Effect of Topical Losartan in the Treatment of Established Corneal Fibrosis in Rabbits.

Purpose: The purpose of this study was to evaluate the safety and efficacy of topical losartan in the therapeutic treatment of established corneal scaring fibrosis at 1 month after alkali burn in rabbits. Methods: Standardized alkali burns were performed in 1 eye of 24 rabbits with 0.75N NaOH for 15 seconds. Corneas were allowed to heal and develop scaring of the cornea for 1 month. Twelve eyes per group were treated with 50 µL of topical 0.8 mg/mL losartan in balanced salt solution (BSS), pH 7.0, and 12 eyes were treated with vehicle BSS 6 times per day. Six corneas were analyzed at 1 week or 1 month in each group. Standardized slit lamp photographs were obtained at the end point for each cornea and opacity was quantitated using ImageJ. Corneoscleral rims were cryofixed in optimum cutting temperature (OCT) solution and combined duplex immunohistochemistry for myofibroblast marker alpha-smooth muscle actin (α-SMA), mesenchymal cell marker vimentin, and TUNEL assay for apoptosis was performed on all corneas. Results: Topical losartan was effective in the treatment of established stromal fibrosis following alkali burn injury to the rabbit cornea. Stromal myofibroblast density was decreased and stromal cell apoptosis was increased (included both α-SMA-positive myofibroblasts and α-SMA-negative, vimentin-positive cells) at both 1 week and 1 month in the topical losartan-treated compared with vehicle-treated groups. Conclusions: Topical losartan is effective in the treatment of established stromal fibrosis in rabbits. Most myofibroblasts disappear from the stroma within the first month of losartan treatment. Longer treatment with topical losartan is needed to allow time for corneal fibroblast regeneration of the epithelial basement membrane (in coordination with epithelial cells) and the removal of disordered extracellular matrix produced by myofibroblasts.

Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome.

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and ß-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of ß-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a ß-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.

Pharmacokinetics of a Fixed-Dose Combination Product of Amlodipine, Losartan, Ezetimibe, and Rosuvastatin and Its Comparison with Co-administration of Four Individual Components in Healthy Participants.

BACKGROUND AND OBJECTIVE: This study aimed to assess and compare the pharmacokinetics, safety, and tolerability of a fixed-dose combination product (FDCP) comprising four different drugs (two antihypertensive drugs, amlodipine and losartan, and two lipid-lowering agents, ezetimibe and rosuvastatin) with their separate tablets. METHODS: A total of 60 participants were enrolled in this open-label, randomized, single-dose crossover study. Each participant received a single dose of FDCP and individual tablets during each period, with a 14-day washout period between the periods. The pharmacokinetic parameters of amlodipine, losartan, EXP3174 (an active metabolite of losartan), rosuvastatin, free ezetimibe, and total ezetimibe were evaluated and compared. RESULTS: The pharmacokinetic profiles of amlodipine, losartan, rosuvastatin, and ezetimibe after administration of the individual products were similar to those of FDCP. The geometric mean ratios and 90% confidence intervals for maximum concentration (Cmax) and area under the curve (AUC) of FDCP to individual tablets were within 0.8-1.25 for all six analytes. No clinically relevant changes were observed in the vital signs or physical, biochemical, hematological, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were reported. CONCLUSION: This study demonstrated that a newly developed FDCP containing amlodipine, losartan, ezetimibe, and rosuvastatin exhibited pharmacokinetic equivalence with the individual products and met the regulatory criteria. Both formulations were well tolerated. CLINICAL TRIAL REGISTRATION: This trial (NCT04322266) was retrospectively registered on 9 September 2019.

Assembly of In-Situ Gel Containing Nano-Spanlastics of an Angiotensin II Inhibitor as a Novel Epitome for Hypertension Management: Factorial Design Optimization, In-vitro Gauging, Pharmacokinetics, and Pharmacodynamics Appraisal.

More than 1 billion people worldwide suffer from hypertension; therefore, hypertension management has been categorized as a global health priority. Losartan potassium (LP) is an antihypertensive drug with a limited oral bioavailability of about 33% since it undergoes the initial metabolic cycle. Thus, nasal administration is a unique route to overcome first-pass metabolism. The investigation focused on the potential effects of LP-loaded spanlastic vesicles (SNVs) on LP pharmacodynamics and pharmacokinetic parameters, utilizing a thin-film hydration methodology established on a 3122 full factorial design. Entrapment efficiency (EE%) ranged from 39.8 ± 3.87.8 to 83.8 ± 2.92% for LP-SNVs. Vesicle size (VS) varied from 205.5 ± 6.5.10 to 445.1 ± 13.52 nm, and the percentage of LP released after 8 h (Q8h) ranged from 30.8 ± 3.10 to 68.8 ± 1.45%. LP permeated through the nasal mucosa during 24 h and flocculated from 194.1 ± 4.90 to 435.3 ± 13.53 µg/cm2. After twenty-four hours, the optimal LP-SNVs in-situ gel showed 2.35 times more permeation through the nasal mucosa than the LP solution. It also lowered systolic blood pressure, so it is thought to be better than the reference formulation in terms of pharmacodynamics. The pharmacokinetics studies demonstrated that the intranasal LP-SNVs gel boosted its bioavailability approximately 6.36 times compared to the oral LP solution. Our research showed that intranasal LP-SNVs could be a good nanoplatform because they are well-tolerated and have possible pharmacokinetics and pharmacodynamics.

