In 2008 the global prevalence of hypertension [high blood pressure (BP), systolic ≥140 mmHg and/or diastolic ≥90 mmHg] was around 40% in adults > 25 yrs of age, according to the 2013 WHO statistics. Hypertension is a major risk factor for myocardial infarction, heart failure and stroke. Currently, around 20% of the Canadian population is affected by hypertension. Hypertension is more closely associated with diabetes. More than two thirds of people with diabetes have hypertension, alongwith increased activity of the renin angiotensin aldosterone (RAAS) system. The RAAS plays a major role in maintaining fluid balance, vascular tone and BP. The components of the RAAS include the hormone renin, which cleaves angiotensinogen, a circulating inactive peptide into angiotensin I. Angiotensin converting enzyme (ACE) converts angiotensin I into the active peptide angiotensin II (Ang II). Ang II causes vasoconstriction, sodium reabsorption from the kidney tubules and also release of the hormone, aldosterone, from the adrenal cortex. The epidemic of hypertension, diabetes and obesity is widely attributed to a high carbohydrate diet, containing mainly high fructose corn syrup and sucrose. However, the underlying molecular mechanisms are far from clear. A high fructose diet increases BP in Sprague-Dawley (SD) rats; along with elevated plasma and aortic levels of methylglyoxal (MG). MG is a reactive dicarbonyl compound mainly formed as an intermediate during glycolysis. Small amounts of MG are also formed during amino acid (threonine) and fatty acid metabolism. MG reacts with certain proteins to form irreversible advanced glycation end products (AGEs). MG has high affinity for arginine, lysine and cysteine. Plasma MG levels are increased in hypertensive rats and diabetic patients. However, it is not yet clear whether MG is the cause or effect of hypertension. Moreover, safe and specific MG scavengers are not available. The aim of the project was to determine the effect of MG and a high fructose diet on the RAAS and the BP in male SD rats. The hypothesis that L-arginine, and its inactive isomer D-arginine, can efficiently scavenge MG in vitro, was also tested. Male SD rats were treated with a continuous infusion of MG with a subcutaneous minipump for 4 weeks, or with a high fructose diet (60% of total calories) for 16 weeks. We also used isolated aortic rings from 12 week old normal male SD rats to study endothelial function. Organs / tissues, cultured human umbilical vein endothelial cells (HUVECs) and vascular smooth muscle cells (VSMCs) were used for molecular studies. HPLC, Western blotting and Q-PCR were used to measure MG, reduced glutathione (GSH), proteins and mRNA, respectively. siRNA for angiotensinogen and the receptor for advanced glycation endproducts (RAGE) were used to study mechanisms. MG treated rats developed a significant increase in BP and plasma levels of aldosterone, renin, angiotensin and catecholamines. MG level, and protein and mRNA for angiotensin, AT1 receptor, adrenergic α1D receptor and renin were significantly increased in the aorta and/or kidney of MG treated rats, a novel finding. Alagebrium, a MG scavenger and AGEs breaker, attenuated the above effects of MG. Treatment of cultured VSMCs with MG or high glucose (25mM) significantly increased cellular MG, and protein and mRNA for nuclear factor kappa B (NF-κB), angiotensin, AT1 and α1D receptors, which were prevented by inhibition of NF-κB, and by alagebrium. Silencing of mRNA for RAGE prevented the increase in NF-kB induced by MG. Silencing of mRNA for angiotensinogen prevented the increase in NF-κB, angiotensin, AT1 and α1D receptors’ protein. Fructose treated rats developed a significant increase in BP. MG level and protein and mRNA for angiotensin II, AT1 receptor, adrenergic α1D receptor and renin were significantly increased, whereas GSH levels were decreased, in the aorta and/or kidney of fructose fed rats. The protein expression of the receptor for AGEs (RAGE) and NF-κB were also significantly increased in the aorta of fructose fed rats. MG treated VSMCs showed increased protein for angiotensin II, AT1 receptor, and α1D receptor. The effects of fructose and MG were attenuated by metformin, a MG scavenger and AGEs inhibitor. In experiments to test the MG scavenging action of arginine, both D-arginine and L-arginine prevented the attenuation of acetylcholine-induced endothelium-dependent vasorelaxation by MG and high glucose. However, the inhibitory effect of the NOS inhibitor, Nω-nitro-L-arginine methyl ester, on vasorelaxation was prevented only by L-arginine, but not by D-arginine. MG and high glucose increased protein expression of arginase, a novel finding, and also of NADPH oxidase 4 and NF-κB, and production of reactive oxygen species in HUVECs and VSMCs, which were attenuated by D- and L-arginine. However, D- and L-arginine did not attenuate MG and high glucose-induced increased arginase activity in VSMCs and the aorta. D- and L-arginine also attenuated the increased formation of the MG-specific AGE, Nε-carboxyethyl lysine, caused by MG and high glucose in VSMCs. In conclusion, MG activates NF-κB through RAGE and thereby increases renin angiotensin levels, a novel finding, and a probable mechanism of increase in BP. There is a strong association between elevated levels of MG, RAGE, NF-κB, mediators of the RAAS and BP in high fructose diet fed rats. Arginine attenuates the increased arginase expression, oxidative stress, endothelial dysfunction and AGEs formation induced by MG and high glucose, by an endothelial NOS independent mechanism.

