Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Bc. Lenka Jančíková Supervisor: PharmDr. Jana Pourová, Ph.D. Title of diploma thesis: Cardiovascular effects of isoflavonoids Background: The aim of this thesis is to summarize existing findings about natural vegetable substances known as phytoestrogens-isoflavones and to map the results of latest studies focused on cardiovascular effects of isoflavones. Main findings: Available data suggest that isoflavones and their metabolites have positive effect on human organism. These include antiaterosclerotic, antimenopausal and anticarcinogenic effects and a positive effect on osteoporosis. Positive effect on cardiovascular system includes antihypertensive, anti-inflammatory, anti-angiogenic, antiproliferative and antiaggregating effects. On the other hand, there are studies that point out possible risks related to mainly long-term use of isoflavones. Nevertheless, even though the findings of cardiovascular effects are not always consistent, most of them confirm positive effects of isoflavones on cardiovascular system. Conclusion: Isoflavones and their metabolites are a very interesting group of substances with natural origin and carry a potential for possible development of new drugs. Therefore, they...

Made available in DSpace on 2014-06-11T19:22:49Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-12-11Bitstream added on 2014-06-13T20:09:54Z : No. of bitstreams: 1 manzano_bm_me_prud.pdf: 326376 bytes, checksum: 0b7d0d1cb3bdf834e64a73541c8ddedd (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O tabagismo é considerado um dos principais fatores de risco modificáveis de doenças cardiovasculares e suas complicações, dentre as quais doença vascular aterosclerótica, hipertensão, infarto do miocárdio, angina instável e morte súbita. Os efeitos cardiovasculares promovidos pela nicotina ocorrem principalmente, devido ao aumento da atividade simpática, decorrente do estímulo de liberação de catecolaminas, por meio da ativação dos receptores nicotínicos localizados nas terminações nervosas simpáticas pós-ganglionares periféricas e medula adrenal. Além disso, o fumo acarretada uma disfunção autonômica a qual pode ser avaliada por meio da variabilidade da freqüência cardíaca (VFC) que descreve as oscilações dos intervalos entre batimentos consecutivos (intervalos RR) e reflete a atividade do sistema nervoso autônomo (SNA) sobre o nódulo sinusal, sendo uma ferramenta clínica para avaliar e identificar comprometimentos na saúde. Estudos demonstram que o tabagismo crônico leva a ativação simpática e redução da modulação vagal, de forma que essas alterações autonômicas basicamente se expressam por diminuição dos índices de VFC em fumantes. A redução da VFC é considerada uma condição de alta morbidade e mortalidade cardíaca, no entanto, alguns estudos apontam que a cessação do tabagismo pode levar a restauração da função autonômica... / Smoking is considered an important modifiable risk factor for cardiovascular disease and its complications, such as atherosclerosis, hypertension, myocardial infarction, instable angina and sudden death. The cardiovascular effects promoted by nicotine are caused by increased sympathetic activity occurred because of catecholamine release by nicotinic receptors activation at peripheral postganglionic sympathetic nerve endings and adrenal medulla. Moreover, smoking leads to autonomic dysfunction that can be evaluated by heart rate variability (HRV) which describes the oscillations in the interval between consecutive heart beats (RR interval) and reflects the autonomic nervous system (ANS) activity on the sinus node and as a clinical instrument to assess and identify health involvements. Studies have been demonstrated that chronic smoking causes sympathetic activation and reduces vagal modulation and that autonomic alterations basically are showed by decreases of HRV indices in smokers... (Complete abstract click electronic access below)

