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Anthracycline Cardiotoxicity and Study of New Pharmacological Cardioprotectants
Pokorná, Zuzana ; Štěrba, Martin (advisor) ; Červenka, Luděk (referee) ; Štengl, Milan (referee)
Title: Anthracycline cardiotoxicity and study of new pharmacological cardioprotectants This Ph.D. thesis is a commented collection of 3 original articles published in international journals. The first part deals with cardiotoxicity of proteasome inhibitors (PI) bortezomib and carfilzomib, which are biologically targeted drugs with a suspected risk of cardiotoxicity and heart failure (HF). As PIs are now being combined with anthracycline (ANT) anticancer drugs, which are well known for their damaging impact on the heart, a special attention was paid to this potentially risky combination. In vitro experiments with primary cardiomyocytes yielded different results depending on the employment of either neonatal or adult rat cardiomyocyte model (NVCM and AVCM, respectively). In particular, both PIs significantly increased toxicity of ANTs to NVCM, but not to AVCM, even though they inhibited proteasome activity in AVCM even more effectively. Both PIs administered in maximally tolerated doses in combination with ANT did not have a significant impact on the development of chronic ANT cardiotoxicity and HF in rabbits. Both PIs induced significant but relatively short-lived inhibition of proteasome activity in the heart, which might explain why they did not have a significant impact on a protein homeostasis...
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The role of the endothelin system in development of hypertension and hypertensive end-organ damage in Ren-2 transgenic rats
Opočenský, Martin ; Červenka, Luděk (advisor) ; Neckář, Jan (referee) ; Widimský, Jiří (referee)
The role of the endothelin system in development of hypertension and hypertensive end- organ damage in Ren-2 transgenic rats Endothelin-I (ET-I) has been described as one ofthe most powerful vasoconstrictors, that also play a role in the regulation of renal hemodynamics. ET system plays an important role in the pathogenesis of salt-sensitive models of hl'pertension. The benefícial effects of ET receptor blockers in modulating target-organ damage arise rrom their antiproliferative action. There is, however, a large discrepancy in the effect of ET between various models of hypertension. The hypertensive rat strain transgenic for the mouse Ren-2 (TGR) renin gene is a valuable monogenetic model of renin-dependent and thus angiotensin lI(Ang ll) - dependent hypertension, which exhibits typical signs of fulminant hypertension,i.e. reduced glomerular fíltration rate and proteinuria associated with g1omerulosderosis. Moreover, it carries a salt- sensitive component. We have recently found that nonselective endothelin ETA/ETB receptor blockade markedly improves survival rate and ameliorates end'-organ damage in malcTGR without lowering blood pressure. Because activation ofthe ETA receptor may be responsible for the detrimental effects of ET in the development of hypertension, our study was performed to...
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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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Endothelin and renin - the angiotensin system and its relation to hypertension and hypertension organ damage
Dvořák, Pavel ; Červenka, Luděk (advisor) ; Herget, Jan (referee) ; Janda, Jan (referee) ; Tesař, Vladimír (referee)
Renin-angiotensin and endothelin system play important role in blood pressure regulation. ln order to determine the contribution of an interaction between ET-I and ANG II to the development of hypertension and related end-organ damage in an ANG lI-dependent model of hypertension, we utilized a rat strain transgenic for the mouse Ren-2 renin gene (TGR; strain name TGR(mRen2)27). All our experimental studies have confirmed the crucial effect of increased natrium intake in a diet on development of arterial hypertension and hypertensive end- organ damage (especially kidneys and heart) in this model of arterial hypertension. Previous studies have demonstrated the presence of several types of endothelin system receptors - ETA and ET6 receptors with two subtypes- ETBl and ET62. Our study has brought a new knowledge of physiologic and pathophysiologic function of these receptors. The non- selective blockade of ETA and ETB receptors by Bosentan, improves survival rate of both homozygous and heterozygous transgenic animals, declines extent of hypertensive cardiac end-organ damage and reduce proteinuria and glomeru losclerosis. However, this positive effect of nonselective endothelin blockade is not caused due to decrease of arterial blood pressure. The reason for this fact is probably in various effects of...
