Diferenças Raciais no Controle da Pressão Arterial em Usuários de Anti-Hipertensivos em Monoterapia: Resultados do Estudo ELSA-Brasil / Racial Differences in Blood Pressure Control from Users of Antihypertensive Monotherapy: Results from the ELSA-Brasil Study

Resumo Fundamento Aparentemente, a pior resposta a algumas classes de anti-hipertensivos, especialmente inibidores da enzima conversora da angiotensina e bloqueadores de receptor de angiotensina, pela população negra, explicaria, pelo menos parcialmente, o pior controle da hipertensão entre esses indivíduos. Entretanto, a maioria das evidências vêm de estudos norte-americanos. Objetivos Este estudo tem o objetivo de investigar a associação entre raça/cor da pele autorrelatadas e controle de PA em participantes do Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil) utilizando várias classes de anti-hipertensivos em monoterapia. Métodos O estudo envolveu uma análise transversal, realizada com participantes da linha de base do ELSA-Brasil. O controle de pressão arterial foi a variável de resposta, participantes com valores de PA ≥140/90 mmHg foram considerados descontrolados em relação aos níveis de pressão arterial. A raça/cor da pele foi autorrelatada (branco, pardo, negro). Todos os participantes tiveram que responder perguntas sobre uso contínuo de medicamentos. A associação entre o controle de PA e raça/cor da pele foi estimada por regressão logística. O nível de significância adotado nesse estudo foi de 5%. Resultados Do total de 1.795 usuários de anti-hipertensivos em monoterapia na linha de base, 55,5% se declararam brancos, 27,9%, pardos e 16,7%, negros. Mesmo depois de padronizar em relação a variáveis de confusão, negros em uso de inibidores da enzima conversora de angiotensina (IECA), bloqueadores de receptor de angiotensina (BRA), diuréticos tiazídicos (DIU tiazídicos) e betabloqueadores (BB) in monoterapia tinham controle de pressão arterial pior em comparação a brancos. Conclusões Os resultados deste estudo sugerem que, nesta amostra de brasileiros adultos utilizando anti-hipertensivos em monoterapia, as diferenças de controle de pressão arterial entre os vários grupos raciais não são explicadas pela possível eficácia mais baixa dos IECA e BRA em indivíduos negros.

Abstract Background It seems that the worst response to some classes of antihypertensive drugs, especially angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, on the part of the Black population, would at least partially explain the worse control of hypertension among these individuals. However, most of the evidence comes from American studies. Objectives This study aims to investigate the association between self-reported race/skin color and BP control in participants of the Longitudinal Study of Adult Health (ELSA-Brasil), using different classes of antihypertensive drugs in monotherapy. Methods The study involved a cross-sectional analysis, carried out with participants from the baseline of ELSA-Brasil. Blood pressure control was the response variable, participants with BP values ≥140/90 mmHg were considered out of control in relation to blood pressure levels. Race/skin color was self-reported (White, Brown, Black). All participants were asked about the continuous use of medication. Association between BP control and race/skin color was estimated through logistic regression. The level of significance adopted in this study was of 5%. Results Of the total of 1,795 users of antihypertensive drugs in monotherapy at baseline, 55.5% declared themselves White, 27.9% Brown, and 16.7% Black. Even after adjusting for confounding variables, Blacks using angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blocker (ARB), thiazide diuretics (thiazide DIU), and beta-blockers (BB) in monotherapy had worse blood pressure control compared to Whites. Conclusions Our results suggest that in this sample of Brazilian adults using antihypertensive drugs in monotherapy, the differences in blood pressure control between different racial groups are not explained by the possible lower effectiveness of ACEIs and ARBs in Black individuals.

Qual o papel do bloqueio sequencial do néfron na hipertensão resistente? / What is the role of sequential nephron blockade in resistant hypertension?

A hipertensão resistente (HAR) ocorre quando a pressão arterial (PA) permanece acima da meta recomendada após o uso de três fármacos anti-hipertensivos com ação sinérgica em suas doses máximas toleradas recomendadas, preferencialmente incluindo um diurético. A identificação da contribuição do volume intravascular e da renina sérica na manutenção dos níveis elevados da PA permite um tratamento mais eficaz da hipertensão, ao atuar sobre o controle do volume intravascular, equilíbrio de sódio e sobre os efeitos do sistema renina-angiotensina-aldosterona (SRAA) no rim. Bloqueio sequencial do néfron (BSN) consiste em um aumento progressivo na depleção de sódio usando um diurético tiazídico, um bloqueador do receptor mineralocorticoide (espironolactona), furosemida e, finalmente, amilorida. Os mecanismos de ação, as indicações e os efeitos adversos são discutidos na presente revisão.

