Endothelial expression of the receptor for advanced glycation end products in experimental diabetes / Expresión endotelial del receptor para productos finales de glicación avanzada en diabetes experimental

The receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of several chronic diseases including diabetes. The interaction between RAGE and advanced glycation end products (AGEs) promotes gene expression, enhances the release of proinflammatory molecules and causes the generation of oxidative stress in numerous cell types. The aim of this investigation was to evaluate the effect of enalapril and losartan on RAGE expression in abdominal aortic endothelium of rats with experimentally induced diabetes. Male Sprague-Dawley rats, weighing approximately 150 - 200 g, were used. Diabetes was induced in 30 rats by intravenous administration of a single dose of 55 mg/kg body weight of streptozotocin (ETZ). The following groups were studied: control (n=10), diabetic (n=10), losartan-treated diabetic (n=10) and enalapril-treated diabetic (n=10) rats. RAGE expression in aortic endothelium was determined by indirect immunofluorescence. A significant increase in RAGE expression was observed in diabetic animals versus controls (p<0.001), there was a decrease in RAGE expression, in animals treated with losartan versus controls (p<0.01) and in those treated with enalapril (p<0.05) versus control and versus diabetes + vehicle. In conclusion, in the experimental model of ETZ-induced diabetes, there is an increase in RAGE expression at the level of the abdominal aortic endothelium, which can be reversed by treatment with losartan and/or enalapril, two drugs that block the renin-angiotensin system, suggesting its involvement in the molecular events related to vascular damage during diabetes.

El receptor para productos finales de glicación avanzada (RAGE) está implicado en la patogénesis de varias enfermedades crónicas incluyendo la diabetes. La interacción entre RAGE y los productos finales de glicación avanzada (AGEs), promueve la expresión génica, potencia la liberación de moléculas proinflamatorias y provoca la generación de estrés oxidativo en numerosos tipos de células. El objetivo de esta investigación fue evaluar el efecto del enalapril y el losartán sobre la expresión de RAGE en el endotelio de la aorta abdominal de ratas con diabetes inducida experimentalmente. Se utilizaron ratas Sprague-Dawley machos, con un peso aproximado de entre 150 - 200 g. La diabetes se indujo en 30 ratas mediante la administración intravenosa de una sola dosis de 55 mg/Kg de peso corporal de estreptozotocina (ETZ). Se estudiaron los siguientes grupos: ratas control (n=10), diabéticas (n=10), diabéticas tratadas con losartán (n=10) y diabéticas tratadas con enalapril (n=10). La expresión de RAGE en el endotelio aórtico se determinó por inmunofluorescencia indirecta. Se observó un incremento significativo en la expresión de RAGE en los animales diabéticos versus los controles (p<0.001), hubo una disminución en la expresión de RAGE, en los animales tratados con losartán versus los controles (p<0.01) y en los tratados con enalapril (p<0.05) versus control y versus diabetes + vehículo. En conclusión, en el modelo experimental de diabetes inducida por ETZ, existe un incremento en la expresión de RAGE a nivel del endotelio de la aorta abdominal, la cual puede revertirse mediante el tratamiento con losartán y/o enalapril, dos fármacos bloqueadores del sistema renina-angiotensina, lo cual sugiere la participación del mismo en los acontecimientos moleculares relacionados con el daño vascular durante la diabetes.

Fluorofenidone inhibits apoptosis of renal tubular epithelial cells in rats with renal interstitial fibrosis

