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Role of KCNQ channels in response of the pulmonary circulation to hypoxia
Šedivý, Vojtěch ; Herget, Jan (advisor) ; Melenovský, Vojtěch (referee) ; Neckář, Jan (referee)
Reaction of pulmonary vascular bed to hypoxia is different than in systemic vasculature. Acute ventilatory hypoxia constricts pulmonary arteries (HPV), diverts blood to better oxygenated alveoli and optimises arterial pO2. Chronic hypoxia causes pulmonary hypertension (HPH) and exposure to hypoxia at birth (perinatal hypoxia) results in longterm changes of pulmonary vasculature, which makes it more susceptible to develop pulmonary hypertension in adulthood. Reaction of pulmonary artery smooth muscle cells (PASMCs) to hypoxia involves membrane depolarization by inhibition of voltage gated potassium channels (Kv). Among them KCNQ (Kv7) channels have biophysical properties (low voltage threshold for activation and lack of inactivation during sustained depolarization) which suggest them to play a key role in hypoxic response. Specific KCNQ channel inhibitor linopirdine primes HPV in saline perfused lungs, but in not primed lungs does not cause vasoconstriction, it behaves in the same way as acute ventilatory hypoxia. Moreover, in primed lungs linopirdin potentiates HPV and prevents non- specific Kv inhibitor 4-aminopyridine to potentiate HPV. It seems, that KCNQ channel inhibition has a key role in HPV. In rats exposed to hypoxia for 3-5 days (normobaric chamber, FiO2 0,1) we examined relationship of...
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Myocardial tolerance to ischemia/reperfusion injury - possible protective mechanisms
Alánová, Petra ; Neckář, Jan (advisor) ; Nováková, Olga (referee) ; Vaněčková, Ivana (referee)
Ischemic heart disease is the leading cause of death and disability worldwide. The effects of ischemic heart disease are usually attributable to the detrimental effects of acute myocardial ischemia/reperfusion (I/R) injury. The aim of the thesis was to contribute to current effort to clarify the basis of mechanisms that could save the heart from I/R injury. The whole thesis is based on four studies; while the first three are published, the fourth one has been under revision. In the first study, we proved the involvement of nitric oxide (NO) in the cardioprotective mechanism of chronic hypoxia (CH). We described that exogenously increased availability of NO as well as inhibition of phosphodiesterase type 5 led to increased myocardial tolerance of normoxic and chronically hypoxic rats. The effects of both interventions were not additive, suggesting that NO is included in cardioprotective signaling of CH. Second study continued in investigating molecular mechanisms underlying cardioprotection induced by CH. We showed that infarct size-limiting effect of adaptation to CH was accompanied by increased myocardial concentration of tumor-necrosis factor alpha (TNF-α) and TNF-α receptor R2. In the third study, we examined the effect of dexrazoxane (DEX), the only clinically approved drug against...
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Reactivity of pulmonary vessels to hypoxia
Koubský, Karel ; Herget, Jan (advisor) ; Červenka, Luděk (referee) ; Neckář, Jan (referee)
Hypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism that maintains optimal oxygenation of blood in the lungs. However, chronic hypoxia causes hypoxic pulmonary hypertension (HPH). Increased reactive oxygen species (ROS) participate in the pathogenesis of HPH. Oxidative stress can cause NO synthase uncoupling and subsequent production of superoxide instead of NO. Increase in intracellular Ca2+ concentration in pulmonary smooth muscle cells is required for pulmonary vasoconstriction. However, vessel tone can also be regulated by vascular smooth muscle cells' calcium sensitivity (without Ca2+ concentration changes). Increase of calcium sensitivity plays a role in HPV and HPH. This study focuses on three mechanisms to influence the increased calcium sensitivity in HPV a HPH: (1) Rho kinase inhibition, (2) effort to re-couple NO synthase, and (3) vasorelaxant effect of tyrosine kinase inhibitors. Normobaric hypoxic chamber (10% O2) or the combination of hypoxia and vascular endothelial growth factor receptor blockade was used to induce pulmonary hypertension in rats. (1) The effect of acute and chronic Rho kinase inhibition was studied on pressure-flow relationship (P/Q) in isolated perfused lungs. Acute Rho kinase inhibition decreased the basal tone of pulmonary vessels in HPH...
