<p>Tulbaghia violacea Harv. (Alliaceae) is a small bulbous herb which belongs to the family, Alliaceae, most commonly associated with onions and garlic. In South Africa (SA), this&nbsp / herb has been traditionally used in the treatment of various ailments, including fever, colds, asthma, paralysis, hypertension (HTN) and stomach problems. The aim of this study&nbsp / was to evaluate the effect of methanol leaf extracts (MLE) of T. violacea on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive rats / &nbsp / and to find out the mechanism(s) by which it acts. The MLE of T. violacea (5 - 150 mg/kg), angiotensin I (ang I, 3.1 - 100 &mu / g/kg), captopril (10 mg/kg), angiotensin II (ang II, 3.1 - 50&nbsp / g/kg), losartan (30 mg/kg), phenylephrine (0.01 &ndash / 0.16 mg/kg), prazosin (1 mg/kg), dobutamine (0.2 &ndash / 10.0 &mu / g/kg), propranolol (0.1 - 12.8 mg/kg), muscarine (0.16 -10 &mu / g/kg),&nbsp / and atropine (0.02 - 20.48 mg/kg) were administered intravenously into male spontaneously hypertensive rats (SHR) weighing between 300 g and 350 g and aged less than 5&nbsp / months. The MLE of T. violacea and/or the standard drugs were infused alone, simultaneously, or separately into each animal. The BP and HR were measured via a pressure&nbsp / transducer connecting the femoral artery and the Powerlab. The vehicle (0.2 mls of a mixture of dimethylsulfoxide and normal saline), T. violacea (60 mg/kg) and captopril (10&nbsp / mg/kg) were injected intraperitoneally into some SHR for 21 days to investigate the chronic effect of these agents on plasma levels of aldosterone. The mean change, the mean&nbsp / of the individual percentage changes and the percentage difference (in mean) observed with each intervention was calculated and statistically analyzed using the Student&rsquo / s t test&nbsp / for significant difference (p &lt / 0.05). The Microsoft Excel software was used for statistical analysis. T. violacea significantly (p &lt / 0.05) reduced the systolic, diastolic, and mean&nbsp / arterial BP / and HR dose-dependently. In a dose-dependent manner, ang I, ang II, phenylephrine significantly (p &lt / 0.05) increased the BP, while propranolol, muscarine and&nbsp / atropine reduced the BP. The increases in BP due to dobutamine were not dose-dependent. In a dose dependent manner, phenylephrine and propranolol reduced the HR, while dobutamine increased the HR. The effect of ang I, ang II, muscarine and atropine on HR were not dose-dependent / with both increases as well as decreases observed with ang&nbsp / I, and II and atropine, while decreases were seen with muscarine. Captopril produced&nbsp / significant (p &lt / 0.05) reduction in BP which were not associated with any change in HR. The co-infusion of ang I with the MLE produced significant (p &lt / 0.05) reduction in BP, which were not associated with significant changes in HR. The co-infusion of ang II with the&nbsp / MLE did not produce any significant changes in BP or HR when compared to the infusion of the standard drug alone. The co-infusion of phenylephrine with the MLE did not&nbsp / produce any significant change in BP or HR when compared to the values obtained with the infusion of the standard drug alone, in both the absence and presence of prazosin.&nbsp / The co-infusion of dobutamine with T. violacea produced siginificant (p &lt / 0.05) increases in DBP which were associated with significant (p &lt / 0.05) reductions in HR, when&nbsp / compared to the values obtained with the infusion of the standard drug alone. Theco-infusion of atropine with the MLE did not produce any significant change in BP or HR when&nbsp / compared to the values obtained with the infusion of atropine alone. However, the infusion of T. violacea, 20 minutes after pre-treating animals with atropine (5.12 mg/kg) lead to&nbsp / dose dependent significant (p &lt / 0.05) increases in BP, which were associated with dose-dependent increases in HR. The chronic treatment of animals with T. violacea or&nbsp / captropril produced (a) signicant (p &lt / 0.05) reductions in the plasma levels of aldosterone when compared to the values obtained in the vehicle-treated group, (b) produced&nbsp / signifiant (p &lt / 0.05) reduction in BP in the captopril treated group when compared to the vehicle-treated, (c) did not produce any signficant change in BP in the T. violacea-treated&nbsp / group when compared to the vehicle-treated group and (d) did not produce any signifiant change in HR or body weight in any of the groups. The result obtained in this study&nbsp / suggests that T. violacea reduced BP and HR in the SHR. Secondly, the BP and HR reducing effect of the MLE may involve a) the inhibition of the ACE, b) the inhibition of the &beta / 1&nbsp / adrenoceptors, c) the stimulation of the muscarinic receptors and d) the reduction of the levels of aldosternone in plasma. The results also&nbsp / suggest that the MLE may not act&nbsp / through the angiotensin II receptors or the &alpha / 1 adrenergic receptors.&nbsp / </p>