Losartan ameliorates renal fibrosis by inhibiting tumor necrosis factor signal pathway / Losartán mejora la fibrosis renal al inhibir la vía de señalización del factor de necrosis tumoral

Losartan is widely used in the treatment of chronic kidney disease (CKD) and has achieved good clinical efficacy, but its exact mechanism is not clear. We performed high-throughput sequencing (HTS) technology to screen the potential target of losartan in treating CKD. According to the HTS results, we found that the tumor necrosis factor (TNF) signal pathway was enriched. Therefore, we conducted in vivo and in vitro experiments to verify it. We found that TNF signal pathway was activated in both unilateral ureteral obstruction (UUO) rats and human proximal renal tubular epithelial cells (HK-2) treated with transforming growth factor-β1 (TGF-β1), while losartan can significantly inhibit TNF signal pathway as well as the expression of fibrosis related genes (such as COL-1, α-SMA and Vimentin). These data suggest that losartan may ameliorate renal fibrosis through modulating the TNF pathway.(AU)

El Losartán es ampliamente utilizado en el tratamiento de la enfermedad renal crónica (CKD) y ha logrado buenos resultados clínicos, pero su mecanismo exacto aún no está claro. Utilizamos la técnica de secuenciación de alto rendimiento (HTS) para detectar posibles dianas de losartán para el tratamiento de la CKD. Según los resultados de HTS, encontramos un enriquecimiento de la vía de señalización del factor de necrosis tumoral (TNF). Así, realizamos experimentos in vivo e in vitro para verificar esto. Encontramos que, tanto en ratas con obstrucción ureteral unilateral (uuo) como en células epiteliales tubulares renales proximal humanas (HK-2) tratadas con factor de crecimiento transformador β1 (TGF-β1), se activó la vía de señalización del TNF. El losartán inhibe significativamente la expresión de las vías de señalización del TNF y genes relacionados con la fibrosis, como COL-1, α-SMA y vicentin. Estos datos sugieren que el losartán puede mejorar la fibrosis renal regulando la vía del TNF.(AU)

Topical Losartan for Treating Corneal Haze After Ultraviolet-A/Riboflavin Collagen Cross-Linking.

PURPOSE: The purpose of this study was to report our first clinical experience using topical losartan for the treatment of severe corneal haze after epithelium-off corneal cross-linking (CXL). METHODS: A 20-year-old man presented with clinically significant corneal haze in the right eye 1 month following Ultraviolet-A/Riboflavin Epithelium-off Collagen CXL. Haze progressed to a deep stromal scar, and vision was 20/150 with no improvement on refraction, 60 days after CXL. After unsuccessful treatment with topical corticosteroids, the patient elected to start off-label treatment with topical losartan 0.8 mg/mL, administered 6 times per day. RESULTS: After 3 months of initiating topical losartan, the right eye vision improved to preoperative vision of 20/40-1. Corneal haze was significantly reduced as observed on slitlamp examination and on Scheimpflug corneal tomography (Pentacam; OCULUS, Inc. Arlington, WA). CONCLUSIONS: Topical losartan, a transforming growth factor-ß inhibitor, is a potential treatment in clinically significant corneal haze following epithelium-off corneal CXL. This clinical experience highlights the potential efficacy of topical losartan as a novel therapeutic option in such cases, but further clinical studies are needed.

Reduction of Aversive Learning Rates in Pavlovian Conditioning by Angiotensin II Antagonist Losartan: A Randomized Controlled Trial.