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Mechanisms of conduction system development in vertebrates
Šaňková, Barbora ; Sedmera, David (advisor) ; Neckář, Jan (referee) ; Melenovský, Vojtěch (referee)
Group of specialized cells that form cardiac conduction system is responsible for generation and coordinated propagation of the electrical impulse in the heart. Changes in its development can be connected with arrhythmias; therefore, a good level of knowledge is necessary and relevant for basic science and clinical practice. For correct development of the conduction system are important genes coding gap junctions proteins, ion channels, transcription factors and other molecules involved in signaling cascades (endothelin, neuregulin). Development of conduction system is determined in addition to genetic factors also by epigenetics and environmental factors. This thesis with its individual papers on which it is based is addressing different aspects of conduction system development, which appears to be a complex process. Another feature which is linking all papers together, is the methodological approach enabling us to study function of the conduction system - optical mapping. In the first publication we studied by the means of in vitro organ culture the impact of work load without interfering hemodynamics on the conduction system maturation in the chick embryonic heart. The phenotype observed during experiments was developmental regression of conduction system maturation together with changes in...
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Role of Nkx2.5 in development and electrophysiology of the mouse heart
Hámor, Peter ; Sedmera, David (advisor) ; Neckář, Jan (referee)
Role of Nkx2.5 in development and electrophysiology of the mouse heart Prague 2016 Peter Hámor, B.S. ABSTRACT The objective of this thesis is to investigate the role of Nkx2.5 gene dosage on electrophysiology of the mouse heart in prenatal stage of its development. The main goal of this work is to search for differences in conduction of electric impulses through the embryonic mouse hearts of different genotype. Special method of capturing the conduction of electric impulse through myocardium, called optical mapping, was used to visualize the electrical activity. Thanks to this method I was able to construct images and videos capturing the spread of the impulse with identification of the beginning of the activation and its direction in the heart. These outputs, or optical maps, help to define anomalies and defects in mutants compared with a normal functioning heart. The thesis focuses on the expression of the transcription factor Nkx2.5 and regulatory components related with the correct formation and physiology of the heart until 9.5 days post coitum. Embryos at this developmental stage were optically mapped and analysed according to their genotype. While the wild type and heterozygote mouse embryos exhibited high degree of similarity, the homozygous mutants were dramatically different. Considering this work...
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Cardioprotective role of epoxyeicosatrienoic acids in ischemia-reperfusion injury.
Veselá, Barbora ; Neckář, Jan (advisor) ; Kolář, David (referee)
Epoxyeicosatrienoic acids (EETs) are arachidonic acids metabolites that importantly contribute to vascular and cardiac physiology and pathophysiology. Current research in the field of EETs shows that these molecules can significantly reduce the rate of acute ischemia- reperfusion injury of the heart. However, they can also contribute significantly to the recovery of the heart muscle following myocardial infarction and to reduce the development of post- ischemic heart failure. The project aims to outline the known cardioprotective effect(-s) of EETs on myocardial ischemia/reperfusion injury and their mechanisms. Key words: heart, ischemia-reperfusion, epoxyeicosatrienoic acids
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Role of Nkx2.5 on development and electrophysiology of the mouse heart
Hámor, Peter ; Sedmera, David (advisor) ; Neckář, Jan (referee)
Role of Nkx2.5 on development and electrophysiology of the mouse heart Prague 2015 Bc. Peter Hámor ABSTRACT The objective of this thesis is to investigate the role of Nkx2.5 gene dosage on electrophysiology of the mouse heart in prenatal stage of its development, in which the physiological functions of the heart fail to function properly. The main goal of this work is to search for differences in conduction of electric impulses through the embryonic mouse heart according to their genotype. Special method of capturing the conduction of electric impulse through myocardium was used for this purpose, called optical mapping. Thanks to this method I was able to construct images and videos capturing transition of the impulse with marked beginning of the activation and its direction in the heart. These outputs, or optical maps, help to define anomalies and defects compared with a normal functioning heart. The thesis focuses on the expression of the transcription factor Nkx2.5 and regulatory components related with the correct formation and physiology of the heart until 9.5 days post coitum. Individuals in this developmental stage were optically mapped and compared according to their genotypes - homozygous non-mutant, heterozygote and homozygous mutant mouse embryos exhibited some degree of similarity, while other...