Resistant hypertension (HAR) occurs when blood pressure (BP) remains above the recommended target after the use of three antihypertensive drugs with synergistic action at their maximum recommended tolerated doses, preferably including a diuretic. The identification of the contribution of intravascular volume and serum renin in maintaining high BP levels allows a more effective treatment of hypertension, by acting on the control of intravascular volume, sodium balance and on the effects of the renin-angiotensin-aldosterone system (RAS) in the kidney. Sequential nephron block (BSN) consists of a progressive increase in sodium depletion using a thiazide diuretic, a mineralocorticoid receptor blocker (spironolactone), furosemide and, finally, amiloride. Mechanisms of action, indications and adverse effects are discussed in the present review

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.

Passive Cigarette Smoking Impact on Blood Pressure Response to Epinephrine and Felypressin in 1K1C Hypertensive Rats Treated or not with Atenolol / Impacto do Tabagismo Passivo na Resposta Pressórica à Epinefrina e Felipressina em Ratos Hipertensos 1K1C Tratados ou não com Atenolol

Abstract Background: Cigarette smoking is usually associated with hypertension and may modify vasoconstrictor response. Objective: The present study aimed to analyze and compare the interaction of passive cigarette smoking and hypertension on epinephrine and felypressin blood pressure effects after intravascular injection. Method: 45-day male Wistar rats had the main left renal artery partially constricted and the right kidney removed (1K1C model). Rats were placed in the chamber for exposition to passive cigarette smoking (10 cigarettes) during 10 min (6 days a week). Hypertensive rats received atenolol (90 mg/kg/day) by gavage for two weeks. Hypotensive and hypertensive response, response duration and heart rate were recorded from direct blood pressure values. The significance level was 5%. Results: Passive cigarette smoking increased maximal hypertensive response to epinephrine in normotensive and 1K1C-atenolol treated rats and to felypressin only in 1K1C-atenolol treated rats; it also reduced epinephrine hypotensive response. Epinephrine increased heart rate in normotensive and hypertensive passive smokers or non-smoker rats. Comparing the two vasoconstrictors, epinephrine showed greater hypertensive response in normotensive smokers, 1K1C-atenolol treated smokers and non-smokers. However, in normotensive-nonsmoker rats, felypressin showed a greater and longer hypertensive effect. Conclusions: Our results suggest that passive cigarette smoking may reduce epinephrine vasodilation and increase hypertensive response when compared to felypressin. Therefore, felypressin may be safe for hypertensive patients to avoid tachycardia and atenolol interaction, but for normotensive and non-smoker patients, epinephrine may be safer than felypressin.

Resumo Fundamento: O tabagismo geralmente está associado à hipertensão e pode modificar a resposta vasoconstritora. Objetivo: O presente estudo teve como objetivo analisar e comparar a interação do tabagismo passivo e hipertensão sobre os efeitos da epinefrina e felipressina na pressão arterial após injeção intravascular. Métodos: Ratos Wistar machos de 45 dias tiveram a artéria renal principal esquerda parcialmente obstruída e o rim direito removido (modelo 1K1C). Os ratos foram colocados na câmara para exposição ao tabagismo passivo (10 cigarros) durante 10 minutos (6 dias por semana). Ratos hipertensos receberam atenolol (90 mg/kg/dia) por gavagem durante duas semanas. A resposta hipotensora e hipertensiva, a duração da resposta e a frequência cardíaca foram registradas a partir da medida dos valores diretos da pressão arterial. O nível de significância foi de 5%. Resultados: O tabagismo passivo aumentou a resposta hipertensiva máxima à epinefrina em ratos normotensos e ratos 1K1C tratados com atenolol e à felipressina apenas em ratos 1K1C tratados com atenolol; também reduziu a resposta hipotensiva à epinefrina. A epinefrina aumentou a frequência cardíaca em ratos fumantes passivos ou não-fumantes, normotensos e hipertensos. Comparando os dois vasoconstritores, a epinefrina apresentou maior resposta hipertensiva em fumantes normotensos, ratos 1K1C fumantes e não fumantes tratados com atenolol. No entanto, em ratos normotensos e não fumantes, a felipressina apresentou um efeito hipertensivo maior e mais prolongado. Conclusões: Nossos resultados sugerem que o tabagismo passivo pode reduzir a vasodilatação da epinefrina e aumentar a resposta hipertensiva quando comparado à felipressina. Portanto, a felipressina pode ser segura para pacientes hipertensos, com o objetivo de evitar a interação entre taquicardia e atenolol, mas para pacientes normotensos e não-fumantes, a epinefrina pode ser mais segura que a felipressina.