<p>Tulbaghia violacea Harv. (Alliaceae) is a small bulbous herb which belongs to the family, Alliaceae, most commonly associated with onions and garlic. In South Africa (SA), this&nbsp / herb has been traditionally used in the treatment of various ailments, including fever, colds, asthma, paralysis, hypertension (HTN) and stomach problems. The aim of this study&nbsp / was to evaluate the effect of methanol leaf extracts (MLE) of T. violacea on the blood pressure (BP) and heart rate (HR) in anaesthetized male spontaneously hypertensive rats / &nbsp / and to find out the mechanism(s) by which it acts. The MLE of T. violacea (5 - 150 mg/kg), angiotensin I (ang I, 3.1 - 100 &mu / g/kg), captopril (10 mg/kg), angiotensin II (ang II, 3.1 - 50&nbsp / g/kg), losartan (30 mg/kg), phenylephrine (0.01 &ndash / 0.16 mg/kg), prazosin (1 mg/kg), dobutamine (0.2 &ndash / 10.0 &mu / g/kg), propranolol (0.1 - 12.8 mg/kg), muscarine (0.16 -10 &mu / g/kg),&nbsp / and atropine (0.02 - 20.48 mg/kg) were administered intravenously into male spontaneously hypertensive rats (SHR) weighing between 300 g and 350 g and aged less than 5&nbsp / months. The MLE of T. violacea and/or the standard drugs were infused alone, simultaneously, or separately into each animal. The BP and HR were measured via a pressure&nbsp / transducer connecting the femoral artery and the Powerlab. The vehicle (0.2 mls of a mixture of dimethylsulfoxide and normal saline), T. violacea (60 mg/kg) and captopril (10&nbsp / mg/kg) were injected intraperitoneally into some SHR for 21 days to investigate the chronic effect of these agents on plasma levels of aldosterone. The mean change, the mean&nbsp / of the individual percentage changes and the percentage difference (in mean) observed with each intervention was calculated and statistically analyzed using the Student&rsquo / s t test&nbsp / for significant difference (p &lt / 0.05). The Microsoft Excel software was used for statistical analysis. T. violacea significantly (p &lt / 0.05) reduced the systolic, diastolic, and mean&nbsp / arterial BP / and HR dose-dependently. In a dose-dependent manner, ang I, ang II, phenylephrine significantly (p &lt / 0.05) increased the BP, while propranolol, muscarine and&nbsp / atropine reduced the BP. The increases in BP due to dobutamine were not dose-dependent. In a dose dependent manner, phenylephrine and propranolol reduced the HR, while dobutamine increased the HR. The effect of ang I, ang II, muscarine and atropine on HR were not dose-dependent / with both increases as well as decreases observed with ang&nbsp / I, and II and atropine, while decreases were seen with muscarine. Captopril produced&nbsp / significant (p &lt / 0.05) reduction in BP which were not associated with any change in HR. The co-infusion of ang I with the MLE produced significant (p &lt / 0.05) reduction in BP, which were not associated with significant changes in HR. The co-infusion of ang II with the&nbsp / MLE did not produce any significant changes in BP or HR when compared to the infusion of the standard drug alone. The co-infusion of phenylephrine with the MLE did not&nbsp / produce any significant change in BP or HR when compared to the values obtained with the infusion of the standard drug alone, in both the absence and presence of prazosin.&nbsp / The co-infusion of dobutamine with T. violacea produced siginificant (p &lt / 0.05) increases in DBP which were associated with significant (p &lt / 0.05) reductions in HR, when&nbsp / compared to the values obtained with the infusion of the standard drug alone. Theco-infusion of atropine with the MLE did not produce any significant change in BP or HR when&nbsp / compared to the values obtained with the infusion of atropine alone. However, the infusion of T. violacea, 20 minutes after pre-treating animals with atropine (5.12 mg/kg) lead to&nbsp / dose dependent significant (p &lt / 0.05) increases in BP, which were associated with dose-dependent increases in HR. The chronic treatment of animals with T. violacea or&nbsp / captropril produced (a) signicant (p &lt / 0.05) reductions in the plasma levels of aldosterone when compared to the values obtained in the vehicle-treated group, (b) produced&nbsp / signifiant (p &lt / 0.05) reduction in BP in the captopril treated group when compared to the vehicle-treated, (c) did not produce any signficant change in BP in the T. violacea-treated&nbsp / group when compared to the vehicle-treated group and (d) did not produce any signifiant change in HR or body weight in any of the groups. The result obtained in this study&nbsp / suggests that T. violacea reduced BP and HR in the SHR. Secondly, the BP and HR reducing effect of the MLE may involve a) the inhibition of the ACE, b) the inhibition of the &beta / 1&nbsp / adrenoceptors, c) the stimulation of the muscarinic receptors and d) the reduction of the levels of aldosternone in plasma. The results also&nbsp / suggest that the MLE may not act&nbsp / through the angiotensin II receptors or the &alpha / 1 adrenergic receptors.&nbsp / </p>