Thesis (M.Sc.)--Memorial University of Newfoundland, Faculty of Medicine, 2001. / Typescript. Bibliography: leaves 161-195.

Η ασβέστωση της αορτικής βαλβίδας σχετίζεται με αυξημένη νοσηρότητα και θνητότητα, ιδιαίτερα στους ηλικιωμένους. Μέχρι σήμερα η φαρμακευτική θεραπεία δεν έχει αποδειχθεί τόσο αποτελεσματική, όσο η χειρουργική. Στην παρούσα εργασία χρησιμοποιήθηκε μοντέλο υπερλιπιδαιμικών κονίκλων προκειμένου να μελετηθεί η επίδραση του εκλεκτικού ανταγωνισμού της αλδοστερόνης στα πρώιμα στάδια της ασβέστωσης της αορτικής βαλβίδας. Αυτή η φαρμακευτική προσέγγιση δεν είχε προηγουμένως διερευνηθεί. Σαράντα αρσενικοί κόνικλοι τύπου Νέας Ζηλανδίας παρέμειναν για 4 εβδομάδες σε κανονική διατροφή και στη συνέχεια χωρίστηκαν σε 3 ομάδες: (1) ομάδα ελέγχου (control) που αποτελούνταν από 10 πειραματόζωα και συνέχισαν να τρέφονται με κανονική διατροφή για 8 εβδομάδες ακόμη, (2) ομάδα vehicle που αποτελούνταν από 15 πειραματόζωα και συνέχισαν να τρέφονται με υπερλιπιδαιμική διατροφή (1% χοληστερόλη) για 8 εβδομάδες ακόμη συν ένα διάλυμα γλυκόζης 5% (vehicle), για τις τελευταίες 4 εβδομάδες και (3) ομάδα επλερενόνης που αποτελούνταν από 15 πειραματόζωα και συνέχισαν να τρέφονται με υπερλιπιδαιμική διατροφή για 8 εβδομάδες ακόμη και τουs χορηγούνταν επλερενόνη 100 mg/kgr/day σε διάλυμα γλυκόζης 5%, για τις τελευταίες 4 εβδομάδες. Πριν από τη θυσία κάθε πειραματοζώου γινόταν μέτρηση της αρτηριακής πίεσης καθώς και των επιπέδων καλίου, ολικής χοληστερόλης και αλδοστερόνης στο πλάσμα. Μετά τις 8 εβδομάδες όλα τα πειραματόζωα θυσιάστηκαν και οι παρασκευασμένες αορτικές βαλβίδες εξετάσθηκαν με χρώση αιματοξυλίνης – ηωσίνης και Von Kossa silver stain και με ανοσοχρώσεις για τους υποδοχείς των αλατοκορτικοειδών (αλδοστερόνης), τα μακροφάγα και το μετατρεπτικό ένζυμο της αγγειοτενσίνης. Η παρουσία εναποθέσεων ασβεστίου επιβεβαιώθηκε με ηλεκτρονικό μικροσκόπιο σάρωσης. Η επλερενόνη αύξησε τα επίπεδα αλδοστερόνης στο πλάσμα, αλλά δεν επηρέασε την αρτηριακή πίεση και τα επίπεδα χοληστερόλης και καλίου. Η υπερλιπιδαιμία προκάλεσε συνάθροιση μακροφάγων και αύξηση της έκφρασης του μετατρεπτικού ενζύμου, όπως επίσης και μικροσκοπική εναπόθεση ασβεστίου στις γλωχίνες. Όλοι αυτοί οι δείκτες ελαττώθηκαν με τη χορήγηση της επλερενόνης. Η ανοσοϊστοχημία για τους υποδοχείς των αλατοκορτικοειδών ανέδειξε παρόμοια έκφραση στις γλωχίνες της ομάδας ελέγχου και της υπερλιπιδαιμικής ομάδας (vehicle). Συμπερασματικά τα αποτελέσματα αυτά δείχνουν πως οι υποδοχείς της αλδοστερόνης εκφράζονται στην αορτική βαλβίδα και πως η εκλεκτική αναστολή τους με τη χορήγηση της επλερενόνης αναστέλλει το σχηματισμό των σκληρυντικών αλλοιώσεων που προκαλούνται από την υπερλιπιδαιμική διατροφή. / Calcific aortic valve disease is associated with increased morbidity and mortality, especially in the elderly. To date, pharmacological therapies have not proven as effective as surgical intervention. Here, we used a hyperlipidemic rabbit model to investigate the potential effects of selective aldosterone inhibition on the early stages of