Orientador: Dionei Ramos / Banca: Moacir Fernandes de Godoy / Banca: Ercy Mara Cipulo Ramos / Resumo: O tabagismo é considerado um dos principais fatores de risco modificáveis de doenças cardiovasculares e suas complicações, dentre as quais doença vascular aterosclerótica, hipertensão, infarto do miocárdio, angina instável e morte súbita. Os efeitos cardiovasculares promovidos pela nicotina ocorrem principalmente, devido ao aumento da atividade simpática, decorrente do estímulo de liberação de catecolaminas, por meio da ativação dos receptores nicotínicos localizados nas terminações nervosas simpáticas pós-ganglionares periféricas e medula adrenal. Além disso, o fumo acarretada uma disfunção autonômica a qual pode ser avaliada por meio da variabilidade da freqüência cardíaca (VFC) que descreve as oscilações dos intervalos entre batimentos consecutivos (intervalos RR) e reflete a atividade do sistema nervoso autônomo (SNA) sobre o nódulo sinusal, sendo uma ferramenta clínica para avaliar e identificar comprometimentos na saúde. Estudos demonstram que o tabagismo crônico leva a ativação simpática e redução da modulação vagal, de forma que essas alterações autonômicas basicamente se expressam por diminuição dos índices de VFC em fumantes. A redução da VFC é considerada uma condição de alta morbidade e mortalidade cardíaca, no entanto, alguns estudos apontam que a cessação do tabagismo pode levar a restauração da função autonômica... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Smoking is considered an important modifiable risk factor for cardiovascular disease and its complications, such as atherosclerosis, hypertension, myocardial infarction, instable angina and sudden death. The cardiovascular effects promoted by nicotine are caused by increased sympathetic activity occurred because of catecholamine release by nicotinic receptors activation at peripheral postganglionic sympathetic nerve endings and adrenal medulla. Moreover, smoking leads to autonomic dysfunction that can be evaluated by heart rate variability (HRV) which describes the oscillations in the interval between consecutive heart beats (RR interval) and reflects the autonomic nervous system (ANS) activity on the sinus node and as a clinical instrument to assess and identify health involvements. Studies have been demonstrated that chronic smoking causes sympathetic activation and reduces vagal modulation and that autonomic alterations basically are showed by decreases of HRV indices in smokers... (Complete abstract click electronic access below) / Mestre

One of the age-related changes associated with normal aging is the inability to maintain normal blood pressure homeostasis, a common clinical condition known as orthostatic intolerance. There are little data on the effects of strength training in healthy adults and orthostatic intolerance, and only one study on strength training and elderly adults diagnosed with orthostatic intolerance. Therefore, the purpose of the present study was to evaluate the effects of resistance training on the cardiovascular respones of elderly individuals during an orthostatic challenge. Thirteen subjects were assigned to either a resistance (RES; n=7; 66±5 yrs.) or a control (CON; n=6; 71±6 yrs.) group. During the 12-week treatment period, the RES trained 2x/wk, while the CON was asked not to change their normal lifestyles. The resistance training consisted of 3 sets of 8-12 repetitions using 12 machines at approximately 22% to 57% of 1RM. Before and after the training and control period, subjects were tested using a 70 degree head-up tilt. Tilt consisted of 30 minutes of supine rest while heart rate(HR) was recorded every minute and blood pressure (BP) was taken every 5 minutes. After the rest period, subjects were tilted to 70 degrees for 30 minutes unless subjects experienced presyncopal symptoms. During the tilt period, HR and BP were recorded every minute. After the tilt, subjects were placed in a supine position for 15 minutes of recovery, HR was taken every minute, and BP was taken every 5 minutes. A 2X2X8(test X group X time) Repeated Measures Analysis of Variance was used to analyze data. Significance was accepted at p ≤ 0.05. After the 12 weeks of training, the RES significantly increased upper (46±24 to 55±29kg) and lower (62±20 to 80±31kg) body strength while the CON showed no changes. Body composition measurements by DEXA showed lean mass to increase significantly (50.5±12.9 to 52.7±13.1kg) for the RES group, while the CON showed no changes. Of the 13 subjects only 9 subjects completed the pre and post tilt tests. Of the 9 completing both tilt periods, there were no significant differences between groups for any of the dependent measures of HR, systolic blood pressure, diastolic blood pressure and mean arterial pressure. In conclusion, this study demonstrated that a resistance training program was well tolerated and improved strength and lean mass in the RES. However, training did not help these individuals improve cardiovascular responses to an orthostatic challenge.