Recomendación rápida sobre el uso de antihipertensivos IECA/ARA II en pacientes con riesgo o documentación de COVID-19 / Rapid recommendation on the use of ACEI/ARA antihypertensives in patients at risk or with documented COVID-19

Ciertos hallazgos preclínicos generaron preocupación en la comunidad científica y en la población general sobre el uso de inhibidores de la enzima convertidora de angiotensina (IECA) y los antagonistas del receptor de la angiotensina II (ARAII), y los posibles desenlaces adversos asociados con relación a la infección por el nuevo Coronavirus (SARS-Cov-2).Por este motivo, nos planteamos como objetivo proveer de recomendaciones dinámicas (living recommendations) para el tratamiento con fármacos IECA o ARA II en pacientes con riesgo o documentación de infección por SARS-CoV-2 (en todo su espectro de gravedad). Se utilizó como metodología la adaptación/adopción de guías de práctica clínica bajo el enfoque GRADE, actualizando la evidencia al 7 de abril de 2020 mediante búsquedas en múltiples bases de datos y consultando a un panel multidisciplinario libre de conflictos de interés. Como resultado de este proceso se arribó a la siguiente afirmación: se recomienda, en contexto de la pandemia de COVID-19, en personas que se encuentran en tratamiento con IECA/ARAII, mantener el tratamiento sin cambios por sobre suspenderlo o reemplazarlo por otros fármacos (Recomendación fuerte a favor - calidad de evidencia baja). (AU)

Certain preclinical findings raised concerns in the scientific community and in the general population about the use ofangiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor antagonists (ARA) and the possible adverse outcomes associated with the infection with the new Coronavirus (SARS-Cov-2). For this reason, our objective is to provide living recommendations for treatment with ACEI or ARA in patients with risk or documentation of SARS-CoV-2 infection (inall its severity spectrum). The adaptation/adoption of clinical practice guidelines under the GRADE approach was used as a methodology, updating the evidence as of April 7, 2020, by searching multiple databases and consulting a multidisciplinary panel free of conflicts of interest. As a result of this process, the following statement was reached: it is recommended, in the context of the COVID-19 pandemic, in people who are undergoing treatment with ACEI/ARA, to maintain the treatment unchanged instead of its suspension or replacement with other drugs (Strong recommendation in favor - low quality ofevidence). (AU)

Resistant and refractory hypertension: two sides of the same disease? / Hipertensão resistente e refratária: duas faces de uma mesma doença?

Abstract Refractory hypertension (RfH) is an extreme phenotype of resistant hypertension (RH), being considered an uncontrolled blood pressure besides the use of 5 or more antihypertensive medications, including a long-acting thiazide diuretic and a mineralocorticoid antagonist. RH is common, with 10-20% of the general hypertensives, and its associated with renin angiotensin aldosterone system hyperactivity and excess fluid retention. RfH comprises 5-8% of the RH and seems to be influenced by increased sympathetic activity. RH patients are older and more obese than general hypertensives. It is strongly associated with diabetes, obstructive sleep apnea, and hyperaldosteronism status. RfH is more frequent in women, younger patients and Afro-americans compared to RFs. Both are associated with increased albuminuria, left ventricular hypertrophy, chronic kidney diseases, stroke, and cardiovascular diseases. The magnitude of the white-coat effect seems to be higher among RH patients. Intensification of diuretic therapy is indicated in RH, while in RfH, therapy failure imposes new treatment alternatives such as the use of sympatholytic therapies. In conclusion, both RH and RfH constitute challenges in clinical practice and should be addressed as distinct clinical entities by trained professionals who are capable to identify comorbidities and provide specific, diversified, and individualized treatment.