BACKGROUND: Angiotensin receptor blockade has been linked to aspects of aversive learning and memory formation and to the prevention of posttraumatic stress disorder symptom development. METHODS: We investigated the influence of the angiotensin receptor blocker losartan on aversive Pavlovian conditioning using a probabilistic learning paradigm. In a double-blind, randomized, placebo-controlled design, we tested 45 (18 female) healthy volunteers during a baseline session, after application of losartan or placebo (drug session), and during a follow-up session. During each session, participants engaged in a task in which they had to predict the probability of an electrical stimulation on every trial while the true shock contingencies switched repeatedly between phases of high and low shock threat. Computational reinforcement learning models were used to investigate learning dynamics. RESULTS: Acute administration of losartan significantly reduced participants' adjustment during both low-to-high and high-to-low threat changes. This was driven by reduced aversive learning rates in the losartan group during the drug session compared with baseline. The 50-mg drug dose did not induce reduction of blood pressure or change in reaction times, ruling out a general reduction in attention and engagement. Decreased adjustment of aversive expectations was maintained at a follow-up session 24 hours later. CONCLUSIONS: This study shows that losartan acutely reduces Pavlovian learning in aversive environments, thereby highlighting a potential role of the renin-angiotensin system in anxiety development.

Enhanced Tumor Targeting of Radiolabeled Mouse/Human Chimeric Anti-Tn Antibody in Losartan-Treated Mice Bearing Tn-Expressing Lung Tumors.

Aim: ChiTn, a mouse/human chimeric anti-Tn monoclonal antibody, was radiolabeled with iodine-131 (131I) and technetium-99m (99mTc) to assess its biodistribution and internalization in Tn-expressing (Tn+) and wild-type (Tn-) LL/2 lung cancer cells. Results: Selective accumulation and gradual internalization of ChiTn were observed in Tn+ cells. Biodistribution in mice with both Tn+ or Tn- lung tumors indicated that the uptake of radiolabeled ChiTn within tumors increased over time. Dual-labeling experiments with 99mTc and 131I showed different biodistribution patterns, with 99mTc exhibiting higher values in the liver, spleen, and kidneys, while 131I showed higher uptake in the thyroid and stomach. However, tumor uptake did not significantly differ between Tn+ and Tn- tumors. To improve tumor targeting, Losartan, an antihypertensive drug known to enhance tumor perfusion and drug delivery, was investigated. Biodistribution studies in Losartan-treated mice revealed significantly higher radiolabeled ChiTn uptake in Tn+ tumors. No significant changes were observed in the uptake of the control molecule IgG-HYNIC™99mTc. Conclusions: These findings demonstrate the enhanced tumor targeting of radiolabeled ChiTn in Losartan-treated mice with Tn-expressing lung tumors. They highlight the potential of ChiTn as a theranostic agent for cancer treatment and emphasize the importance of Losartan as an adjunctive treatment to improve tumor perfusion and drug delivery.

Combinação fixa de losartana associada a hidroclorotiazida para adultos com hipertensão arterial sistêmica com controle inadequado da pressão arterial / Fixed combination of losartan associated with hydrochlorothiazide for adults with controlled systemic arterial hypertension inadequate blood pressure

INTRODUÇÃO: A hipertensão arterial sistêmica (HAS), uma doença crônica, é um grave problema de saúde pública, caracterizada por níveis elevados e persistentes da pressão sanguínea, medidos em geral como uma razão da pressão arterial sistólica e diastólica (respectivamente maior ou igual a 140 mmHg; e/ou maior ou igual a 90 mmHg). Esta é uma doença altamente prevalente em todo o mundo. No Brasil, os números podem variar de acordo com a metodologia utilizada. Reportou-se na Pesquisa Nacional de Saúde de 2013, cujos dados são obtidos por autorrelato, a prevalência de hipertensão em 21% dos pacientes, mas ao considerar a aferição da pressão arterial e uso de medicamentos, o percentual de adultos com pressão arterial ≥140/90 mmHg foi de 32%. Sabe-se que a falta de controle da pressão arterial pode elevar o risco de ocorrência de eventos cardiovasculares, como infarto agudo do miocárdio, insuficiência cardíaca, acidente vascular cerebral, doenças renais, entre outros. Isso consequentemente pode causar problemas crônicos que reduzem a qualidade de vida do indivíduo, e até mesmo o óbito. Além de toda carga da doença gerada ao paciente, a HAS ainda está relacionada a uma carga econômica. PERGUNTA

Losartan treatment significantly attenuates the fibrotic changes in the corpus cavernosum of castrated rats / El tratamiento con losartán atenúa de manera importante los cambios fibróticos en el cuerpo cavernoso de ratas castradas