Background: Air pollution is associated with negative health effects. Exposure to combustion-derived particulate matter (PM) air pollution has been related to increased incidence of cardiovascular and respiratory morbidity and mortality, specifically in susceptible populations. Ambient particles, with a diameter of less than 2.5 mm, have been suggested to be the strongest contributor to these health effects. Diesel exhaust (DE) is a major source of small combustion-derived PM air pollution world wide.  In healthy volunteers, exposure to DE, has been associated with airway inflammation and impaired vasomotor function and endogenous fibrinolysis. The aims of this thesis were to further elucidate the underlying mechanisms to the reported cardiovascular effects following exposure to DE, with specific focus on endothelin-1 (ET-1). Additionally, the vascular effects of the major gaseous component of DE, nitrogen dioxide (NO2), were assessed together with the impact of an exhaust particle trap to reduce the observed negative vascular effects after DE exposure. Methods: In all studies healthy, non-smoking male volunteers were included and exposed for one hour during intermittent exercise in a randomised double-blind crossover fashion. In studies I-III, subjects were exposed to DE at a particulate matter concentration of approximately 300 μg/m3 and filtered air, on two different occasions. In study V an additional exposure was employed, during which DE was filtered through an exhaust particle trap. In study IV subjects were exposed to nitrogen dioxide (NO2) at 4 ppm or filtered air. In study I, thrombus formation and platelet activation were assessed using the Badimon ex vivo perfusion chamber and flow cytometry. Study II comprised the determination of arterial stiffness including pulse wave analysis and velocity. In studies III-V, vascular assessment was performed using venous occlusion plethysmography. In studies IV and V, the vascular responses to intra-arterially infused endothelial-dependent and endothelial-independent vasodilatators were registered. In study III, vascular responses to intra-arterial infusion of Endothelin-1 (ET-1) and ET-1-receptor antagonists were assessed. Venous occlusion phlethysmography was in all cases performed 4-6 hours following exposures. Blood samples for markers of inflammation, coagulation and platelet activation were collected before and throughout the study periods in studies III and V. Results: Exposure to DE increased ex vivo thrombus formation and arterial stiffness, in terms of augmentation index. DE inhalation impaired vasomotor function and endogenous fibrinolysis. The exhaust particle trap reduced the particle concentration by 98% and abolished the effects on vasomotor function, endogenous fibrinolysis and ex vivo thrombus formation. Plasma concentrations of ET-1 and its precursor big-ET-1 were unchanged following exposure. Dual endothelial receptor antagonism caused similar vasodilatation after both exposures, although vasodilatation to the endothelin-A receptor alone was blunted after DE exposure. ET-1 infusion induced vasoconstriction only following DE exposure. Exposure to nitrogen dioxide did not affect vascular function. Conclusion: Inhalation of diesel exhaust in young healthy men impaired important and complementary aspects of vascular function in humans; regulation of vascular tone and endogenous fibrinolysis as well as increased ex vivo thrombus formation. The use of an exhaust particle trap significantly reduced particle emissions and abolished the DE-induced vascular and prothrombotic effects. The adverse vascular effects following DE exposure do not appear to be directly mediated through the endothelin system. Neither is NO2 suggested to be a major arbiter of the DE-induced cardiovascular responses. Arterial stiffness is a non-invasive and easily accessible method and could thus be employed to address vascular function in larger field studies. Taken together, this thesis has given further knowledge about the mechanisms underlying the DE-induced vascular effects.