This study aimed to investigate the mechanism of fluorofenidone (AKF-PD) in treating renal interstitial fibrosis in rats with unilateral urinary obstruction (UUO). Thirty-two male Sprague-Dawley rats were randomly divided into sham, UUO, UUO + enalapril, and UUO + AKF-PD groups. All rats, except sham, underwent left urethral obstruction surgery to establish the animal model. Rats were sacrificed 14 days after surgery, and serum was collected for renal function examination. Kidneys were collected to observe pathological changes. Immunohistochemistry was performed to assess collagen I (Col I) protein expression, and terminal deoxynucleotidyl transferase-mediated nick end-labeling staining to observe the apoptosis of renal tubular epithelial cells. The expression of Fas-associated death domain (FADD), apoptotic protease activating factor-1 (Apaf-1), and C/EBP homologous protein (CHOP) proteins was evaluated by immunohistochemistry and western blot analysis. AKF-PD showed no significant effect on renal function in UUO rats. The pathological changes were alleviated significantly after enalapril or AKF-PD treatment, but with no significant differences between the two groups. Col I protein was overexpressed in the UUO group, which was inhibited by both enalapril and AKF-PD. The number of apoptotic renal tubular epithelial cells was much higher in the UUO group, and AKF-PD significantly inhibited epithelial cells apoptosis. The expression of FADD, Apaf-1, and CHOP proteins was significantly upregulated in the UUO group and downregulated by enalapril and AKF-PD. In conclusion, AKF-PD improved renal interstitial fibrosis by inhibiting apoptosis of renal tubular epithelial cells in rats with UUO.

Un novedoso agente en el tratamiento de la insuficiencia cardiaca con función sistólica deprimida / A novel agent in the treatment of heart failure with depressed systolic function

Resumen Introducción: Se revisará la evolución del tratamiento farmacológico de la insuficiencia cardiaca (IC) en los últimos 25 an˜os, desde el concepto de tratamiento con vasodilatadores, pasando por el bloqueo o inhibición del sistema renina-angiotensina-aldosterona y la inhibición betaadrenérgica y su importante contribución en la disminución de la morbimortalidad por IC, el papel de los péptidos natriuréticos y, finalmente, se conocerá uno de los estudios más importantes en el área cardiológica y específicamente en el manejo de la IC, en el cual se demuestra un enfoque modulador de los sistemas neuro humorales que se activan en estos pacientes. Objetivos: La IC constituye la etapa final de la mayoría de las enfermedades cardiovasculares, con una alta tasa de hospitalización y de morbimortalidad cardiovascular, siendo, por lo tanto, de interés constante la necesidad de encontrar un agente terapéutico innovador que disminuya significativamente estas complicaciones y también que mejore la calidad de vida de los que la presentan. Metodología: Se realizará una descripción del PARADIGM-HF Clinical Trial, que utilizó un compuesto sacubitrilo/valsartán para el manejo de la IC con un mecanismo modulador diferente del concepto de bloqueador de sistemas deletéreos que se activan cuando un paciente presenta síntomas y signos de IC. Conclusiones: La muerte por causas cardiovasculares u hospitalización por IC (el punto final primario) se produjo en 914 pacientes (21.8%) en el grupo sacubitrilo/valsartán y 1,117 pacientes (26.5%) en el grupo de enalapril (razón de riesgo en el grupo sacubitrilo/valsartán, 0.80; intervalo de confianza (IC) del 95%: 0.73 a 0.87; p < 0.001 (exacta p = 4.0 × 10 - 7)). De los pacientes que recibieron sacubitrilo/valsartán, 537 (12.8%) fueron hospitalizados por IC, en comparación con los 658 pacientes (15.6%) que recibieron enalapril (razón de riesgo, 0.79; IC del 95%, 0.71 a 0.89; p < 0.001). Un total de 711 pacientes (17.0%) en el grupo sacubitrilo/valsartán y 835 pacientes (19.8%) en el grupo de enalapril murió (razón de riesgo de muerte por cualquier causa, 0.84; IC del 95%, 0.76 a la 0.93; p < 0.001).