aortic valve calcification, a pharmacological strategy that has not yet been tested. Forty New Zealand male rabbits fed a standard diet for 4 weeks were separated into three groups: (1) control (n = 10), fed a standard diet; (2) vehicle (n = 15), fed a hyperlipidemic diet (cholesterol 1%) plus vehicle; and (3) eplerenone (n = 15), fed a hyperlipidemic diet plus 100 mg/kg/d eplerenone (last 4 weeks). After 8 weeks, animals were sacrificed and prepared aortic valve sections were examined with Von Kossa silver stain and by immunostaining for mineralocorticoid receptor, macrophages and angiotensin-converting enzyme. The presence of calcium deposits was confirmed by scanning electron microscopy. Eplerenone increased aldosterone levels but did not affect blood pressure, cholesterol or potassium levels. Hyperlipidemia induced macrophage accumulation and angiotensin-converting enzyme expression, as well as calcium deposition in the leaflets. All markers were decreased by eplerenone treatment. Immunohistochemistry for mineralocorticoid (aldosterone) receptors revealed similar expression in the leaflets of both control and hyperlipidemic groups. Collectively, these results indicate that aldosterone receptors are present in rabbit aortic valve leaflets and their selective blockade with eplerenone inhibits formation of the sclerotic lesions induced by a high fat diet.

Primary aldosteronism (PA) is a common form of secondary hypertension with an international prevalence rates between 5 and 10 %. It is characterized by a high autonomous aldosterone production that causes cardiovascular damage, renin suppression, hypertension, sodium retention, potassium excretion and hypokalemia. The screening of PA is a simple test measuring aldosterone to renin ratio (ARR) with immunoassay method. This test is currently considered as the most reliable screening tool for PA.     The main objective of the study was to evaluate an ELISA-method, for detection of aldosterone and renin in blood plasma, to be used for routine analysis in the laboratory. The second aim was to investigate the effect of refreezing samples, considering that cryoactivation of prorenin might occur.     One hundred blood samples were analysed, in regard to aldosterone and renin, by using two commercial ELISA assays (DRG ELISA from DRG Diagnostics, Germany) on a Dynex DS2 instrument. In addition, the accuracy and precision of the methods were calculated. The effect of refreezing was investigated with a series of eight samples, which were analyzed twice on the same instrument.     Both assays performed well. The resulting data showed good precision and accuracy. The correlation between the original and refreezed samples was good, r = 0.989 and r = 1.0 for aldosterone and renin respectively. Considering that the study only included eight samples, further investigation is recommended.     Evaluation showed that both immunoassays are reliable in diagnostic use and the ELISA-method is suitable to implement in the laboratory for routine analysis.