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The monoterpene citral is the major constituent of the essential oil of Cymbopogon citratus, medicinal plant popularly known as capim-limão or capim-santo , widely used to treat hypertension. This study evaluated the cardiovascular effects induced by the citral in normotensive rats by using in vivo and in vitro approaches. In non-anaesthetized rats, citral (1, 5, 10, and 20 mg/kg, i.v.) induced transient hypotension and bradycardia. Both effects were significantly attenuated by the pre-treatment with atropine (2 mg/kg, i.v.), hexamethonium (20 mg/kg, i.v.), sodium thiopental (45 mg/kg; i.p.) or indomethacin (5 mg/kg, i.v.) after dose of 5 mg/kg of the citral. After pre-treatment with L-NAME (20 mg/kg, i.v.), hypotension was significantly attenuated, while bradycardia was not altered. Furthermore, electrocardiogram records demonstrated that citral (10 and 20 mg/kg) was also able to induce sinoatrial block, which was reverted by atropine (2 mg/kg). In rings of rat mesenteric artery pre-contracted with phenylephrine (10 μM), citral (10-5 - 10-2 M) was able to induce relaxations (pD2 = 2.52 ± 0.10; Emax = 103.4 ± 10.2%) that was not affected after removal of the endothelium (pD2 = 2.34 ± 0.15; Emax = 107.2 ± 4.3%) or in rings without endothelium pre-contacted with KCl 80 mM (pD2 = 2.04 ± 0.12; Emax = 101.3 ± 7.1%) or in rings without endothelium after tetraethylammonium (pD2 = 3.25 ± 0.05; Emax = 109.3 ± 9.8%). At concentrations of 3 x 10-4 and 10-3 M, citral was able significantly to inhibit the contractions induced by CaCl2 (from 10- 5 to 10-2 M) or sodium orthovanadate (from 3 x 10-4 to 3 x 10-2 M) up to 88.6 ± 3.1% and 93.3 ± 3.8%, respectively. These results demonstrate that citral induces hypotension, which appears to be caused by activation of muscarinic receptors, NO release and, in part, by PGI2 release, associated to bradycardia, which seems to be due to an activation of muscarinic and nicotinic receptors, involving compounds of central nervous system, and sinoatrial block. Furthermore, citral induces vasorelaxation of mesenteric artery possibly caused by the inhibition of the Ca2+ influx through voltage-operated Ca2+ channels associated to a decrease of calcium sensitivity. / O monoterpeno citral é o composto majoritário do óleo essencial de Cymbopogon citratus, planta medicinal conhecida popularmente como capim-santo ou capim-limão , e é utilizada na medicina popular brasileira para o tratamento da hipertensão. Este estudo buscou investigar os efeitos cardiovasculares do citral em ratos normotensos através de experimentos in vivo e in vitro. Em animais não-anestesiados, a administração i.v. do citral (1, 5, 10 e 20 mg/kg) induziu uma resposta transiente caracterizada por hipotensão associada à bradicardia. Estes efeitos foram significativamente atenuados em animais pré-tratados com atropina (2 mg/kg, i.v.), hexametônio (20 mg/kg, i.v.), tiopental (45 mg/kg; i.p.) ou indometacina (5 mg/kg, i.v.) após dose de 5 mg/kg do citral. Em animais pré-tratados com L-NAME (20 mg/kg, i.v.), o efeito hipotensor foi significativamente atenuado, enquanto que a bradicardia não foi alterada. Além disso, registros de ECG mostraram que o citral (10 e 20 mg/kg) foi capaz de induzir bloqueio sinoatrial e que este efeito foi inibido totalmente com a administração de atropina (2 mg/kg; i.v.). Em anéis de artéria mesentérica de rato précontraídas com FEN (10 μM), o citral (10-5 - 10-2 M) induziu relaxamento (pD2 = 2,52 ± 0,10; Emáx = 103,4 ± 10,2%) que não foi alterado após a remoção do endotélio (pD2 = 2,34 ± 0,15; Emáx = 107,2 ± 4,3%), nem em preparações, sem endotélio, pré-contraídas com KCl 80 mM (pD2 = 2,04 ± 0,12; Emáx = 101,3 ± 7.1%) e nem em anéis, sem endotélio, após incubação com 100 μM de TEA (pD2 = 3,25 ± 0,05; Emáx= 109,3 ± 9,8%). Nas concentrações de 3 x 10-4 e 10-3 M, o citral foi capaz de inibir significativamente as contrações induzidas por CaCl2 (10-5 - 10-2 M) e por ortovanadato de sódio (3 x 10-4 - 3 x 10-2 M) em 88,6 ± 3,1% e 93,3 ± 3,8%, respectivamente. Estes resultados demonstram que o citral induz hipotensão, que parece ser causada por ativação de receptores muscarínicos, liberação de NO e em parte, por liberação de PGI2, associada à bradicardia, que parece ser causada pela ativação de receptores muscarínicos cardíacos, nicotínicos ganglionares, envolvendo componentes do sistema nervoso central, e bloqueio sinoatrial. Além disso, o citral induz vasorelaxamento que parece ser causado por bloqueio do influxo de Ca2+ através dos canais de Ca2+ operados por voltagem associado à diminuição da sensibilidade ao Ca2+.