Abstract Introduction: A review is presented on the evolution of the pharmacological treatment of heart failure (HF) in the last 25 years, from the concept of treatment with vasodilators to the blocking or inhibition of the renin angiotensin aldosterone system. Beta-adrenergic inhibition and its important contribution in the reduction of morbidity and mortality due to HF will be discussed along with the role of the natriuretic peptides. One of the most important studies in the cardiology area, and specifically in the management of HF, is presented, in which an approach is demonstrated of the modulator of the neurohumoral systems that are activated in these patients. Objectives: HF is the final stage of most cardiovascular diseases, and has a high rate of hospital admission, as well as cardiovascular morbidity and mortality. Therefore, there is constant interest in the need to find an innovative therapeutic agent that significantly reduces these complications and that improves the quality of life of those who suffer from it. Methods: A description will be presented of the PARADIGM-HF Clinical Trial using a sacubitril/valsartán compound for the management of HF with a modulating mechanism different from the concept of a deleterious system blocker that is activated when a patient has symptoms and signs of heart failure. Conclusions: Death due to cardiovascular causes, or hospital admission due to heart failure (the primary endpoint) occurred in 914 patients (21.8%) in the Sacubitril / valsartán group, and 1117 patients (26.5%) in the enalapril group (risk ratio in the sacubitril / valsartán group, 0.80, with a 95% confidence interval [CI]: 0.73 to 0.87, P<0.001 ;exact P= 4.0 × 10 --7;). Of the patients receiving sacubitril / valsartán, 537 (12.8%) were hospitalised due to heart failure, compared with 658 patients (15.6%) receiving enalapril (hazard ratio 0.79, 95% CI: 0.71 to 0.89, P<.001). A total of 711 patients (17.0%) in the sacubitril / valsartán group, and 835 patients (19.8%) in the enalapril group, died (all-cause death rate, 0.84, 95% CI: 0.76 to 0.93, P<.001)

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.

Efecto del aliskireno sobre la angiogénesis en modelo de membrana alantocoriónica (MAC) de pollo / Effect of aliskiren on angiogenesis in chick embryo chorioallantoic membrane (CAM) assay

La acción antiangiogénica de los inhibidores del receptor de angiotensina II (ARA II), ha sido documentada previamente, sin embargo, no ha sido descrita la relación entre angiogénesis e inhibidores directos de la renina (DRIs), los cuales participan regulando el sistema renina-angiotensina-aldosterona (SRAA). El objetivo fue demostrar el efecto antiangiogénico de aliskireno, un DRI, en membranas alantocoriónicas (MAC) de pollo, para lo cual fueron instilados aliskireno y enalapril sobre MAC en distintas concentraciones para realizar su comparación posterior. En secciones histológicas seriadas se registró el número de vasos sanguíneos presentes en 9000 µm2 bajo microscopio de luz a máximo aumento, y se realizó análisis estadístico utilizando ANOVA y el test de Tukey para demostrar posibles diferencias. Los receptores tratados con aliskireno, en ambas concentraciones utilizadas, presentaron menor densidad vascular, en comparación con los controles, siendo ésta estadísticamente significativa a mayor concentración. Aliskireno en concentraciones altas tiene un efecto antiangiogénico en un modelo experimental de MAC. Este hallazgo plantea la necesidad de estudios posteriores, dada la proyección que podría tener el uso inhibidores directos de la renina. A partir de estos resultados, se podría pensar en la factibilidad del uso de aliskireno para la modulación de la angiogénesis en diversas enfermedades crónicas no transmisibles.

Angiogenesis is the formation of new blood vessels from pre-existing ones. Antiangiogenic effect of angiotensin receptor blockers has been reported, however, the relationship between direct renin inhibitors and angiogenesis has not been well described. To assess the antiangiogenic effect of aliskiren, a direct renin inhibitor, on chick embryo chorioallantoic membrane (CAM) assay. Aliskiren and enalapril were instilled in different concentrations and compared. In serial histological sections, the number of blood vessels per 9000 µm2 area under observation through optical microscope using maximum zoom, was registered. Statistical analysis using Anova and Tukey test in order to show possible differences, was performed. Receptors treated with aliskiren presented lower vascular density, which was statistically significant when a higher concentration was administered. High concentrations of aliskiren have an antiangiogenic effect on CAM assay. This finding means further studies are needed, because of the usefulness direct renin inhibitors could have. These results, also, might enhance the possibility of using aliskiren for regulating angiogenesis in the context of non-transmissible chronic diseases.