Em células endoteliais e músculo liso vascular, aldosterona regula processos associados ao remodelamento vascular como crescimento, expressão de marcadores inflamatórios e estresse oxidativo. Os mecanismos exatos desses efeitos ainda são desconhecidos, mas é sugerido que o influxo de Mg2+ através recém caracterizados TRPM7 seja importante. O objetivo de nosso estudo foi determinar o papel do Mg2+ na função celular e hipertensão induzida pela aldosterona em camundongos com níveis normais (MgH) e baixos (MgL) de Mg2+. A deficiência de Mg2+ e inibição do TRPM7 aumentaram a ativação de vias pró-inflamatórias e fibrogênicas induzidas pela aldosterona. Nós também demonstramos que a infusão de aldosterona é acompanhada de efeitos deletérios sobre o rim e coração, associados ao estresse oxidativo e alterações na concentração de eletrólitos. Esses resultados fornecem novos mecanismos pelos quais aldosterona modula a função celular e ressaltam a importância do Mg2+ e seus transportadores nesses processos e na hipertensão induzida pela aldosterona. / In vascular smooth muscle and endothelial cells, aldosterone induces growth, inflammation and oxidative stress. Exact mechanisms underlying aldo-mediated vascular effects remain unclear, but intracellular magnesium (Mg2+) influx through the novel Mg2+ transporter, TRPM7 may be important. Here we sought to determine the role of Mg2+ in cell function and in aldosterone-induced hypertension in mice genetically bred to have normal (MgH) or low (MgL) intracellular Mg2+ levels. Findings from the present study demonstrate that Mg2+ deficiency and inhibition of TRPM7 amplify aldosterone-induced activation of vascular inflammatory, fibrogenic and growth signaling pathways. We also show that aldosterone infusion in MgH and MgL mice are accompanied by end-organ damage, associated to oxidative stress and changes in electrolytes concentration. Our results provide novel insights into putative mechanisms whereby aldo influences VSMC and EC function and highlights the important role of Mg2+ in the development of aldosterone-induced hypertension.

Apneia obstrutiva do sono (AOS) é um fator de risco independente para o desenvolvimento de hipertensão arterial sistêmica, principalmente hipertensão arterial resistente, e doenças cardiovasculares. Hipertensão arterial resistente está associada à AOS, níveis elevados de aldosterona e dieta rica em sal. O objetivo do presente estudo foi determinar se a quantidade de sal na dieta e os níveis de aldosterona estão associados com a intensidade da AOS em pacientes com hipertensão arterial resistente. Noventa e sete pacientes com hipertensão arterial resistente foram avaliados com polissonografia noturna assistida e dosagem de aldosterona e sódio em urina coletada por 24h durante a dieta habitual. Hiperaldosteronismo foi definido como atividade da renina plasmática < 1 ng/mL/h e aldosterona urinária >= 12 ?g/24h. Na população total estudada, a média de idade foi 55±9 anos e 47,4% dos pacientes eram do sexo masculino. Em média, os pacientes estavam em uso de 4,3±1,1 medicamentos anti-hipertensivos e a pressão arterial foi 156,3±22,4/88,9±13,3 mmHg. A prevalência de AOS foi de 77,3% na população total estudada. Vinte e oito (28,9%) pacientes foram diagnosticados como portadores de hiperaldosteronismo. A prevalência de AOS foi maior nos pacientes com do que nos pacientes sem hiper-aldosteronismo (82,1% vs 75,4%), mas sem significância estatística. A análise univariada na população total demonstrou que o índice de apneia-hipopneia correlacionou-se positiva e significantemente com a circunferência do pescoço (rho=0,4362, p<0,0001) e com o sódio urinário (rho=0,2269, p=0,0254). Sexo masculino, circunferência do pescoço e sódio urinário estiveram positiva e significantemente associados ao índice de apneia-hipopneia em pacientes com hiperaldosteronismo. Nenhuma das variáveis selecionadas se associou com o índice de apneia-hipopneia entre os pacien-tes sem hiperaldosteronismo. Em conclusão, níveis elevados de aldosterona e dieta com sal estão associados com a severidade da AOS em pacientes com hipertensão arterial resistente. Esses achados sugerem que a restrição de sal na dieta pode ser uma estratégia terapêutica para a redução da severidade da AOS em pacientes com hipertensão arterial resistente e hiperaldosteronismo. / Obstructive sleep apnea is a strong and independent risk factor for the development of