Resumo A Hipertensão Arterial Refratária (HARf) representa um fenótipo extremo da hipertensão arterial resistente (HAR), sendo considerada a falência ao tratamento apesar do uso de 5 ou mais classes de anti-hipertensivos, incluindo um diurético tiazídico de longa ação e um antagonista mineralocorticoide. A HAR é comum (10-20%) entre os hipertensos em geral, sendo decorrente de hiperatividade do Sistema Renina Angiotensina Aldosterona e retenção hidrossalina. Aqueles com HARf correspondem a 5-8% dos resistentes e parecem sofrer maior influência catecolaminérgica. Os resistentes tendem a ter maior idade, ao sobrepeso e à obesidade. Comorbidades incluem diabetes, apneia obstrutiva do sono e status de hiperaldosteronismo. Refratários são afro-americanos em maior proporção, mais jovens e, predominantemente, mulheres. Ambos são fortemente associados à elevada albuminúria, HVE, doenças cardio e cerebrovasculares, além da doença renal crônica. O fenômeno do jaleco branco parece ser mais evidente nos resistentes. Quanto ao tratamento, a intensificação da terapia diurética está indicada nos resistentes, enquanto na HARf, a falência à terapia impôs novas alternativas de tratamento ("simpaticolíticas"). Em conclusão, tanto a HAR quanto a HARf constituem-se desafios na prática clínica e devem ser abordadas como entidades clínicas distintas por profissionais especialistas que identifiquem comorbidades e venham a prover um tratamento específico, diversificado e individualizado.

Evaluation of smooth muscle relaxant potential of Bismarckia nobilis (Hildebr. & Wendl.) in diarrhea, hypertension and asthma by ex-vivo and in-vivo method / Evaluación del potencial relajante en músculo liso de Bismarckia nobilis (Hildebr. & Wendl.) en diarrea, hipertensión y asma por métodos ex vivo e in vivo

To explore the mechanistic basis behind smooth muscle relaxant prospective of Bismarckia nobilis in gastrointestinal, respiratory and cardiovascular ailments. The methanolic extract of B. nobilis and sub-fractions have been evaluated in vitro rabbit isolated tissues, in vivo castor oil-induced diarrhea in rats and charcoal meal activity in mice. The B. nobilis extract relaxed spontaneous and K+(80 mM)- induced contractions in rabbit isolated jejunum preparations, CCh (1 µM) and K+ (80 mM)-induced contractions in tracheal and bladder preparations, PE (1 µM) and K+ (80 mM)-induced concentrations in aorta preparations, likewise verapamil. Spasmolytic activity of dichloromethane fraction is stronger as compared to aqueous fraction. In vivo castor oil-induced diarrhea in rats and charcoal meal activity in mice further supported spasmolytic activity. B. nobilis extract possess anti-spasmodic, anti-diarrheal, airway relaxant and vasodilator activities possible mediated through calcium channel blocking mechanism, justifying therapeutic utility of B. nobilis in diarrhea, asthma and hypertension.

El objetivo de trabajo fue explorar el mecanismo de acción relacionado con el efecto relajante del músculo liso inducido por Bismarckia nobilis (B. nobilis) en enfermedades gastrointestinales, respiratorias y cardiovasculares. El extracto metanólico de B. nobilis y subfracciones fue evaluado in vitro en tejidos aislados de conejos. Además se evaluó diarrea in vivo inducida con aceite de ricino en ratas y la actividad de harina de carbón vegetal en ratones. El extracto de B. nobilis relajó tanto las contracciones espontáneas como las inducidas por K+(80 mM) en preparaciones de yeyuno aisladas de conejos, las contracciones inducidas por PE (1 µM) y K+(80 mM) inducidas en preparaciones de aorta; de manera similar a verapamilo. La actividad espasmolítica de la fracción de diclorometano es más potente en comparación con la fracción acuosa. La diarrea inducida in vivo por el aceite de ricino en ratas y la actividad de la harina de carbón vegetal en ratones apoyaron aún más la actividad espasmolítica. El extracto de B. nobilis posee actividades antiespasmódicas, antidiarreicas, relajantes de las vías respiratorias y vasodilatadoras, posibles a través del mecanismo de bloqueo de los canales de calcio, lo que justifica la utilidad terapéutica de B. nobilis en la diarrea, el asma y la hipertensión.

