Considerations on the use of antihypertensive blockers of the renin-angiotensin system in adults and children in the face of the COVID-19 pandemic / Consideraciones sobre el uso de antihipertensivos bloqueadores del sistema renina-angiotensina en adultos y niños ante la pandemia de COVID-19

Abstract As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients with hypertension and other cardiovascular comorbidities develop more severe coronavirus disease (COVID)-19 and are at high risk of death, a controversy arose about the use of antihypertensives as angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs). Such drugs might increase the expression of the fundamental receptor of this new infectious agent: the angiotensin-converting enzyme 2 (ACE2). Preclinical observations indicate that the increase of ACE2 expression or the activity by ACEis and ARBs leads to a greater transformation of angiotensin (Ang)-II to Ang-(1-7), which is associated with positive effects on cardiovascular and pulmonary pathophysiology. This association has been demonstrated in observational studies in patients with cardiovascular pathology and pneumonia. It has not been possible to confirm whether users of ACEis or ARBs are more infected by the new coronavirus, due to methodological issues in studies with patients infected with SARS-CoV-2. However, the use of such antihypertensive treatments in both children and adults might reduce the virulence of infection. Therefore, changes in the antihypertensive therapy of patients at risk of contracting COVID-19 are not recommended.

Resumen Los pacientes con hipertensión y otra comorbilidad cardiovascular infectados con SARS-CoV-2 desarrollan cuadros más graves de COVID-19 y con mayor frecuencia fallecen. Este hecho ha originado una controversia acerca del uso de antihipertensivos inhibidores de la enzima convertidora de la angiotensina (IECA) y de antagonistas de los receptores de la angiotensina II (ARA-II), pues tales medicamentos pueden incrementar la expresión del receptor funcional de este nuevo agente infeccioso: la enzima convertidora de la angiotensina 2 (ECA2). Las observaciones preclínicas indican que el aumento de la expresión o de la actividad de la ECA2 por uso de IECA o ARA-II conduce a una mayor transformación de angiotensina 2 a a angiotensina 1-7, la cual se asocia con efectos positivos sobre la fisiopatología pulmonar y cardiovascular. En estudios observacionales de pacientes con patología cardiovascular y neumonía se ha confirmado esta asociación. La falta de evidencia contundente debida a aspectos metodológicos en estudios con pacientes infectados con SARS-CoV-2 no permite confirmar si los usuarios de IECA o ARA-II se contagian más con el nuevo coronavirus. Sin embargo, continuar con tales medicamentos antihipertensivos, tanto en adultos como en niños, podría reducir la virulencia de la infección. Por ello, no se recomienda cambiar la terapia antihipertensiva en los pacientes susceptibles a la COVID-19.

Plasma Renin in Women Using and not Using Combined Oral Contraceptive

Abstract Backgroud: Recent studies show that women on combined oral contraceptives (COC) present abnormal fasting lipid profile, increased postprandial lipemia, plasma C-reactive protein (CRP) and blood pressure (BP) compared to women not on combined oral contraceptives. Plasma renin is one of the factors responsible for abnormal BP. Objectives: To assess plasma renin levels in women using or not using COC, the correlation between renin and CRP, as well as divergences in lipid profile. Methods: A cross-sectional study with apparently healthy women aged 20 to 30, eutrophic, irregularly active, and with fasting triglycerides < 150 mg/dL. The sample was stratified into two groups: the No Combined Oral Contraceptive Group (NCOCG), comprised of women who did not use any type of hormone contraceptive, and the Combined Oral Contraceptive Group (COCG) comprised of women on low-dose COC for at least one year. After a 12-hour fast, 5 ml of blood was collected for renin dosing and PCR. Data were analyzed by the t-Test and bidirectional Mann-Whitney Test, both with significance < 0.05. Results: We evaluated 44 women equally distributed between the groups, age 23 ± 1.2 years, BMI 21.0 ± 3.2 kg/m2. Median and interquartile deviation of renin in the NCOCG and the COCG were, respectively, 0.5 (0.1-1.0) and 3.0 (2-6) (p < 0.01). A positive correlation between PCR and renin (p < 0.01 and r = 0.68) was found. Conclusion: The plasma renin levels of women using COC were higher, with a strong correlation with CRP.

COVID-19 y el sistema renina, angiotensina, aldosterona. Una relación compleja / COVID-19 and the renin, angiotensin, aldosterone system. A complex relationship

Resumen La pandemia por COVID-19 ha tenido muy importantes repercusiones negativas, sanitarias, psicológicas, sociales y económicas para las personas, las familias, las comunidades, los países y para las para la humanidad en general. La interrelación con la edad y la presencia de enfermedades crónicas no trasmisibles (hipertensión, diabetes, obesidad, tabaquismo) parece ir mas lejos que lo que explicaría la prevalencia y distribución de ambas. Los medicamentos que actúan sobre el sistema renina-angiotensina-aldosterona, son pilares básicos en el manejo de estas enfermedades. Se sabe de tiempo atrás que estos fármacos aumentan en forma significativa la expresión en el tejido pulmonar de receptores para la enzima de conversión de angiotensina de tipo 2. Este hecho junto con el conocimiento de que la vía de entrada del virus a la célula es precisamente el receptor de ECA-2, inició una hipótesis, basada en evidencia de muy baja calidad, que rápidamente se generalizó en los medios de comunicación, de que el empleo de estos medicamentos podría ser negativo y que deberían suspenderse. La respuesta de prácticamente todas las sociedades científicas fue casi inmediata, con la indicación precisa de que no debería suspenderse el tratamiento con estos fármacos, puesto que la evidencia de su utilidad está basada en una evidencia muy sólida y de gran calidad. Casi simultáneamente también apareció la hipótesis, también basada en evidencia muy preliminar, de que estos medicamentos no solo resultan dañinos sino que son benéficos, tampoco se aceptan todavía como agentes para la prevención o tratamiento de esta enfermedad o sus complicaciones. La presente revisión relata los conocimientos actuales sobre la relación entre COVID-19 y SRAA.