hypertension, particularly resistant hypertension, and cardiovascular diseases. Patients with resistant hypertension have a high prevalence of obstructive sleep apnea in association with elevated aldosterone levels and high salt intake. The objective was to determine if dietary salt and aldosterone levels are associated with severity of obstructive sleep apnea in patients with resistant hypertension. Ninety-seven patients with resistant hypertension were evaluated by overnight polysomnography and 24-hour urinary sodium excretion and aldosterone while ingesting their usual diet. Hyperaldosteronism was defined as plasma renin activity <1 ng/mL/h and urinary aldosterone >= 12 ?g/24 h. Overall, mean age was 55±9 years and 47.4% were males. Mean clinic blood pressure was 156.3±22.4/88.9±13.3 mmHg on an average 4.3±1.1 antihypertensive medications. Prevalence of obstructive sleep apnea was 77.3% within the entire population. Twenty-eight (28.9%) of patients were diagnosed with hyperaldosteronism. The prevalence of obstructive sleep apnea tended to be higher in patients with than without (82.1% vs 75.4%) hyperaldosteronism, but the difference did not reach statistical significance. In the univariate analysis among all patients, apnea-hypopnea index correlated significantly with neck circumference (rho=0.4362, p<0.0001) and urinary sodium excretion (rho=0.2269, p=0.0254). Gender, neck circumference and urinary sodium excretion were positively and significantly associated with apnea-hypopnea index in patients with hyperaldosteronism. None of the selected variables were associated with apnea-hypopnea index in patients without hyperaldosteronism. In conclusion, the current findings suggest that both aldosterone and dietary salt are related to severity of obstructive sleep apnea in patients with resistant hypertension. Our results support dietary salt restriction as a treatment strategy for reduction of obstructive sleep apnea severity in patients with resistant hypertension and hyperaldosteronism.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-06-14T17:57:28Z No. of bitstreams: 1 danielleguedesandradeezequiel.pdf: 3466091 bytes, checksum: 7a4699e1003d06d31bf08aac9caeb175 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-06-29T12:15:00Z (GMT) No. of bitstreams: 1 danielleguedesandradeezequiel.pdf: 3466091 bytes, checksum: 7a4699e1003d06d31bf08aac9caeb175 (MD5) / Made available in DSpace on 2017-06-29T12:15:00Z (GMT). No. of bitstreams: 1 danielleguedesandradeezequiel.pdf: 3466091 bytes, checksum: 7a4699e1003d06d31bf08aac9caeb175 (MD5) Previous issue date: 2013-10-03 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Introdução: A aldosterona tem sido implicada na fisiopatologia da síndrome metabólica, assim como da hipertensão arterial a ela associada, entretanto, o uso de antagonistas do receptor mineralocorticoide, neste grupo de indivíduos, foi pouco estudado. Objetivos: Avaliar os efeitos do bloqueio mineralocorticoide no comportamento pressórico, em parâmetros metabólicos, renais de indivíduos com síndrome metabólica e comparar com um grupo controle em uso de amlodipino. Métodos: Vinte e sete indivíduos com síndrome metabólica foram avaliados em estudo prospectivo que se consistiu de dois períodos: basal (2 semanas), no qual foram obtidos dados demográficos e suspensa a medicação anti-hipertensiva e período de tratamento, no qual foi administrada espironolactona (25 a 50 mg/dia) ou amlodipino (5 a 10 mg/dia), por 16 semanas. Em ambos os períodos, foram avaliados parâmetros metabólicos, inflamatórios e renais, além da realização da monitorização ambulatorial da pressão arterial (MAPA). Resultados: Após pareamento dos grupos, foram selecionados 16 indivíduos para o grupo de tratamento com espironolactona e 11 indivíduos para o grupo controle com amlodipino. Após período de intervenção terapêutica, houve redução significante da pressão arterial sistólica de 24 horas de -23,98 mmHg (IC:-34,85 a -13,11) e de -14,36 mmHg (IC: 25,83 a -2,89) e da pressão arterial diastólica de -12,84 mmHg (IC: -9,82 a -5,87) e de -9,59 mmHg (IC: -16,97 a - 2,21), nos grupos espironolactona e amlodipino, respectivamente. Em relação ao perfil metabólico, houve aumento significante do colesterol HDL no grupo espironolactona (p=0.001), independente do grau de inflamação, sem alterações significativas no grupo amlodipino. Não foram observadas alterações significantes no Homeostasis Model