Enhancement of anti-OVA IgG2c production in vivo by enalapril

Angiotensin-converting enzyme (ACE) inhibitors have non-hemodynamic, pleiotropic effects on the immune response. The effects of ACE inhibitors on the production of cytokines and T-cell functions are well established. However, little is known on the effects of these medicines on humoral response to foreign antigens. In this study, we investigated the effect of enalapril treatment on ovalbumin (OVA)-specific IgG1 and IgG2c production in mice determined by ELISA. Two groups of 8-week-old C57BL/6 females mice (3–4/group) were subcutaneously immunized with OVA (10 μg/animal) in presence of Alhydrogel (1 mg/mouse) and boosted at day 21. The mice were treated with enalapril (5 mg/kg daily, po) or were left without treatment for one month. The animals were bled from the orbital plexus on days 0, 7, 14, 21, and 28 after the first immunization and the sera were stored at –20°C until usage. OVA-specific serum IgG1 and IgG2c were determined by ELISA using serum from each individual animal. The results showed that enalapril significantly increased anti-OVA serum IgG2c in the secondary response without affecting IgG1 synthesis. These data expand our understanding on the properties of enalapril on the immune response, including antibody production.

Interacciones potenciales de fármacos antihipertensivos en un año de estudio de pacientes con hipertensión arterial atendidos en hospitales de 11 municipios del Departamento de Risaralda-Colombia / Antihypertensive medicaments potential interactions in one year of study in hypertensive patients attended in hopitals from 11 country of the Risaralda Department-Colombia

En enfermedades como la hipertensión arterial con frecuencia deben utilizarse tratamientos con dos o más medicamentos, por lo cual el uso incorrecto de ellos puede conllevar a interacciones de fármacos. En el contexto de la hipertensión arterial en América Latina, existen escasos estudios evaluando la magnitud de este problema. Se realizó el presente estudio, observacional, transversal, con un muestreó censal, con el fin de establecer la ocurrencia de potenciales interacciones de fármacos en pacientes con hipertensión arterial de hospitales de 11 municipios de Risaralda, Colombia, agosto 2009 a agosto 2010, usando un algoritmo diseñado para identificar posibles interacciones de fármacos. Se obtuvieron 65.535 registros de prescripción de antihipertensivos, de 3.813 pacientes hipertensos, 28,46% correspondieron con hidroclorotiazida y 2007% enalapril, entre otros. Del total de pacientes 17,60% (IC95% 16,34%-18,82%) presentaron interacciones potenciales de fármacos, siendo la mayor en el municipio Dosquebradas (21,09%; IC95% 18,79%-23,36%). La interacción más frecuente fue enalapril-hidroclorotiazida (45,58% de los pacientes) y la de mayor riesgo y frecuencia fue enalapril-espironolactona (2,41%). estos resultados, reflejan en parte, falta de cumplimiento de normas de tratamiento de la hipertensión arterial, asi como poca implementación de conductas de tratamiento basadas en evidencia, y también posiblemente dificultades en la formación universitaria, falta de programas de educación médica continuada, falta de interés y tiempo para acceder a los alertas y reportes de nuevas condicones de uso de los medicamentos y poca instrucción y enseñanza de la medicina basada en evidencias, aspectos sobre los cuales se debe intervenir integralmente con distintos enfoques

In diseases such as hypertension, commonly treatments with two or more drugs should be used, then their incorrect use can lead to drug interactions. In the context of the hypertension in Latin America, there are few studies assessing the magnitude of this problem. Current, observational, cross-sectional and census study was made in order to establish the potential ocurrence of drug interactions in patients with hypertension from hospitals of 11 municipalities of Risaralba, Colombia, august 2009 to august 2010, using an algorithm designed to identify possible drug interactions. A total of 5.535 antihypertensive prescription records from 3.813 hypertension patients, 28.46% corresponding to hydrochlorothiazide and 20.07% to enalapril, among others, were obtained. From the total of patients 17.60% (95% CI 16.34 %-18.32%) presented potential drug interactions, being highest at the municipality Dosquebradas (21.09%; 95% CI 18.79%-23.36%). Most frequent interaction was enalapril-hydrochlorothiazide (45.58% of patients) and that of higher risk and frequency was enalapril-spironolactone (2.41%). These results, reflected in part, the lack of adherence to hypertension treatment guidelines, as well few implementation of evidenced based treatment conducts, and possibly too defficulties in the university formation, lack of continue medical education programs. Lack of interest and time to access to the alerts and reports of new conditions of drugs use and few instructions and teaching of evidence based medicine, aspects that needs tobe integrally intervened with different approaches