Diuretics are Similar to Losartan on Echocardiographic Target-Organ Damage in Stage I Hypertension. PREVER-Treatment Study / Diuréticos são Similares à Losartana na Avaliação Ecocardiográfica de Lesão a Órgãos-Alvo no Estágio I da Hipertensão. Estudo PREVER-Treatment

Abstract Blood pressure (BP)-lowering therapy improves left ventricular (LV) parameters of hypertensive target-organ damage in stage II hypertension, but whether there is a drug-class difference in echocardiographic parameters in stage I hypertension patients is less often studied. In the PREVER treatment study, where individuals with stage I hypertension were randomized for treatment with diuretics (chlorthalidone/amiloride) or losartan, 110 participants accepted to participate in a sub-study, where two-dimensional echocardiograms were performed at baseline and after 18 months of antihypertensive treatment. As in the general study, systolic BP reduction was similar with diuretics or with losartan. Echocardiographic parameters showed small but significant changes in both treatment groups, with a favorable LV remodeling with antihypertensive treatment for 18 months when target blood pressure was achieved either with chlorthalidone/amiloride or with losartan as the initial treatment strategy. In conclusion, even in stage I hypertension, blood pressure reduction is associated with improvement in echocardiographic parameters, either with diuretics or losartan as first-drug regimens.

Resumo A terapia de redução da pressão arterial (PA) melhora os parâmetros do ventrículo esquerdo (VE) na lesão a órgãos-alvo causada pela condição hipertensiva na hipertensão de estágio II; no entanto, se existem ou não diferenças relacionadas à classe de medicamentos nos parâmetros ecocardiográficos de pacientes com hipertensão estágio I é menos frequentemente estudado. No estudo PREVER-treatment, em que indivíduos com hipertensão estágio I foram randomizados para tratamento com diuréticos (clortalidona/amilorida) ou losartana, 110 participantes aceitaram participar de um subestudo, no qual foram realizados ecocardiogramas bidimensionais basais e após 18 meses de tratamento anti-hipertensivo. Como no estudo geral, a redução da PA sistólica foi semelhante com diuréticos ou com losartana. Os parâmetros ecocardiográficos mostraram pequenas mas significativas alterações em ambos os grupos de tratamento, com um remodelamento favorável do VE com tratamento anti-hipertensivo por 18 meses, quando a pressão arterial alvo foi atingida com clortalidona/amilorida ou com losartana como estratégia inicial de tratamento. Em conclusão, mesmo na hipertensão estágio I, a redução da pressão arterial está associada à melhora nos parâmetros ecocardiográficos tanto com o uso de diuréticos ou losartana como primeiro esquema de tratamento farmacológico.

Losartan improves alveolar bone dynamics in normotensive rats but not in hypertensive rats

Abstract Hypertension is one of the main causes of premature death in the world; also, it is associated with several bone alterations. Preclinical studies have demonstrated delayed alveolar bone healing in hypertensive rats. However, losartan has been favorable for consolidation of bone grafts and reduction in active periodontitis. Therefore, losartan is suggested to be effective in bone formation stages, as well as in the synthesis of matrix proteins and mineralization. Objectives: To evaluate the alveolar bone dynamics in hypertensive rats treated with losartan by laser confocal microscopy and histological analysis. Methodology: Thirty-two rats, 16 spontaneously hypertensive rats (SHR) and 16 Wistar albinus rats, treated or not with losartan (30 mg/kg/day) were used. Calcein fluorochrome at 21 days and alizarin red fluorochrome at 49 days were injected in rats (both 20 mg/kg). The animals were submitted to euthanasia 67 days after treatment, and then the right maxilla was removed for laser confocal microscopy analysis and the left maxilla for histological analysis. Results: This study showed a greater calcium marking in normotensive animals treated with losartan in relation to the other groups. Laser confocal microscopy parameters showed higher values of bone volume formed, mineralized surface, active surface of mineralization and bone formation rate in normotensive animals treated with losartan. However, a smaller mineralized surface was observed in all hypertensive animals. Conclusion: Losartan can improve bone mineralization parameters under normal physiological conditions, but the same anabolic effect does not occur under hypertension.

Antihypertensive treatment adherence in workers of a General Hospital / Adhesión al tratamiento antihipertensivo en trabajadores de un Hospital General / Adesão ao tratamento anti-hipertensivo em trabalhadores de um Hospital Geral

ABSTRACT Objective: to assess antihypertensive treatment adherence and associated factors in workers from a hospital. Method: cross-sectional research, consisting of 108 workers who self-reported as being hypertensive. Associations between sociodemographic, work and health variables were assessed regarding adherence. Results: the mean age was 44.2 years, with predominance of the female sex and workers from the nursing area. Through blood pressure measurement, 25% of participants were classified as non-controlled hypertensive patients. Approximately 88% reported taking some sort of medication; however, 79.6% did not adhere to the antihypertensive treatment. In the multiple regression analysis, the independent factors for non-adherence were hypercholesterolemia (OR=8.10; p=0.024) and missing medical appointments (OR=4.06; p=0.048). Conclusion: we verified a significant percentage of non-adherence. Since hypertension and cholesterol are asymptomatic diseases that require continuous treatment, hypertensive patients have difficulties to understand the importance of adhering to the treatment, even being health professionals or working in hospitals.

