The binding of [3H]SCH 23390 has been studied in various brain regions of male mice with the experience of repeated victory (winners) or defeat (losers) gained over 10 (T10) and 20 (T20) days of daily agonistic confrontations. In the frontal cortex, Bmax of [3H]SCH 23390 binding sites was found to be increased in T10 losers and decreased in T20 losers when compared to the control mice. In the striatum, T10 and T20 winners had reduced values of [3H]SCH 23390 binding sites than the ones in the control mice. The Kd was increased in the frontal cortex of T10 losers and T10 winners as well as in the amygdala of T20 losers. Reduced Kd values were found in the striatum of all experimental groups as well as in the amygdala of T20 winners. Thus, both specific changes relating to social behavior patterns and non-specific ones in [3H]SCH 23390 binding were found in the brain regions of mice after 10 and 20 days of intermale confrontations., D. F. Avgustinovich, O. V. Alekseyenko., and Obsahuje bibliografii a bibliografické odkazy
The aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) T-786C and G894T in the gene encoding eNOS with blood pressu re variability (BPV) in man. Blood pressure was recorded beat-t o-beat at rest three times in periods of one week (5 min, Finapres, breathing at 0.33 Hz) in 152 subjects (19-24 years). Systolic (SBPV0.1r/SBPV 0.1a) and diastolic (DBPV0.1r/DBPV 0.1a) blood pressure variabilities in relative (r.u.) and absolute (mmHg2/Hz) units were determined by the spectral method as spectral po wer at the frequency of 0.1 Hz. Genotypes of both polymorphisms were detected using polymerase chain reaction and re striction analysis using enzymes Msp I and Ban II. Significant diffe rences were observed in BPV among genotypes of T-786C SNP (p<0.05; Kruskal-Wallis), and among haplotypes of both SNPs (p<0.05; Kruskal-Wallis) as well. In T-786C SNP, carriers of less frequent allele (CC homozygotes and TC heterozygotes) showed significantly greater SBPV0.1r and SBPV0.1a compared to TT homozygote s (Mann-Whitney; p<0.05). The G894T variant showed no sign ificant differences, but, both SNPs were in linkage disequilib rium (D’=0.37; p<0.01). Carriers of haplotype CT/CT (CC homozygotes of -786C/T and TT homozygotes of G894T) displaye d significantly greater SBPV0.1r, SBPV0.1a and DBPV0.1a compared to carriers of other haplotype combinations (Kruskal-Wallis; p=0.015, p=0.048, and p=0.026, respectively). In conclusion, the haplotype formed by less frequent alleles of both eNOS variants was associated with increased systolic and diastolic BPV in this study., M. Jíra ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
1a_It has been known for many years that baroreflex sensitivity is lowered in hypertensive patients. There are several known factors implicating this association, e.g. high blood pressure leads to remodeling of the carotid arterial wall, to its stiffness and to a diminished activation of baroreceptors; leptin released from a fatty tissue activates the sympathetic nervous system etc. On the other hand, low baroreflex sensitivity (BRS, usually quantified in ms/mmHg) can be inborn. Studies on primary hypertension in children and adolescents have brought new information about the role of baroreflex in the development of an early stage of primary hypertension. BRS lower than 3.9 ms/mmHg was found in 5 % of healthy subjects. This value approaches the critical value for the risk of sudden cardiac death in patients after myocardial infarction and corresponds to the value present in hypertensive patients. A decreased BRS and BRSf (baroreflex sensitivity expressed in mHz/mmHg, index independent of the mean cardiac interval), was found not only in children with hypertension, but also in those with white-coat hypertension. This is in accordance with a single interpretation. The decrease of BRS/BRSf precedes a pathological blood pressure increase., 2a_The contribution of obesity and BRS/BRSf to the development of hypertension in adolescents was also compared. Both factors reach a sensitivity and a specificity between 60 % and 65 %, but there is no correlation between the values of the body mass index and BRS either in the group of hypertensive patients or in healthy controls. If a receiver operating curve (sensitivity versus specificity) is plotted for both values together using logistic regression analysis, a sensitivity higher than 70 % and a specificity over 80 % are reached. This means that low baroreflex sensitivity is an independent risk factor for the development of primary hypertension. Studies demonstrate that adolescents with increased blood pressure and with BRS under 7 ms/mmHg should be given care and intensively motivated to change their lifestyle including a change in diet and increase in physical activity., and N. Honzíková, B. Fišer.