Abstract The COVID-19 pandemic has had major negative health, psychological, social and economic repercussions for individuals, families, communities, countries and for humanity in general. The interrelation with age and the presence of chronic non-communicable diseases (hypertension, diabetes, obesity, smoking) seems to go further than what would be explained by the prevalence and distribution of both. The drugs that act on the renin-angiotensin-aldosterone system are in many cases the backbone for the management of these diseases, it has been known for a long time that these drugs significantly increase the expression of receptors for angiotensin conversion enzyme type 2 in the lung tissue. This fact, together with the knowledge that the route of entry of the virus into the cell is precisely the ACE-2 receptor, initiated a hypothesis, based on very low-quality evidence, which quickly became generalized in the media, that the use of these drugs could be negative and that they should be interrupted immediately. The response of practically all Scientific Societies was almost immediate, with the precise indication that treatment with these drugs should not be discontinued, since the evidence of their usefulness is based on very solid and high-quality evidence. Simultaneously, a different hypothesis also appeared, also based on very preliminary evidence, that these drugs are not only harmful but also beneficial, however these medicaments are not yet accepted as agents for the prevention or treatment of this disease or its complications. This review reports current knowledge on the relationship between COVID-19 and SRAA.

Uso de medicamentos e fatores associados à polifarmácia em indivíduos com diabetes mellitus em Minas Gerais, Brasil / Drug utilization and factors associated with polypharmacy in individuals with diabetes mellitus in Minas Gerais, Brazil

Resumo O objetivo deste estudo foi avaliar o uso de medicamentos, a prevalência e os fatores associados à polifarmácia em pacientes com diabetes mellitus (DM) em Minas Gerais. Realizou-se um estudo transversal com descrição dos medicamentos em uso e análise da associação entre características sociodemográficas e clínicas com polifarmácia, por meio de regressão logística. Dos 2619 entrevistados, 56,5% estavam em polifarmácia. Medicamentos para DM, agentes no sistema renina-angiotensina e diuréticos foram os mais usados. Fatores como envelhecimento, presença de comorbidades e maior acesso aos serviços de saúde foram associados à polifarmácia. Observou-se elevada prevalência de polifarmácia, o que requer um cuidado adequado e melhor qualidade do uso de medicamentos para essa população.

Abstract The objective of this study was to evaluate the use of drugs and the factors associated with polypharmacy in patients with diabetes mellitus (DM) in Minas Gerais. Descriptive analysis of drugs in use and logistic regression to estimate the association between socio-demographic and clinical characteristics with polypharmacy were performed. Of the 2619 respondents, 56.5% were in polypharmacy. Drugs for DM, agent in renin-angiotensin system, and diuretics are the most frequently used. Factors such as age, comorbidities and increased access to health services were associated with polypharmacy. It was observed high prevalence of polypharmacy, which requires a suitable care and better quality of drug use in this population.

Inappropriate activity of local renin-angiotensin-aldosterone system during high salt intake: impact on the cardio-renal axis / Atividade inadequada do sistema renina-angiotensina-aldosterona local durante período de alta ingestão de sal: impacto sobre o eixo cardiorrenal

ABSTRACT Although there is a general agreement on the recommendation for reduced salt intake as a public health issue, the mechanism by which high salt intake triggers pathological effects on the cardio-renal axis is not completely understood. Emerging evidence indicates that the renin-angiotensin-aldosterone system (RAAS) is the main target of high Na+ intake. An inappropriate activation of tissue RAAS may lead to hypertension and organ damage. We reviewed the impact of high salt intake on the RAAS on the cardio-renal axis highlighting the molecular pathways that leads to injury effects. We also provide an assessment of recent observational studies related to the consequences of non-osmotically active Na+ accumulation, breaking the paradigm that high salt intake necessarily increases plasma Na+ concentration promoting water retention

RESUMO Apesar de haver uma concordância geral sobre a necessidade de redução na ingestão de sal como questão de saúde publica, o mecanismo pelo qual a alta ingesta de sal deflagra efeitos patológicos sobre o eixo cardiorrenal não está ainda completamente elucidado. Cada vez mais evidencias indicam que o sistema renina-angiotensina-aldosterona (SRAA) seja o principal alvo da alta ingesta de Na+. Uma ativação inadequada do SRAA tecidual pode causar hipertensão e dano ao órgão. Nós revisamos o impacto da dieta com alto teor de sódio sobre o eixo cardiorrenal, destacando as vias moleculares que causam a lesão. Também fizemos uma avaliação de recentes estudos observacionais relacionados às consequências do acúmulo de Na+ não osmoticamente ativo, quebrando assim o paradigma de que a alta ingestão de sódio necessariamente aumenta a concentração sérica de Na+, assim promovendo a retenção de água.

