This review concerns the role of nitric oxide (NO) in the pathogenesis of different models of experimental hypertension (NO-deficient, genetic, salt-dependent), which are characterized by a wide range of etiology. Although the contribution of NO may vary between different models of hypertension, a unifying characteristic of these models is the presence of oxidative stress that participates in the maintenance of elevated arterial pressure and seems to be a common denominator underlying endothelial dysfunction in various forms of experimental hypertension. Besides the imbalance between the endothelial production of vasorelaxing and vasoconstricting compounds as well as the relative insufficiency of vasodilator systems to compensate augmented vasoconstrictor systems, there were found numerous structural and functional abnormalities in blood vessels and heart of hypertensive animals. The administration of antihypertensive drugs, antioxidants and NO donors is capable to attenuate blood pressure elevation and to improve morphological and functional changes of cardiovascular system in some but not all hypertensive models. The failure to correct spontaneous hypertension by NO donor administration reflects the fact that sympathetic overactivity plays a key role in this form of hypertension, while NO production in spontaneously hypertensive rats might be enhanced to compensate increased blood pressure. A special attention should be paid to the modulation of sympathetic nervous activity in central and peripheral nervous system. These results extend our knowledge on the control of the balance between NO and reactive oxygen species production and are likely to be a basis for the development of new approaches to the therapy of diseases associated with NO deficiency., J. Török., and Obsahuje bibliografii a bibliografické odkazy
The aim of the present study was to examine the effect of prolonged passive smoking (lasting 3 weeks) on plasma catecholamine levels and reactivity of isolated rabbit arteries. Plasma noradrenaline, adrenaline and dopamine levels were determined radioenzymatically. Isolated rings of the thoracic aorta and carotid artery were suspended in organ chambers and connected to a force transducer for the recording of isometric tension. Plasma noradrenaline levels were found to be significantly elevated in rabbits subjected to passive smoking for 3 weeks. Plasma adrenaline and dopamine levels were not changed. Transmural nerve stimulation of arterial rings evoked frequency-dependent contractions. Prolonged passive smoking did not affect neurogenic contractions of the arteries tested. On the other hand, endothelium-dependent relaxations of phenylephrine-precontracted arteries were significantly impaired. Furthermore, hypertrophy of the left ventricle was observed. In conclusion, passive smoking impairs endothelium-dependent relaxations but not neurogenic contractions of systemic arteries. The impaired relaxations of arteries may be, at least in part, mediated through the degradation of released nitric oxide by superoxide anions derived from cigarette smoke., J. Török, A. Gvozdjáková, J. Kucharská, I. Balažovjech, S. Kyselá, F. Šimko, J. Gvozdják., and Obsahuje bibliografii
The pathological potential of glial cells was recognized already by Rudolf Virchow, Santiago Ramon y Cajal and Pio Del Rio-Ortega. Many functions and roles performed by astroglia in the healthy brain determine their involvement in brain diseases; as indeed any kind of brain in sult does affect astrocytes, and their performance in pathological conditions, to a very large extent, determines the survival of the brain parenchyma, the degree of damage and neurological defect. Astrocytes being in general responsible for overall brain homeostasis are involved in virtually every form of brain pathology. Here we provide an overview of recent developments in identifying the role and mechanisms of the pathological potential of astroglia., A. Chvátal, M. Anděrová, H. Neprašová, I. Prajerová, L. Benešová, O. Butenko, A. Verkhratsky., and Obsahuje bibliografii a bibliografické odkazy
