Bloqueo del eje renina angiontensina aldosterona (RAAS) en la enfermedad renal diabética. Más allá del control de la hipertensión arterial / Renin angiotensin aldosterone system (RAAS) and its suppression in diabetic kidney disease. Control of arterial hypertension and beyond

La enfermedad renal diabética (ERD) es una comorbilidad con alta prevalencia a nivel mundial, siendo una de las complicaciones más frecuentes de la diabetes mellitus (DM). La ERD se relaciona con complicaciones cardiovasculares y progresión de la enfermedad renal crónica (ERC), por ello la identificación de factores modificables, como el control de la presión arterial, es uno de los pilares más importantes en el manejo integral. En esta revisión hacemos un recorrido sobre el papel de la hipertensión y el bloqueo del eje renina angiotensina aldosterona (RAAS) en el curso de la ERD y las estrategias terapéuticas orientadas a la reducción de la presión arterial (PA), el bloqueo RAAS y el impacto en resultados renales y cardiovasculares. El objetivo de este artículo es hacer una revisión de las intervenciones más importantes que actúan bloqueando el eje renina angiotensina aldosterona (RAAS) y determinar si estas medidas en los pacientes con ERD, solo tienen impacto en el control de la presión arterial o si también son estrategias de nefro y cardio-protección. Conclusión: La ERD es una de las complicaciones más frecuentes de la diabetes mellitus (DM). El control de la PA sigue siendo un pilar fundamental para lograr estos objetivos. Los bloqueadores del RAAS (iECAS y BRAs) son los antihipertensivos de elección con efecto terapéutico por el bloqueo RAAS y esto les permite tener además del control de la PA, efectos nefroprotectores y cardioprotectores importantes en pacientes con ERD, sobre todo cuando hay la presencia de albuminuria. Evaluamos que además de los inhibidores de la enzima convertidora de angiotensina (iECAs) y los bloqueadores del receptor de angiotensina (BRAs), vienen tomando importancia los antagonistas selectivos del receptor mineralocorticoide (ARM) como Finerenona.

Diabetic kidney disease (DKD) is a comorbidity with a high worldwide prevalence, and one of the most frequent complications of diabetes mellitus (DM). CKD is related to cardiovascular complications and the progression of chronic kidney disease (CKD), therefore the identification of modifiable factors, such as blood pressure control, is one of the most important pillars in comprehensive management. In this review, we will analyze the role of hypertension and the renin-angiotensin-aldosterone system (RAAS) and its suppression in the course of CKD, and therapeutic strategies aimed at reducing blood pressure (BP), RAAS blockade, and the impact on renal and cardiovascular outcomes. The objective of this article is to review the most important interventions that act by blocking the renin-angiotensin-aldosterone system (RAAS) and to determine if these measures in patients with CKD only have an impact on blood pressure control or if they are also nephron and cardio-protective strategies. Conclusion: DKD is one of the most frequent complications of diabetes mellitus (DM). BP control continues to be a fundamental pillar to achieve these objectives. RAAS blockers (iECAS and ARBs) are the first-line antihypertensive with a therapeutic effect due to RAAS blockade and this allows them to have, in addition to BP control, important nephroprotective and cardioprotective effects in patients with CKD, especially when there is albuminuria. We evaluated that in addition to angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), selective mineralocorticoid receptor antagonists (MRA) such as Finerenone are gaining importance.

Pronóstico de los pacientes hospitalizados por Covid-19 que utilizaban inhibidores de la enzima convertidora de angiotensina o antagonistas del receptor de angiotensina II / Prognósis of patients hospitalized due to Covid-19 who were taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers

Introducción: existe controversia acerca de la seguridad del uso de inhibidores de la enzima convertidora de angiotensina (iECA) o antagonistas de los receptores de angiotensina II (ARA II) en pacientes con COVID-19, debido a que la ECA-2 sirve de entrada del virus a la célula. Objetivo: evaluar la asociación del antecedente del uso de iECA o ARA II con el ingreso a UCI o la muerte intrahospitalaria. Metodología: cohorte prospectiva multicéntrica que incluyó pacientes adultos hospitalizados por coronavirus COVID-19 en tres hospitales de Bogotá, Colombia, entre abril y noviembre 2020. Se realizó un análisis univariado evaluando la asociación de los iECA y ARA II con el ingreso a UCI o la muerte intrahospitalaria. Resultados: se incluyeron 592 pacientes de los cuales 225 (38.0%) cursaban con hipertensión arterial, 108 (18.2%) diabetes y 50 (8.4%) enfermedad cardiovascular crónica, 160 (27.0%) ingresaron a UCI y 107 (18.1%) fallecieron, 32% tenía el antecedente de uso de iECA o ARA II. En el análisis univariado no se obtuvo ninguna asociación con ingreso a UCI o muerte intrahospitalaria, uso de inhibidores de la ECA OR= 1.017 (IC95% 0.887 - 1.152, p=0.800), OR=1.072 (0.952 - 1.19, p=0.968) respectivamente; uso de ARA II OR= 0.998 (IC95% 0.913-1.086, p=0.968), OR=1.045 (IC95% 0.969 - 1.122, p=0.235), respectivamente. Conclusiones: el antecedente del uso de los iECA o ARA II no se asoció con el ingreso a UCI o la muerte intrahospitalaria en pacientes hospitalizados por COVID-19.