Farmácia Popular Program: pharmaceutical market analysis of antihypertensive acting on the renin-angiotensin system medicines / Programa Farmácia Popular: análise do mercado farmacêutico de anti-hipertensivos do sistema renina-angiotensina

Abstract This paper aims to analyse changes in the retail pharmaceutical market following policy changes in the Farmácia Popular Program (FP), a medicines subsidy program in Brazil. The retrospective longitudinal analyses focus on therapeutic class of agents acting on the renin-angiotensin system. Data obtained from QuintilesIMS (formerly IMS Health) included private retail pharmacy sales volume (pharmaceutical units) and sales values from 2002 to 2013. Analyses evaluated changes in market share following key FP policy changes. The therapeutic class was selected due to its relevance to hypertension treatment. Market share was analysed by therapeutic sub-classes and by individual company. Losartan as a single product accounted for the highest market share among angiotensin II antagonists. National companies had higher sales volume during the study period, while multinational companies had higher sales value. Changes in pharmaceutical market share coincided with the inclusion of specific products in the list of medicines covered by FP and with increases in or exemption from patient copayment.

Resumo Este artigo visa analisar as mudanças no mercado de varejo farmacêutico, seguindo as alterações de diretiva no Programa Farmácia Popular (FP), que realiza subvenção de medicamentos no Brasil, em parceria pública privada. Foi realizada análise longitudinal retrospectiva dos medicamentos da classe terapêutica dos agentes que atuam sobre o sistema renina-angiotensina. Os dados obtidos do QuintilesIMS incluíram o varejo farmacêutico em termos do volume e valores de vendas de 2002 a 2013. Análises realizadas consideraram intervenções e reformas ocorridas no FP e seu impacto no mercado farmacêutico da classe terapêutica selecionada, devido a sua relevância para o tratamento da hipertensão. Também se examinou o comportamento do mercado tomando por base as empresas farmacêuticas produtoras. Losartan monodroga representou a maior fatia de mercado entre os antagonistas de angiotensina II. Empresas nacionais obtiveram maior volume de vendas durante o período de estudo, enquanto as empresas multinacionais exibiram maior valor de vendas. Mudanças no mercado farmacêutico coincidiram com a inclusão de produtos específicos na lista de medicamentos abrangidos pelo FP e com aumentos ou isenção de copagamento pelos pacientes.

Urinary cytokine profiles according to the site of blockade of the renin-angiotensin system in nephrectomized rats / Perfil de citocinas urinárias de acordo com o local de bloqueio do sistema renina angiotensina em ratos nefrectomizados

Abstract Introduction: It is still unknown how the pharmacological inhibition of the Renin Angiotensin System (RAS) impacts the levels of inflammation and fibrosis biomarkers. Objective: This study sought to evaluate the effect of enalapril, candesartan and aliskiren on urinary levels of cytokines in a model of chronic kidney disease (CKD). Methods: Male Wistar rats were submitted to surgical removal of ¾ of renal parenchyma to induce CKD (¾ nephrectomy), or subjected to sham surgery (control). Animals were then randomized into five groups: Sham surgery receiving vehicle; ¾ Nephrectomy receiving vehicle; ¾ Nephrectomy receiving enalapril (10 mg/kg); ¾ Nephrectomy receiving candesartan (10 mg/kg) and ¾ Nephrectomy receiving aliskiren (10 mg/kg). Urine output, water intake, mean arterial pressure (MAP) and urinary concentrations of creatinine, urea, albuminuria, Na+, K+, interleukin (IL) -1β, IL-6, IL-10 and transforming growth factor beta (TGF-β) were measured. Results: Nephrectomy significantly impaired renal function, increased MAP and altered the levels of all evaluated cytokines in urine. Enalapril, candesartan and aliskiren improved renal function and decreased MAP and IL-6 when compared to vehicle-treated nephrectomized group. Candesartan and aliskiren decreased IL-1β, while only candesartan reduced TGF-β and only aliskiren increased IL-10. Conclusion: Enalapril, candesartan and aliskiren presented similar effects on improving renal function and reducing MAP and urinary levels of IL-6 in rats with CKD. On the other hand, cytokine profile differed according to the treatment, suggesting that differential mechanisms were triggered in response to the site of RAS blockade.

Resumo Introdução: Ainda não se sabe como a inibição farmacológica do Sistema Renina Angiotensina (SRA) afeta os níveis de biomarcadores de inflamação e fibrose. Objetivo: Este estudo pretendeu avaliar o efeito de enalapril, candesartan e alisquireno sobre os níveis urinários de citocinas em um modelo de doença renal crônica (DRC). Métodos: Ratos Wistar machos foram submetidos à remoção cirúrgica de ¾ do parênquima renal para induzir DRC (nefrectomia), ou submetidos à cirurgia fictícia (controle). Animais foram então randomizados em cinco grupos: Cirurgia fictícia recebendo veículo; Nefrectomia recebendo veículo; Nefrectomia recebendo enalapril (10 mg/kg); Nefrectomia recebendo candesartan (10 mg/kg) e Nefrectomia recebendo alisquireno (10 mg/kg). Débito urinário, ingesta hídrica, pressão arterial media (PAM) e concentrações urinárias de creatinina, ureia, albumina, Na+, K+, interleucina (IL) -1β, IL-6, IL-10 e fator de transformação e crescimento beta (TGF-β) foram medidas. Resultados: A nefrectomia comprometeu significativamente a função renal, aumentou a PAM e alterou os níveis de todas as citocinas avaliadas na urina. Enalapril, candesartan e alisquireno melhoraram a função renal e diminuíram a PAM e a IL-6 quando comparado aos grupo de animais nefrectomizados tratados com veículo. Candesartan e alisquireno reduziram IL-1β, enquanto somente candesartan diminuiu o TGF-β e somente alisquireno aumentou a IL-10. Conclusão: Enalapril, candesartan e alisquireno apresentaram efeitos similares em relação à melhora da função renal e redução da PAM e dos níveis urinários de IL-6 em ratos com DRC. Por outro lado, o perfil de citocinas diferiu de acordo com o tratamento, sugerindo que diferentes mecanismos sejam desencadeados em resposta ao local de bloqueio do SRA.

Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro

Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (−19% of maximal response and −60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (−19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients.

The Beneficial Effect of Renin-Angiotensin-Aldosterone System Blockade in Marfan Syndrome Patients after Aortic Root Replacement

PURPOSE: In this study, we evaluated the long term beneficial effect of Renin-Angiotensin-Aldosterone System (RAAS) blockade therapy in treatment of Marfan aortopathy. MATERIALS AND METHODS: We reviewed Marfan syndrome (MFS) patients who underwent aortic root replacement (ARR) between January 1996 and January 2011. All patients were prescribed beta-blockers indefinitely. We compared major aortic events including mortality, aortic dissection, and reoperation in patients without RAAS blockade (group 1, n=27) to those with (group 2, n=63). The aortic growth rate was calculated by dividing the diameter change on CT scans taken immediately post-operatively and the latest scan available. RESULTS: There were no differences in clinical parameters except for age which was higher in patients with RAAS blockade. In group 1, 2 (7%) deaths, 5 (19%) aortic dissections, and 7 (26%) reoperations occurred. In group 2, 3 (5%) deaths, 2 (3%) aortic dissections, and 3 (5%) reoperations occurred. A Kaplan-Meier plot demonstrated improved survival free from major aortic events in group 2. On multivariate Cox, RAAS blockade was an independent negative predictor of major aortic events (hazard ratio 0.38, 95% confidence interval 0.30-0.43, p=0.002). Mean diameter change in descending thoracic and supra-renal abdominal aorta was significantly higher in patients without RAAS blockade (p<0.05). CONCLUSION: In MFS patients who underwent ARR, the addition of RAAS blockade to beta-blocker was associated with reduction of aortic dilatation and clinical events.

Concomitant inhibition of renin angiotensin system and Toll-like receptor 2 attenuates renal injury in unilateral ureteral obstructed mice

BACKGROUND/AIMS: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. METHODS: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. RESULTS: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor beta (TGF-beta) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-beta in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. CONCLUSIONS: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.

Renin-Angiotensin System Blockade Associated with Statin Improves Endothelial Function in Diabetics / Bloqueio do Sistema Renina-Angiotensina Associado a Estatina Melhora a Função Endotelial em Diabéticos

Abstract Background: Studies suggest that statins have pleiotropic effects, such as reduction in blood pressure, and improvement in endothelial function and vascular stiffness. Objective: To analyze if prior statin use influences the effect of renin-angiotensin-aldosterone system inhibitors on blood pressure, endothelial function, and vascular stiffness. Methods: Patients with diabetes and hypertension with office systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 80 mmHg had their antihypertensive medications replaced by amlodipine during 6 weeks. They were then randomized to either benazepril or losartan for 12 additional weeks while continuing on amlodipine. Blood pressure (assessed with ambulatory blood pressure monitoring), endothelial function (brachial artery flow-mediated dilation), and vascular stiffness (pulse wave velocity) were evaluated before and after the combined treatment. In this study, a post hoc analysis was performed to compare patients who were or were not on statins (SU and NSU groups, respectively). Results: The SU group presented a greater reduction in the 24-hour systolic blood pressure (from 134 to 122 mmHg, p = 0.007), and in the brachial artery flow-mediated dilation (from 6.5 to 10.9%, p = 0.003) when compared with the NSU group (from 137 to 128 mmHg, p = 0.362, and from 7.5 to 8.3%, p = 0.820). There was no statistically significant difference in pulse wave velocity (SU group: from 9.95 to 9.90 m/s, p = 0.650; NSU group: from 10.65 to 11.05 m/s, p = 0.586). Conclusion: Combined use of statins, amlodipine, and renin-angiotensin-aldosterone system inhibitors improves the antihypertensive response and endothelial function in patients with hypertension and diabetes.