The chronic blockade of angiotensin I-converting enzyme eliminates the sex differences of serum cytokine levels of spontaneously hypertensive rats

Sex hormones modulate the action of both cytokines and the renin-angiotensin system. However, the effects of angiotensin I-converting enzyme (ACE) on the proinflammatory and anti-inflammatory cytokine levels in male and female spontaneously hypertensive rats (SHR) are unclear. We determined the relationship between ACE activity, cytokine levels and sex differences in SHR. Female (F) and male (M) SHR were divided into 4 experimental groups each (n = 7): sham + vehicle (SV), sham + enalapril (10 mg/kg body weight by gavage), castrated + vehicle, and castrated + enalapril. Treatment began 21 days after castration and continued for 30 days. Serum cytokine levels (ELISA) and ACE activity (fluorimetry) were measured. Male rats exhibited a higher serum ACE activity than female rats. Castration reduced serum ACE in males but did not affect it in females. Enalapril reduced serum ACE in all groups. IL-10 (FSV = 16.4 ± 1.1 pg/mL; MSV = 12.8 ± 1.2 pg/mL), TNF-α (FSV = 16.6 ± 1.2 pg/mL; MSV = 12.8 ± 1 pg/mL) and IL-6 (FSV = 10.3 ± 0.2 pg/mL; MSV = 7.2 ± 0.2 pg/mL) levels were higher in females than in males. Ovariectomy reduced all cytokine levels and orchiectomy reduced IL-6 but increased IL-10 concentrations in males. Castration eliminated the differences in all inflammatory cytokine levels (IL-6 and TNF-α) between males and females. Enalapril increased IL-10 in all groups and reduced IL-6 in SV rats. In conclusion, serum ACE inhibition by enalapril eliminated the sexual dimorphisms of cytokine levels in SV animals, which suggests that enalapril exerts systemic anti-inflammatory and anti-hypertensive effects.

The Effects of Antihypertensive Drugs on Bone Mineral Density in Ovariectomized Mice

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.

The Effects of Antihypertensive Drugs on Bone Mineral Density in Ovariectomized Mice

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.

Comparative interaction of few antihypertensive drugs with cyclosporine-A in rats.

The maximal endothelial dependent relaxation of isolated aortic rings to cumulative doses of acetylcholine was significantly decreased in the Cyclosporine-A (CSA, 20 mg kg(-1) day(-1)) treated animals compared to olive oil (CSA vehicle) treated control. Administration of antihypertensive drugs like diltiazem, enalapril or propranolol to CSA treated animals augmented the endothelial damage induced by CSA. These drugs also increased the bioavailability of CSA. However, administration of losartan to CSA treated animals produced a significant increase in endothelial dependent relaxation as compared to CSA treated control but did not affect the bioavailability of CSA significantly. The results suggest that losartan is safer compared to other antihypertensives for the treatment of CSA induced hypertension.

El aumento de la actividad y expresión de la enzima convertidora de angiotensina I homóloga (ECA2) inducido por enalapril se asocia a menor fibrosis e hipertrofia ventricular izquierda post infarto al miocardio en la rata / Enalapril induced increase in Homologous Angiotensin I converting enzyme (ECA2) is associated to decreased fibrosis and decreased left ventricular hypertrophy post myocardial infarction in rats

