Myofibrillar creatine kinase (CK) that buffers ATP during fluctuating muscle energy metabolism has been selected for studies of conformational changes underlying the cellular control of enzyme activity. The force field was computed for three energetic states, namely for the substrate-free CK molecule, for the molecule conjugated with the MgATP complex, and for the molecule conjugated with the pair of reactants MgATP-creatine. Without its substrates, the enzyme molecule assumes an inactive "open" form. Upon binding of the MgATP complex, the CK molecule takes up a reactive "closed" conformation. Subsequent binding of creatine yields a nonreactive "intermediary" conformation. Acid-base catalysis is considered to be the basic principle for the reversible transfer of the phosphoryl group between the substrates. The results indicate that the substrate-induced energy minimizing conformational changes do not represent a sufficient condition for CK activity and that some other essential component of physiological control at the cellular level is involved in the transition from the intermediary to the closed structure of the molecule., J. A. Mejsnar, B. Sopko, M. Gergor., and Obsahuje bibliografii
Cardiovascular disease, while rare in women of reproductive age, is the main cause of mortality in menopause. The purpose of our study was to determine the association of natural menopause with cardiovascular risk factors, including their clustering into metabolic syndrome (MS). A random 5 % representative population sample of women aged 45-54 years was examined. In 575 women, we were able to determine their natural reproductive aging status. Multiple regression analysis was used to calculate the association between age, menopausal status, and risk factors under study. After adjustment for age, there was an increase in the odds ratio of developing MS, as defined by NCEP (OR=2.0; 95 % CI [1.1; 3.7]), and an increase in plasma lipid ratios (total cholesterol/HDL-C, LDL-C/HDL-C, apolipoprotein-B/ apolipoprotein-A1; p<0.05 for all) in postmenopausal women. Age, but not menopausal status, was associated with some single components of MS; only waist circumference significantly increased after menopause, independently of age. Clustering of risk factors in MS and lipid ratios (combined factors) was strongly associated with menopause whereas worsening of single components of MS was strongly associated with age. In conclusion, based on our results, the menopause may pose a risk to women through clustering of cardiovascular risk factors beyond simple aging., M. Lejsková ... [et al.]., and Obsahuje seznam literatury
In previous studies, it has been shown that recombinant human neuregulin-1(rhNRG-1) is capable of improving the survival rate in animal models of doxorubicin (DOX)-induced cardiomyopathy; however, the underlying mechanism of this phenomenon remains unknown. In this study, the role of rhNRG-1 in attenuating doxorubicin-induce apoptosis is confirmed. Neonatal rat ventricular myocytes (NRVMs) were subjected to various treatments, in order to both induce apoptosis and determine the effects of rhNRG-1 on the process. Activation of apoptosis was determined by observing increases in the protein levels of classic apoptosis markers (including cleaved caspase-3, cytochrome c, Bcl-2, BAX and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining). The activation of Akt was detected by means of western blot analysis. The study results showed that doxorubicin increased the number of TUNEL positive cells, as well as the protein levels of cleaved caspase-3 and cytochrome c, and reduced the ratio of Bcl-2/Bax. However, all of these effects were markedly antagonized by pretreament with rhNRG-1. It was then further demonstrated that the effects of rhNRG-1 could be blocked by the phosphoinositole-3-kinase inhibitor LY294002, indicating the involvement of the Akt process in mediating the process. RhNRG-1 is a potent inhibitor of doxorubicin-induced apoptosis, which acts through the PI3K-Akt pathway. RhNRG-1 is a novel therapeutic drug which may be effective in preventing further damage from occurring in DOX-induced damaged myocardium., T. An, ... [et al.]., and Obsahuje seznam literatury
The review concerns a number of basic molecular pathways that play a crucial role in perception, transmission, and modulation of the stress signals, and mediate the adaptation of the vital processes in the cardiovascular system (CVS). These highly complex systems for intracellular transfer of information include stress hormones and their receptors, stress-activated phosphoprotein kinases, stress-activated heat shock proteins, and antioxidant enzymes maintaining oxidoreductive homeostasis of the CVS. Failure to compensate for the deleterious effects of stress may result in the development of different pathophysiological states of the CVS, such as ischemia, hypertension, atherosclerosis and infarction. Stress-induced dysbalance in each of the CVS molecular signaling systems and their contribution to the CVS malfunctioning is reviewed. The general picture of the molecular mechanisms of the stress-induced pathophysiology in the CVS pointed out the importance of stress duration and intensity as etiological factors, and suggested that future studies should be complemented by the careful insights into the individual factors of susceptibility to stress, prophylactic effects of 'healthy' life styles and beneficial action of antioxidant-rich nutrition., S. B. Pajović, M. B. Radojčić, D. T. Kanazir., and Obsahuje bibliografii a bibliografické odkazy
The main neuromodulatory methods using neurostimulation principles are described. It concerns peripheral nerve stimulation (PNS), spinal cord stimulation (SCS), deep brain stimulation (DBS), motor cortex stimulation (MSC), and repetitive transcranial magnetic stimulation (rTMS). For each method the history, pathophysiology, the principles for use and the associated diagnoses are mentioned. Special attention is focused on the most common neuromodulatory invasive methods like SCS and MCS and non-invasive methods such as rTMS. In addition to the positive effects, side effects and complications are described and discussed in detail. In conclusion, neuromodulatory (neurostimulatory) techniques are highly recommended for the treatment of different types of pharmacoresistant pain., R. Rokyta, J. Fricová., and Obsahuje seznam literatury