RESUMEN Objetivo: evaluar la adhesión al tratamiento antihipertensivo en los trabajadores de una institución hospitalaria y los factores asociados. Método: investigación transversal, compuesta por 108 trabajadores que se autorrefirieron hipertensos. Se analizaron relaciones entre variables sociodemográficas, de trabajo y salud con la adhesión. Resultados: la edad media fue de 44,2 años, con predominio del sexo femenino y trabajadores del área de enfermería. Mediante la medición de la presión arterial, el 25 % fueron clasificados como hipertensos no controlados. Alrededor del 88 % declararon tomar algún medicamento, sin embargo, el 79,6 % no adherían a tratamiento antihipertensivo. En el análisis de regresión múltiple, los factores independientes para la no adhesión fueron la hipercolesterolemia (OR=8,10; p=0,024), así como la falta del paciente a la consulta médica (OR=4,06; p=0,048). Conclusión: se constató porcentaje de no adhesión expresivo. Debido a que la hipertensión y el colesterol alto son enfermedades asintomáticas y de tratamiento continuo, el paciente hipertenso tiene dificultades para comprender la importancia de la adhesión al tratamiento, incluso siendo un profesional de la salud o trabajando en un entorno hospitalario.

RESUMO Objetivo: Avaliar a adesão ao tratamento anti-hipertensivo nos trabalhadores de uma instituição hospitalar e os fatores associados. Método: pesquisa transversal, composta por 108 trabalhadores que se autorreferiram hipertensos. Foram analisadas associações entre variáveis sociodemográficas, de trabalho e saúde com adesão. Resultados: a idade média foi de 44,2 anos, com predomínio do sexo feminino e trabalhadores da área de enfermagem. Por meio da medida da pressão arterial, 25% foram classificados hipertensos não controlados. Aproximadamente 88% referiram tomar algum medicamento, porém, 79,6% não aderiam ao tratamento anti-hipertensivo. Na análise de regressão múltipla, os fatores independentes para a não adesão foram a hipercolesterolemia (OR=8,10; p=0,024) e faltar à consulta médica (OR=4,06; p=0,048). Conclusão: constatou-se percentual de não adesão expressivo. Em razão da hipertensão e o colesterol serem doenças assintomáticas e de tratamento contínuo, o paciente hipertenso tem dificuldades de compreender a importância da adesão ao tratamento, mesmo sendo um profissional da saúde ou trabalhando em ambiente hospitalar.

Effect of atenolol pre-treatment in heart damage in a model of intestinal ischemia-reperfusion

Abstract Purpose: To investigate the effects of atenolol in inflammatory mediator and oxidative stress in a myocardial injury by intestinal ischemia/reperfusion in rat model. Methods: Adult Wistar male rats were randomly (n=8), anesthetized and divided in: Sham: submitted to operation only; group SS+IR: intravenous saline infusion following superior mesenteric artery occlusion during 60 minutes (ischemia) and open for 120 minutes (reperfusion); group AT+IR: intravenous atenolol infusion (2 mg/kg) following superior mesenteric artery occlusion during 60 minutes (ischemia) and open for 120 minutes (reperfusion); and group AT+I+AT+R: intravenous atenolol infusion following superior mesenteric artery occlusion during 60 minutes (ischemia) and in the time 45 minutes other atenolol doses were administrated and the artery was open for 120 minutes (reperfusion), all animals were submitted to muscular relaxation for mechanical ventilation. In the end of experiment the animals were euthanized and the hearts tissue were morphology analyzed by histology and malondialdehyde by ELISA, and the plasma were analyzed for tumor necrosis factor-alpha by ELISA. Results: The group SS+IR demonstrated the higher malondialdehyde levels when compared with the atenolol treated-groups (p=0.001) in the heart tissue. The tumor necrosis factor-alpha level in plasma decrease in the treated groups when compared with SS+IR group (p=0.001). Histology analyses demonstrate pyknosis, edema, cellular vacuolization, presence of inflammatory infiltrate and band contraction in the heart tissue of the rats. Conclusion: Atenolol significantly reduce the degree of cardiac damage after intestinal ischemia-reperfusion.

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.

