Portal-systemic shunting is an important circulatory abnormality in patients with liver cirrhosis. Glyceryl trinitrate (GTN) that is normally subject to first pass elimination, may exhibit higher bioavailability in these patients. This study compares the pharmacodynamic effects of GTN after peroral and sublingual administration for noninvasive assessment of shunting. Six control subjects and 15 patients with cirrhosis were studied after oral and sublingual application of 0.5 mg of GTN. Liver cirrhosis was complicated by portal hypertension in 7 of the patients and 4 patients had surgically implanted portocaval anastomosis. Digital plethysmography, which is highly sensitive and is essentially noninvasive in nature, was used to assess and compare the pharmacodynamic effects of GTN. The following values of the ratio of areas under the pharmacodynamic effects/time curve were obtained: 0.08±0.06 in healthy subjects, 0.52±0.21 in patients with uncomplicated cirrhosis, 0.99±0.34 in patients with portal hypertension and 1.24±0.43 in patients with portal-systemic shunts. We conclude that increased bioavailability of GTN reflects portal-systemic shunting and might be used providing that the pharmacodynamic data reflect both pharmacokinetic variability and the pharmacokinetic-pharmacodynamic interrelations., O. Slanař, J. Aubrecht, F. Perlík., and Obsahuje bibliografii
Local application of four concentrations of bicuculline methiodide (a specific antagonist of GABAA receptors) was used to study a sensitivity of somatosensory cortex in four age groups of immature rats with implanted electrodes. Presence and latencies of two epileptic phenomena (focal discharges and seizures) were evaluated. Focal discharges exhibited moderate tendency to a decrease of sensitivity to bicuculline methiodide with maturation. Concentration-effect relation of incidence of focal discharges was observed only in 7- and 12-day-old but not in older animals. Results with incidence and latencies of seizures did not show relations to age or concentration of bicuculline. Neither of the epileptic phenomena can be used as a reliable index of cortical maturation., P. Mareš, K. Bernášková, H. Kubová., and Seznam literatury
Extensive osteolysis adjacent to orthopedic implants is often associated with wear particles of prosthetic material. The activation of the RANKL/RANK/OPG system is considered to be a likely cause of periprosthetic osteolysis leading to implant failure. The aim of this study was to examine the possible correlation between the clinical extent of osteolysis, the number of wear particles and expression of the osteoclastic mediator RANKL (receptor activator of nuclear factor kappa B ligand) in the tissues aro und aseptically loosened cemented and non-cemented total hip replacements. Periprosthetic tissues were harvested from 59 patients undergoing revision of hip replacement for aseptic loosening. We observed RANKL-positive cells in 23 of our 59 patients, their presence was noted predominantly in tissues with a loosened cemented endoprosthesis. We have found that RANKL is present only in tissues with a large amount of wear debris and predominantly in cases involving loosened cemented implants., D. Veigl, J. Niederlová, O. Kryštůfková., and Obsahuje bibliografii a bibliografické odkazy
Exposure to chronic hypoxia results in hypoxic pulmonary hypertension characterized by structural remodeling of peripheral pulmonary vasculature. An important part of this remodeling is an increase of collagen turnover and deposition of newly formed collagen fibrils in the vascular walls. The activity of collagenolytic metalloproteinases in the lung tissue is notably increased in the first days of exposure to hypoxia. The increased collagenolytic activity results in the appearance of collagen cleavages, which may be implied in the triggering of mesenchymal proliferation in peripheral pulmonary arteries. We hypothesize that radical injury to pulmonary vascular walls is involved in collagenolytic metalloproteinase activation., J. Novotná, J. Herget., and Obsahuje bibliografii
Neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are increasing in prevalence. Currently, there are no effective and specific treatments for these disorders. Recently, positive effects of the orexigenic hormone ghrelin on memory and learning were demonstrated in mouse models of AD and PD. In this study, we tested the potential neuroprotective properties of a stable and long-lasting ghrelin analog, Dpr3ghrelin (Dpr3ghr), in SH-SY5Y neuroblastoma cells stressed with 1.2 mM methylglyoxal (MG), a toxic endogenous by-product of glycolysis, and we examined the impact of Dpr3ghr on apoptosis. Pre-treatment with both 10-5 and 10-7 M Dpr3ghr resulted in increased viability in SH-SY5Y cells (determined by MTT staining), as well as reduced cytotoxicity of MG in these cells (determined by LDH assay). Dpr3ghr increased viability by altering pro-apoptotic and viability markers: Bax was decreased, Bcl-2 was increased, and the Bax/Bcl-2 ratio was attenuated. The ghrelin receptor GHS-R1 and Dpr3ghr-induced activation of PBK/Akt were immuno-detected in SH-SY5Y cells to demonstrate the presence of GHS-R1 and GHS-R1 activation, respectively. We demonstrated that Dpr3ghr protected SH-SY5Y cells against MG-induced neurotoxicity and apoptosis. Our data suggest that stable ghrelin analogs may be candidates for the effective treatment of neurodegenerative disorders., A. Popelová, A. Kákonová, L. Hrubá, J. Kuneš, L. Maletínská, B. Železná., and Seznam literatury