Assessment (HOMA-IR), triglicérides e potássio, em ambos os grupos. Observou-se ainda, redução significante na albuminúria no grupo espironolactona sem alteração significante no grupo amlodipino, acompanhada de redução significante da proteína C reativa, no grupo espironolactona e aumento significante da proteína C reativa, no grupo amlodipino. Conclusão: O tratamento de indivíduos hipertensos com síndrome metabólica com espironolactona, em monoterapia, foi eficaz no controle da pressão arterial, apresentou benefícios metabólicos adicionais como elevação do colesterol HDL e redução da proteína C reativa, além de efeito nefroprotetor com redução da albuminúria. / Introduction: Although aldosterone has been implicated in the pathophysiology not only of the metabolic syndrome (MS) but also of the MS-associated arterial hypertension, the use of mineralocorticoid receptor antagonists in these situations has been little studied. Objectives: Assess the effects of mineralocorticoid blockade on the pressoric behavior and metabolic and renal parameters of individuals with the MS in comparison with a control group on amlodipine. Methods: 27 individuals with the MS were assessed in a prospective study consisting of two periods: baseline (2 weeks), during which demographic data were obtained and all anti-hypertensive medication withdrawn, and treatment period, during which spironolactone (25 to 50 mg/day) or amlodipine (5 to 10 mg/day) were administered for 16 weeks. Individuals had their metabolic, inflammatory and renal parameters assessed, and underwent 24-hour ambulatory blood pressure monitoring during both study periods. Results: After the groups were paired, 16 individuals were enrolled in the spironolactone group and 11 in the amlodipine group (controls). After the intervention, there was a significant decrease of both the 24-hour systolic (-23.98 mmHg, CI:-34.85 to -13.11, in the spironolactone group, and -14.36 mmHg, CI: -25.83 to 2.89, in the amlodipine group) and diastolic pressure (-12.84 mmHg, CI: -9.82 to -5.87, in the spironolactone group and -9.59 mmHg, CI: -16.97 to – 2.21, in the amlodipine group. As for the metabolic profile, there was a significant increase of HDL-cholesterol in the spironolactone group (p=0.001), regardless of the degree of inflammation, without significant alterations in the amlodipine group. There were no significant alterations in the Homeostasis Model Assessment (HOMA-IR), triglycerides and potassium in both groups. There was also a significant albuminuria reduction in the spironolactone group, without significant alterations in the amlodipine group, along with a significant reduction of C-reactive protein in the spironolactone group and a significant increase of C-reactive protein in the amlodipine group. Conclusion: Spironolactone as monotherapy for hypertensive individuals with the metabolic syndrome showed efficacy in blood pressure control, had additional metabolic benefits, such as an increase of HDLcholesterol and reduction of C-reactive protein, and showed a renal protective effect through albuminuria reduction.

Orientador: Heitor Moreno Junior / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T05:00:13Z (GMT). No. of bitstreams: 1 Martins_LeandrodeMattosBoer_D.pdf: 9156362 bytes, checksum: bf77ceb230427d245fc7f1ce0e5d047c (MD5) Previous issue date: 2011 / Resumo: Considerando a forte associação entre a atividade do sistema nervoso autônomo, a obesidade e a resistência insulínica na hipertensão arterial resistente (HAR), esta pesquisa teve a finalidade de identificar a associação entre a função do sistema nervoso autonômico e importantes hormônios relacionados à síndrome cardiometabólica como adiponectina, leptina e aldosterona. Vinte e cinco pacientes portadores de hipertensão arterial resistente foram divididos em dois grupos: com (DM2) e sem diabetes mellitus tipo 2 (NDM2). Ambos os grupos foram avaliados em relação à variabilidade da frequência cardíaca (VFC) pelo sistema Holter de 24 horas, nos domínios do tempo e da frequência, e aos hormônios plasmáticos adiponectina, leptina e aldosterona. A análise dos resultados demonstrou maior disfunção autonômica e hipoadiponectinemia no subgrupo DM2 em relação ao subgrupo NDM2, correlação positiva entre VFC no domínio do tempo e a adiponectina no total de pacientes, ruptura do ritmo circadiano de ambos os grupos (tônus simpático aumentado no período noturno e diminuído no