Influence of antihypertensive drugs on aortic and coronary effects of Ang-(1-7) in pressure-overloaded rats

This study investigated the influence of antihypertensive drugs, such as angiotensin-converting enzyme inhibitors (ACEIs), AT1 receptor blockers (ARBs), voltage-gated L-type calcium channel blockers, and mineralocorticoid receptor antagonists (MRAs), on the effects of angiotensin-(1-7) [Ang-(1-7)] on aorta and coronary arteries from pressure-overloaded rats. Pressure overload was induced by abdominal aortic banding (AB). To evaluate the role of antihypertensive drugs on the effect of Ang-(1-7), AB male Wistar rats weighing 250–300 g were treated with vehicle or low doses (5 mg·kg-1·day-1, gavage) of losartan, captopril, amlodipine, or spironolactone. Isolated aortic rings and isolated perfused hearts under constant flow were used to evaluate the effect of Ang-(1-7) in thoracic aorta and coronary arteries, respectively. Ang-(1-7) induced a significant relaxation in the aorta of sham animals, but this effect was reduced in the aortas of AB rats. Chronic treatments with losartan, captopril or amlodipine, but not with spironolactone, restored the Ang-(1-7)-induced aorta relaxation in AB rats. The coronary vasodilatation evoked by Ang-(1-7) in sham rats was blunted in hypertrophic rats. Only the treatment with losartan restored the coronary vasodilatory effect of Ang-(1-7) in AB rat hearts. These data support a beneficial vascular effect of an association of Ang-(1-7) and some antihypertensive drugs. Thus, this association may have potential as a new therapeutic strategy for cardiovascular diseases.

Decades of research in drug targeting using gastroretentive drug delivery systems for antihypertensive therapy

ABSTRACT The limitations in absorption of drugs with narrow absorption window, or those unstable in the intestinal pH or those exhibiting low solubility at high pH are primary candidates for gastroretentive drug delivery systems (GRDDS). The delivery system has been widely explored for its commercial potential for a wide variety of therapeutic agents. GRDDS offer clinical therapeutics for acute and chronic management. Hypertension is a chronic disease that requires long term treatment and its management by patient compliant dosage forms would be clinically useful. Antihypertensives belonging to different classes have proved good candidates for the formulation of GRDDS. The review aims to discuss various GRDDS researched for antihypertensive drugs to increase the gastric residing time, bioavailability, henceforth to reduce the dose of the drug, dosing frequency and increase patient compliance. It also explores various marketed products and the patents filed/granted for GRRDS of antihypertensives. The GRDDS investigated include effervescent and non-effervescent floating drug delivery systems, swelling and expanding systems and bio/mucoadhesive systems. Many other systems that provided research platforms include high density systems, raft forming systems and osmotic delivery systems. In clinical context, wherein combination of antihypertensives is indicated, dual release delivery systems may also be explored.

Effects of prostaglandin analogs on blood flow velocity and resistance in the ophthalmic artery of rabbits / Efeitos dos análogos da prostaglandina na velocidade do fluxo sanguíneo e resistência na artéria oftálmica de coelhos

ABSTRACT Purpose: The aim of this study was to investigate the effects of prostaglandin analogs on blood flow in the ophthalmic artery of clinically healthy rabbits. Methods: Fifty-five clinically healthy New Zealand white rabbits were divided into six groups, and the left eyes were treated for four weeks with the preservative benzalkonium chloride (BAK) only or a topical formulation of different prostaglandin analogs (bimatoprost BAK, tafluprost BAK-free, travoprost BAK, travoprost POLYQUAD, and latanoprost BAK). Color Doppler imaging was performed before and after the treatments. The mean values of the peak systolic velocity (PSV) and end diastolic velocity and the resistive index (RI) were calculated. Statistical analysis was performed to compare the differences pre- and post-treatment for each drug and post-treatment among the drugs. Results: The prostaglandin analogs did not affect PSV. Bimatoprost BAK, travoprost POLYQUAD, and latanoprost BAK did not change RI. Tafluprost BAK-free and travoprost BAK therapy resulted in similar reductions in RI. No significant differences pre- and post-treatment were found when BAK was administered alone. Conclusion: The prostaglandin analogs tafluprost BAK-free and travoprost BAK improved blood flow in the ophthalmic artery in healthy New Zealand white rabbits, which suggests that these drugs enhance the prevention of the progression the progression of glaucoma.

