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General Physiology and Biophysics


Volume 25, 2006, No. 4

Content:


  Role of dihydroxyvitamin D3 and its nuclear receptor in novel directed therapies for cancer
S Ondková 1), D Macejová 2), J Brtko 3)

1)Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlárska 3, 833 06 Bratislava 37, Slovakia. ueensavi@savba.sk.
2)Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlárska 3, 833 06 Bratislava 37, Slovakia..
3)Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlárska 3, 833 06 Bratislava 37, Slovakia. julius.brtko@savba.sk.


Dihydroxyvitamin D3 is known to affect broad spectrum of various biochemical and molecular biological reactions in organisms. Research on the role and function of nuclear vitamin D3 receptors (VDR) playing a role as dihydroxyvitamin D3 inducible transcription factor belongs to dynamically developing branches of molecular endocrinology. In higher organisms, full functionality of VDR in the form of heterodimer with nuclear 9-cis retinoic acid receptor is essential for biological effects of dihydroxyvitamin D3. This article summarizes selected effects of biologically active vitamin D3 acting through their cognate nuclear receptors, and also its potential use in therapy and prevention of various types of cancer.

General Physiology and Biophysics. Volume 25, 2006, No. 4: 339-353.

 
  Gene expression of the phenylethanolamine n-methyltransferase is differently modulated in cardiac atria and ventricles
A Tillinger 1), V Bruderova 2), L Kubovcakova 3), M Zeman 4), J Kopacek 5), M Novakova 6), R Kvetnansky 7), O Krizanova 8)

1)Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia. umfgkriz@savba.sk.
2)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia..
3)Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia..
4)Department of Animal Physiology and Ethology, Comenius University, Bratislava, Slovakia..
5)Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia..
6)Faculty of Medicine, Masaryk University, Komenského nám. 2, 662 43 Brno, Czech Republic..
7)Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia..
8)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia. olga.krizanova@savba.sk.


Phenylethanolamine N-methyltransferase (PNMT) is a final enzyme in catecholamine synthesizing cascade that converts noradrenaline to adrenaline. Although most profuse in adrenal medulla, PNMT is expressed also in the heart, particularly in cardiac atria and ventricles. In atria, the PNMT mRNA is much more abundant compared to ventricles. In present study we aimed to find out whether there is a difference in modulation of the PNMT gene expression in cardiac atria and ventricles. We used three methodological approaches: cold as a model of mild stress, hypoxia as a model of cardiac ischemic injury, and transgenic rats (TGR) with incorporated mouse renin gene (mREN-2)27, to determine involvement of renin-angiotensin pathway in the PNMT gene expression. We have found that PNMT gene expression was modulated differently in cardiac atria and ventricles. In atria, PNMT mRNA levels were increased by hypoxia, while cold stress decreased PNMT mRNA levels. In ventricles, no significant changes were observed by cold or hypoxia. On the other hand, angiotensin II elevated PNMT gene expression in ventricles, but not in atria. These results suggest that PNMT gene expression is modulated differently in cardiac atria and ventricles and might result in different physiological consequences.

General Physiology and Biophysics. Volume 25, 2006, No. 4: 355-364.

 
  Inhibitory effect of C-type natriuretic peptide on L-type calcium channel currents in gastric antral myocytes of guinea pigs
J Sun 1), X Huang 2), H Xu 3), X Li 4), L Gao 5), Y Kim 6), W Xu 7)

1)Department of Physiology, Medical College, Shanghai Jiaotong University, Shanghai, China. Bin012@163.com.
2)Department of Physiology, Medical College, Shanghai Jiaotong University, Shanghai, China..
3)Department of Physiology, Yanbian University College of Medicine, 133-000 Yanji, China..
4)Department of Physiology, Yanbian University College of Medicine, 133-000 Yanji, China..
5)Department of Physiology, Medical College, Shanghai Jiaotong University, Shanghai, China..
6)Department of Physiology, Chungbuk National University, College of Medicine, Cheongju, 361-763 Chungbuk, Korea..
7)Department of Physiology, Medical College, Shanghai Jiaotong University, 800 Dongchuan Rd., 328 Wenxuan Medical Building, 200-240 Shanghai, China. wenxiexu@sjtu.edu.cn.