período diurno; tônus parassimpático aumentado no período diurno e diminuído no período noturno) e correlação positiva entre a banda de baixa de frequência em unidades normalizadas (LFnu) e aldosterona, e correlação negativa entre a banda de alta frequência em unidades normalizadas (HFnu) e aldosterona no total de pacientes e em ambos os grupos. O grupo DM2 obteve maiores valores de leptina e índice de massa corporal. Entretanto, não houve correlação entre a VFC e leptina em ambos os grupos. Desta forma, identificou-se ruptura do ritmo circadiano e a associação entre o balanço autonômico e os níveis de adiponectina e aldosterona plasmática na HAR com e sem diabetes tipo 2 / Abstract: Considering the strong association between the autonomic nervous system activity, obesity and insulin resistance in resistant hypertension (RH), this research aimed to identify the association of the autonomic nervous system function and important hormones related to the cardiometabolic syndrome such as adiponectin, leptin and aldosterone. Twenty five RH patients were divided into two groups: with (T2D) and without type-2 diabetes (NT2D). Both groups were evaluated regarding the heart rate variability (HRV) by the Holter system in 24 hours, in time and frequency domains, and the plasma hormones adiponectin, leptin and aldosterone. The analysis of the results demonstrated greater autonomic dysfunction and hypoadiponectinemia in T2D subgroup compared to the NT2D subgroup, positive correlation between HRV in time domain and adiponectin in all patients, circadian disruption in both groups (increased sympathetic drive during nighttime and decreased during daytime; increased parasympathetic drive during daytime and decreased during nighttime) and positive correlation between the low frequency band in normalized units (LFnu) and aldosterone, and negative correlation between the high frequency band in normalized units (HFnu) and aldosterone in all patients and both subgroups. The T2D subgroup had higher levels of leptin and body mass index. However, there was no correlation between HRV and leptin in both groups. Thereby, it was found circadian disruption and the relationship between autonomic balance and plasma adiponectin and aldosterone in RH with or without type 2 diabetes / Doutorado / Doutor em Farmacologia

Orientador: Heitor Moreno Junior / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T18:55:59Z (GMT). No. of bitstreams: 1 Moraes_CarolinadeHaro_M.pdf: 1230072 bytes, checksum: 59e16a99829a6260d186488a3bdf60e3 (MD5) Previous issue date: 2012 / Resumo: A leptina, um hormônio derivado de adipócitos, e a aldosterona, têm sido associados aos mecanismos fisiopatológicos da hipertensão. Entretanto, apesar de estudos demonstrarem a associação da leptina com o espeçamento íntimo-carotídeo, distensibilidade arterial, ativação do sistema nervoso simpático, a relação entre os níveis plasmáticos de leptina e a pressão arterial em hipertensos resistentes ainda é desconhecida. Nosso objetivo foi avaliar a correlação entre os níveis de leptina plasmática, a concentração plasmática de aldosterona (CPA) e a pressão arterial em hipertensos resistentes não controlados (HARNC) e hipertensos resistentes controlados (HARC). Foram avaliados os níveis plasmáticos de leptina e a concentração plasmática de aldosterona (ensaio imuno-enzimático - ELISA), medidas de pressão arterial de consultório e da MAPA. Nenhuma diferença estatística foi encontrada entre os grupos HARNC (n=41) e HARC (n=39) em relação ao gênero, a idade e índice de massa corpórea. O grupo de HARNC apresentou valores maiores de leptina (38,2 ± 21,4 vs 19,6 ± 8,7 ng/mL, p<0,05) e CPA (9,6 ± 3,8 vs. 8,1 ± 5,0 ng/dL, p<0,05). As concentrações de leptina plasmática se correlacionaram com a PA sistólica (r=0,43, p<0,05), PA diastólica (r=0,35, p<0,05) e CPA (r=0,47, p<0,05). A regressão linear simples mostrou que a PAS, a PAD e a CPA podem ser preditas pela leptina (r²=0,16, p<0,05, r²=0,15, p=0<05 e r²=0.19, p<0.05, respectivamente) somente no grupo de HARNC. Esses dados sugerem que as concentrações elevadas de leptina circulante podem ser associadas com o aumento de concentração plasmática de aldosterona e indiretamente ser responsáveis, ao menos em parte, pela falta de controle da pressão arterial em HARNC / Abstract: Leptin, an adipocyte-derived hormone, and aldosterone have been associated with the pathophysiological mechanisms of