Introduction: controversy remains about the safety of using angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) in patients with COVID-19, since ACE2 receptor mediates the entry of the virus into the cell. Objective: to evaluate the association of past history of ACEIs or ARBs use with admission to the ICU or in-hospital death. Methodology: prospective multicenter cohort that included adult patients hospitalized due to COVID-19 coronavirus in three hospitals in Bogota, Colombia, between April and November 2020. A univariate analysis was performed evaluating the association of ACEIs and ARBs with ICU admission or in-hospital death. Results: 592 patients were included of whom 225 (38.0%) had hypertension, 108 (18.2%) diabetes and 50 (8.4%) chronic cardiovascular disease, 160 (27.0%) were admitted to the ICU and 107 (18.1%) died, 32% had a history of prior ACEIs or ARBs use. In the univariate analysis no association was found with ICU admission or in-hospital death, ACEIs use OR= 1.017 (CI95% 0.887 - 1.152, p=0.800), OR=1.072 (0.952 - 1.19, p=0.968) respectively; use of ARBs OR= 0.998 (CI95% 0.913-1.086, p=0.968), OR=1.045 (CI95% 0.969 - 1.122, p=0.235), respectively. Conclusions: a history of prior ACEIs or ARBs use was not associated with admission to the ICU or in-hospital death in patients hospitalized due to COVID-19.

Receptor de la enzima convertidora de angiotensina y su correlación con COVID-19 ¿Qué conocemos hasta el momento? / Angiotensin Converting Enzime Receptor and COVID-19 Correlation ¿What do we know so far?

Resumen Introducción: el SARS-COV-2 es un nuevo virus que ha traído nuevos retos a los sistemas de salud a nivel mundial y que ha generado controversia en la continuidad en el uso de bloqueadores del receptor de angiotensina por su correlación fisiopatológica con el SARS-COV-2. Objetivo: presentar la evidencia disponible y las actuales recomendaciones sobre el uso de receptores de la enzima convertidora de angiotensina en el tratamiento para COVID-19. Materiales y métodos: se realizó una búsqueda narrativa en la base de datos PubMed sobre artículos que hablaran acerca del receptor de la enzima convertidora de angiotensina asociado a la pandemia actual por COVID-19. El límite de publicación fue el 13 de abril de 2020 y se incluyeron artículos en todos los idiomas. Resultados: se encontraron 14 artículos con contenido científico significativo para el objetivo de la presente revisión. Conclusión: la fisiopatología del SARS-COV-2 aún es desconocida, así como la efectividad de diferentes fármacos de uso cotidiano para su tratamiento. Dentro de los diferentes medicamentos que se han probado para detener el contagio y sus efectos están aquellos con efecto sobre el receptor de la enzima convertidora de angiotensina.

Abstract Introduction: As a new disease, SARS-COV-2 is a new challenge for healthcare system worldwide, with physiopathology under study and controversy about Angiotensin Converting Enzyme Blockers use because of It's physiopatological correlation with SARS-Cov-2. Objetive: Search for novel literature and recent recomendations about use of Angiotensin Converting Enzyme Blockers during Covid-19 illness. Materials and Methods: We look for narrative literature at PubMed Database for articles about Angiotensin Converting Enzyme and Covid-19 pandemic. Searching limit was April 13 of2.020, we included all languages. Results. We included 14 articles with significative scientific content for review objetive. Conclusion: SARS-Cov-2 Physiopatology is still unclear, also, pharmacology effectiveness in it's treatment. One of these pharmacology groups are the Angiotensin Converting Enzyme Blockers with uncertainty about it's safety during COVID-19 illness.