a1_The modern concept of causality of diseases emphasizes the study of natural defense functions of the organism and possibilities of influencing them, which will lead to effective prevention of these diseases. A great deal of information has been obtained on the system growth hormone (GH)/insulin-like growth factor (IGF)-I, which is of quite fundamental importance for the integrity of the organism. A dysbalance of the system may be the cause of diseases of the neonatal period, as well as diseases associated with aging. In old age, the synthesis of the crucial peptide system, IGF-I, declines as well as the sensitivity of tissues to this hormone. At the same time the changes in the expression of IGF-binding proteins (IGFBP) occur. Systemic growth factors are present in measurable concentrations in the circulation, they are, however, taken up or synthesized by some tissues, where they act as local cellular regulators. IGF-I is produced by many tissues, including bones under the control of estrogens, growth hormone and the parathyroid hormone. A decline of bone IGF-I in the cortical portion of bones is one of the many mechanisms leading to the development of involutional osteoporosis. Correlation studies, which have provided evidence of a relationship between the IGF system and the building of peak bone mass and its subsequent loss contributed to the understanding of the pathogenesis of this disease. It may be foreseen that the results of intervention studies focused on the effects of the recombinant IGF-I will also influence therapeutic and preventive approaches. Modern antiresorption pharmacotherapy stabilizes or enhances bone density and reduces the risk of fractures. The addition of effective anabolics might increase the effectiveness of treatment by shifting the remodeling equilibrium in favor of formative processes., a2_Because both recombinant GH and IGF-I have certain therapeutic limitations, it is considered to utilize substances which either stimulate endogenous IGF-I production directly in the bone or modulate synthesis and distribution of binding proteins for the peptide. Further new findings related to physiology and pathophysiology of this peptide will contribute to designing new strategies in the prevention of osteoporosis and other serious diseases of old age, such as diabetes, neoplasias or cardiovascular diseases., I. Žofková., and Obsahuje bibliografii
Solid organ transplantation is an established treatment modality in patients with end-stage organ damage in cases where other therapeutic options fail. The long-term outcomes of solid organ transplant recipients have improved considerably since the introduction of the first calcineurin inhibitor (CNI) - cyclosporine. In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered. The immunosuppressive effects of CNIs result from the inhibition of interleukin-2 synthesis and reduced proliferation of T cells due to calcineurin blockade. The considerable side effects that are associated with CNIs therapy include arterial hypertension and nephrotoxicity. The focus of this article was to review the available literature on the pathophysiological mechanisms of CNIs that induce chronic nephrotoxicity and arterial hypertension. CNIs lead to activation of the major vasoconstriction systems, such as the reninangiotensin and endothelin systems, and increase sympathetic nerve activity. On the other hand, CNIs are known to inhibit NO synthesis and NO-mediated vasodilation and to increase free radical formation. Altogether, these processes cause endothelial dysfunction and contribute to the impairment of organ function. A better insight into the mechanisms underlying CNI nephrotoxicity could assist in developing more targeted therapies of arterial hypertension or preventing CNI nephrotoxicity in organ transplant recipients, including heart transplantation., L. Hošková, I. Málek, L. Kopkan, J. Kautzner., and Obsahuje bibliografii
Glucocorticoid (GC) therapy is one of the methods of choices for treatment of autoimmune diseases (ADs). In addition, adrenal androgens are known as immunoprotective GC-antagonists. Adrenal steroids preferentially influence the Th1-components over the Th2 ones. We investigated steroid metabolome (using gas chromatography-mass spectrometry) in healthy controls (H), GC-untreated patients with ADs different from IgA nephropathy (U), GC-treated patients with ADs different from IgA nephropathy (T) and in patients with IgA nephropathy (IgAN), which were monitored on the beginning (N0), after one week (N1) and after one month (N2) of prednisolone therapy (60 mg of prednisolone/day/m2 of body surface). Between-group differences were assessed by one-way ANOVA, while the changes during the therapy were evaluated by repeated measures ANOVA. The ANOVA testing was followed by Duncan’s multiple comparisons. IgAN patients and patients with other ADs exhibited lack of adrenal androgens due to attenuated activity of adrenal zona reticularis (ZR). Androgen levels including their 7α-, 7β-, and 16α-hydroxy-metabolites were further restrained by GC-therapy. Based on these results and data from the literature, we addressed the question, whether a combination of GCs with Δ5-steroids or their more stable synthetic derivatives may be optimal for the treatment of antibodies-mediated ADs., I. Šterzl, M. Hill, L. Stárka, M. Velíková, R. Kančeva, J. Jemelková, L. Czerneková, P. Kosztyu, J. Zadražil, K. Matoušovic, K. Vondrák, M. Raška., and Obsahuje bibliografii