hypertension. However, despite studies showing the association of leptin with intima-media thickness, arterial distensibility, sympathetic nerve activation, the relationship between leptin levels and blood pressure in resistant hypertension is unknown. We aimed to assess the correlation between plasma leptin levels, plasma aldosterone concentration, and blood pressure in uncontrolled (UCRHTN) and controlled resistant hypertension (CRHTN) patients. Plasma leptin and aldosterone levels (enzyme-linked immunosorbent assay - ELISA), office BP and ambulatory blood pressure monitoring (ABPM) were measured in 41 UCRHTN and 39 CRHTN patients. No statistical differences were observed between the UCRHTN and CRHTN subgroups with respect body mass index and age. The UCRHTN subgroup had higher values of leptin (38.2 ± 21.4 vs 19.6 ± 8.7 ng/mL; p<0.05) and plasma aldosterone concentration (PAC) (9.6 ± 3.8 vs. 8.1 ± 5.0 ng/dL; p<0.05). Plasma leptin levels significantly correlated with systolic BP (r=0.43, p<0.05), diastolic BP (r=0.35, p=0.02) and PAC (r=0.47, p<0.05) in the UCRHTN subgroup, but not in the CRHTN, systolic BP(r=0.14, p>0.05), diastolic BP(r=0.24, p> 0.05) and PAC(r=0.21, p>0.05). Simple linear regression showed that SBP, DBP and PAC may be predicted by leptin (r²=0.16, p,0.05, r²=0.15, p<0.05 and r²=0.19, p<0.05 respectively) only in the UCRHTN subgroup. These data support that UCRHTN patients have higher-circulating leptin levels associated with increased plasma aldosterone and BP levels.than CRHTN subjects which indicates the possible contribution of this adipokine for the lack of BP control in this subset / Mestrado / Farmacologia / Mestre em Farmacologia

High salt intake contributes to the development of hypertension in salt-sensitive humans and animals and the mechanistic causes are poorly understood. In Dahl salt-sensitive (S) but not salt-resistant (R) rats, high salt diet increases cerebrospinal fluid (CSF) [Na+] and activates an aldosterone-mineralocorticoid receptor-epithelial sodium channel-endogenous ouabain (MR-ENaC-EO) neuromodulatory pathway in the brain that enhances the activity of sympatho-excitatory angiotensinergic and glutamatergic pathways, leading to an increase in sympathetic nerve activity (SNA) and blood pressure (BP). We hypothesize that high salt diet in Dahl S rats enhances Ang II release in the paraventricular nucleus (PVN), causing a decrease in local nitric oxide (NO) action and an increase in local glutamate release thereby elevating SNA, BP and heart rate (HR). The present study evaluated the effects of agonists or blockers of MR, ENaC, EO, nitric oxide synthase (NOS) or glutamate and AT1-receptors on the BP and HR responses to acute infusions of Na+ rich aCSF, intracerebroventricularly (icv), or in the PVN of Dahl S, R or Wistar rats or to high salt diet in Dahl S and R rats. In Wistar rats, aldosterone in the PVN enhanced the BP and HR responses to infusion of Na+ rich aCSF in the PVN, but not in the CSF, and only the enhancement was prevented by blockers of MR, ENaC and EO in the PVN. AT1-receptor blockers in the PVN fully blocked the enhancement by aldosterone and the responses to infusion of Na+ rich aCSF icv, or in the PVN. Na+ rich aCSF in the PVN caused larger increases in BP and HR in Dahl S vs. R rats and the responses to Na+ were fully blocked by an AT1-receptor blocker in the PVN. BP and HR responses to a NOS blocker in the PVN were the same, but L-NAME enhanced Na+ effects more in Dahl R than S rats. High salt diet attenuated increases in BP from L-NAME in the PVN of Dahl S but not R rats. AT1 and glutamate receptor blockers candesartan and kynurenate in the PVN decreased BP in Dahl S but not R rats on high salt diet. At the peak BP response to candesartan, kynurenate in the PVN further decreased BP whereas candesartan did not further decrease BP at the peak BP response to kynurenate. Our findings indicate that both an acute increase in CSF [Na+] and high salt intake in Dahl S rats increases AT1-receptor activation and decreases NO action in the PVN thereby contributing to the pressor responses to Na+ and presumably, to dietary salt-induced hypertension. The increased BP response to AT1-receptor activation in the PVN of Dahl S is mediated by enhanced local glutamate receptor activation. An MR-ENaC-EO pathway in the PVN can be functionally active and further studies need to assess its role in Dahl S rats on high salt intake.