The role of C-type natriuretic peptide (CNP) in the gastrointestinal tract is still unclear. This study was designed to investigate the effect of CNP on barium current (IBa) through the L-type calcium channel in gastric antral myocytes of guinea pigs. The whole-cell patch clamp technique was performed in gastric antral myocytes isolated by collagenase in guinea pigs. CNP significantly inhibited IBa in a dose-dependent manner at the concentrations of 0.001, 0.01, and 0.1 µmol/l, CNP inhibited IBa to 81.56 ± 2.48 %, 73.64 ± 3.65 %, and 57.77 ± 4.93 % of control at 0 mV, respectively. The values of steady-state half-inactivation voltage (33.6 ± 2.6 mV and 33.8 ± 3.4 mV, in control and CNP groups, respectively) or the half-activation voltage (−12.6 ± 2.2 mV and 12.4 ± 1.8 mV) of IBa were not significantly changed (p > 0.05, n = 6). 8-br-cGMP (1 mmol/l) mimicked the effect of CNP on IBa, and the peak current of IBa was inhibited from −403.84 ± 61.87 pA to 318.94 ± 67.17 pA (p < 0.05, n = 5). In the presence of LY83583 (0.1 µmol/l), a nonspecific inhibitor of guanylate cyclase, CNP (0.1 µmol/l)-induced inhibition of IBa was partially blocked (n = 13, p < 0.05 ). However, when the cell was pretreated with zaprinast (0.1 µmol/l), an inhibitor of cyclic guanosine monophosphate (cGMP) sensitive phosphoesterase, the inhibitory effect of CNP on IBa was significantly potentiated (n = 11, p < 0.05). KT5823 (1 µmol/l), a cGMP-dependent protein kinase (PKG) inhibitor, almost completely blocked CNP-induced inhibition of IBa. The results suggested that CNP can inhibit L-type calcium channel currents, and the inhibitory effect is mediated by pGC-cGMP-PKG-dependent signal pathway in gastric antral myocytes of guinea pigs.

General Physiology and Biophysics. Volume 25, 2006, No. 4: 365-377.

 
  The combined effect of pycnogenol® with ascorbic acid and trolox on the oxidation of lipids and proteins
M Sivoňová 1), I Žitňanová 2), Ľ Horáková 3), M Štrosová 4), J Muchová 5), P Balgavý 6), D Dobrota 7), Z Ďuračková 8)

1)Department of Medical Biochemistry, Comenius University, Jessenius Faculty of Medicine, Martin, Slovakia. sivonova@jfmed.uniba.sk.
2)Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Comenius University, Faculty of Medicine, Bratislava, Slovakia..
3)Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava..
4)Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava..
5)Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Comenius University, Faculty of Medicine, Bratislava, Slovakia..
6)Department of Physical Chemistry of Drugs, Comenius University, Faculty of Pharmacy, Bratislava, Slovakia..
7)Department of Medical Biochemistry, Comenius University, Jessenius Faculty of Medicine, Martin, Slovakia..
8)Institute of Medical Chemistry, Biochemistry and Clinical Biochemistry, Comenius University, Faculty of Medicine, Sasinkova 2, 813 72 Bratislava 1, Slovakia. zdenka.durackova@fmed.uniba.sk.


Pycnogenol® (PYC), a procyanidin-rich extract of French maritime pine bark (Pinus pinaster) has strong antioxidant potential and promotes cellular health. The aim of this study was to investigate a possible cooperation of natural antioxidant PYC with synthetic antioxidants ascorbic acid and trolox in the model system of lipid peroxidation determined as conjugated dienes formation in liposomes and on the oxidation of proteins (in BSA and plasma proteins) determined as protein carbonyls. The present study shows that PYC and trolox significantly increased inhibition of lipid peroxidation initiated by copper acetate and tert-butylhydroperoxide in concentration and time dependence compared with untreated unilamellar liposomes. PYC and trolox added simultaneously to the oxidized liposomes exerted an additive preventive effect. PYC´s inhibitory effect on formation of carbonyl compounds in BSA and plasma proteins, oxidized by two oxidative systems – H2O2/FeSO4 and HOCl, were studied in co-operation with other synthetic antioxidants – ascorbic acid and trolox. We found the synergistic or additive effect of PYC with mentioned antioxidants.

General Physiology and Biophysics. Volume 25, 2006, No. 4: 379-396.

 
  Functional remodeling of heart mitochondria in acute diabetes: interrelationships between damage, endogenous protection and adaptation
M Ferko 1), A Gvozdjaková 2), J Kucharská 3), J Mujkošová 4), I Waczulíková 5), J Styk 6), T Ravingerová 7), B Ziegelhöffer-Mihalovičová 8), A Ziegelhöffer 9)

1)Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia. usrdmife@savba.sk.
2)Laboratory of Pharmacobiochemistry, 3rd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia..
3)Laboratory of Pharmacobiochemistry, 3rd Department of Internal Medicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia..
4)Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia..
5)Division of Biomedical Physics, Faculty of Mathematics, Physics and Informatics, Comenius University, Bratislava, Slovakia..
6)Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia..
7)Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia..
8)Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia..
9)Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, P.O.Box 104, 840 05 Bratislava 45, Slovakia. usrdzigy@savba.sk.


