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Combined pharmacotherapy of different types of pulmonary hypertension
Krása, Kryštof ; Hampl, Václav (advisor) ; Neckář, Jan (referee) ; Al-Hiti, Hikmet (referee)
Pulmonary hypertension is a group of diseases characterized by increased mean pulmonary artery pressure. Especially in group 2, which is associated with heart disease and is the most prevalent of all types, and in group 3, associated with lung disease, no sufficiently effective treatment has yet been developed beyond the treatment of the underlying disease, which is problematic in many cases. Dehydroepiandrosterone sulfate (DHEA S) and statins have different mechanisms of action on pulmonary hypertension in some respects, so the question of the effectiveness of combining them on pulmonary hypertension versus either agent alone has been offered. To test this hypothesis, we induced pulmonary hypertension in adult male rats by three weeks of exposure to hypoxia (10% O2) and treated them with simvastatin (60 mg/L) and DHEA S (100 mg/L) in drinking water, either alone or in combination. Both simvastatin and DHEA S reduced mean pulmonary artery pressure (from a mean ± s.d. value of 34.4 ± 4.4 to 27.6 ± 5.9 and 26.7 ± 4.8 mmHg, respectively), but their combination was not more effective (26.7 ± 7.9 mmHg). Differences in the degree of oxidative stress (as indicated by malondialdehydedehydplasma concentration), the degree of superoxide production (electron paramagnetic resonance) or blood nitric oxide...
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Treatment of pulmonary hypertension affect the metabolism of cyclic guanosine monophosphate
Al-Hiti, Hikmet ; Kettner, Jiří (advisor) ; Ošťádal, Petr (referee) ; Goncalvesová, Eva (referee)
Chronic damage to pulmonary vessels leads to pulmonary hypertension (PH). Different forms of PH are quite frequent and are associated with significant morbidity and mortality. The treatment of PH is most successful, if its cause can be identified and removed before irreversible damage to the pulmonary vascular bed occurs. For patients, in whom the elimination of the underlying cause is not possible or where the cause is unknown, the treatment is aimed at reduction of pulmonary vascular resistance and improvement of cardiac and circulatory response to pressure overload of the right ventricle. One option for the PH treatment is modification of metabolism of cyclic guanosine monophosphate (GMP), which is the second messenger of nitric oxide and induces vascular vasodilation. Cyclic GMP is degraded by phosphodiesterases (PDE 5). In the clinical part, we tested the hypothesis that acute inhibition of PDE5 by sildenafil provides more selective pulmonary vasodilation than high doses of prostaglandin E1 (PGE1). The study showed that the vasodilator effects of sildenafil on pulmonary circulation is more pronounced than in the systemic circulation and that sildenafil had a greater ability to detect reversible component precapillary PH due to advanced chronic heart failure than PGE1. The aim of our...
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NITRIC OXIDE AND REACTIVE OXYGEN SPECIES IN ACUTE CORONARY SYNDROME
Šnorek, Michal ; Herget, Jan (advisor) ; Ošťádal, Petr (referee) ; Al-Hiti, Hikmet (referee)
In cardiology, there are different conditions associated with the release of free radicals in some forms of hypoxia, such as ventilatory hypoxia or reduced perfusion. The role of free radicals during hypoxia in cardiology is the key point of our interest. In presented thesis, we have focused on hypoxia-induced pulmonary vasoconstriction and acute myocardial ischemia. Hypoxic pulmonary vasoconstriction (HPV), an important physiological mechanism, is regulated by changes in the production of and interactions among reactive oxygen species (ROS). There is controversy, however, over whether HPV is mediated by an increase or a decrease in ROS production. Also, the role of nitric oxide (NO) in HPV remains unclear. Our results indicate that inhibition of HPV by the superoxide dismutase mimetic tempol does not depend on either NO production or a decrease in basal vascular tone. The effect of three-day fasting on cardiac ischemic tolerance was investigated in another experimental model. Short-term fasting conclusively decreases ROS production. Three-day fasting effectively protected rat hearts against major endpoints of acute ischemia-reperfusion injury. It prevented severe ventricular arrhythmias and reduced the extent of myocardial infarction. These beneficial effects can be linked to altered mitochondrial redox...
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Treatment of pulmonary hypertension affect the metabolism of cyclic guanosine monophosphate
Al-Hiti, Hikmet ; Kettner, Jiří (advisor) ; Ošťádal, Petr (referee) ; Goncalvesová, Eva (referee)
Chronic damage to pulmonary vessels leads to pulmonary hypertension (PH). Different forms of PH are quite frequent and are associated with significant morbidity and mortality. The treatment of PH is most successful, if its cause can be identified and removed before irreversible damage to the pulmonary vascular bed occurs. For patients, in whom the elimination of the underlying cause is not possible or where the cause is unknown, the treatment is aimed at reduction of pulmonary vascular resistance and improvement of cardiac and circulatory response to pressure overload of the right ventricle. One option for the PH treatment is modification of metabolism of cyclic guanosine monophosphate (GMP), which is the second messenger of nitric oxide and induces vascular vasodilation. Cyclic GMP is degraded by phosphodiesterases (PDE 5). In the clinical part, we tested the hypothesis that acute inhibition of PDE5 by sildenafil provides more selective pulmonary vasodilation than high doses of prostaglandin E1 (PGE1). The study showed that the vasodilator effects of sildenafil on pulmonary circulation is more pronounced than in the systemic circulation and that sildenafil had a greater ability to detect reversible component precapillary PH due to advanced chronic heart failure than PGE1. The aim of our...
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