La néphropathie diabétique est une maladie rénale caractérisée par un syndrome néphrotique et de la glomérulosclérose. Celle-ci est reliée à l’angiopathie de capillaires suite au diabète. Il s’agit d’une importante cause d’insuffisance rénale en Amérique. Or, les anomalies tubulaires comme l’apoptose ou le détachement de tubules des glomérules sont reconnues comme étant de bons marqueurs de progression de cette maladie. Ainsi, il a été proposé au cours des travaux reliés à cette thèse d’étudier les différents mécanismes moléculaires reliés à l’apoptose des tubules proximaux, en particulier dans un thème de relation avec les dommages reliés aux espèces réactives oxygénées (ROS). Une des hypothèses développée au cours de précédents travaux faisait état que l’une des sources initiales qui entrainent le développement de dommages tubulaires soit régulée à travers la production de ROS dérivés des NADPH oxydases. Ainsi, une des premières séries d’expériences entreprises au cours de cette thèse a été effectuée sur un modèle animal de diabète de type 2, la souris db/db. Suite à la caractérisation des différentes pathologies rénales et leur réduction par la surexpression de l’enzyme antioxydante catalase dans les tubules proximaux, des expériences de micro-puces d’expression génétiques furent effectuées. À l’aide de cet outil et par des analyses bioinformatiques, il a été possible d’établir un profilage de gènes reliés à différentes voies de signalisation modulées par le diabète et la catalase. Ainsi, il a été possible d’effectuer de plus amples études sur des gènes reliés à l’apoptose surexprimé dans les tubules proximaux de souris diabétiques. Un des gènes pro-apoptotique mieux caractérisé durant cette thèse fut le gène Bmf, un membre de la famille des régulateurs de Bcl-2 impliqués dans l’apoptose via le relâchement de cytochrome c de la mitochondrie. Ainsi, il a été déterminé que ce gène est surexprimé dans les tubules proximaux de souris diabétiques, et que celui-ci était augmenté dans différents modèles in vitro de diabète. Cela a permis de conclure que Bmf joue sans doute un rôle important la régulation de l’apoptose et de l’atrophie des tubules proximaux. Une autre étude effectuée dans le cadre de cette thèse était reliée avec l’utilisation d’un modèle transgénique afin de mieux définir le rôle que jouent les dommages reliés au stress oxydatif dans la progression des pathologies rénales reliées à l’induction du système rénine-angiotensine. Les résultats obtenus ont permis de déterminer que la surexpression de l’enzyme antioxydante catalase a permis de réduire les différentes pathologies rénales observées dans les souris transgéniques, ce qui permet de conclure que les espèces réactives oxygénées jouen un rôle important dans le développement de l’hypertension et des dommages rénaux. / Diabetic nephropathy is a disease characterized by a nephrotic syndrome and glomerulosclerosis. It is related to capillaries angiopathy caused by diabetes. It is one of the main sources of end stage renal disease in America. Tubular anomalies such as apoptosis or tubular detachment from glomeruli are known to be efficient markers for the progression of this disease. Thus, it has been proposed during the work related to this thesis to study the different molecular mechanisms linked with proximal tubules apoptosis, particularly those related with reactive oxygen species (ROS). A previously stated hypothesis made by our laboratory stated that one of the initial sources of the development of tubular damages may be regulated by the production of ROS by NADPH oxidases. Thus, one of the first series of experiments carried during this thesis was done on an animal model of type 2 diabetes, the db/db mouse. Following the characterization of different renal pathologies and their reduction in the proximal tubules by the antioxidant enzyme catalase, experiment with genetics expression microarrays were carried. Using this tool and bioinformatics analysis, it was possible to profile different genes linked to pathways involved by diabetes and the catalase enzyme. Thus, it was possible to carry further studies on these genes linked to apoptosis and overexpressed in the proximal tubules of diabetic mice. One of the pro apoptotic genes characterized in this thesis was the Bmf gene, a member of the family of Bcl-2 regulator, involved in apoptosis related to the release of cytochrome c from the mitochondria. Thus, it was determined that this gene is overexpressed in the proximal tubules of diabetic mice, and that it was also upregulated by in vitro models of diabetes. This enabled our team to conclude that Bmf must play an important role in the regulation of apoptosis and atrophy of the proximal tubules. Another study carried during this thesis was linked with the use of a transgenic animal model to better define the role played by damages related to oxidative stress in the progression of renal pathologies related to renin-angiotensin system activation. The results obtained by this study stated that overexpression of the antioxidant enzyme catalase managed to reduce the different kidney pathologies observed in the transgenic model, which let us conclude that reactive oxygen species have an important role to play in the development of hypertension and kidney damages.