INTRODUCTION AND OBJECTIVES: The aim of this study is to evaluate the effects of castration and subsequent losartan administration on the fibrosis-related parameters in the corpora cavernosa of castrated rats. MATERIAL AND METHODS: Twenty-four male rats were divided into four equal groups. Group 1:sham surgery plus vehicle (0.9% NaCl) (control:con), group 2:sham surgery plus losartan (con+los), group 3: castration plus vehicle (castration:cast) and group 4:castration plus losartan (cast+los). After four weeks of oral losartan treatment, corporal levels of transforming growth factor-beta (TGF-beta), thrombospondin-1 (TSP-1), alpha-actin, beta-actin and fibronectin were investigated by ELISA kits. Changes in the collagen and smooth muscle content were evaluated by histological analysis with Masson trichrome staining. RESULTS: Initial and post-treatment body weights of rats were similar among groups. Castration significantly increased the expression of TGF-beta, TSP-1 and fibronectin and resulted in a significant decrease in alpha-actin levels in the corpora cavernosa. Administration of losartan reduced the levels of TGF-beta, TSP-1 and fibronectin in castrated rats. Alpha actin levels also increased after losartan treatment. Beta-actin levels were not significantly different among 4 groups. The levels of all markers were similar in group 1 and 2. Rate of fibrosis was significantly higher in castrated rats and treatment with losartan reduced this rate. CONCLUSION: Castration increased the expression of fibrosis-related markers in the corpora cavernosa of rats. Administration of losartan significantly attenuated those changes and exerted an antifibrotic effect

INTRODUCCIÓN Y OBJETIVOS: El objetivo de este estudio es evaluar los efectos de la castración y la posterior administración de losartán en los parámetros relacionados con la fibrosis en los cuerpos cavernosos de ratas castradas. MATERIAL Y MÉTODOS: Veinticuatro ratas macho se dividieron en 4 grupos iguales. Grupo 1: cirugía simulada más vehículo (0,9% NaCl) (control:con); grupo 2: cirugía simulada más losartán (con+los); grupo 3: castración más vehículo (castración:cast) y grupo 4: castración más losartán (cast+los). Después de 4 semanas de tratamiento oral con losartán se analizaron los niveles de factor de crecimiento transformante beta (TGF-beta), trombospondina-1 (TSP-1), alfa-actina, beta-actina y fibronectina mediante kits de ELISA. Cambios en el colágeno y el contenido de músculo liso se evaluaron mediante análisis histológico con tinción con tricrómico de Masson. RESULTADOS: Los pesos corporales iniciales y posteriores al tratamiento de las ratas fueron similares entre los grupos. La castración aumentó considerablemente la expresión de TGF-beta, TSP-1 y fibronectina, y dio como resultado una disminución importante de los niveles de alfa-actina en los cuerpos cavernosos. La administración de losartán redujo los niveles de TGF-beta, TSP-1 y fibronectina en ratas castradas. Los niveles de alfa-actina también aumentaron después del tratamiento con losartán. Los niveles de beta-actina no fueron muy diferentes entre los 4 grupos. Los niveles de todos los marcadores fueron similares en los grupos 1 y 2. La tasa de fibrosis fue mucho mayor en las ratas castradas y el tratamiento con losartán redujo esta tasa. CONCLUSIÓN: La castración aumentó la expresión de marcadores relacionados con la fibrosis en los cuerpos cavernosos de las ratas. La administración de losartán atenuó considerablemente esos cambios y ejerció un efecto antifibrótico

Efecto de las variantes de CYP2C9 sobre la dosis de losartán en hipertensos chilenos / Association between cytochrome p4502c9 polymorphisms and losartan dosing in hypertensive patients

Background Losartan is widely used in many clinicals settings. Its dosage is related to the genetic characteristics of CYP2C9 enzymatic activity, which metabolizes losartan to its active form E-3174, responsible for the antihypertensive effect. Aims To identify the frequency of allelic variants CYP2C9*2 and CYP2C9*3 in hypertensive patients and to compare genotypes with a healthy Chilean population. To relate polymorphisms with the losartan dosing to obtain an optimal blood pressure. Material and Methods We studied 30 patients with controlled essential hypertension using losartan with normal liver function, and 202 healthy people. Peripheral blood DNA genotyping was performed by polymerase chain reaction to identify the polymorphisms. Allelic and genotypic frequencies were compared. Results In hypertensive patients, allelic frequencies were 0.85 (CYP2C9*1), 0.05 (CYP2C9*2) and 0.1 (CYP2C9*3). Genotypic frequencies were 73.3% (CYP2C9*1/*1), 6.7% (CYP2C9*1/*2), 16.7% (CYP2C9*1/*3) and 3.3% (CYP2C9*2/3); observing a significantly higher frequency of the allele CYP2C9*3 (p=0.041) and CYP2C9*1/*3 genotype (p=0.04). A non-significant tendency to need a larger dose of losartan was observed with the CYP2C9 * 3 allele, with an odds ratio (OR) of 1.46 (95% confidence intervals (CI) 0.01-18.64). The same tendency was observed with the need to use losartan twice a day, obtaining an OR of 5.88 (CI 0.54 -62.14). Conclusions There could be a relationship between the presence of CYP2C9 polymorphisms and the pathogenesis of hypertension. The presence of CYP2C9*3 is associated with the need for higher doses of losartan, possibly due to a decrease in the conversion of losartan to E-3174.