Rats with streptozotocin-diabetes develop mechanisms of endogenous protection (MEP) that participate actively in functional remodeling of cardiac sarcolemma. Remodeling of sarcolemma is a sign of damage but it also protects the cells of the diabetic heart (DH) against additional energy disbalance due to excessive Ca2+ entry. Since yet, cardiac mitochondria (MIT) were investigated predominantly from the aspect of damage only. Aims of the present study were: i) to distinguish between acute diabetes-induced changes in function of rat heart MIT which clearly belong to damage from those that reflect the MEP and participate in functional remodeling of the MIT; ii) elucidate the significance of MEP-induced changes in heart MIT for cardiac energetics. Acute diabetes (8 days) was induced in adult male Wistar rats by streptozotocin (STZ, 65 mg·kg-1 i.p., single dose). On the day 8 after STZ administration, the diabetic animals exhibited 300–330 % increase in blood glucose, triacylglycerols and cholesterol as well as 89.6 % increase in glycohemoglobin (all p < 0.01). The blood level of insulin dropped by 53 % (p < 0.02). State 3 and state 4 oxygen consumptions of DH MIT were decreased against the controls, leading to drop of the respiratory control index (17.9 and 7.3 %) and oxidative phosphorylation rate (OPR, 27.5 and 24.6 %; all p < 0.003–0.02). These effects of damage yielding in strained energy balance of the acute DH were partially alleviated by MEP. The latter involved temporary preservation of the ADP : O ratio, with participation of elevated MIT Mg2+-ATPase activity as well as increased formation of MIT substrate and energy transition pores (both p < 0.05). Hence, the energy disbalance of the acute DH was finally manifested in 13 % loss in its AMP content only (p < 0.05). Results indicate that MIT in STZ-DH are functionally remodeled. Defective O2 consumption by MIT renders molecular changes suggestive of a mild hypoxic state but an increase in Mg2+-ATPase activity and facilitated energy delivery from MIT to the cytoplasm indicate the presence of MEP acting in the MIT and alleviating the effect of decreased oxidative energy production in the acute DH.

General Physiology and Biophysics. Volume 25, 2006, No. 4: 397-413.

 
  In vitro inhibition of lens aldose reductase by (2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-acetic acid in enzyme preparations isolated from diabetic rats
P Djoubissie 1), V Snirc 2), R Sotnikova 3), J Zurova 4), Z Kyselova 5), S Skalska 6), A Gajdosik 7), V Javorkova 8), J Vlkovicova 9), N Vrbjar 10), M Stefek 11)

1)Institute of Experimental Pharmacology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava 4, Slovakia. exfastfk@savba.sk.
2)Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovakia..
3)Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovakia..
4)Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovakia..
5)Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovakia..
6)Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovakia..
7)Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovakia..
8)Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 840 05 Bratislava 45, Slovakia..
9)Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 840 05 Bratislava 45, Slovakia..
10)Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, 840 05 Bratislava 45, Slovakia..
11)Institute of Experimental Pharmacology, Slovak Academy of Sciences, Dúbravská cesta 9, 841 04 Bratislava 4, Slovakia. exfastfk@savba.sk.


(2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-yl)-acetic acid (compound 1), a novel aldose reductase inhibitor, was assayed for efficacy and selectivity to inhibit rat lens aldose reductase under in vitro conditions by using enzyme preparations obtained from diabetic animals. The inhibitory efficiency was characterized by IC50 in micromolar region. Enzyme kinetics analysis revealed uncompetitive type of inhibition, both in relation to the D,L-glyceraldehyde substrate and to the NADPH cofactor. In testing for selectivity, comparisons to rat kidney aldehyde reductase, an enzyme with the highest homology to aldose reductase, was used. The inhibition selectivity of the compound tested was characterized by selectivity factor around 20 and was even slightly improved under conditions of prolonged experimental diabetes. These findings were identical with those in the control rats. To conclude, the inhibitory mode, efficacy and selectivity of compound 1, a novel aldose reductase inhibitor, was preserved even under the conditions of prolonged STZ-induced experimental diabetes of rats.

General Physiology and Biophysics. Volume 25, 2006, No. 4: 415-425.

 
  Structural differences between sensitive and resistant L1210 cells
B Uhrík 1), A El-Saggan 2), M Šereš 3), L Gibalová 4), A Breier 5), Z Sulová 6)

1)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava 37, Slovakia. branislav.uhrik@savba.sk.
2)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava 37, Slovakia..
3)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava 37, Slovakia..
4)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava 37, Slovakia..
5)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava 37, Slovakia..
6)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava 37, Slovakia..