Le système cardiovasculaire est composé d'un cœur qui pompe régulièrement le sang à travers des artères afin d'alimenter tous les tissus corporels en oxygène et nutriments qui leur sont nécessaires. Une caractéristique particulière de ce système est son aspect fermé, où le sang fait un cycle constant commençant par le ventricule gauche, allant vers tous les tissus corporels, revenant vers le cœur et le ventricule droit, étant propulsé vers la circulation pulmonaire en retournant au ventricule gauche. L'insuffisance cardiaque est alors une incapacité du cœur à effectuer sa tâche de pomper le sang efficacement. Une série d'ajustements sont alors enclenchés pour rétablir un débit sanguin adéquat; cette réponse systémique est principalement menée par le système rénine-angiotensine-aldostérone ainsi que par le système adrénergique. À court terme, le flot sanguin est rétabli et le métabolisme corporel continue comme si rien n'était, de telle sorte que, souvent ce stade passe inaperçu et les individus qui en sont affectés sont asymptomatiques. Cependant, le cœur doit alors fournir un effort constant supérieur et si la cause n'est pas résolue, la condition cardiaque se dégradera encore plus. Si tel est le cas, pour s'ajuster à cette nouvelle réalité, le cœur, comme tout muscle, deviendra plus massif et changera de conformation afin de répondre à sa nouvelle charge de travail. Cette transformation cardiaque est communément connue sous le terme de remodelage. Par contre, le remodelage cardiaque est délétère à long terme et entrave encore plus le cœur à bien effectuer sa tâche. Au fur et à mesure que la fonction cardiaque décline, les systèmes compensatoires persistent et s'intensifient; il y a alors établissement d'un cercle vicieux destructeur qui ne peut être renversé que par une transplantation cardiaque. Entre temps, des thérapies inhibant le système rénine-angiotensine-aldostérone et le système adrénergique se sont avérés très efficaces pour prolonger la survie, diminuer la mortalité, réduire les hospitalisations ainsi que soulager la symptomatologie associée à l'insuffisance cardiaque. Par contre, ces régimes thérapeutiques ne semblent pas induire une réponse positive chez tous les patients, de sorte que certains n'en retirent pas de bénéfices tangibles, tandis que d'autres éprouvent plusieurs difficultés à les tolérer. Suite à des analyses rétrospectives, surtout en comparant la réponse thérapeutique entre des populations de diverses ethnies, les variations génétiques, particulièrement les polymorphismes ayant le potentiel de moduler le mécanisme d'action de la pharmacothérapie, furent proposés comme responsables de cette variabilité dans la réponse aux médicaments. Certains ont aussi proposé que certains polymorphismes pourraient être considérés comme des facteurs de risque prédisposant à l'insuffisance cardiaque ou coupables de moduler sa progression en tant que facteurs aggravants ou atténuants. Avec de telles hypothèses proposées, plusieurs associations génétiques furent étudiées en commençant par des gènes directement impliqués dans la pathogénèse de cette maladie. Dans le cadre de cette thèse, nous allons revoir les diverses données disponibles dans la littérature au sujet de l'influence que peuvent avoir les divers polymorphismes impliqués dans la prédisposition, la progression et la pharmacogénétique de l'insuffisance cardiaque. / The cardiovascular system is composed of a heart that regularly pumps blood through the arteries in order to meet the peripheral tissues' demand for oxygen and nutrients. One particularity of this system is its closed aspect where the blood constantly travels in a circular fashion: starting from the left ventricle it is thrusted towards the body tissues, returns to the right side of the heart, is propelled through the pulmonary circulation by the right ventricle and returns again to its starting point, the left ventricle. Heart failure is then the incapacity of the heart to perform its task of appropriately pumping blood. A series of adjustments are then put in place in order to restore an adequate blood flow; this systemic response is mainly lead by the renin-angiotensin-aldosterone and the adrenergic systems. In the short term, the proper blood flow is re-established and the body's metabolism is mainly not affected. This initial stage goes frequently unnoticed and the affected individuals are essentially asymptomatic. However, the heart now needs to deliver a constantly elevated effort and if the precipitating cause is not resolved, the cardiac condition will degrade even further. If this is the case, to adjust itself to this new state, as would any muscle, the heart will become more massive and change its conformation in order to respond to this new workload. This transformation of the heart is commonly referred to as remodelling. However, in the long run, this cardiac remodelling is detrimental and hinders even further the ability of the heart to effectively perform its task. As the cardiac function declines, the compensatory systems persist and intensify; a destructive vicious cycle is then established which will ultimately lead to a heart transplantation or death. In the meantime, therapies inhibiting the renin-angiotensin-aldosterone and the adrenergic systems were found to be very effective in prolonging lifespan, diminishing mortality, reducing hospitalisations and relieving some of the symptomatology associated with heart failure. However, these therapeutic strategies do not seem to induce a positive response in all, thus some patients do not derive any tangible benefits, whereas others experience many difficulties in tolerating them. Following retrospective analysis, especially when comparing the therapeutic response between different ethnic populations, the genetic variations, particularly polymorphisms having the potential to modulate the mechanism of action of pharmacotherapy, were put forward as culprits of this variability in response to medications. Furthermore, some researchers have also suggested that certain polymorphisms might be considered as risk factors predisposing towards heart failure or capable of modulating its progression, whether they act as aggravating or attenuation factors. With such hypothesis, many genetic associations were studied, many starting with genes directly implicated in the pathogenesis of this disease. Within the framework of this thesis, we will review the current data available in the literature as it pertains to the influence that various polymorphisms can have on the predisposition, the progression and the pharmacogenetics of heart failure.