Prescripción de fármacos bloqueadores del sistema renina angiotensina en pacientes con enfermedad renal crónica etapa 3 en atención primaria de salud / Prescription of renin-angiotensin-aldosterone system blockers in patients with stage 3 chronic kidney disease

Background: To reduce the progression of chronic kidney disease (CKD) and cardiovascular risk, the guidelines recommend the blockade of the renin-angiotensin-aldosterone system (RAAS) in patients with proteinuria. Aim: To assess the frequency of enalapril or losartan use in diabetics or hypertensive patients with stage 3 CKD. Material and Methods: Review of clinical records of patients with CKD in an urban primary care clinic. Results: We identified 408 subjects aged 40 to 98 years (66% women) with stage 3 CKD. Sixty six percent had only hypertension and 34% were diabetic with or without hypertension. Seventy four percent received RAAS blockers (52% used enalapril, 45% losartan and 2% both medications). RAAS blockers were used in 70% of hypertensive and 78% of diabetic patients. The prescription in hypertensive diabetics with microalbuminuria was lower than in those without microalbuminuria (72% vs 87%, p < 0.05), but the opposite occurred in pure hypertensive patients with and without microalbuminuria (88% vs 69%, p < 0.05). There were no significant differences in blood pressure levels, microalbuminuria or serum potassium levels between RAAS blocker users and non-users. No differences were observed either between enalapril and losartan users. Conclusions: The adherence to clinical guidelines is insufficient and users of the recommended drugs did not achieve the expected goals.

Comparison of the efficacy of losartan, hydrocortisone and acetylsalicylic acid (ASA) in preventing the development of fibrous scar tissue in skeletal muscle / Comparação da eficácia de losartana, hidrocortisona e ácido acetilsalicílico (AAS) na prevenção do desenvolvimento de tecido cicatricial fibroso nos músculos esqueléticos / Comparación de la eficacia de losartán, hidrocortisona y ácido acetilsalicílico (AAS) en la prevención del desarrollo de tejido cicatricial fibroso en los músculos esqueléticos

OBJECTIVE: To analyze fibrous scar tissue inhibition capacity with the use of losartan, hydrocortisone and acetylsalicylic acid. METHOD: The sample consisted of 120 male heterogeneic Wistar rats with a muscle laceration model. The rats were divided into four groups of 30 animals each: control group, losartan group, ASA group and hydrocortisone group. The animals were anesthetized and a 2.5 cm longitudinal incision was made in the left thoracolumbar paravertebral region. The muscles were subjected to a Grade III lesion caused by applying Kelly hemostatic forceps for 60 seconds, followed by sectioning with scissors. The skin was sutured with 3-0 nylon monofilament thread. The animals were placed in individual cages with plenty of food and water. The losartan group received losartan diluted in water at a dose of 0.1 mg/mL (10 mg/kg/day), the ASA Group received a 3 mg/mL ASA solution (300 mg/kg/day), and the hydrocortisone group received a 0.2 mg/mL hydrocortisone solution (20 mg/kg/day). RESULTS: The control, losartan, hydrocortisone and aspirin groups had a fibrotic area of 0.95 ± 0.35 mm, 0.55 ± 0.34 mm, 0.93 ± 0.33 mm, and 0.66 ± 0.36 mm, respectively. We observed a significantly smaller fibrotic area in the losartan group compared to the control (p=0.01) and hydrocortisone (p=0.01) groups. There were no significant differences among the other groups. CONCLUSION: The healing of striated skeletal muscle produced less fibrous scar tissue when exposed to losartan in comparison to the control group or the hydrocortisone group. Level of Evidence I; Randomized double-blind placebo-controlled study.

OBJETIVO: Analisar a capacidade de inibição de formação de tecido cicatricial fibroso com losartana, hidrocortisona e AAS. MÉTODOS: A amostra consistiu em 120 ratos Wistar heterogênicos machos com modelo de laceração muscular. Os ratos foram distribuídos em quatro grupos de 30 animais: grupo controle, grupo losartana, grupo AAS e grupo hidrocortisona. Os animais foram anestesiados e submetidos a uma incisão em sentido longitudinal de 2,5 cm de extensão na região paravertebral toracolombar esquerda, e os músculos sofreram uma lesão grau III com pinça hemostática de Kelly durante 60 segundos e posterior secção com tesoura. A pele foi suturada com nylon monofilamentar 3-0. Os animais foram colocados em gaiolas individuais, com água e alimento à vontade. O grupo losartana recebeu losartana diluída em água na dose de 0,1 mg/ml (10 mg/kg/dia), o grupo AAS recebeu solução de AAS 3 mg/ml (300 mg/kg/dia), o grupo hidrocortisona recebeu solução de hidrocortisona 0,2 mg/ml (20 mg/kg/ dia). RESULTADOS: Os grupos controle, losartana, hidrocortisona e AAS apresentaram área fibrótica de0,95 ± 0,35 mm, 0,55 ± 0,34 mm, 0,93 ± 0,33 mm, 0,66 ± 0,36 mm, respectivamente. Observou-se área fibrótica significativamente menor do grupo losartana em comparação com o grupo controle (p = 0,01) e hidrocortisona (p = 0,01). Nos demais grupos não houve diferença significativa. CONCLUSÃO: A cicatrização do músculo estriado esquelético produziu menos tecido cicatricial fibroso quando exposto à losartana do que quando comparado com o grupo controle ou o grupo hidrocortisona. Nível de Evidência I; Estudo duplo-cego randomizado controlado por placebo.