Hypertension is a major health problem throughout the world because of its high prevalence and its association with increased risk of cardiovascular disease. Two independent studies discovered a locus conferring susceptibility to essential hypertension on chromosome 2, in the 2p25 region, but the causative gene remains unknown. Grainyhead-like 1 (GRHL1) is one of the genes located in this region. Our experiments determined that the Grhl1-null mice, when fed standard diet, have the same blood pressure as their wild type littermate controls. However, we discovered that blood pressure of these mice increases following high sodium diet and decreases when they are fed low sodium diet, and similar effect s were not observed in the control wild type littermates. This suggests that the Grhl1-null mice are sensitive to the development of salt-sensitive hypertension. Thus it is possible that the GRHL1 gene is involved in the regulation of blood pressure, and it may be the causative gene for the locus of susceptibility to essential hypertension in the 2p25 region., A. Walkowska, M. Pawlak, S. M. Jane, E. Kompanowska-Jezierska, T. Wilanowski., and Obsahuje bibliografii
Patch clamp method developed more than 30 years ago is widely used for investigation of cellular excitability manifested as transmembrane ionic current and/or generation of action potentials. This technique could be applied to measurement of ionic currents flowing through individual (single) ion channels or through the whole assembly of ion channels expressed in the whole cell. Whole cell configuration is more common for measurement of ion currents and the only one enabling measurement of action potentials. This method allows detailed analysis of mechanisms and structural determinants of voltagedependent gating of ion channels as well as regulation of channel activity by intracellular signaling pathways and pharmacological agents., M. Karmažínová, L'. Lacinová., and Obsahuje bibliografii a bibliografické odkazy
Disorders of ATP synthase, the key enzyme of mitochondrial energy provision belong to the most severe metabolic diseases presenting as early- onset mitochondrial encephalo- cardiomyopathies. Up to now, mutations in four nuclear genes were associated with isolated deficiency of ATP synthase. Two of them, ATP5A1 and ATP5E encode enzyme’s st ructural subunits α and ε , respectively, while the other two ATPAF2 and TMEM70 encode specific ancillary factors that facilitate the biogenesis of ATP synthase. All these defects share a similar biochemical phenotype with pronounced decrease in the content of fully assembled and functional ATP synthase complex. However, substantial differences can be found in their frequency, molecular mechanism of pathogenesis, clinical manifestation as well as the course of the disease progression. While for TMEM70 the number of reported patients as well as spectrum of the mutations is steadily increasing, mutations in ATP5A1, ATP5E and ATPAF2 genes are very rare. Apparently, TMEM70 gene is highly prone to mutagenesis and this type of a rare mitochondrial disease has a rather frequent incidence. Here we present overview of individual reported cases of nuclear mutations in ATP synthase and discuss, how their analysis can improve our understanding of the enzyme biogenesis., K. Hejzlarová ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
The objective of the current study was to search for genetic determinants associated with antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitor captopril. Linkage and correlation analyses of captopril-induced effects on blood pressure (BP) with renal transc riptome were performed in the BXH/HXB recombinant inbred (RI) strains derived from spontaneously hypertensive rat (SHR) and Brown Norway (BN-Lx) progenitors. Variability of blood pressure lowering effects of captopril among RI strains was continuous suggesting a polygenic mode of inheritance. Linkage analysis of captopril- induced BP effects revealed a significant quantitative trait locus (QTL) on chromosome 15. This QTL colocalized with cis regulated expression QTL (eQTL) for the Ednrb (endothelin receptor type B) gene in the kidney (SHR allele was associated with increased renal expression) and renal expression of Ednrb correlated with captopril-induced BP effects. These results suggest that blood pressure lowering effects of ACE inhibitor captopril may be modulated by the variants at the Ednrb locus., J. Zicha ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