Caracterización clínica y demográfica de pacientes adultos sometidos a valoración de la presión arterial con monitorización ambulatoria de la presión arterial. Registro EPEDMAPA / Clinical and demographic profile of adult patients subjected to an assessment of arterial hypertension with an ambulatory blood pressure monitoring device. EPEDMAPA Registry

Resumen Introducción: la hipertensión arterial es un problema de salud pública que aumenta la mortalidad en todos los escenarios clínicos, pero es, además, el principal factor de riesgo modificable. Es una enfermedad altamente prevalente; cerca de un cuarto de la población del mundo la padece. Pocos pacientes la conocen y pocos están tratados de manera óptima. Objetivo: evaluar las características de pacientes a quienes se les realizó una monitorización ambulatoria de la presión arterial en un Hospital Universitario, con miras a describir el perfil clínico y demográfico. Métodos: estudio descriptivo retrospectivo, llevado a cabo en pacientes sometidos a monitorización ambulatoria de la presión arterial de 24 horas durante los meses de octubre y noviembre de 2015. Resultados: se confirmó hipertensión (de reciente diagnóstico o conocida) en el 75% de los estudios realizados. Se descartó hipertensión arterial en el 31% de los pacientes previamente clasificados como hipertensos. El 61% de los pacientes que se encontraban bajo tratamiento estaban bien controlados, la mayoría de ellos con un solo medicamento, principalmente antagonistas del receptor de angiotensina II. El patrón circadiano más prevalente en esta cohorte de pacientes fue el dipper (48%) seguido por el patrón de non-dipper (29%). Conclusiones: el monitorización ambulatoria de la presión arterial permite evaluar con exactitud el estado de la presión arterial de los pacientes con sospecha de hipertensión arterial. Esto aclara si los pacientes son realmente normotensos o hipertensos y discrimina las condiciones de la bata blanca y la hipertensión enmascarada, con lo cual se evitan tratamientos innecesarios y se favorece un mejor control de la presión arterial.

Abstract Introduction: Arterial hypertension is a public health problem that increases mortality in all clinical situations. It is also the main modifiable risk factor. It is a highly prevalent condition that is suffered by around 25% of the world population. Few patients are aware of it, and few receive the optimum treatment. Objective: To evaluate the characteristics of the patients on whom ambulatory blood pressure monitoring was carried out in a University Hospital, with a view to describing the clinical and demographic profile. Methods: A descriptive retrospective study was conducted on patients subjected to 24-hour ambulatory blood pressure monitoring, during the months of October and December 2015. Results: Hypertension (recently diagnosed or known) was confirmed in 75% of the studies performed. Arterial hypertension was ruled out in 31% of the patients previously classified as hypertensive. Of the patients that were receiving treatment, 61% were well-controlled, with the majority of them with a single drug, mainly an angiotensin II receptor agonist. The dipper was most prevalent circadian pattern, with 48%, followed by the non-dipper pattern in 29%. Conclusions: Ambulatory blood pressure monitoring helps in the evaluation of the blood pressure status accurately in patients with a suspicion of arterial hypertension. This clarifies whether the patients are really normotensive or hypertensive and discriminates between the "white coat" and masked hypertension conditions. This avoids unnecessary treatments and favours a better control of the blood pressure.

COVID-19, ACE -inhibitors and angiotensin receptor blockers: The need to differentiate between early infection and acute lung injury / COVID-19, y IECA -inhibidores y bloqueadores de los receptores de angiotensina: la necesidad de diferenciar entre una infección temprana y una lesión pulmonar aguda

SARS-CoV-2, along with SARS-CoV and MERS-CoV, forms part of the three highly pathogenic coronaviruses identified since the start of the millennium.1,2 While SARS-CoV was identified on 2003 and MERS-CoV on 2012, the initial reports of SARS-CoV-2 (the etiological agent of COVID-19) were first released at the end of December 2019.3,4 Now, after less than four months, the virus has distributed globally and has become the focus of extensive medical research, as the number of cases keeps rising.A significant part of the investigative effort has been directed to the search for an effective therapy or intervention that could stop the spread of the disease or be used to effectively treat infected patients. Likewise, potential predisposing factors to develop a more severe clinical presentation are progressively being identified. Some of the more relevant are older age and the presence of certain comorbidities, such as cerebrovascular and coronary heart disease, hypertension and diabetes.5­8 It is important to highlight that the last two are chronic conditions commonly treated with ACE-inhibitors and angiotensin II type-I receptor blockers.9­11 However, the evidence suggests that these medications can upregulate the expression of angiotensin converting enzyme 2 (ACE2), the cellular receptor for both SARS-CoV and SARS-CoV-2.11­16 Thus, a group of researchers hypothesized that ACE2-increasing drugs could raise the risk of infection and prompt a more severe clinical course or a fatal outcome in diabetic and hypertensive patients.