Preeclampsia is among the leading causes of perinatal mortality and morbidity, affecting 2-7% of pregnancies. Its incidence increases to 10-25% in already hypertensive women. To date, no treatment, aside from delivery, is known. Interestingly, several studies have reported that exercise training (ExT) can reduce preeclampsia prevalence although the available studies are considered insufficient. Therefore, the aim of this study is to determine the impact of ExT when practiced before and during gestation on pregnancy outcome in a mouse model of preeclampsia superimposed on chronic hypertension (SPE). To do so, mice overexpressing both human angiotensinogen and renin (R+A+) were used because they are hypertensive at baseline and they develop many hallmark features of SPE. Mice were trained by placing them in a cage with access to a running wheel 4 weeks before and during gestation. ExT in this study prevented the rise in blood pressure at term observed in the sedentary transgenic mothers. This may be realized through an increased activity of the angiotensin-(1-7) axis in the aorta. In addition, ExT prevented the increase in albumin/creatinine ratio. Moreover, placental alterations were prevented with training in transgenic mice, leading to improvements in placental and fetal development. Placental mRNA and circulating levels of sFlt-1 were normalized with training. Additionally, the increase in angiotensin II type I receptor and the decrease in Mas receptor protein were reversed with training. ExT appears to prevent many SPE-like features that develop in this animal model and may be of use in the prevention of preeclampsia in women. / La prééclampsie est l’une des causes primaires de mortalité et morbidité périnatales, touchant 2-7% des grossesses. Sa prévalence augmente à 10-25% chez les femmes hypertendues. Jusqu’à maintenant, aucun traitement, mis à part l’accouchement précoce, n’est connu. Néanmoins, plusieurs études épidémiologiques suggèrent une diminution de l’incidence de la prééclampsie chez les femmes entraînées quoique, ces études sont considérées insuffisantes. Ainsi, le but de cette étude est de déterminer si l’entraînement avant et pendant la grossesse prévient la maladie dans un modèle animal de prééclampsie superposée à de l’hypertension chronique (SPE). Nous avons utilisé des souris double transgéniques, surexpirmant la rénine et l’angiotensinogène humaines (R+A+), puisqu'elles sont hypertensives à la base, et développent plusieurs symptômes de la prééclampsie. Pour l'entraînement, les souris ont été mises dans des cages d’exercice 4 semaines avant leur grossesse et y sont restées jusqu’au sacrifice. L'entraînement physique a prévenu la hausse de pression artérielle en fin de gestation présente chez les souris R+A+ sédentaires, possiblement via l’axe de l’angiotensine-(1-7). Le rapport entre l’albumine: créatinine a également été réduit avec l’entraînement. Les altérations placentaires ont été prévenues chez les souris entraînées, améliorant le développement placentaire et fœtal. Ceci était accompagné d'une normalisation de sFlt-1 circulant et placentaire. De plus, l’augmentation du récepteur à l’angiotensine II de type 1 et la diminution du récepteur Mas dans le placenta étaient renversées. L’entraînement semble prévenir plusieurs symptômes de la SPE dans un modèle animal suggérant qu'il pourrait être d'une grande utilité dans la prévention de la maladie chez la femme.

No description available.

O hipertireoidismo é uma patologia epidemiologicamente importante, que afeta o sistema cardiovascular de forma proeminente. O estado hipertireoideo pode afetar o metabolismo basal, consumo de O2 celular, sistema renina angiotensina, assim como, estimular a produção de espécies ativas de oxigênio. Estas alterações produzem consequências morfológicas, funcionais, bioquímicas e moleculares no tecido cardíaco. A hipertrofia cardíaca, decorrente do hipertireoidismo, instala-se devido a uma série de eventos que sinalizam à proliferação e sobrevivência celular, envolvendo as espécies ativas de oxigênio, a ativação do sistema renina angiotensina cardíaco e o sistema nervoso autonômico. Neste estudo, bloqueamos o receptor AT1 da angiotensina II para avaliarmos a influência do sistema renina angiotensina cardíaco sobre o desenvolvimento da hipertrofia cardíaca, a participação do balanço autonômico sobre o coração e o papel das espécies ativas de oxigênio neste processo, em modelo experimental de hipertireoidismo. Para isto, foram utilizados ratos Wistar machos, pesando cerca de 220g, divididos em 4 grupos experimentais: Controle (C), Losartan (L) (10 mg/Kg de peso corporal/dia, 28 dias, sonda intragástrica) , T4 (12mg/L água de beber, 28 dias), e T4+L. Foram avaliados a massa cardíaca, análise espectral do balanço simpato-vagal, a expressão protéica do receptor AT1 da Angiotensina II e da gp91phox, peróxido de hidrogênio (H2O2), Nrf-2 e Heme-oxigenase-1 (HO-1) no tecido cardíaco. A hipertrofia cardíaca e o desequilíbrio autonômico induzidos pelo hipertireoidismo foram atenuados no grupo T4+L. Os níveis de H2O2, Nrf-2, gp91phox e HO-1 foram elevados no grupo T4, e significativamente reduzidos no grupo T4+L, quando comparados ao grupo Controle. A expressão protéica do receptor AT1 esteve elevada nos dois grupos hipertireoideos. Os resultados obtidos sugerem que o bloqueio do receptor AT1 promove importante impacto sobre o balanço simpato-vagal e a hipertrofia cardíaca, no hipertireoidismo, sendo as espécies ativas de oxigênio e o sistema Nrf-2/HO-1 possíveis mediadores destas alterações. / Hyperthyroidism is an epidemiologic relevant pathology, which substantially affects the cardiovascular system. The hyperthyroid state may affect basal metabolism, O2 cell consumption, renin-angiotensin system, and increase reactive oxygen species production. Those alterations produce morphological, biochemical, functional and molecular consequences in cardiac tissue. Hyperthyroidism induced cardiac hypertrophy develops due to a set of events, which signals cell survival and proliferation, including reactive oxygen species, cardiac rennin-angiotensin system, and autonomic nervous system. In the present study, the role of cardiac renin-angiotensin system on development of hyperthyroidism induced cardiac hypertrophy, and the involvement of autonomic nervous system and reactive oxygen species, were assessed trough blockade of angiotensin II receptor AT1. For that, were used male Wistar rats, weighting about 220g, divided in 4 experimental groups,: Control (C), Losartan (L) (10mg/Kg body weight/day, 28 days, intragastric probe), T4 (12mg/L L-thyroxin in drinking water, 28 days), and T4+L. Cardiac mass, spectral analysis (autonomic balance), hydrogen peroxide (H2O2), and myocardial protein expression of angiotensin II receptor (AT1), NADPH oxidase, Nrf-2, and heme-oxygenase-1 (HO-1), were quantified. Cardiac hypertrophy and autonomic umbalance induced by thyroid hormones were attenuated in the T4+losartan group. The H2O2, as well as Nrf-2, gp91phox, AT1 and HO-1 immunocontent were elevated in T4 group. All these effects were attenuated by losartan, except AT1 levels. The overall results suggest that blockade of AT1 receptor lead to relevant impact on autonomic balance and cardiac hypertrophy, being ROS and Nrf-2/ HO-1 system possible mediators in this alterations in experimental hyperthyroidism.