OBJETIVO: Analizar la capacidad de inhibición de formación de tejido cicatricial fibroso con losartán, hidrocortisona y AAS (ácido acetilsalicílico). MÉTODOS: La muestra consistió en 120 ratas Wistar heterogéneas machos con modelo de laceración muscular. Las ratas fueron distribuidas en cuatro grupos de 30 animales: grupo control; grupo losartán; grupo AAS y grupo hidrocortisona. Los animales fueron anestesiados y sometidos a una incisión longitudinal de 2,5 cm de extensión en la región paravertebral toracolumbar izquierda y los músculos sufrieron una lesión de grado III con pinza hemostática de Kelly durante 60 segundos y posterior sección con tijera. La piel se suturó con monofilamento de nylon 3-0. Los animales fueron dispuestos en jaulas individuales con abundante comida y agua. El grupo losartán recibió losartán diluido en agua a una dosis de 0,1 mg/ml (10 mg/kg/día), el grupo AAS recibió solución de AAS de 3 mg/ml (dosis 300 mg/kg/día), el grupo hidrocortisona recibió solución hidrocortisona de 0,2 mg/ml (20 mg/kg/día). RESULTADOS: Los grupos control, losartán, hidrocortisona y AAS mostraron área fibrótica de 0,95 ± 0,35 mm, 0,55 ± 0,34 mm, 0,93 ± 0,33 mm, 0,66 ± 0,36 mm, respectivamente. Se observó área fibrótica significativamente menor del grupo losartán en comparación con el grupo control (p = 0,01) e hidrocortisona (p = 0,01). En los demás grupos no hubo diferencias significativas. CONCLUSIÓN: La cicatrización del músculo estriado esquelético produjo menos tejido cicatricial fibroso cuando fue expuesto a losartán que cuando fue comparado con el grupo control o el grupo hidrocortisona. Nivel de Evidencia I; Estudio doble ciego aleatorio controlado por placebo.

Efeito a curto prazo do losartan comparado ao enalapril na função ventricular esquerda e na capacidade de pacientes com insuficiência aórtica crônica grave oligo grave ou assintomáticos / Effect in short term of losartan compared with the enalapril in the left ventricular function and the physical capacity of patients with asymptomatic or minimally symptomatic chronic severe aortic regurgitation

Objetivo: analisar o efeito a curto prazo do lasartan comparado ao enalapril sobre a função ventricular esquerda em pacientes com insuficiência valvar aórtica grave, oligo ou assintomáticos, testar a segurança do lasartan nessas condições e estudar o impacto destas drogas sobre a capacidade física. Métodos: Dez pacientes com insuficiência valvar aórtica (IAo)crônica grave e com função ventricular esquerda preservada (fração de ejeção menor ou igual 0,55), foram estudados de forma prospectiva em um estudo de intervenção medicamentosa cross-over, comparando-se duas drogas: losartan e o enalapril, através de avaliação clínico-laboratorial, ecocardiograma de repouso e teste cardiopulmonar em três momentos diferentes: sem medicação, em uso de losartan, em uso de enalapril. Resultados: Foram estudados 7 (70 por cento homens e 3 (30 por cento) mulheres com idade entre 15 e 41 anos (média de 26 anos). A dose média diária de enalapril foi de 38mg com tempo médio de 3,9 meses e a de losartan foi de 90mg com tempo médio de três meses. Não houve efeitos adversos graves....