A tumor-targeting drug delivery system consists of a tumor recognition moiety and a directly linked cytotoxic agent or an agent attached to a water-soluble synthetic polymer carrier through a suitable linker. Conjugation of a drug with a polymer carrier can change its solubility, toxicity, biodistribution, blood clearance and therapeutic specificity. Increased therapeutic specificity of a polymer drug can be achieved by the attachment of a targeting moiety (e.g. a lectin, protein, antibody, or peptide) that specifically interacts with receptors on the target cells. A large number of tumor-specific peptides were described in recent years. After a short introduction, some important examples of peptide-targeted conjugates will be described and discussed., E. Böhmová, R. Pola., and Obsahuje bibliografii
The purpose of the present study was to define the indirect central effect of hydrogen sulfide (H2S) on baroreflex control of sympathetic outflow. Perfusing the isolated carotid sinus with sodium hydrosulfide (NaHS), a H2S donor, the effect of H2S was measured by recording changes of renal sympathetic nerve activity (RSNA) in anesthetized male rats. Perfusion of isolated carotid sinus with NaHS (25, 50, 100 μmol/l) dose and timedependently inhibited sympathetic outflow. Preconditioning of glibenclamide (20 μmol/l), a ATP-sensitive K+ channels (KATP) blocker, the above effect of NaHS was removed. With 1, 4-dihydro-2, 6-dimethyl-5-nitro-4-(2-[trifluoromethyl] phenyl) pyridine-3-carboxylic acid methyl ester (Bay K8644, 500 nmol/l) pretreatment, which is an agonist of L-calcium channels, the effect of NaHS was eliminated. Perfusion of cystathionine γ-lyase (CSE) inhibitor, DL-propargylglycine (PPG, 200 μmol/l), increased sympathetic outflow. The results show that exogenous H2S in the carotid sinus inhibits sympathetic outflow. The effect of H2S is attributed to opening KATP channels and closing the L-calcium channels., Qi Guo, Yuming Wu, Hongmei Xue, Lin Xiao, Shneg Jin, Ru Wang., and Obsahuje bibliografii
The most dramatic changes in pulmonary circulation occur at the time of birth. We hypothesized that some of the effects of perinatal hypoxia on pulmonary vessels are permanent. We studied the consequences of perinatal exposure to hypoxia (12 % O2 one week before and one week after birth) in isolated lungs of adult male rats (~12 weeks old) perfused with homologous blood. Perfusion pressure-flow relationship was tilted towards lower pressures in the perinatally hypoxic as compared to the control, perinatally normoxic rats. A non-linear, distensible vessel model analysis revealed that this was due to increased vascular distensibility in perinatally hypoxic rats (4.1±0.6 %/mm Hg vs. 2.3±0.4 %/mm Hg in controls, P = 0.03). Vascular occlusion techniques showed that lungs of the perinatally hypoxic rats had lower pressures at both the pre-capillary and post-capillary level. To assess its role, basal vascular tone was eliminated by a high dose of sodium nitroprusside (20 µM). This reduced perfusion pressures only in the lungs of rats born in hypoxia, indicating that perinatal hypoxia leads to a permanent increase in the basal tone of the pulmonary vessels. Pulmonary vasoconstrictor reactivity to angiotensin II (0.1-0.5 µg) was reduced in rats with the history of perinatal hypoxia. These data show that perinatal hypoxia has permanent effects on the pulmonary circulation that may be beneficial and perhaps serve to offset the previously described adverse consequences., V. Hampl, J. Bíbová, J. Herget., and Obsahuje bibliografii
The 24-hour periodicity of supraventricular (SVPB) and ventricular (VEB) extrasystoles in healthy elderly men (age 49-69 years) was studied at two altitudes during 24 h Holter ECG monitoring. At the low altitude (200 m, n = 26), SVPB were more frequent than VEB. The highest occurrence of SVPB was at 17:00 h, the lowest at 01:00 and 02:00 h (P<0.001). The highest occurrence of VEB was at 09:00 h, the lowest one at 04:00 h (P<0.001). At 1350 m (n=9) the incidence of both SVPB and VEB was approximately twofold higher compared to that at the low altitude (P<0.001). The highest occurrence of SVPB was at 13:00 h, the lowest at 06:00 h (P<0.001). VEB were the most frequent at 10:00 h and 13:00 h, while the lowest frequency was observed at 06:00 h (P<0.001). Our results indicate that the incidence of SVPB and VEB in healthy persons at the moderate altitude is twofold and its periodicity is shifted compared to the low altitude. The cause of increased occurrence of extrasystoles is probably due to β-adrenergic activation of the heart at the higher altitude., Š. Kujaník, M. Sninčák, J.Vokáľ, J. Podracký, J. Koval., and Obsahuje bibliografii