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Endothelin and renin - the angiotensin system and its relation to hypertension and hypertension organ damage
Dvořák, Pavel ; Červenka, Luděk (advisor) ; Herget, Jan (referee) ; Janda, Jan (referee) ; Tesař, Vladimír (referee)
Renin-angiotensin and endothelin system play important role in blood pressure regulation. ln order to determine the contribution of an interaction between ET-I and ANG II to the development of hypertension and related end-organ damage in an ANG lI-dependent model of hypertension, we utilized a rat strain transgenic for the mouse Ren-2 renin gene (TGR; strain name TGR(mRen2)27). All our experimental studies have confirmed the crucial effect of increased natrium intake in a diet on development of arterial hypertension and hypertensive end- organ damage (especially kidneys and heart) in this model of arterial hypertension. Previous studies have demonstrated the presence of several types of endothelin system receptors - ETA and ET6 receptors with two subtypes- ETBl and ET62. Our study has brought a new knowledge of physiologic and pathophysiologic function of these receptors. The non- selective blockade of ETA and ETB receptors by Bosentan, improves survival rate of both homozygous and heterozygous transgenic animals, declines extent of hypertensive cardiac end-organ damage and reduce proteinuria and glomeru losclerosis. However, this positive effect of nonselective endothelin blockade is not caused due to decrease of arterial blood pressure. The reason for this fact is probably in various effects of...
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The role of arachidonic acid metabolites in regulation of blood pressure in experimental models of angiotensin II- dependent hypertension
Jíchová, Šárka ; Červenka, Luděk (advisor) ; Zicha, Josef (referee) ; Štengl, Milan (referee)
Introduction: Two major product groups originate from the arachidonic acid metabolic pathway of cytochromes P450: epoxyeicosatrienoic acid (EETs) and 19 and 20-hydroxyeicosatetraenoic acid (19- and 20-HETE). These metabolites play an important role in the regulation of blood pressure, inflammatory responses, regulation of sodium excretion and other crucial physiological processes. Hypothesis: Our studies were based on the hypothesis that abnormalities in the production and function of these cytochrome P450 metabolites significantly contribute to the pathophysiology of hypertension development, in particular in the angiotensin II-dependent models. Objective: To investigate if the increased bioavailability of the above-mentioned metabolites in the kidney tissue will result in blood pressure reduction in the ANG II - dependent rat model of hypertension. Methods: The two methods to increase the concentration of EETs was chosen. In the first part of the study, we administered a soluble epoxide hydrolase inhibitor cAUCB [cis-4- [4- (3-adamantan-1-yl- ureido) cyclohexyloxy] benzoic acid, at a dose of 26 mg.l-1 administered in drinking water], an enzyme responsible for inactivation of biologically active forms of EETs. In the second series of the experiments we applied a synthetic EET analogue, called...
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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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Metabolic and structural differences in primary aldosteronism and essential hypertension
Šomlóová, Zuzana ; Widimský, Jiří (advisor) ; Mlíková Seidlerová, Jitka (referee) ; Červenka, Luděk (referee)
Hypertension is a major risk factor for cardiovascular (CV) disease, and patients with primary aldosteronism (PA) - the most common endocrine cause of hypertension - have a higher incidence of CV complications. The aim of this study was to evaluate the incidence of metabolic differences and organ complications - kidney, heart and blood vessels damage in patients with essential hypertension (EH), PA and its most common forms - idiopathic hyperaldosteronism (IHA) and aldosterone-producing adenoma (APA). We found a higher incidence of metabolic syndrome and a higher incidence of metabolic abnormalities in IHA compared to APA - higher prevalence of metabolic syndrome, higher levels of triglycerides and lower levels of HDL cholesterol and thereby a higher cardiometabolic risk. Metabolic profile of patients with IHA is similar to EH in contrast to APA. Arterial stiffness was expressed as pulse wave velocity (PWV), in central arteries as carotid-femoral PWV and at peripheral level as femoral-ankle PWV. Patients with PA with comparable levels of blood pressure (BP) have higher stiffness of central elastic and peripheral muscular arteries than patients with EH. The main predictor of impaired peripheral arterial stiffness is the plasma aldosterone level. Patients with IHA have higher central arterial...
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