The relationship between heart rate reserve and oxygen uptake reserve in heart failure patients on optimized and non-optimized beta-blocker therapy

BACKGROUND: The relationship between the percentage of oxygen consumption reserve and percentage of heart rate reserve in heart failure patients either on non-optimized or off beta-blocker therapy is known to be unreliable. The aim of this study was to evaluate the relationship between the percentage of oxygen consumption reserve and percentage of heart rate reserve in heart failure patients receiving optimized and non-optimized beta-blocker treatment during a treadmill cardiopulmonary exercise test. METHODS: A total of 27 sedentary heart failure patients (86 percent male, 50±12 years) on optimized beta-blocker therapy with a left ventricle ejection fraction of 33±8 percent and 35 sedentary non-optimized heart failure patients (75 percent male, 47±10 years) with a left ventricle ejection fraction of 30±10 percent underwent the treadmill cardiopulmonary exercise test (Naughton protocol). Resting and peak effort values of both the percentage of oxygen consumption reserve and percentage of heart rate reserve were, by definition, 0 and 100, respectively. RESULTS: The heart rate slope for the non-optimized group was derived from the points 0.949±0.088 (0 intercept) and 1.055±0.128 (1 intercept), p<0.0001. The heart rate slope for the optimized group was derived from the points 1.026±0.108 (0 intercept) and 1.012±0.108 (1 intercept), p=0.47. Regression linear plots for the heart rate slope for each patient in the non-optimized and optimized groups revealed a slope of 0.986 (almost perfect) for the optimized group, but the regression analysis for the non-optimized group was 0.030 (far from perfect, which occurs at 1). CONCLUSION: The relationship between the percentage of oxygen consumption reserve and percentage of heart rate reserve in patients on optimized beta-blocker therapy was reliable, but this relationship was unreliable in non-optimized heart failure patients.

Expression of NAD(P)H Oxidase Subunits and Their Contribution to Cardiovascular Damage in Aldosterone/Salt-Induced Hypertensive Rat

NAD(P)H oxidase plays an important role in hypertension and its complication in aldosterone-salt rat. We questioned whether NAD(P)H oxidase subunit expression and activity are modulated by aldosterone and whether this is associated with target- organ damage. Rats were infused with aldosterone (0.75 microgram/hr/day) for 6 weeks and were given 0.9% NaCl+/-losartan (30 mg/kg/day), spironolactone (200 mg/kg/ day), and apocynin (1.5 mM/L). Aldosterone-salt hypertension was prevented completely by spironolactone and modestly by losartan and apocynin. Aldosterone increased aortic NAD(P)H oxidase activity by 34% and spironolactone and losartan inhibited the activity. Aortic expression of the subunits p47(phox), gp91(phox), and p22(phox) increased in aldosterone-infused rats by 5.5, 4.7, and 3.2-fold, respectively, which was decreased completely by spironolactone and partially by losartan and apocynin. Therefore, the increased expression of NAD(P)H oxidase may contribute to cardiovascular damage in aldosterone-salt hypertension through the increased expression of each subunit.

Papel del sistema renina angiotensina en la respuesta simpática inducida por la prueba presora al frío en humanos / Role of the renin-angiotensin system on the sympathetic response induced by the cold pressor test in humans

El objetivo del presente estudio fue evaluar el papel del receptor AT1 de la angiotensina sobre la respuesta simpática inducida por la prueba presora al frío (PPF), en voluntarios sanos. Se incluyeron 82 sujetos sanos, en un estudio doble ciego controlado con placebo. Se determinaron los valores de la presión arterial y la frecuencia cardiaca, antes y 175 minutos después de la administración oral única de placebo, losartan (59 mg), valsartan (80 mg) o eprosartan (600 mg). Inmediatamente después, los sujetos fueron sometidos a la prueba presora al frío (PPF), midiéndose los mismos parámetros hemodinámicos. La PPF incrementó la presión arterial sistólica, diastólica y media así como la frecuencia cardíaca en el grupo placebo. El pretratamiento con losartan, valsartan o eprosartan bloqueó la respuesta presora a la PPF sin producir cambios en la respuesta de frecuencia cardiaca. Nuestros resultados demuestran que la angiotensina II endógena, a través del receptor AT1, contribuye a la respuesta al estrés mediada simpáticamente en humanos.

Perfil do tratamento da insuficiência cardíaca na era dos betabloqueadores / Heart failure treatment profile at the beta blockers era