Resumo Fundamentos: Estudos sugerem que as estatinas possuem efeitos pleotrópicos, como melhora da função endotelial, da rigidez vascular e redução da pressão arterial. Objetivo: Analisar se o uso prévio de estatina influenciou o efeito sobre a pressão arterial, a função endotelial e a rigidez vascular de drogas inibidoras do sistema renina-angiotensina-aldosterona. Métodos: Pacientes hipertensos e diabéticos com pressão arterial de consultório sistólica ≥ 130 mmHg e/ou diastólica ≥ 80 mmHg tiveram suas medicações anti-hipertensivas substituídas por anlodipino durante 6 semanas. Em seguida, foram randomizados para associação de benazepril ou losartana por mais 12 semanas. Pressão arterial (através da monitorização ambulatorial da pressão arterial), função endotelial (dilatação mediada por fluxo da artéria braquial) e rigidez vascular (velocidade da onda de pulso) foram avaliados antes e após o tratamento combinado. Neste trabalho, uma análise post-hoc foi realizada para comparar pacientes que vinham (grupo CE) ou não (grupo SE) em uso de estatina. Resultados: O grupo CE apresentou maior redução na pressão arterial sistólica nas 24 horas (134 para 122 mmHg, p = 0,007) e na dilatação mediada por fluxo da artéria braquial (6,5 para 10,9%, p = 0,003) quando comparado com o grupo SE (137 para 128 mmHg, p = 0,362, e 7,5 para 8,3%, p = 0,820). Não houve diferença estatisticamente significante na velocidade de onda de pulso (grupo CE 9,95 para 9,90 m/s, p = 0,650 e grupo SE 10,65 para 11,05 m/s, p = 0,586). Conclusão: O uso combinado de estatinas, anlodipino e inibidores do sistema renina-angiotensina-aldosterona melhora a resposta anti-hipertensiva e a função endotelial em pacientes hipertensos e diabéticos.

Betabloqueantes e inhibidores del sistema renina-angiotensina-aldosterona en el síndrome coronario agudo / Beta-blockers and inhibitors of the renin-angiotensin-aldosterone system in acute coronary syndrome

Los betabloqueantes y los inhibidores de la enzima convertidora de angiotensina / antagonistas de los receptores de angiotensina II (I-ECA/ARA II) son medicamentos esenciales en el manejo del síndrome coronario agudo (SCA) con un efecto beneficioso en la sobrevida, aditivo al obtenido con otros fármacos, como aspirina y estatinas, reduciendo la morbi-mortalidad temprana y tardía en pacientes revascularizados o no. Los pacientes pos IAM con fracción de eyección del ventrículo izquierdo (FEVI) < 40% e insuficiencia cardíaca o diabetes, se pueden beneficiar del tratamiento con antagonistas de los receptores mineralocorticoides si se aplican en forma temprana.

Dietary potassium intake and renal handling, and their impact on the cardiovascular health of normotensive Afro-Caribbeans / Ingesta dietética de potasio y manejo renal, y su impacto en la salud cardiovascular de los normotensos Afrocaribeños

OBJECTIVE: Recent nutritional profiles of dietary intake have indicated a shift from the ancient diet to the Western diet. The ancient diet provided high potassium and low sodium intake, which in turn led to sodium conservation and potassium excretion. This change in the dietary intake is expected to affect potassium and sodium handling in the kidneys. Numerous studies have been done to emphasize the importance of sodium handling by the kidneys and its impact on cardiovascular health . This study will investigate potassium intake and handling, and its impact on the cardiovascular health of a sample of normotensive Afro-Caribbeans by the possible modulation of the renin angiotensin aldosterone system (RAAS). METHODS: A sample of 51 normotensive Afro-Caribbean participants was recruited for the study. Participants were observed over a two-day period in which they were given a 24-hour ambulatory blood pressure monitor and a container to collect blood pressure data and a 24-hour urine sample. Anthropometric measurements were noted. Urinary electrolytes and supine plasma renin activity (PRA) were determined from the 24-hour urine collection and a blood sample. Dietary potassium intake was estimated based on dietary intake observations, and calculated based on the urinary potassium excretion. SPSS version 19 was used to analyse the data to make inferences. RESULTS: The daily potassium intake was observed to be 2.95 g/day and measured intake from the urinary potassium was between 4.95 and 7.32 g/day. Urinary potassium excretion was 3.66 (± 1.40) g/day. The urinary potassium excretion in the Afro-Caribbean sample in Barbados was higher than the other population samples. The averaged PRA of the participants (supine) was 0.778 (± 1.072) ng/mL/hour. The averaged nocturnal systolic blood pressure dip of the participants was 5.97 (± 4.324) %. There was no significant correlation between urinary potassium excretion, blood pressure, nocturnal systolic blood pressure dip and PRA. CONCLUSIONS: The Afro-Caribbean sample has an inadequate daily potassium intake based on the observed intake and recommended values, with a high urinary excretion of the electrolyte compared to other values in the literature. This high potassium excretion could have been partly due to low plasma renin activity levels in the study participants. As a possible consequence, an increase in the nocturnal peripheral resistance is a likely cause for the diminished systolic dip. The lack of correlations between dietary potassium excretion and the blood pressure parameters does not allow any firm inference of the electrolyte's handling and its impact on cardiovascular health in the normotensive Afro-Caribbean participants. However, further research is needed to get a more accurate daily potassium intake value, and a more statistically robust sample to assess whether potassium handling and blood pressure would be affected by a change in potassium intake.