Recientemente se ha descubierto el gen de una nueva enzima convertidora de angiotensina I- homóloga a ECA y denominada ECA-2 que finalmente lleva a producir angiotensina 1-7. Esta segunda vía del sistema reninaangiotensina (SRA), con la ECA-2 tendría acciones opuestas a la ECA. Objetivo y Métodos: Determinar la actividad y expresión de la ECA2 en el tratamiento de la hipertrofia y fibrosis ventricular izquierda tardía post IAM en la rata. Se usaron ratas Sprague Dawley 200 +/- 10 g sometidas a ligadura de la coronaria izquierda. Como controles se usaron ratas sham (S). 48 hrs. post cirugía, un grupo de ratas IAM recibió enalapril (IAM-ENA; 10 mg/kg, gavage). A las 8 semanas post-operatorias se determinó la presión arterial sistólica (PAS), masa corporal(MC), masa cardíaca relativa (MCR, mg VI/100 g MC, expresión proteica de la cadena pesada de la miosina beta(betaMHC) por Western blot, mRNA por RT-PCR, las actividades enzimáticas de ECA y de ECA-2 por fluorimetría tanto circulante como en ventrículo izquierdo (VI), el contenido de colágeno total por rojo picrosirio y la actividad de metaloproteasa 2 (MMP-2) por zimografía. Conclusión: El aumento de la actividad y expresión de la ECA2 (a nivel circulante y tisular cardíaco) se asocia a menor fibrosis e hipertrofia ventricular izquierda, lo que podría aumentar – en ese periodo - el efecto cardioprotector de Ang-(1-7).

Background. Recently the gene of a new angiotensin-1 converting homologous enzyme (ACE-2) which leads to the production of angiotensin 1-7 (Ang (1-7) has been reported. This new pathway of the renin-angiotensin system(RAS) is supposed to have opposite effects to those of ACE. Aim: To determine the activity and expression of ACE-2 in the development of left ventricular hypertrophy and fibrosis late after induced myocardial infarction (AMI) in rats. Methods: 200 +/- 10g Sprague-Dawley rats were submitted to left coronary artery ligation. Sham operated rats were used as controls. 48 hr after surgery, one group of AMI rats received enalapril (AMI-En), 10mg/Kg. 8 weeks after surgery the systolic blood pressure (SBP), body mass (BM) and relative cardiac mass (RCM, mg/100g BM) were measured. The protein expression of heavy weight chain beta myosin (beta HCM) was determined by Western Blot, mRNA through RT-PCR, circulating and left ventricular ACE and ACE-2 activities through fluorometry, total collagen content by the pycrosirius red method and metaloproteinase-2 (MMP-2) through zymography were determined. Conclusion: The increased activity and expression of ACE-2 both in plasma and the LV is associated to less fibrosis and left ventricular hypertrophy after AMI. This could temporarily boost the cardioproctive effect of Ang (1-7).

Effect of losartan and enalapril on cognitive deficit caused by Goldblatt induced hypertension.

The present study was designed to evaluate the learning and memory, in an altered physiological state associated with increased blood pressure and activated renin angiotensin system in Wistar rats. The role of angiotensin in cognitive function was assessed by treatment with angiotensin converting enzyme (ACE) inhibitor enalapril (2 mg/kg), angiotensin 1 receptor (AT(1)) antagonist losartan (5 mg/kg) and their combination. The experimental renal hypertension was induced by the method of Goldblatt. Learning and memory was assessed using the radial arm maze test. Acetylcholine esterase (AChE) levels in the pons medulla, hippocampus, striatum and frontal cortex were measured as a cholinergic marker of learning and memory. Results indicate that in comparison to normotensive rats, renal hypertensive rats committed significantly higher number of errors and took more trials and days to learn the radial arm maze learning and exhibited memory deficit in the radial arm maze retrieval after two weeks of retention interval, indicating impaired acquisition and memory. Treatment with enalapril, losartan and their combination attenuated the observed memory deficits indicating a possible role of renin angiotensin system in cognitive function. AChE level was reduced in hippocampus and frontal cortex of renal hypertensive rats which could be attributed to the observed memory deficit in hypertensive rats. It can be concluded that, renal hypertensive rats had a poor acquisition, retrieval of the learned behavior, perhaps a possible disturbance in memory consolidation process and that this state was reversed with ACE inhibitor enalapril and AT 1 receptor antagonist losartan.