Planejamento e desenvolvimento de ligantes não peptídicos com atividade agonista enviesada no receptor de angiotensina II tipo 1 empregando-se técnicas de modelagem molecular e ensaios in vitro / Drug design of non-peptidic biased agonists for angiotensin II type 1 receptor using molecular modeling techniques and in vitro tests

A insuficiência cardíaca (IC) é uma síndrome de elevada morbimortalidade, correspondendo a um grave problema de saúde pública. Uma das abordagens terapêuticas para IC consiste no uso de antagonistas do receptor de angiotensina II do tipo 1 (AT1R), conhecidos como sartanas. Estudos apontam que uma nova classe de compostos, os agonistas enviesados, é capaz de induzir a sinalização da via da ß-arrestina sem ativação da via da proteína G. Essa seletividade funcional é particularmente interessante, pois a via dependente da proteína G é responsável pelo aumento da pressão arterial, morte celular e fibrose tecidual, levando a hipertrofia cardíaca e progressão da IC. No entanto, a via da ß-arrestina está associada com renovação celular e aumento do inotropismo. Além disso, estudos in vivo sugerem que agonistas enviesados poderiam corresponder a uma terapia superior à dos antagonistas convencionais, que bloqueiam ambas as vias. Apesar do potencial terapêutico, esses compostos possuem estrutura peptídica e, por isso, tem sua administração restrita à via intravenosa. A resolução da estrutura cristalográfica do AT1R permitiu estudos de modelagem molecular mais acurados. Tendo isso em mente, nesse trabalho foram propostos agonistas enviesados de natureza não peptídica para o AT1R por meio de técnicas de modelagem molecular e validação das hipóteses levantadas por ensaios in vitro. Foram realizados estudos de dinâmica molecular com o AT1R (PDB ID: 4YAY) em uma bicamada lipídica e ensaios de ancoramento molecular da angiotensina II (AngII) e do ligante enviesado TRV027. As poses de ancoramento molecular selecionadas foram utilizadas em dinâmicas de complexo, que revelaram diferenças entre os sistemas apo (sem nenhum ligante) e holo (com o ligante no sitio de ligação). Nossos resultados sugerem que o TRV027 induz um padrão exclusivo de ligações de hidrogênio e de estrutura secundária, enquanto que a AngII afeta os resíduos do bolso hidrofóbico do sitio de ligação, principalmente a conformação do Trp2536.48. Com base nas simulações, três farmacóforos foram criados e utilizados de maneira complementar em triagens virtuais na base de dados ZINC15, resultando na seleção de cinco compostos. Um desses compostos apresentou afinidade pelo receptor AT1R e, ainda que estudos complementares de ativação de vias especificas sejam necessários para que o composto possa ser classificado como agonista enviesado, já se constitui em molécula potencialmente promissora. Além disso, esses estudos permitiram a proposição de estruturas inéditas que podem vir a ser hits no processo de desenvolvimento de agonistas enviesados para AT1R. Portanto, como continuidade desse trabalho, essas moléculas serão sintetizadas e investigadas quanto à possível interação com o receptor.

Heart Failure (HF) is a common syndrome with high morbimortality, being considered a serious public health problem. One of the therapeutic approaches for HF consists in the use of the sartan class, which are angiotensin II type 1 receptor (AT1R) antagonists. Recent studies have shown that a new class of compounds, known as biased agonists, is able to induce signaling via ß-arrestin without G-protein activation. This functional selectivity is particularly interesting since G-protein dependent signaling is responsible for cell death and cardiac tissue fibrosis, which leads to cardiac muscle hypertophy and HF progression. On the other hand, ß-arrestin signaling is associated with cellular renewal and increased inotropism. In vivo studies suggests that biased agonists could correspond to a superior therapy over conventional angiotensin II type 1 receptor antagonists, which blocks cell signaling as a whole, however their peptidic structure restricts their use to intravenous administration. Moreover, the AT1R crystal structure determination holds great promise for more accurate molecular modeling studies. With that being said, the aim of this work was to plan and develop new non-peptidic biased agonists for ATR1 employing molecular modeling techniques and in vitro tests for hypothesis validation. Molecular dynamics (MD) simulations of the refined AT1R crystal (PDB ID: 4YAY) embedded in a lipid bilayer and molecular docking studies with angiotensin II (AngII) and TRV027 (biased agonist) were conducted. Selected docking poses from both ligands underwent complex MD simulations revealing differences between apo (ligand free) and holo (ligand in the binding site) systems. Our results suggest that TRV027 induces an exclusive hydrogen bond and secondary structure pattern, while AngII affects the hydrophobic pocket conformation, mainly Trp253. Based on the simulations, three pharmacophore models were created and used in virtual screenings in the ZINC15 database, resulting in the selection of five compounds that were tested in vitro. One of the compounds displayed affinity for AT1R and is a promising molecule. Nonetheless, it needs further pathway activation characterization in order to be a classified as a biased agonist. Furthermore, these results have contributed significantly for the proposition of new structures that could be hits with biased agonist activity for AT1R. Thus, for future works, we point out the necessity for synthesis and characterization of this new compounds