OBJETIVO: Los perfiles nutricionales recientes de ingesta dietética han indicado un cambio de la dieta antigua a la dieta occidental. La dieta antigua ofrecía un consumo alto de potasio frente a un consumo bajo de sodio, lo que a su vez llevaba a la conservación del sodio y a la excreción del potasio. Se espera que este cambio en la ingesta dietética afecte el manejo del potasio y el sodio en los riñones. Se han realizado numerosos estudios con el fin de enfatizar la importancia del manejo del sodio por los riñones y su impacto en la salud cardiovascular. Este estudio investigará la ingesta y manejo del potasio, y su impacto en la salud cardiovascular de una muestra de normotensos afrocaribeños mediante la posible modulación del sistema renina-angiotensina-aldosterona (SRAA). MÉTODOS: Una muestra de 51 participantes normotensos afrocaribeños fue reclutada para el estudio. Los participantes fueron puestos bajo observación por un período de dos días, en los que recibieron un monitor ambulatorio para registrar la presión arterial por 24 horas, y un recipiente para recoger los datos de la presión arterial, y una muestra de orina de 24 horas. Se observaron las mediciones antropométricas. Los electrolitos urinarios y la actividad de renina plasmática (ARP) en posición supina, se determinaron a partir de la orina de 24 horas y una muestra de sangre. La ingesta dietética de potasio fue estimada en base a las observaciones hechas de la ingesta dietética, y se calculó a partir de la excreción del potasio urinario. La versión 19 del SPSS fue utilizada para analizar los datos y hacer inferencias. RESULTADOS: Se observó una ingestión diaria de potasio de 2.95 g/día, y la ingestión medida a partir del potasio urinario estuvo entre 4.95 y 7,32 g/día. La excreción del potasio urinario fue 3.66 (± 1.40) g/día. La excreción del potasio urinario en la muestra afrocaribeña en Barbados fue mayor que en las otras poblaciones. La actividad ARP promedio (supina) de los participantes fue 0.778 (± 1.072) ng/mL/hora. La caída nocturna promedio de la presión arterial sistólica de los participantes fue (± 4.324) 5.97%. No hubo ninguna correlación significativa entre la excreción del potasio urinario, la presión arterial, la caída nocturna de la presión arterial sistólica, y la actividad ARP. CONCLUSIONES: Partiendo de la base del consumo observado y los valores recomendados, la muestra afrocaribeña presenta una ingesta diaria inadecuada de potasio, con una alta excreción urinaria de electrólito, en comparación con otros valores en la literatura. Esta elevada excreción de potasio podría haberse debido en parte a niveles bajos de actividad de renina plasmática en los participantes del estudio. Una posible consecuencia es el aumento de la resistencia periférica nocturna como causa probable del descenso sistólico. La falta de correlación entre los parámetros de la presión arterial y la excreción de potasio dietético no permite ninguna inferencia sólida del manejo del electrólito y su impacto sobre la salud cardiovascular en los normotensos afrocaribeños participantes. Sin embargo, es necesario investigar más a fin de obtener un valor más exacto de la ingesta diaria de potasio y una muestra estadísticamente más sólida para evaluar si el manejo del potasio y la presión arterial podrían ser afectados por un cambio en la ingesta de potasio.

Effect of renin-angiotensin-system blockers on contrast-medium-induced acute kidney injury after coronary angiography

BACKGROUND/AIMS: With the increasing incidence of cardiovascular disease, angiocardiography using contrast-enhancing media has become an essential diagnostic and therapeutic tool, despite the risk of contrast-medium-induced acute kidney injury (CIAKI). CIAKI may be exacerbated by renin-angiotensin-system (RAS) blockers, which are also used in a variety of cardiovascular disorders. This study evaluated the effects of RAS blockade on CIAKI after coronary angiography. METHODS: Patients who underwent coronary angiography in our hospital between May 2009 and July 2011 were reviewed. Serum creatinine levels before and after coronary angiography were recorded. CIAKI was diagnosed according to an increase in serum creatinine > 0.5 mg/dL or 25% above baseline. RESULTS: A total of 1,472 subjects were included in this study. Patients taking RAS blockers were older, had a higher baseline creatinine level, lower estimated glomerular filtration rate (eGFR), and had received a greater volume of contrast medium. After propensity score matching, no difference was observed between the RAS (+) and RAS (.) groups. Multiple logistic regression identified RAS blockade, age, severe heart failure, contrast volume used, hemoglobin level, and eGFR as predictors of CIAKI. Multiple logistic regression after propensity matching showed that RAS blockade was associated with CIAKI (odds ratio, 1.552; p = 0.026). CONCLUSIONS: This study showed that the incidence of CIAKI was increased in patients treated with RAS blockers.

Dissociação da resposta anti-hipertensiva e metabólica à losartana e espironolactona em ratos com síndrome metabólica experimental / Dissociation of antihypertensive and metabolic response to losartan and spironolactone in experimental rats with metabolic sindrome

INTRODUÇÃO: O tratamento da hipertensão arterial (HA) em indivíduos com síndrome metabólica (SM) é um desafio, uma vez que terapias não medicamentosas são de difícil implementação e o tratamento farmacológico ideal não está totalmente estabelecido. OBJETIVO: Avaliar o bloqueio do sistema renina angiotensina aldosterona (SRAA) na pressão arterial (PA), na função e na morfologia renais em modelo experimental de SM induzida por dieta hiperlipídica. MÉTODOS: Ratos Wistar receberam ração hiperlipídica a partir da quarta semana de vida, por 20 semanas. Os grupos tratados receberam Losartana ou Espironolactona a partir da oitava semana de vida. Avaliou-se semanalmente o peso corporal e a PA de cauda por pletismografia. Ao final do experimento, foram realizados testes de tolerância oral à glicose, perfil lipídico, clearance de creatinina, medida direta da PA, análise morfométrica renal. RESULTADOS: A administração de dieta hiperlipídica se associou ao desenvolvimento de SM, caracterizada por acúmulo central de gordura, hipertensão arterial, hiperglicemia e hipertrigliceridemia. Nesse modelo não foram observadas alterações da histomorfometria renal. O bloqueio do receptor AT1 da angiotensina II (Ang II) preveniu o desenvolvimento da HA. O bloqueio mineralocorticoide não apresentou eficácia anti-hipertensiva, porém, associou-se à redução da gordura abdominal. CONCLUSÃO: A dissociação da resposta anti-hipertensiva aos bloqueios dos receptores da Ang II e mineralocorticoide indica a participação da Ang II na gênese da HA associada à obesidade. A redução da obesidade central com a Espironolactona sugere a presença de efeito adipogênico mineralocorticoide.