Made available in DSpace on 2015-07-22T20:50:31Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-08-26 / Obesidade, hipertensão, dislipidemia e diabetes tipo 2 são os principais fatores de risco que caracterizam a síndrome metabólica quando presentes simultaneamente. Com o aumento dos níveis de leptina em quadros de obesidade e a correlação desta patologia com a hipertensão, objetivou-se neste trabalho o estudo das possíveis implicações do hormônio leptina na hipertensão de forma central e periférica e a interação com o principal sistema no controle da pressão arterial (PA), o sistema renina-angiotensina (SRA). Neste trabalho nós mostramos que camundongos com mutação espontânea no gene da leptina, ob/ob, ou no receptor de leptina, db/db apresentam deficiências no controle da PA e ritmo circadiano, alterações no SRA e disfunção autonômica. Em camundongos ob/ob, a atividade da ECA, uma das principais enzimas do SRA, apresentou-se reduzida em condições basais e foi restabelecida após o tratamento agudo com leptina. Cronicamente, a administração de leptina aumentou a atividade dessa enzima e a concentração de fatores que compõem o SRA, como o peptídeo vasoconstritor angiotensina II em camundongos ob/ob. No entanto, não houve aumento da PA. Os camundongos ob/ob apresentaram menor baroreflexo, diminuição da ativação parassimpática e aumento da ativação simpática. Os camundongos db/db também apresentaram o mesmo fenótipo. O tratamento com leptina provocou diminuição do peso e restabeleceu a disfunção autonômica em camundongos ob/ob. Surpreendentemente, o tratamento com enalapril também restabeleceu o tônus autônomo, simpático e parassimpático, assim como o baroreflexo em ob/ob e db/db sugerindo a importância da angiotensina II no controle autônomo concomitante com a ausência na sinalização de leptina. Nossos dados sugerem uma nova interação da via de leptina com o SRA, sendo a angiotensina II um possível fator necessário para a manutenção da ativação autonômica e sobrevivência desses camundongos. / The leptin deficient ob/ob mice are insulin resistant and obese. However, the control of blood pressure in this model is not well defined. The goal of this study was to evaluate the role of leptin and the renin-angiotensin system (RAS) in the cardiovascular abnormalities observed in obesity using a model lacking leptin. Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here we tried to answer the question whether ACE and leptin could influence blood pressure control being a link between renin-angiotensin system and obesity in ob/ob mice, a model lacking leptin. These mice are obese and diabetic, but have normal 24h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Leptin chronic infusion increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion could restore ACE activity in leptin deficient mice. Moreover, the effect of ACE inhibitor on blood pressure during leptin treatment was not changed in lean, but increased four times in obese mice. In a second part of the study we measured blood pressure in ob/ob and control animals by radiotelemetry combined with fast Fourier transformation before and after both leptin and enalapril treatment. Autonomic function was assessed pharmacologically. Blood pressure during daytime was slightly higher in the ob/ob compared to control mice while no difference in heart rate was observed. Blood pressure response to trimetaphane and heart rate response to metoprolol were greater in ob/ob mice than in control littermates indicating an activated sympathetic nervous system. Heart rate response to atropine was attenuated. Baroreflex sensitivity and heart rate variability were blunted in ob/ob mice, while low frequency of systolic blood pressure variability was found increased. Chronic leptin replacement reduced blood pressure and reversed the impaired autonomic function observed in ob/ob mice. Inhibition of ACE by enalapril treatment had similar effects prior loss of weight. These findings suggest that the RAS is involved in the autonomic dysfunction caused by the lack of leptin in ob/ob mice. In summary, our findings show that the RAS is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible correlation between RAS and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems and may contribute to clarify the role played by these systems in the pathogenesis of obesity, hypertension, and metabolic syndrome. / TEDE / BV UNIFESP: Teses e dissertações

