-MF significantly induced concomitant increase in superoxide dismutase without alteration in glutathione peroxidase activity. While glutathione contents were not altered, ascorbic acid levels were significantly decreased by ELF-MF exposure. These results indicate that ELF-MF may induce oxidative stress in mouse cerebellum. However, the mechanism remains further to be characterized.

General Physiology and Biophysics. Volume 30, 2011, No. 4: 415-421.