INTRODUCTION: The treatment of arterial hypertension (AH) in patients with metabolic syndrome (MS) is a challenge, since non drug therapies are difficult to implement and optimal pharmacological treatment is not fully established. OBJECTIVE: To assess the blockade of the rennin angiotensin aldosterone system (RAAS) in blood pressure (BP) in renal function and morphology in an experimental model of MS induced by high fat diet. METHODS: Wistar rats were fed on high fat diet from the fourth week of life, for 20 weeks. The groups received Losartan or Spironolactone from the eighth week of life. We weekly evaluated the body weight and BP by tail plethysmography. At the end of the experiment oral glucose tolerance, lipid profile, creatinine clearance tests, and the direct measurement of BP were performed. A morphometric kidney analysis was performed. RESULTS: The administration of high-fat diet was associated with the development of MS, characterized by central fat accumulation, hypertension, hyperglycemia and hypertriglyceridemia. In this model there were no changes in renal histomorphometry. The blockade of angiotensin II (Ang II) receptor AT1 prevented the development of hypertension. The mineralocorticoid blockage did not have antihypertensive efficacy but was associated with reduction of abdominal fat. CONCLUSION: The dissociation of the antihypertensive response to the blockades of Ang II receptors and mineralocorticoid indicates the involvement of Ang II in the pathogenesis of hypertension associated with obesity. Reduction of central obesity with Spironolactone suggests the presence of mineralocorticoid adipogenic effect.

El sistema renina angiotensina y el estrés oxidativo en un modelo experimental de preeclampsia en ratas / The renin angiotensin system and the oxidative stress in a animal model of preeclampsia in rats

La preeclampsia es un síndrome exclusivo de la gestación humana y responsable de una alta morbimortalidad perinatal, cuyas manifestaciones incluyen: hipertensión arterial, proteinuria y edema. Un mecanismo postulado en la fisiopatología de la preeclampsia, es la reducción de la perfusión placentaria y el desarrollo del síndrome clínico materno ocasionado por la liberación de factores placentarios que afectan la regulación de la presión arterial y la función renal. Uno de los factores que ocasiona el trastorno endotelial son las especies reactivas de oxígeno, el incremento de elementos vasoactivos, así como la disminución de agentes vasorelajantes como el óxido nítrico. Todas estas alteraciones vasculares conducen no sólo a la hipertensión sino también a la disfunción renal. Debido a la importancia del papel del óxido nítrico y su desregulación en la preeclampsia, en el presente trabajo se caracterizó un modelo experimental de preeclampsia que resulta de la inhibición de la síntesis de óxido nítrico mediante la administración de L-NAME a ratas preñadas y no preñadas. En el mismo se evaluó el estatus oxidativo y, el papel del sistema renina angiotensina en la contribución de la disfunción renal. Los resultados demuestran el papel primordial del óxido nítrico y su desregulación en este modelo de preeclampsia experimental. En efecto, se demostró que el tratamiento durante siete días con L-NAME incrementó la presión arterial media, aumentó la sensibilidad vascular, inhibió la actividad de la sintasa del óxido nítrico renal y redujo el guanilil monofosfato cíclico urinario. La disfunción endotelial renal en este modelo experimental se manifiesto por proteinuria, incremento de la creatinina plasmática, disminución de la excreción urinaria de sodio, potasio y creatinina, así como, evidencia morfológica de endoteliosis glomerular. Al caracterizar el papel de las enzimas antioxidantes renales se encontró una reducción significativa de la actividad de las mismas, y un incremento de la peroxidación lipídica asociada a una elevada concentración de agentes pro-oxidantes. Nuestro modelo experimental constituye una buena aproximación a la preeclampsia humana y no un efecto inespecífico del L-NAME, ya que aún cuando la inhibición crónica de la síntesis de óxido nítrico en ratas no preñadas induce un incremento de la presión arterial media, proteinuria, reducción de la actividad de la sintasa del óxido nítrico renal y de la excreción urinaria de guanilil monofosfato cíclico similar a las ratas preñadas, los efectos sobre la proteinuria, las acciones morfológicas renales, la excreción urinaria de sodio, potasio y creatinina, y sobre el sistema renina angiotensina son específicos de la preeclampsia experimental en ratas. Así, se demostró que en las ratas preñadas tratadas con L-NAME la actividad de la enzima convertidora de angiotensina plasmática, los niveles de renina plasmática, y la aldosterona amniótica se encuentran marcadamente disminuidos, cuando se comparan con las ratas preñadas normotensas. Estos hallazgos sugieren que la preeclampsia experimental se caracteriza por la supresión de los componentes circulantes del sistema renina angiotensina, que podrían ser responsables del desbalance entre los sistemas vasoconstrictores y vasodilatadores observados en la preeclampsia, así como de algunos de los signos de la preeclampsia, similar a lo que ocurre en la mujer embarazada hipertensa. Por otra parte, al evaluar la contribución del estrés oxidativo en el daño renal en la preeclampsia experimental, se demostró una disminución de la actividad de las enzimas antioxidantes renales. Asimismo, la disminución de la actividad de la glutatión peroxidasa plasmática y la tendencia a la reducción en la glutatión peroxidasa en el líquido amniótico, con el simultáneo incremento de los valores de las sustancias que reaccionan con el ácido tiobarbitúrico (TBARS) plasmático, sugiriéndose que la desregulación generalizada y renal está asociada a una baja protección oxidativa durante la preeclampsia, que favorece a la insuficiencia renal. El incremento temprano del estrés oxidativo placentario juega un papel fundamental en la disfunción endotelial generalizada y el daño renal en la preeclampsia. Debido a ello, nos planteamos que el tratamiento temprano con antioxidantes o con desacoplantes de la NAD (P) H oxidasa podría interrumpir el proceso de este síndrome. Efectivamente, el tratamiento crónico con un compuesto que mimetiza a la superóxido dismutasa, el tempol, o el desacoplante del ensamblaje de la NAD(P)H oxidasa (apocinina), fueron capaces de reducir significativamente la hipertensión inducida por el L-NAME. Igualmente, ambos compuestos fueron capaces de prevenir la proteinuria y la reducción de la actividad de las enzimas antioxidantes renales estudiadas. En conclusión, la preeclampsia experimental inducida por la inhibición crónica de la síntesis de óxido nítrico en ratas preñadas, reproduce los signos clásicos de la preeclampsia humana, y se acompaña de la desregulación del sistema renina angiotensina y de disfunción renal. Esto nos permite aseverar que este modelo experimental de preeclampsia constituye una buena aproximación a la preeclampsia humana. Se demuestra que el daño renal encontrado en este modelo experimental se asocia a una disminución de los mecanismos antioxidantes renales, que lleva a un incremento del estrés oxidativo, y a una reducción de la protección de la función renal. Estos resultados indican que la sobreproducción de especies reactivas de oxígeno tanto placentaria como renal, son causa fundamental de la disfunción endotelial generalizada y del daño renal. Finalmente, la inhibición del estrés oxidativo mediante el uso de agentes antioxidantes como el tempol o la apocinina, pudiese ser una de las posibles estrategias terapéuticas en el tratamiento de la hipertensión inducida por el embarazo humano y abre nuevos horizontes en el tratamiento de este síndrome.