a1_A new concept of cardioprotection based on the exploitation of endogenous mechanisms is known as ischemic preconditioning (IPC). It has been hypothesized that substances released during brief ischemic stress (e.g. catecholamines) stimulate the receptors and trigger multiple cell signaling cascades. Opening of ATP-sensitive K+ channels [K(ATP)] has been suggested as a possible final step in the mechanisms of protection. In this study, the role of adrenergic activation was tested in Langendorff-perfused rat hearts subjected to test ischemia (TI; 30 min occlusion of LAD coronary artery) by: 1) mimicking IPC (5 min ischemia, 10 min reperfusion) with short-term (5 min) administration of norepinephrine (NE, 1 µM), 15 min prior to TI; 2) blockade with b- or a1-receptor antagonists, propranolol (10 µM) and prazosin (2 µM), respectively, applied 15 min prior to TI during IPC. The role of K(ATP) opening was examined by perfusion with a K(ATP) blocker glibenclamide (10 mM) during IPC. Both IPC and NE-induced PC effectively reduced the incidence of ventricular tachycardia (VT) to 33 % and 37 %, respectively, vs 100 % in the non-PC controls, whereby ventricular fibrillation (VF) was totally abolished by IPC and markedly suppressed by PC with NE (0 % and 10 %, respectively, vs 70 % in the non-PC hearts; P<0.05). The severity of arrhythmias (arrhythmia score, AS) was also markedly attenuated by both interventions (IPC: AS 1.7±0.4; NE-PC: AS 1.8±0.3 vs AS 4.1±0.2 in the controls; P<0.05). Protection was not suppressed by propranolol (VT 28 %; VF 14 %; AS 2.2±0.6), whereas prazosin reversed the protective effect of PC (VT 83 %; VF 67 %; AS 4.0±0.8). Antiarrhythmic protection afforded by NE-PC was abolished by pretreatment of rats with pertussis toxin (25 mg/kg, i.p.) given 48 h prior to the experiments., a2_Glibenclamide did not suppress the IPC-induced protection. In conclusion, the sensitivity of the rat heart to ischemic arrhythmias can be modulated by IPC. Protection is mediated via stimulation of a1-adrenergic receptors coupled with Gi-proteins but glibenclamide-sensitive K(ATP) channels do not appear to be involved in the mechanisms of antiarrhythmic protection in this model., T. Ravingerová, D. Pancza, A. Ziegelhoffer, J. Styk., and Obsahuje bibliografii
Reactive oxygen species can be generated by daily exposure of the skin to ultraviolet light and may cause some subchronic and chronic skin disorders. The aim of this study was to investigate a possible preventive role of a-tocopherol acetate (ATA) on ultraviolet B (UVB) induced peroxidation by assessing lipid peroxide (LPO) levels and activity of reactive oxygen scavenging enzymes including glutathione peroxidase and superoxide dismutase (SOD) in guinea pigs. ATA was topically applied to the skin for three weeks before a single dose of 0.9 J/cm2 UVB irradiation on the skin and lipid peroxide levels and antioxidants in plasma, skin and liver and erythrocytes were determined after decapitation. Topical application of ATA prevented the UVB irradiation-induced reduction of scavenging enzyme activities in skin and erythrocytes. In conclusion, we suggest that topical applications of ATA before UVB irradiation is effective in protecting the skin from unwanted effects of UVB irradiation., Y. Saral, B. Uyar, A. Ayar, M. Naziroglu, S. Yilmaz., and Obsahuje bibliografii
Summary Mitochondria are exposed to reactive nitrogen species under physiological conditions and even more under several pathologic states. In order to reveal the mechanism of these processes we studied the effects of peroxynitrite on isolated beef heart mitochondria in vitro. Peroxynitrite has the potential to nitrate protein tyrosine moieties, break the peptide bond, and eventually release the membrane proteins into the solution. All these effects were found in our experiments. Mitochondrial proteins were resolved by 2D electrophoresis and the protein nitration was detected by immunochemical methods and by nano LC-MS/MS. Mass spectrometry confirmed nitration of ATP synthase subunit beta, pyruvate dehydrogenase E1 component subunit beta, citrate synthase and acetyl-CoA acetyltransferase. Immunoblot detection using chemiluminiscence showed possible nitration of other proteins such as cytochrome b-c1 complex subunit 1, NADH dehydrogenase [ubiquinone] ironsulfur protein 2, elongation factor Tu, NADH dehydrogenase [ubiquinone] flavoprotein 2, heat shock protein beta-1 and NADH dehydrogenase [ubiquinone] iron-sulfur protein 8. ATP synthase beta subunit was nitrated both in membrane and in fraction prepared by osmotic lysis. The high sensitivity of proteins to nitration by peroxynitrite is of potential biological importance, as these enzymes are involved in various pathways associated with energy production in the heart., M. Kohutiar, A. Eckhardt, I. Mikšík, P. Šantorová, J. Wilhelm., and Seznam literatury