Aim of the study was to test the effect of nicotine (NIC) and kainic acid (KA) co-treatment in immature rats. Male Wistar albino rats (two different age groups) were chosen for the study. Experiments started on postnatal day (PD) 8 or 21 and animals were treated twice a day for three days with nicotine, fourth day KA was administered. Animals at PD12 (PD25 respectively) were examined electrophysiologically for cortical epileptic afterdischarges (ADs). First cortical ADs in PD12 animals were longer, when compared to PD25 rats (group treated with both substances). Nor NIC or KA treatment affected the length of discharges in PD12 rats. Older experimental group exhibited the shortening of the first ADs (group treated with NIC and KA, compared with groups exposed to single treatment). Few changes were found in KA treated group – 2nd and 4th ADs were shorter when compared with first ADs. These results demonstrate that NIC treatment played minor role in seizure susceptibility of PD12 rats, sensitivity to NIC differs during ontogenesis and subconvulsive dose of KA influenced the length of discharges only in PD25 animals., V. Riljak ... [et al.]., and Obsahuje seznam literatury
a1_The effect of lesions induced by bilateral intracerebroventricular (ICV) injection of quinolinate (250 nmol of QUIN/ventricle), a selective N-methyl-D-aspartate (NMDA) receptor agonist, on [3H]glutamate ([3H]Glu) binding to the main types of both ionotropic and metabotropic glutamate receptors (iGluR and mGluR) was investigated in synaptic membrane preparations from the hippocampi of 50-day-old rats. The membranes from QUIN injured brains revealed significantly lowered binding in iGluR (by 31 %) as well as in mGluR (by 22 %) as compared to the controls. Using selected glutamate receptor agonists as displacers of [3H]Glu binding we found that both the NMDA-subtype of iGluR and group I of mGluR are involved in this decrease of binding. Suppression of nitric oxide (NO) production by NG-nitro-L-arginine (50 nmol of NARG/ventricle) or the increase of NO generation by 3-morpholinylsydnoneimine (5 nmol of SIN-1/ventricle) failed to alter [3H]Glu or [3H]CPP (3-((D)-2-carboxypiperazin-4-yl)-[1,2-3H]-propyl-1-phosphonic acid; NMDA-antagonist) binding declines caused by QUIN-lesions. Thus, our findings indicate that both the NMDA-subtype of iGluR and group I of mGluR are susceptible to the QUIN-induced neurodegeneration in the rat hippocampus. However, the inhibition of NO synthesis did not reveal any protective action in the QUIN-evoked, NMDA-receptor mediated decrease of [3H]Glu binding., a2_Therefore, the additional mechanisms of QUIN action, different from direct NMDA receptor activation/NO production (e.g. lipid peroxidation induced by QUIN-Fe-complexes) cannot be excluded., V. Lisý, F. Šťastný., and Obsahuje bibliografii
The protective effect of therapeutic hypothermia in cardiac arrest survivors (CAS) has been previously well documented. Animal studies have indicated that attenuation of tissue oxidative stress (OS) may be involved in the mechanisms that lead to the beneficial effect of hypothermia. The extent of OS and nitric oxide (NO) production in adult CAS treated with endovascular hypothermia is, however, unknown. A total of 11 adult patients who experienced cardiac arrest out of hospital were included in the present study, and all were treated with mild hypothermia using the Thermogard XP (Alsius, USA) endovascular system. A target core temperature of 33 °C was maintained for 24 hours, with a subsequent rewarming rate of 0.15 °C per hour, followed by normothermia at 36.8 °C. Blood samples for the measurement of nitrotyrosine and nitrate/nitrite levels were drawn at admission and every 6 hours thereafter for two days. During the hypothermic period, the levels of nitrotyrosine and nitrates/nitrites were comparable with baseline values. During the rewarming period, serum levels of both parameters gradually increased and, during the normothermic period, the levels were significantly higher compared with hypothermic levels (nitrotyrosine, P<0.001; nitrates/nitrites, P<0.05). In our study, significantly lower levels of nitrotyrosine and nitrates/nitrites were demonstrated during hypothermia compared with levels during the normothermic period in adult CAS. These data suggest that attenuation of OS and NO production may be involved in the protective effect of hypothermia in adult CAS., A. Krüger ... [et al.]., and Obsahuje seznam literatury
The key role of the vagus nerves in the reflex control of breathing is generally accepted. Cardiopulmonary vagal receptors and their afferent connection with the medullary respiratory centers secures the proper regulatory feedback. Section of the vagi at the midcervical level interrupts primary vagal reflexes and those due to activation of lung afferents by neuroactive substances. In this context the present review focuses on the reflex contribution of the inferior (nodose) vagal ganglia to the respiratory pattern, considering that this structure contains perikarya of vagal afferent neurons which house neurotransmitters, neuropeptides and neurochemical substances. In experimental animals with removed sensory input from the lungs (midcervical vagotomy) the following evidence was reported. Transient respiratory suppression in the form of apnoea, occuring after systemic injection of serotonin, adenosine triphosphate and anandamide (N-arachidonoyl-ethanolamine-endogenous cannabinoid neurotransmitter), which was abrogated by nodose ganglionectomy. Preserved nodose-NTS connection conditioned respiratory depression affecting the timing component of the breathing pattern evoked by N-6-cyclopentyl-adenosine (CPA) and inhibition of both respiratory constituents induced by NPY. Stimulatory effect of NPY13-36 on tidal volume required nodosal connection. The cardiovascular effects of majority of the tested substances occurred beyond the nodose ganglia (with exclusion of serotonin and anandamide)., K. Kaczyńska, M. Szereda-Przestaszewska., and Obsahuje seznam literatury
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