Hypertensive effects of the iv administration of picomoles of ouabain

Ouabain, an endogenous digitalis compound, has been detected in nanomolar concentrations in the plasma of several mammals and is associated with the development of hypertension. In addition, plasma ouabain is increased in several hypertension models, and the acute or chronic administration of ouabain increases blood pressure in rodents. These results suggest a possible association between ouabain and the genesis or development and maintenance of arterial hypertension. One explanation for this association is that ouabain binds to the α-subunit of the Na+ pump, inhibiting its activity. Inhibition of this pump increases intracellular Na+, which reduces the activity of the sarcolemmal Na+/Ca2+ exchanger and thereby reduces Ca2+ extrusion. Consequently, intracellular Ca2+ increases and is taken up by the sarcoplasmic reticulum, which, upon activation, releases more calcium and increases the vascular smooth muscle tone. In fact, acute treatment with ouabain enhances the vascular reactivity to vasopressor agents, increases the release of norepinephrine from the perivascular adrenergic nerve endings and promotes increases in the activity of endothelial angiotensin-converting enzyme and the local synthesis of angiotensin II in the tail vascular bed. Additionally, the hypertension induced by ouabain has been associated with central mechanisms that increase sympathetic tone, subsequent to the activation of the cerebral renin-angiotensin system. Thus, the association with peripheral mechanisms and central mechanisms, mainly involving the renin-angiotensin system, may contribute to the acute effects of ouabain-induced elevation of arterial blood pressure.

Effect of RAAS Inhibition on the Incidence of Cancer and Cancer Mortality in Patients with Glomerulonephritis

Angiotensin II type 1 receptor blocker (ARB), which is frequently prescribed in patients with glomerulonephritis (GN), is suggested to increase the risk of cancer. We registered 3,288 patients with renal biopsy and analyzed the relationship between the use of renin-angiotensin-aldosterone system (RAAS) blockade and the incidence of cancer or cancer mortality. After renal biopsy, cancer developed in 33 patients with an incidence rate of 1.0% (95% of CI for incidence: 0.7%-1.3%). There was no difference in the cancer incidence among the groups according to the use of angiotensin-converting enzyme inhibitors (ACEI) or ARB: 1.2% in the None (23/1960), 0.7% in the ARB-only (5/748), 0.4% in the ACEI-only (1/247), and 1.2% in the ACEI-ARB (4/333) (P = 0.487) groups. The cancer mortality was 2.1%, 0.4%, 0.0%, and 0.3% in None, ACEI-only, ARB-only, and ACEI-ARB group, respectively (P < 0.001). The risk of cancer mortality in patients with ARB was only 0.124 (0.034-0.445) compared to that of non-users of ARB by Cox's hazard proportional analysis. In conclusion, prescription of ACEI or ARB in patients with GN does not increase cancer incidence and recipients of ARB show rather lower rates of all-cause mortality and cancer mortality.