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / As associações entre obesidade, doença hepática gordurosa não alcoólica (NAFLD) e diabetes mellitus tipo 2 (DM2) são bem estabelecidas, e o sistema renina-angiotensina (SRA) pode proporcionar uma ligação entre eles. O bloqueio do SRA em diferentes níveis pode estar relacionado a respostas na resistência à insulina, remodelagem do pâncreas e do fígado em um modelo de obesidade induzida por dieta. Camundongos C57BL/6 foram alimentados com uma dieta hiperlipídica (HF) durante oito semanas e depois tratados com alisquireno (50 mg/kg/dia), enalapril (30 mg/kg/dia) ou losartana (10 mg/kg/dia) por um período adicional de seis semanas. As drogas foram incorporadas na dieta. Avaliou-se a massa corporal (MC), pressão arterial, consumo e gasto energético (GE), metabolismo da glicose e lipídico, histopatologia pancreática e hepática, análise hormonal, imunohistoquímica, perfil gênico e/ou proteico do SRA no pâncreas, gliconeogênese hepática, sinalização da insulina, oxidação e acúmulo lipídico. Todos os inibidores do SRA reduziram significativamente o aumento da pressão arterial nos camundongos alimentados com dieta HF. O tratamento com enalapril, mas não alisquireno ou losartana, reduziu o ganho de MC e a ingestão alimentar; aumentou o GE; amenizou a intolerância à glicose e resistência à insulina; melhorou a massa de células alfa e beta; impediu a redução da adiponectina plasmática e restaurou a sensibilidade à leptina. Além disso, o tratamento com enalapril melhorou a expressão proteica nas ilhotas pancreáticas de Pdx1, GLUT2, ECA2 e do receptor Mas. O tratamento com losartana apresentou uma elevação na expressão proteica de AT2R no pâncreas. No fígado, a administração de enalapril atenuou a esteatose hepática, o acúmulo de triglicerídeos e preveniu o aumento dos níveis de PEPCK, G6Pase e do GLUT2. Do mesmo modo, o enalapril melhorou a transdução dos sinais da insulina através da via IRS-1/Akt, bem como reduziu os níveis de expressão gênica e/ou proteica de PPAR-gama, SREBP-1c e FAS. Esses resultados sugerem que a inibição da ECA com enalapril atenuou muitos efeitos deletérios provocados pelo consumo da dieta HF, incluindo: normalização da morfologia e função das ilhotas pancreáticas, proteção contra a resistência à insulina e acúmulo de lipídios no fígado. Estes efeitos protetores do enalapril podem ser atribuídos, principalmente, à redução no ganho de MC e ingestão alimentar, aumento do GE, ativação do eixo ECA2/Ang(1-7)/receptor Mas e dos níveis de adiponectina, o que promove uma melhora na ação hepática da insulina e leptina, normalização da gliconeogênese, amenizando a NAFLD. / The associations between obesity, NAFLD (non-alcoholic fatty liver disease) and diabetes are well established, and the reninangiotensin system (RAS) may provide a link among them. . The blocking of the RAS at different levels may be related to responses on insulin resistance, remodeling of the pancreas and liver in a model of diet-induced obesity. Mice (C57BL/6) were fed on a high-fat (HF) diet for 8 weeks and then treated with aliskiren (50 mg/kg/day), enalapril (30 mg/kg/day) or losartan (10 mg/kg/day) for an additional 6 weeks. The drugs were incorporated into the diet. We assessed body mass (BM), blood pressure, energy intake and expenditure (EE), glucose and lipid metabolism, pancreatic and hepatic histopathology, hormonal analysis, immunohistochemistry, the expression profile of genes and/or proteins affecting pancreas RAS, hepatic gluconeogenesis, insulin signaling and lipid oxidation and accumulation. All RAS inhibitors significantly attenuated the increased blood pressure in mice fed a HF diet. Treatment with enalapril, but not aliskiren or losartan, significantly attenuated BM gain, increased EE, enhanced the glucose intolerance and insulin resistance; improved the alpha and beta cell mass; prevented the reduction of plasma adiponectin and restored leptin sensibility. Furthermore, enalapril treatment improved the protein expression of the pancreatic islet Pdx1, GLUT2, ACE2 and Mas receptors. Losartan treatment showed the greatest AT2R expression in the pancreas. In the liver, the enalapril administration improved hepatic steatosis, triglycerides and prevented the increase hepatic protein levels of PEPCK, G6Pase and GLUT2. Additionally, enalapril improved the deleterious effects on the HF diet by upregulating the signal transduction through the IRS-1/Akt pathway, as well as downregulatin the protein levels and mRNA expression of PPAR-gamma, SREBP-1c and FAS. Our findings indicate that ACE inhibition with enalapril attenuated several of the deleterious effects of the HF diet. In summary, enalapril appears to be responsible for the normalization of islet morphology and function, a protective role against hepatic insulin resistance and lipid accumulation in the liver. These protective effects of enalapril were attributed, primarily, to the reduction in body mass gain and food intake, increasing EE, the enhancement of the ACE2/Ang (1-7)/Mas receptor axis and adiponectin levels, enhancing hepatic insulin action, leptin and gluconeogenesis, and attenuating NAFLD.