Functional C(-260)→T polymorphism in the promoter of the CD14 gene has been reported to be associated with coronary heart disease (CHD). The functional role of the polymorphism, however, is still a matter of debate, since several studies have not proved its effect on clinical outcomes associated with atherosclerosis. Cardiovascular-related morbidity and mortality was assessed in a post-hoc approach four years after baseline characterization of patients (male/female n = 36/32) with angiographically proven coronary heart disease. CD14 C(-260)→T promoter genotype was determined at baseline. Seventeen out of 20 CHD patients with non-lethal cardiovascular events carried at least one T-allele. CD14 T-260 allele carriers have a 3.59-fold (95 % confidence interval: 1.11-6.75) increased risk for non-lethal cardiovascular events (Kaplan-Meier plot: log rank test p = 0. 029). All patients with lethal outcomes (n = 6) were also T-allele carriers. Multivariate logistic regression analysis among CHD patients including age, established risk factors and the C(-260)→T polymorphism as covariates and non-lethal events as a dependent variable confirmed the independent prospective effect of the T-allele on cardiovascular outcomes in this subset. Further evidence is provided for the role of CD14 C(-260)→T promoter polymorphism as a genetic susceptibility marker of atherosclerosis in patients with an advanced clinical course of the disease. Due to the small sample size and post-hoc character of the study large-scale prospective studies that monitor patients with proven CHD are needed to confirm these findings., M. Porsch-Öucürümez, J.Hucke, S. Westphal, J. A. Hubáček, G. Schmitz, C. Luley., and Obsahuje bibliografii a bibliografické odkazy
Prague hereditary hypercholesterolemic (PHHC) rat – rat strain crossbred from Wistar rats – is a model of hypercholesterolemia induced by dietary cholesterol. Importantly, no bile salts and/or antithyroid drugs need to be added to the diet together with cholesterol to induce hypercholesterolemia. PHHC rats have only modestly increased cholesterolemia when fed a standard chow and develop hypercholesterolem ia exceeding 5 mmol/l on 2 % cholesterol diet. Most of the cholesterol in hypercholesterolemic PHHC rats is found in VLDL that become enriched with cholesterol (VLDL-C/VLDL-TG ratio > 1.0). Concurrently, both IDL and LDL concentrations rise without any increase in HDL. PHHC rats do not markedly differ from Wistar rats in the activities of enzymes involved in intravascular remodelation of lipoproteins (lipoprotein and hepatic lipases and lecithin:cholesterol acyltransferase), LDL catabolism, cholesterol turnover rate and absorption of dietary cholesterol. The feeding rats with cholesterol diet results in development of fatty liver in spite of suppression of cholesterol synthesis. However, even though cholesterolemia in PHHC rats is comparable to human hypercholesterolemia, the PHHC rats do not develop atherosclerosis even after 6 months on 2 % cholesterol diet. Importantly, the crossbreeding experiments documented that hypercholesterolemia of PHHC rats is polygenic. To identify the genes that may be involved in pathogenesis of hypercholesterolemia in this strain, the studies of microarray gene expression in the liver of PHHC rats are currently in progress., J. Kovář ... [et al.]., and Obsahuje seznam literatury
Over the last decade, C-reactive protein concentration analyzed by the high sensitivity method (hsCRP) has been proven as a marker of premature atherosclerosis. Concentration exceeding 2 mg/l represents an increased individual risk of myocardial infarction and stroke but strict application of this borderline is complicated by relations of CRP concentrations to other risk factors of cardiovascular diseases. In a large 1 % representative sample of the Czech population, a positive relation of hsCRP to BMI, a waist circumference and triglyceride concentration was documented. Substantial sex differences were found in its relationship to age. Whereas it is continuously increasing in men, this increase appears in women only after menopause. A substantial decrease of body weight and visceral fat volume by increased physical activity is accompanied by significant decrease of hsCRP in young obese women. This decrease was not related to a change of interleukin-6 concentration, although it is supposed to regulate CRP production. CRP concentration is partly under genetic control as a higher concentration in young siblings of probands with proved coronary atherosclerosis was documented. The participation of genes related to lipoprotein metabolism (genes for apolipoprotein CI and apolipoprotein E) influence hsCRP concentrations. We hypothesized that an increased concentration of hsCRP represents a certain marker of proinflammatory status related to central obesity and triglyceride metabolism and it might be related to individual properties of monocytes in atherogenesis., R. Poledne ... [et al.]., and Obsahuje seznam literatury