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Cardiac ischemic tolerance of hypertensive rats
Jelínek, Jan ; Neckář, Jan (advisor) ; Sotáková, Dita (referee)
The aim of this thesis is to summarize current knowledge about the influence of the ischemic- reperfusion injury at the myocard of hypertensive subjects. First part of this thesis is focused on the description of ischemia, reperfusion and changes in the myocardial metabolism during these processes. These changes in the myocardial metabolism are for example necrosis or apoptosis of the myocardial cells. The second part describes the currently known cardioprotective phenomena. This part also compares their effects. The signalization of preconditioning, the second window of preconditioning and the postconditioning are described here in more details. Third part is focused on the description of the risk factors connected to the ICHS and hypertension. It describes also classes of hypertension, clinical and experimental methods of hypertension treatment, description of the laboratory breeds of hypertensive rats. In the last part of this thesis I describe the influence of hypertension on the I-R injury in current laboratory studies. In the most studies spontaneously hypertensive rats (SHR) were used. As a normotensive controls Wistar-Kyoto rats were mostly used. For some other experiments transgenic genetic rats (TGR) were used. Powered by TCPDF (www.tcpdf.org)
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The effect of methadone on cardiac ischemic tolerance in rats
Mošovská, Linda ; Neckář, Jan (advisor) ; Říha, Hynek (referee)
Opioids are considered as a dangerous addictive substances which are widely used in medicine for their strong analgetic effects. Opioids (such as morphine and methadon) may nevertheless play an important role in the resistance of the heart to ischemia by reducing the rate of cell damage. This protective effect is well understood about morphine but we don't know almost nothing about effects of methadone on the myocardium. The main aim of this thesis was to find out how chronic methadone treatment affects ischemic tolerance of rat hearts. For our experiments we used Wistar rats in two series. In the first series we administered morphine (10 mg/kg/day, i.m.) or methadone (2 mg/kg/day, i.m.) for 10 days. In the second experiment series we administered methadon for 28 days (2 mg/kg/day, i.m.). For analysis of the ischemic heart tolerance we used the isolated perfused heart method. Incidence and severity of ischemia and reperfusion arrhythmias were analyzed during the 50 min of ischemia and early reperfusion. Infarct size was analyzed histochemically, using tetrazolium salts and KMnO4 1 h after reperfusion and was determined by planimetric method. In the first series of experiments analyzing the effect of 10-day administration of both opioids on the resistance of the heart to ischemia we did not find a...
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The effect of chronic hypoxia on cardiac ischemic tolerance of spontaneously hypersensitive rats
Zajíčková, Pavlína ; Neckář, Jan (advisor) ; Žurmanová, Jitka (referee)
The goal of this thesis was to discover the influence of adaptation to chronic hypoxia on ischemic tolerance of heart - this experiment was carried out on two different hypertension kinds of laboratory rats. Spontaneously hypertensive rats (SHR) and rats from a conplastic strain SHR/OlaIpcv-mtBN/Crl , whose mitochondrial genome of the SHR strain was replaced with a mitochondrial genome of the normotensive strain Brown Norway, were exposed to continuous normobaric hypoxia (10% O2) for a period of 3 weeks. On the other hand, the control group of rats was kept in normoxia. At the end of the adaptation period, the ischemic tolerance of heart and the mitochondrial aconitase expression were examined. In the case of both hypertensive strains, the chronic hypoxia led to a significant drop in the size of a myocardial infarction and also to a drop in the number of reperfusion arrhythmias. In the case of the SHR strain, the incidence of ischemic arrhythmias decreased. Chronic hypoxia had no impact on the aconitase expression for both analysed strains. This thesis showed that the ischemic tolerance of heart can be enhanced in the case of the SHR strain. On the other hand, the mitochondrial genome of the SHR strain does not seem to play any significant role in protection mechanism. Key words: chronic hypoxia,...
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