A disfunção cardíaca é um dos principais desfechos da doença renal crônica, sendo que o eixo sistema renina angiotensina (SRA) é um mediador chave nessa condição. Estudos têm demonstrado que os inibidores da dipeptidil peptidase IV (IDPPIV), uma classe de drogas utilizadas no tratamento do diabetes tipo II, são capazes de exercer efeitos renoprotetores e cardioprotetores, entretanto, os efeitos dos IDDPIV sobre o tecido cardíaco frente a uma injúria renal ainda não foram descritos. Assim, esse estudo teve como objetivo investigar se a inibição da DPPIV atenua a disfunção e o remodelamento cardíaco em ratos com DRC e se esses efeitos se associam a alterações no SRA. Para este fim, ratos Wistar (N=37) com idade entre 2-3 meses, foram submetidos à nefrectomia 5/6 para indução da DRC. Após a cirurgia, os ratos foram randomizados em 2 grupos: Nx (tratados com veículo) e Nx + IDPPIV (tratados com sitagliptina - 200 mg/Kg/dia). Ratos submetidos à cirurgia fictícia foram utilizados como controles (sham). Como esperado, após oito semanas de seguimento, o grupo Nx apresentou acentuada disfunção renal. Por outro lado, nos ratos tratados com sitagliptina, a queda do ritmo de filtração glomerular (RFG) foi significativamente atenuada, bem como a creatinina sérica, albuminúria e pressão arterial caudal em relação ao grupo Nx. Curiosamente, tanto a atividade quanto a expressão proteica e gênica da DPPIV cardíaca estavam aumentadas em ratos Nx comparado aos ratos controles. As análises histológicas mostraram que os cardiomiócitos de ratos Nx apresentaram maior volume nuclear e fibrose intersticial cardíaca em relação ao sham. Por outro lado, nos ratos tratados com sitagliptina o volume nuclear dos cardiomiócitos e fibrose estavam reduzidos em relação aos ratos Nx. A função sistólica não se mostrou distinta entre os três grupos de ratos. Todavia, o tempo de relaxamento isovolumétrico (TRIV) foi maior em Nx do que em sham, como sugestivo de disfunção diastólica associada à DRC e o tratamento com sitagliptina foi capaz de atenuar o TRIV. A concentração de angiotensina II cardíaca estava aumentada nos ratos Nx em relação aos ratos sham e o tratamento com sitagliptina foi capaz de impedir sua elevação. Em conjunto, os nossos dados sugerem que a inibição da DPPIV em ratos com DRC atenua o remodelamento e a disfunção cardíaca, e que esses efeitos estão envolvidos ao menos em parte, com a redução nos níveis de angiotensina II. Esse é o primeiro trabalho a demonstrar a interação da DPPIV com o SRA intracardíaco em modelo de DRC, e abre portas para estudos envolvendo os mecanismos que levam a essa associação nas síndromes cardiorrenais / Cardiac dysfunction is one of the main outcomes of chronic kidney disease, with the axis system renin angiotensin (RAS) being a key mediator in this condition. Studies have shown that dipeptidyl peptidase IV (IDPPIV) inhibitors, a class of drugs used in the treatment of type II diabetes, are capable of exerting renoprotective and cardioprotective effects, however, the effects of IDDPIV on cardiac tissue against renal injury were not described. Thus, this study aimed to investigate whether inhibition of DPPIV attenuates cardiac dysfunction and remodeling in rats with CKD and whether these effects are associated with changes in RAS. For this purpose, Wistar rats (N = 37) aged 2-3 months were subjected to 5/6 nephrectomy for induction of CKD. After surgery, the rats were randomized into 2 groups: Nx (treated with vehicle) and Nx + IDPPIV (treated with sitagliptin - 200 mg/kg/day). Sham operated rats were used as controls. After eight weeks of treatment, we identified that the Nx group had marked renal dysfunction. On the other hand, in rats treated with sitagliptin, the decrease in RFG was significantly attenuated, as well as serum creatinine, albuminuria and caudal blood pressure in relation to the Nx group. Interestingly, both the activity and the protein and gene expression of the cardiac DPPIV were increased in Nx rats compared to the control rats. Additionally, histological analysis showed that the cardiomyocytes of Nx rats presented greater nuclear volume and cardiac interstitial fibrosis compared to sham. Conversely, in animals treated with sitagliptin the nuclear volume of cardiomyocytes and fibrosis were reduced in relation to Nx rats. Systolic function was not different among the three groups of rats. However, the isovolumic relaxation time (IVR) was higher in Nx than in sham, as suggestive of CKD-associated diastolic dysfunction and treatment with sitagliptin was able to attenuate IVRT. Cardiac angiotensin II levels were elevated in Nx rats relative to sham rats. Treatment with sitagliptin prevented their elevation. Taken together, data suggest that inhibition of DPPIV in rats with CKD attenuates remodeling and cardiac dysfunction, and that these effects are at least partially involved with the reduction in angiotensin II levels. This study is the first to demonstrate an interaction of DPPIV with the intracardiac RAS in a CKD model, and will help further studies focusing the mechanisms that lead this association in cardiorrenal syndromes