Enalapril and Verapamil attenuate the aortic wall remodeling in nitric oxide deficiency

Cuatro grupos de 10 ratas cada uno, adultas, machos (Wistar) se mantuvieron vivas por 40 días, divididas en: Control, L-NAME, L-NAME + Enalapril, L-NAME + Verapamil. Tres parámetros de la pared de la aorta fueron analizados: el QA(SMN) (número de núcleos de células musculares lisas de la túnica media por área), la SV(lamellae) (densidad de superficie de las lamelas de la aorta), y AWT ( grosor de la pared de la aorta). Estos tres parámetros mostraron la misma tendencia entre los grupos. Las ratas del grupo L-NAME tuvieron elevación de la presión arterial e hipertrofia cardiaca. El aumento de AWT, o la reducción del QA(SMN) y la SV(lamellae) en las ratas L-NAME no fue completamente prevenido por la administración de enalapril o verapamil. La hipertensión causó aumento del AWT por hipertrofia de las unidades lamelares de la túnica media (SV(lamellae) disminuyó) y la rarefacción de los núcleos de músculo liso (QA(SMN)) disminuyó. El número relativo de núcleos de células musculares lisas (SMC) en ratas L-NAME no fue confirmado cuando este número fue corregido por el área de la pared arterial. La hipótesis de intensa proliferación de SMC en animales con deficiencia de ON, no está confirmada con la dosis de L-NAME usada y la duración del tratamiento de esta investigación.

Estrogen and Enalapril attenuate the Development of Right Ventricular Hypertrophy induced by Monocrotaline in Ovariectomized Rats

The present study evaluated the importance of ovarian functions and the renin-angiotensin system in the progression of the right ventricular (RV) hypertrophy. Female Sprague-Dawley rats were bilaterally ovariectomized (Ovx) and injected with monocrotaline (MCT, 60 mg/kg, sc). Four weeks after MCT-treatment, only the male and Ovx female rats showed marked RV hypertrophy. The hypertrophied RV of the male-MCT and Ovx-MCT rats exhibited remarkably elevated renin mRNA levels. Gene expression levels of angiotensinogen, TGF-beta1, and endothelin-1 in the hypertrophied RV also increased, but to the less degree than did the renin mRNA. To investigate beneficial effects of estrogen or enalapril on progression of the pulmonary hypertension and RV hypertrophy, histological changes of the lung and heart were examined. Sham-MCT female rats showed histological changes indicating pulmonary hypertension without RV hypertrophy. In contrast, Ovx-MCT rats showed marked RV hypertrophy with pathological changes, denoting severe pulmonary and myocardial injuries. Estrogen-or enalapril-treated Ovx-MCT rats did not show RV hypertrophy, and showed remarkably ameliorated ultrastructural changes in the lung and RV. These results from this rat model suggest that both estrogen and inhibition of the renin-angiotensin system have protective functions against the development of the pulmonary hypertension and cardiac remodeling.

Pharmacodynamically-evaluated bioequivalence of two preparations of enalapril maleate

The bioequivalence of two preparations of enalapril maleate [20 mg tablets] manufactured in Iran has been exploited in reference to a standard preparation [Xanef 20 tablets, MSD, Germany] in 14 healthy volunteers. Following oral dosing of a single tablet of each of test and standard products, as a randomized crossover design with 10-day washout intervals, the blood samples were collected in predetermined time points and using a synthetic substrate, Hippuryl-Histidy-Leucine [HHL], the release of hippuric acid from the substrate was determined as Angiotensin-Converting-Enzyme [ACE] activity of serum fractions. The percent of ACE inhibition in each sample was calculated and plotted against time, from which three pharmacodynamic parameters, i.e. Emax, tmax and AUC0-24 were derived. The results of statistical comparison of these parameters showed that both of the test preparations are bioequivalent with reference standard preparation