Purpose of Review: Electronic cigarettes (e-cigarettes) are gaining rapid popularity among all age groups, especially among youth. They have evolved into technologically advanced devices capable of delivering nicotine concentration and other substances. In addition to nicotine, e-cigarettes’ constituents possess variety of toxic chemicals that have adverse effects on human body. Recent Findings: In recent years, steady downward trend in tobacco usage has been observed; however, e-cigarette use is on upward trend. E-cigarettes are advertised as “safer” alternatives to conventional smoking and as an aid to smoking cessation. Emerging studies have, however, shown that e-cigarettes have harmful effects on the cardiovascular system and that most of the e-cigarette users are dual users, concurrently using e-cigarettes and smoking conventional cigarettes. Summary: Despite a gap in clinical studies and randomized trials analyzing adverse cardiovascular effects of e-cigarette use, the existing literature supports that different constituents of e-cigarettes such as nicotine, carbonyls, and particulate matters carry potential risk for cardiovascular diseases (CVD) on its users.

Various models of simulated weightlessness and resulting cardiovascular effects have been researched in the last 50 years of space exploration. Examples of such models are the Alter-G (Alt-G) treadmill used for body unweighting and head-up-tilt (HUT) model each providing similar cardiovascular effects, but differing in their stimulation of vestibular centers . Advantages of using the Alt-G include: use of lower body positive pressure (LBPP) to simulate hypogravity, it acts as a countermeasure to alleviate negative cardiovascular effects of standing and provides a constant vestibular stimulus. In addition, the Alt-G shorts themselves may be providing a certain degree of LBPP, acting as a compression garment. Therefore the purpose of this study was to determine the cardiovascular effects of Alt-G shorts and how effective they are as countermeasure to deconditioning effects of space flight. This study tested cardiovascular changes in 12 men and women at 0 and 80 degrees head-up-tilt (HUT0 / HUT80) with and without Alt-G shorts using 5-lead ECG, 10-lead impedance, heart rate, systolic and diastolic blood pressure measurements at finger and arm. The tilt-induced increase in mean heart rate (HR) was significantly smaller when subjects wore the Alt-G shorts. Shorts ended up reducing HR by 2.3 bpm in supine control and by 6.7 bpm at HUT80 (p0.05. Other cardiovascular variables did not show any significant effect from shorts. In conclusion, this study was in line with results from other studies that used compression garments to determine cardiovascular effects of LBPP.

Sympathovagal imbalance is known to precede the on-set of atrial fibrillation (AF) and has been analyzed extensively based on heart rate variability (HRV). However, the relationship between sympathetic and vagal effects before AF onset and their influence on various HRV features have not been fully elucidated. QT interval variability (QTV) reflects sympathetic activity and may therefore provide further insights into this relationship. Using the time delay stability (TDS) method, we investigated temporal changes in coupling behavior before AF onset between 20 vagal or sympathovagal-associated HRV and QTV features. We applied the TDS method to 26 electrocardiograms from the MIT-BIH AF database with at least one hour of sinus rhythm preceding AF onset. Sinus rhythm segments were split into 5-minute windows with 50 % overlap. Logistic regression analysis revealed significantly (p<0.01) increased coupling between QTV and vagal HRV features from 20 to 15 minutes before AF onset. We found similar behavior between QTV and sympathovagal HRV features. This indicates sympathetic predominance increasing until 15 minutes before the onset of AF and decreasing towards vagal predominance right before AF onset. Our results provide new insights into temporal changes of sympathovagal imbalance preceding AF onset and may improve the prediction of AF in clinical applications.

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 5 uppsatser. Även tryckt utgåva.