Olmesartan is not associated with the risk of enteropathy: a Korean nationwide observational cohort study

BACKGROUND/AIMS: Olmesartan, a widely used angiotensin II receptor blocker (ARB), has been linked to sprue-like enteropathy. No cases of olmesartan-associated enteropathy have been reported in Northeast Asia. We investigated the associations between olmesartan and other ARBs and the incidence of enteropathy in Korea. METHODS: Our retrospective cohort study used data from the Korean National Health Insurance Service to identify 108,559 patients (58,186 females) who were initiated on angiotensin converting enzyme inhibitors (ACEis), olmesartan, or other ARBs between January 2005 and December 2012. The incidences of enteropathy were compared among drug groups. Changes in body weight were compared after propensity score matching of patients in the ACEis and olmesartan groups. RESULTS: Among 108,559 patients, 31 patients were diagnosed with enteropathy. The incidences were 0.73, 0.24, and 0.37 per 1,000 persons, in the ACEis, olmesartan, and other ARBs groups, respectively. Adjusted rate ratios for enteropathy were: olmesartan, 0.33 (95% confidential interval [CI], 0.10 to 1.09; p = 0.070) and other ARBs, 0.34 (95% CI, 0.14 to 0.83; p = 0.017) compared to the ACEis group after adjustment for age, sex, income level, and various comorbidities. The post hoc analysis with matched cohorts revealed that the proportion of patients with significant weight loss did not differ between the ACEis and olmesartan groups. CONCLUSIONS: Olmesartan was not associated with intestinal malabsorption or significant body weight loss in the general Korean population. Additional large-scale prospective studies of the relationship between olmesartan and the incidence of enteropathy in the Asian population are needed.

Effect of Statins, Metformin, Angiotensin-Converting Enzyme Inhibitors, and Angiotensin II Receptor Blockers on Age-Related Macular Degeneration

PURPOSE: Statins, metformin, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) have been suggested for treating age-related macular degeneration (AMD) due to their pleiotropic effects. Therefore, we investigated whether these drugs prevent AMD. MATERIALS AND METHODS: We conducted a nested case-control study using the Korean National Health Insurance Service database. Using risk-set sampling of age, sex, cohort entry date, and follow-up duration, we identified incident patients with AMD and 10 matching controls in cohorts with diabetes mellitus or cardiovascular diseases. Exposure was assessed within one year before the index date using patient prescription records. We conducted conditional logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between cardiovascular medications and AMD. RESULTS: Our study included 2330 cases and 23278 controls from a cohort of 231274 patients. The ORs (95% CI) for AMD occurrence in users prescribed with statins, metformin, ACE inhibitors, and ARBs were 1.12 (0.94–1.32), 1.15 (0.91–1.45), 0.90 (0.61–1.34), and 1.21 (1.05–1.39), respectively. A duration-response was not observed. CONCLUSION: Statins, metformin, ACE inhibitors, and ARBs did not inhibit AMD in elderly patients. The absence of a duration-response supports the lack of a causal relationship.

Fimasartan attenuates renal ischemia-reperfusion injury by modulating inflammation-related apoptosis

Fimasartan, a new angiotensin II receptor antagonist, reduces myocyte damage and stabilizes atherosclerotic plaque through its anti-inflammatory effect in animal studies. We investigated the protective effects of pretreatment with fimasartan on ischemia-reperfusion injury (IRI) in a mouse model of ischemic renal damage. C57BL/6 mice were pretreated with or without 5 (IR-F5) or 10 (IR-F10) mg/kg/day fimasartan for 3 days. Renal ischemia was induced by clamping bilateral renal vascular pedicles for 30 min. Histology, pro-inflammatory cytokines, and apoptosis assays were evaluated 24 h after IRI. Compared to the untreated group, blood urea nitrogen and serum creatinine levels were significantly lower in the IR-F10 group. IR-F10 kidneys showed less tubular necrosis and interstitial fibrosis than untreated kidneys. The expression of F4/80, a macrophage infiltration marker, and tumor necrosis factor (TNF)-α, decreased in the IR-F10 group. High-dose fimasartan treatment attenuated the upregulation of TNF-α, interleukin (IL)-1β, and IL-6 in ischemic kidneys. Fewer TUNEL positive cells were observed in IR-F10 compared to control mice. Fimasartan caused a significant decrease in caspase-3 activity and the level of Bax, and increased the Bcl-2 level. Fimasartan preserved renal function and tubular architecture from IRI in a mouse ischemic renal injury model. Fimasartan also attenuated upregulation of inflammatory cytokines and decreased apoptosis of renal tubular cells. Our results suggest that fimasartan inhibited the process of tubular injury by preventing apoptosis induced by the inflammatory pathway.