Hiponatremia e hipokalemia graves, recientes, asociadas a hidroclorotiazida, enalaprila y citalopram: caso clínico / Severe and recent hyponatremia and hypokalemia associated to the use of hydrochlorothiazide, enalapril and cytalopram: clinical case

We report a 72 years old hypertensive female, treated with enalapril 10 mg/day and hydrochlorothiazide 25 mg/day during three years. She presented a depressive disorder and cytalopram was prescribed in a dose of 10 mg/day. Two weeks before admission, a serum electrolyte analysis disclosed normal results and the cytalopram dose was increased to 20 mg/day. The patient was admitted with a hyponatremic encephalopathy with a plasma sodium of 100 mEq/L and a plasma potassium of 2.0 mEq/L. cytalopram, enalapril and hydrochlorothiazide were discontinued, hypertonic NaCl and KCl were administered. The patient had a favorable evolution with a remarkable improvement of her symptoms

Pharmacokinetics of phenytoin: unaltered by enalapril and amlodipine in rhesus monkeys.

A cross over single and multiple dose study was carried out to find out pharmacokinetic interactions between diphynylhydantoin (DPH) (35 mg/kg, p.o.) and antihypertensives enalapril (1.6 mg/kg; p.o.) and amlodipine (0.4 mg/kg, p.o.) in rhesus monkeys. Neither the plasma concentrations nor the pharmacokinetic parameters of DPH were altered by coadministration of enalapril or amlodipine, suggesting that enalapril and amlodipine can be safely administered to epileptic patients receiving phenytoin.

Effect of prazosin GITS, atenolol, nifedipine SR, and enalapril on ADP-induced platelet aggregation.

A randomized, observer-blind, parallel-group study was carried out to compare the effect of prazosin GITS, atenolol, nifedipine SR, and enalapril on platelet aggregation, measured at a time expected to coincide with trough plasma levels of these drugs. 24 patients (age-30 to 60 yrs) with uncomplicated mild to moderate hypertension who completed a placebo run-in phase successfully were recruited in this study. They were randomly allocated to one of the 4 treatments: prazosin GITS 2.5 mg OD (Group 1), atenolol 50 mg OD (Group II), nifedipine SR 20 mg BD (Group III), and enalapril 5 mg OD (Group IV). All the drugs were given for 7 days, and blood samples were collected at 0 hr on day 1 (pre-treatment) and day 8 (post-treatment). Based on the dose (incremental concentrations of ADP)--response (% maximum aggregation) curve obtained, 2.5 microM/L of ADP was used to compare % inhibition of platelet aggregation among the 4 groups. We found that prazosin GITS inhibited % maximum aggregation significantly (p = 0.02) at 2.5 microM/L of ADP. Such inhibitory effect was not seen in any of the other groups. The inhibition produced by prazosin GITS differed significantly from the action of the other 3 drugs (p < 0.05). This antiplatelet effect of prazosin GITS bears more clinical relevance in view of the fact that it was seen at a time which is expected to coincide with the trough plasma levels of prazosin.

Effect of ACE inhibitors on cisplatin-induced nephrotoxicity in rats

The effects of captopril and enalapril on cisplatin-induced nephrotoxicity in rats were evaluated. Aqueous solution of either captopril or enalapril was administered orally for 7 days. Cisplatin [15 mg/kg,i.p.] was injected in non-treated rats or with last dose of either captopril or enalapril30 hrs before animal sacrificing. Captopril failed to alter serum urea and creatinine, renal non-protein thiol and malondialdehyde contents. However, enalapril in a high dose [20mg/kg] increased serum creatinine, non-protein thiol. Cisplatin increased serum urea and creatinine levels, renal non-protein thiol and malondialdehyde content. Pretreatment with captopril decrease the effects of cisplatin on serum urea, renal RNA and DNA and. non-protein thiol. In contrast, enalapril potentiated the effects of cisplatin. It is concluded that the protective effect of captopril is a function of sulfhydryl group. Further studies are suggested in determining the role of thiol compounds as a basis for cisplatin-induced nephrotoxicity and its prevention