RESUMO Objetivo: O objetivo deste estudo foi investigar os efeitos dos análogos da prostaglandina (PGAs) no fluxo sanguíneo da artéria oftálmica em coelhos. Métodos: Cinquenta e cinco coelhos da raça Nova Zelândia clinicamente saudáveis foram divididos em seis grupos para tratamento com formulação tópica de diferentes APGs (bimatoprosta BAK, tafluprosta BAK-free, travoprosta BAK, travoprosta POLYQUAD e latanoprosta BAK) e formulações contendo apenas o conservante cloreto de benzalcônio (BAK). Foi realizada ultrassonografia com Doppler antes e após os tratamentos. Os valores do pico da velocidade sistólica (PSV) e da velocidade diastólica final foram obtidos e o índice de resistência (RI) foi então calculado. A análise estatística foi realizada para comparar as diferenças entre cada droga no pré e pós-tratamento, além das diferenças no pós-tratamento entre as drogas. Resultados: Estes colírios PGAs não afetaram o PSV. A bimatoprosta com o conservante BAK, travoprosta com o conservante POLYQUAD e latanoprosta com o conservante BAK não alteraram o RI. Já o tratamento com tafluprosta sem conservante (BAK-free) e travoprosta com o conservante BAK promoveram redução similar dos valores do RI. Não houve diferença significativa na comparação entre valores pré e pós-tratamento quando BAK foi administrado isoladamente. Conclusão: Os PGAs tafluprosta BAK-free e travoprosta BAK melhoraram o fluxo sanguíneo na artéria oftálmica em coelhos da raça Nova Zelândia sugerindo que estes medicamentos possam contribuir na prevenção da progressão do glaucoma.

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.

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.

Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats

OBJECTIVES: This study was conducted to determine whether the blood pressure-lowering effect of Nigella sativa might be mediated by its effects on nitric oxide, angiotensin-converting enzyme, heme oxygenase and oxidative stress markers. METHODS: Twenty-four adult male Sprague-Dawley rats were divided equally into 4 groups. One group served as the control (group 1), whereas the other three groups (groups 2-4) were administered L-NAME (25 mg/kg, intraperitoneally). Groups 3 and 4 were given oral nicardipine daily at a dose of 3 mg/kg and Nigella sativa oil at a dose of 2.5 mg/kg for 8 weeks, respectively, concomitantly with L-NAME administration. RESULTS: Nigella sativa oil prevented the increase in systolic blood pressure in the L-NAME-treated rats. The blood pressure reduction was associated with a reduction in cardiac lipid peroxidation product, NADPH oxidase, angiotensin-converting enzyme activity and plasma nitric oxide, as well as with an increase in heme oxygenase-1 activity in the heart. The effects of Nigella sativa on blood pressure, lipid peroxidation product, nicotinamide adenine dinucleotide phosphate oxidase and angiotensin-converting enzyme were similar to those of nicardipine. In contrast, L-NAME had opposite effects on lipid peroxidation, angiotensin-converting enzyme and NO. CONCLUSION: The antihypertensive effect of Nigella sativa oil appears to be mediated by a reduction in cardiac oxidative stress and angiotensin-converting enzyme activity, an increase in cardiac heme oxygenase-1 activity and a prevention of plasma nitric oxide loss. Thus, Nigella sativa oil might be beneficial for controlling hypertension.

Cocos nucifera (L.) (Arecaceae): A phytochemical and pharmacological review

Cocos nucifera (L.) (Arecaceae) is commonly called the “coconut tree” and is the most naturally widespread fruit plant on Earth. Throughout history, humans have used medicinal plants therapeutically, and minerals, plants, and animals have traditionally been the main sources of drugs. The constituents of C. nucifera have some biological effects, such as antihelminthic, anti-inflammatory, antinociceptive, antioxidant, antifungal, antimicrobial, and antitumor activities. Our objective in the present study was to review the phytochemical profile, pharmacological activities, and toxicology of C. nucifera to guide future preclinical and clinical studies using this plant. This systematic review consisted of searches performed using scientific databases such as Scopus, Science Direct, PubMed, SciVerse, and Scientific Electronic Library Online. Some uses of the plant were partially confirmed by previous studies demonstrating analgesic, antiarthritic, antibacterial, antipyretic, antihelminthic, antidiarrheal, and hypoglycemic activities. In addition, other properties such as antihypertensive, anti-inflammatory, antimicrobial, antioxidant, cardioprotective, antiseizure, cytotoxicity, hepatoprotective, vasodilation, nephroprotective, and anti-osteoporosis effects were also reported. Because each part of C. nucifera has different constituents, the pharmacological effects of the plant vary according to the part of the plant evaluated.