Role of the renin-angiotensin system in hepatic fibrosis and portal hypertension

The renin-angiotensin system (RAS) is an important regulator of cirrhosis and portal hypertension. As hepatic fibrosis progresses, levels of the RAS components angiotensin (Ang) II, Ang-(1–7), angiotensin-converting enzyme (ACE), and Ang II type 1 receptor (AT1R) are increased. The primary effector Ang II regulates vasoconstriction, sodium homoeostasis, fibrosis, cell proliferation, and inflammation in various diseases, including liver cirrhosis, through the ACE/Ang II/AT1R axis in the classical RAS. The ACE2/Ang-(1–7)/Mas receptor and ACE2/Ang-(1–9)/AT2R axes make up the alternative RAS and promote vasodilation, antigrowth, proapoptotic, and anti-inflammatory effects; thus, countering the effects of the classical RAS axis to reduce hepatic fibrogenesis and portal hypertension. Patients with portal hypertension have been treated with RAS antagonists such as ACE inhibitors, Ang receptor blockers, and aldosterone antagonists, with very promising hemodynamic results. In this review, we examine the RAS, its roles in hepatic fibrosis and portal hypertension, and current therapeutic approaches based on the use of RAS antagonists in patients with portal hypertension.

Weight loss has an additive effect on the proteinuria reduction of angiotensin II receptor blockers in hypertensive patients with chronic kidney disease

BACKGROUND: Weight reduction is a lifestyle intervention that has been introduced for prevention and management of chronic kidney disease (CKD). We investigate the additive anti-proteinuric effect of weight reduction on the usage of angiotensin II receptor blockers (ARBs) and its potential mechanisms in hypertensive CKD patients. METHODS: This study is a subanalysis of data from an open-label, randomized, controlled clinical trial. Among the 235 participants, 227 were assigned to subgroups according to changes in body weight. RESULTS: Fifty-eight participants (25.6%) were assigned to group 1 (≥1.5% decrease in body weight after 16 weeks), 32 participants (14.1%) were assigned to group 2 (1.5–0.1% decrease in body weight), and 136 participants (59.9%) were assigned to group 3 (≥ 0.0% increase in body weight). Characteristics at enrollment were not different among the three groups, but mean differences in weight and percent changes in urinary sodium excretion over the period were statistically different (P < 0.001 and P = 0.017). Over the study period, unintentional weight loss independently increased the probability of reduced albuminuria (group 1, relative risk 6.234, 95% confidence interval 1.913–20.315, P = 0.002). Among urinary cytokines, only podocalyxin level decreased significantly in participants who lost weight (P = 0.013). CONCLUSION: We observed that weight loss had an additive effect on the anti-proteinuric effects of ARBs in nondiabetic hypertensive CKD patients, although it was minimal. An additive effect was shown in both obese and non-obese participants, and its possible mechanism is related to reduction of podocyte damage.

Extracorporeal Membrane Oxygenation and Continuous Renal Replacement Therapy for Treatment of Calcium Channel Blockers, Angiotensin II Receptor Blockers, and Metformin Overdose

An overdose of antihypertensive agents, such calcium channel blockers (CCBs) and angiotensin II receptor blocker (ARBs), and the antihyperglycemic agent, metformin, leads to hypotension and lactic acidosis, respectively. A 40-year-old hypertensive and diabetic man with hyperlipidemia and a weight of 110 kg presented to the emergency room with vomiting, dizziness, and hypotension following an attempted drug overdose suicide with combined CCBs, ARBs, 3-hydroxy-3-methylglutaryl-coemzyme A reductase inhibitors, and metformins. A conventional medical treatment initially administered proved ineffective. The treatment was then changed to simultaneous extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), which was effective. This shows that simultaneous ECMO and CRRT can be an effective treatment protocol in cases of ineffective conventional medical therapy for hypotension and lactic acidosis due to an overdose of antihypertensive agents and metformin, respectively.