The main structural differences between sensitive L1210 mouse leukaemic cells and their multidrug resistant counterpart, obtained by adaptation of the parental cell line to vincristine (VCR), concern the size and shape of the cells, their surface properties and changes in organelles involved in proteosynthesis and transport of substances. The resistant cells are larger with higher density of microvilli. In light and electron micrographs containing a group of cells, cells were found to be closer to each other in L1210/VCR cells than in L1210 cells. This diference in cell aggregation suggests different surface properties which could be visualised by decreased staining of L1210/VCR cell surface coat (glycocalyx) with a polycationic dye ruthenium red. A decrease in surface to volume ratio as a consequence of increased cell size in resistant cells is compensated by proliferation of villi and cytoplasmic protrusions of the cell surface. L1210/VCR cells were further distinguished by higher amount of euchromatin, increase in density of rough endoplasmic reticulum, more developed Golgi apparatus and aggregation of free ribosomes into tetrameric and pentameric polyribosomes. These structural changes may be interpreted as a sign of increase in proteosynthesis and transport of substances.

General Physiology and Biophysics. Volume 25, 2006, No. 4: 427-438.

 
  Inhibition of (Na+/K+)-ATPase by Cibacron Blue 3G-A and its analogues
A Breier 1), V Boháčová 2), P Dočolomanský 3)

1)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava 37, Slovakia. albert.breier@savba.sk.
2)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava 37, Slovakia..
3)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava 37, Slovakia..


A specific feature of anthraquinone dyes (AD) is to mimic the adenine nucleotides ATP, ADP, NAD and NADH, enabling them to act as ligands in interaction with nucleotide-binding sites of several enzymes and receptors. In the present study, the interactions and/or inhibitory effects of eight AD, including Cibacron Blue 3G-A (Reactive Blue 2), Procion Blue MX-R (Reactive Blue 4) and Remazol Brilliant Blue R (Reactive Blue 19) on the activity of (Na+/K+)-ATPase were investigated. The AD used in this paper could be divided into two groups: i) AD1–AD4 that do not contain the triazine moiety; ii) AD5–AD8 that contain the triazine moiety. Interaction affinity between the respective dye and (Na+/K+)-ATPase was characterized by means of enzyme kinetics. All AD, excluding AD1 and AD2 (which were practically ineffective) exerted effective competitive inhibition to the (Na+/K+)-ATPase activity. Present study is devoted to elucidation of relationship between the inhibitory efficacy of AD against (Na+/K+)-ATPase activity, their acid-basic properties and their three dimensional structure. From the results obtained, the following conclusions could be driven: 1. Similarities in the mutual position of positively and negatively charged parts of ATP and AD are responsible for their interaction with ATP-binding site of (Na+/K+)-ATPase. This may be documented by fact that mutual position of 1-aminogroup of anthraquinone and –SO3- group of benzenesulphonate part of respective AD plays crucial role for inhibition of this enzyme. Distances of these two groups on all effective AD were found to be similar as the distance of the 6-aminogroup of adenine and the second phosphate group on ATP molecule. This similarity could be responsible for biomimetic recognition of AD in ATP-binding loci of (Na+/K+)-ATPase. 2. The affinity of AD to ATP binding site of (Na+/K+)-ATPase increases with increasing values of molar refractivity, i. e., with increasing molecular volume and polarizability.

General Physiology and Biophysics. Volume 25, 2006, No. 4: 439-453.

 
  Effect of peroxisome proliferator-activated receptor α ligand fenofibrate on Kv channels in the insulin-secreting cell line HIT-T15
K Shimomura 1), M Ikeda 2), Y Ariyama 3), P Proks 4), Y Shimomura 5), M Mori 6), S Matsumoto 7)

1)University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, United Kingdom. kenju.shimomura@physiol.ox.ac.uk.
2)Department of Physiology, Nippon Dental University School of Dentistry at Tokyo, Tokyo, Japan..
3)Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma, Japan..
4)Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 833 34 Bratislava 37, Slovakia..
5)Gunma Prefectural College of Medical Sciences, Gunma, Japan..
6)Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma, Japan..
7)Department of Physiology, Nippon Dental University School of Dentistry at Tokyo, Tokyo, Japan..


Ligands for peroxisome proliferator-activated receptors α (PPARα) are clinically used for the treatment of patients with hyperlipidemia. As we have previously shown, a synthetic ligand of PPARα, fenofibrate, has a stimulatory effect on insulin secretion in clonal hamster insulinoma β-cell line HIT-T15 cells. We have also demonstrated that fenofibrate directly inhibits ATP-sensitive potassium (KATP) channels, an effect independent of PPARα. In this study, fenofibrate was shown to be able to reduce voltage-dependent K+ (Kv) channel currents in voltage-independent manner. Therefore, fenofibrate may modulate insulin secretion not only via inhibition of KATP channels but also via reduction of the Kv channel current.

General Physiology and Biophysics. Volume 25, 2006, No. 4: 455-460.