Candesartan Restores the Amyloid Beta-Inhibited Proliferation of Neural Stem Cells by Activating the Phosphatidylinositol 3-Kinase Pathway

BACKGROUND AND PURPOSE: Neurogenesis in the adult brain is important for memory and learning, and the alterations in neural stem cells (NSCs) may be an important aspect of Alzheimer's disease (AD) pathogenesis. The phosphatidylinositol 3-kinase (PI3K) pathway has been suggested to have an important role in neuronal cell survival and is highly involved in adult neurogenesis. Candesartan is an angiotensin II receptor antagonist used for the treatment of hypertension and several studies have reported that it also has some neuroprotective effects. We investigated whether candesartan could restore the amyloid-β(25–35) (Aβ₂₅₋₃₅) oligomer-inhibited proliferation of NSCs by focusing on the PI3K pathway. METHODS: To evaluate the effects of candesartan on the Aβ₂₅₋₃₅ oligomer-inhibited proliferation of NSCs, the NSCs were treated with several concentrations of candesartan and/or Aβ₂₅₋₃₅ oligomers, and MTT assay and trypan blue staining were performed. To evaluate the effect of candesartan on the Aβ-inhibited proliferation of NSCs, we performed a bromodeoxyuridine (BrdU) labeling assay. The levels of p85α PI3K, phosphorylated Akt (pAkt) (Ser473), phosphorylated glycogen sinthase kinase-3β (pGSK-3β) (Ser9), and heat shock transcription factor-1 (HSTF-1) were analyzed by Western blotting. RESULTS: The BrdU assays demonstrated that NSC proliferation decreased with Aβ25-35 oligomer treatment; however, a combined treatment with candesartan restored it. Western blotting displayed that candesartan treatment increased the expression levels of p85α PI3K, pAkt (Ser473), pGSK-3β (Ser9), and HSTF. The NSCs were pretreated with a PI3K inhibitor, LY294002; the effects of candesartan on the proliferation of NSCs inhibited by Aβ₂₅₋₃₅ oligomers were almost completely blocked. CONCLUSIONS: Together, these results suggest that candesartan restores the Aβ₂₅₋₃₅ oligomer-inhibited proliferation of NSCs by activating the PI3K pathway.

Decreased potency of fimasartan in liver cirrhosis was quantified using mixed-effects analysis

Fimasartan is a nonpeptide angiotensin II receptor blocker. In a previous study that compared the pharmacokinetics (PK) of fimasartan between patients with hepatic impairment (cirrhosis) and healthy subjects, the exposure to fimasartan was found to be higher in patients, but the decrease of blood pressure (BP) was not clinically significant in those with moderate hepatic impairment. The aims of this study were to develop a population PK-pharmacodynamic (PD) model of fimasartan and to evaluate the effect of hepatic function on BP reduction by fimasartan using previously published data. A 2-compartment linear model with mixed zero-order absorption followed by first-order absorption with a lag time adequately described fimasartan PK, and the effect of fimasartan on BP changes was well explained by the inhibitory sigmoid function in the turnover PK-PD model overlaid with a model of circadian rhythm (NONMEM version 7.2). According to our PD model, the lower BP responses in hepatic impairment were the result of the increased fimasartan EC₅₀ in patients, rather than from a saturation of effect. This is congruent with the reported pathophysiological change of increased plasma ACE and renin activity in hepatic cirrhosis.

Hypokalemic Hypertension Leading to a Diagnosis of Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease. Hypertension is common and occurs before decline in renal function. However, the coexistence of hypertension and hypokalemia is rare in ADPKD patients. We report on a 32-year-old woman with secondary aldosteronism. Magnetic resonance imaging of the renal arteries revealed multiple cysts of varying sizes in both the kidneys and the liver, compatible with ADPKD. Increased reninangiotensin-aldosterone system activity was secondary to cyst expansion. After initiation of angiotensin II receptor blocker, her blood pressure was controlled without additional requirement of potassium.

Effect of angiotensin receptor blockade on central aortic systolic blood pressure in hypertensive Asians measured using radial tonometry: an open prospective cohort study

<p><b>INTRODUCTION</b>Central aortic systolic pressure (CASP) has been shown to be a stronger predictor of cardiovascular events than brachial blood pressure (BP). Different classes of drugs have differential effects on CASP and brachial BP. This open prospective cohort study aimed to observe changes in CASP (measured using radial tonometry) among hypertensive Asians after 12 weeks of treatment with valsartan, an angiotensin receptor blocker (ARB).</p><p><b>METHODS</b>Patients with treatment-naïve hypertension or uncontrolled hypertension who were on non-ARB therapy were eligible for inclusion. Patients with uncontrolled BP (i.e. ≥ 140/90 mmHg) received valsartan for 12 weeks. The patients' brachial systolic and diastolic BP (SBP and DBP), and CASP changes were monitored using the BPro® watch.</p><p><b>RESULTS</b>The mean age of the 44 enrolled patients was 35 years. At baseline, the mean BP and CASP were 150.2/91.4 ± 10.6/9.4 mmHg and 136.3 ± 12.2 mmHg, respectively. Valsartan reduced SBP, DBP and CASP by 14.9 ± 10.7 mmHg, 10.9 ± 8.4 mmHg and 15.3 ± 10.9 mmHg, respectively (all p < 0.001). Every 1.0-mmHg reduction in brachial SBP resulted in a 0.8-mmHg reduction in CASP (p < 0.001). A CASP cut-off of 122.5 mmHg discriminated between controlled and uncontrolled BP (sensitivity 74%, specificity 88%).</p><p><b>CONCLUSION</b>Using radial tonometry, we demonstrated good correlation between CASP and brachial SBP reductions after 12 weeks of treatment with valsartan in our study cohort. Correlation analysis between CASP and SBP reductions may be useful for demonstrating whether a drug is able to lower CASP beyond lowering SBP.</p>

Blood pressure lowering effect of statin drugs with an application to rosuvastatin

Hyperlipidemia and hypertension are among the major risk factors for cardiovascular disease (CVD) and they often co-exist within a single patient. Recently, many studies published results regarding the potential role of statins in decreasing blood pressure (BP) however there is still a controversy over the efficacy of statin therapy on BP. This study aimed to investigate the potential role of rosuvastatin in BP lowering properties in Korean population. Data were taken from three randomized, multiple-dose cross over studies for rosuvastatin, angiotensin II receptor blocker (ARB) and metformin monotherapies and the combined therapy of rosuvastatin and ARB, in total of 91 healthy male normotensive subjects. Measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP) at the baseline before treatment begins and for 24 hours after the last dose were used in the analysis. The analysis variables used were (i) the mean change in steady-state BP from the baseline, symbolized as ΔBP, and (ii) the difference in ΔBP between the ARB monotherapy and the combined therapy, symbolized as ΔBP,d. The ΔBP and ΔBP,d for SBP from each study varied in -0.1 ~ -1.3 mmHg and 1.2 ~ 1.6 mmHg, respectively, and were not significantly different from zero. The ΔBP and ΔBP,d for DBP from each study varied in -2.8 ~ -1.4 mmHg and -2.9 ~ -1.8, respectively, which were statistically significant for ΔBP (p 0.05). These results indicated that the rosuvastatin monotherapy may produce small blood pressure lowing effect in DBP.

Los estudios económicos en enfermedades crónicas de alta prevalencia / Economic studies in high prevalence chronic diseases

Los estudios económicos han ido ganando importancia en el mundo de las publicaciones científicas. De apenas quinientos estudios registrados en la base de datos de PubMed en 2000 con el descriptor "Costos y Análisis de Costo ("Costs and Cost Analysis"[Mesh]), se ha pasado a nueve mil publicaciones en 2014. Para nadie es un secreto que el costo de una terapia debe entrar en la fórmula, junto a su efectividad y su seguridad, al momento de tomar una decisión clínica. Muchos de los estudios se concentran en enfermedades de alto costo, como el cáncer, que registra 771 estudios publicados en el lapso 2013-2014. Pero también son de interés las enfermedades de alta prevalencia, así el costo del tratamiento del paciente individual no sea tan elevado. Es el caso de la depresión, con 602 estudios económicos en el mismo lapso.Este número de Acta Médica Colombiana presenta los resultados de la "Evaluación económica de las principales intervenciones farmacológicas como monoterapia para el tratamiento de la hipertensión arterial leve a moderada recién diagnosticada" adelantada por el equipo que lideró Rodolfo Dennis, de la Fundación Cardioinfantil de Bogotá (1). Su conclusión es que, en el paciente hipotético de 65 años que inicia terapia antihipertensiva, la monoterapia con diuréticos, al ser similar en efectividad a las terapias con inhibidores de enzima convertidora, bloqueadores del receptor de angiotensina o calcio antagonistas, resulta ser la opción más adecuada, al repre-sentar un ahorro para el sistema de salud de entre seis y veinte millones de pesos de 2011 por paciente, en valor presente, y considerando toda la vida del paciente.