OBJETIVOS: A inibição dos sistemas renina-angiotensina-aldosterona (SRAA) e sistema nervoso autônomo simpático aumentou a perspectiva de sobrevida desses pacientes, além de permitir substancial melhora na qualidade de vida. O objetivo deste trabalho foi avaliar a realidade do tratamento aplicado e seu impacto sobre a doença em pacientes acompanhados em um ambulatório especializado em insuficiência cardíaca(IC). MÉTODOS: Foram estudados 96 pacientes acompanhados no ambulatório de Insuficiência Cardíaca e Transplante do Instituto do Coração, do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP). Os dados foram coletados durante a consulta ambulatorial a partir de prontuário médico e exame clínico. A escolha dos pacientes foi aleatória. RESULTADOS: A maior parte dos pacientes encontrava-se em classe funcional II (42,3 por cento) e em estágio C de evolução (94,9 por cento). A prescrição médica para os pacientes foi bastante próxima do preconizado pelas diretrizes. Aproximadamente 95 por cento recebem inibidores do SRAA (inibidor de ECA - enalapril e captopril - ou antagonista dos receptores de angiotensina-losartan), enquanto 85 por cento dos pacientes recebem, além desses, agentes betabloqueadores (carvedilol). A dose média prescrita também se aproxima das utilizadas nos grandes estudos, e atinge mais de 60 por cento da dose máxima de cada medicação. Os dados hemodinâmicos encontrados mostram pacientes estáveis, apesar da intensidade da disfunção e do remodelamento ventricular destes. CONCLUSÃO: Pacientes portadores de IC acompanhados por equipe médica especializada têm prescrição médica mais próxima do preconizado. Esses pacientes, embora com características marcadas de gravidade da doença, conseguem estabilidade hemodinâmica e clínica com a otimização terapêutica adequada.

OBJECTIVES: The inhibition of the rennin-angiotensin-aldosterone system (RAAS) and sympathetic autonomous nervous system has increased the perspective of survival in these patients, as well as allowing the improvement of the quality of life. The aim of this study was to evaluate the reality of the treatment employed and its impact on the disease in patients followed at a specialized heart failure (HF) outpatient clinic. METHODS: A sample of 96 patients followed at the HF and Transplant Outpatient Clinic of Heart Institute of the University of São Paulo School of Medicine (InCor -HCFMUSP) were evaluated. The data were collected during the ambulatory consultation from the medical files and through physical examination. Patients were randomly selected for the study. RESULTS: Most of the patients were Functional Class II (42.3 percent) and evolution stage C (94.9 percent). The medical prescription given to the patients was quite similar to the one recommended by the directives. Approximately 95 percent of them received RAAS inhibitors (ACE inhibitor - enalapril and captopril - or angiotensin receptor antagonist - losartan), whereas 85 percent of the patients additionally received beta blockers (carvedilol). The mean dose prescribed was also similar to the one used in large studies and reached more than 60 percent of the maximum dose for each medication. The hemodynamic data show that patients were stable, despite the intensity of the dysfunction and ventricular remodeling observed in these patients. CONCLUSION: Patients with HF followed by a specialized medical team receive a medical prescription that is closer to the recommended one. These patients, despite the marked characteristics of disease severity, achieve hemodynamic and clinical stability with an adequate therapeutic optimization.

Inhibitory Effect of Angiotensin Blockade on Hepatic Fibrosis in Common Bile Duct-ligated Rats / 대한간학회지

BACKGROUNDS AND AIMS: Angiotensin receptors are found on hepatic stellate cells, which participate in hepatic fibrosis. Therefore, it is presumed that angiotensin has a role in hepatic fibrosis. The aim of this study was to evaluate the effects of angiotensin blockade on inhibition of hepatic fibrosis in cirrhotic rat model. Material and METHODS: Cirrhosis with portal hypertension was produced by common bile duct ligation (BDL) in the adult Sprague-Dawley rats. They were classified into 4 groups (each group n=6) as follows; G1: BDL without drug, G2: BDL+captopril 100 mg/kg/day beginning 2 weeks after BDL, G3: BDL+captopril 100 mg/kg/day, starting just after BDL, G4: BDL+losartan 10 mg/kg/day, starting just after BDL. After 4 weeks following BDL, hepatic fibrosis was histomorphologically analyzed by Batts & Ludwig score. Alpha smooth muscle actin by immunohistochemical stain, hydroxyproline contents of liver tissue by spectrophotometry and expression of collagen, procollagen, and TGF-beta by real-time PCR were measured. RESULTS: Batts & Ludwig score were 3.8, 3.0, 2.6,and 2.6 in G1, G2, G3, and G4, respectively. The expression of alpha-SMA was significantly lower in G3 and G4 than in G1; 11.9%, 10.9%, 2.6%, and 1.1% in G1, G2, G3, and G4, respectively (p<0.05). The concentration of hydroxyproline (microgram/g liver tissue) was lower in G3 and G4 compared with G1 (p<0.05). Also, the administration of angiotensin blockade just after BDL significantly reduced the expression of collagen, procollagen, and TGF-beta mRNA. CONCLUSIONS: Angiotensin blockades are effective in the prevention of hepatic fibrosis in BDL rats.

Estudo `LOTHAR`: avaliação de eficácia e tolerabilidade da combinação fixa de anlodipino e losartana no tratamento da hipertensão arterial primária / The `LOTHAR` study: evaluation of efficacy and tolerability of the fixed combination of amlodipine and losartan in the treatment of essential hypertension

OBJETIVO: O estudo LOTHAR avaliou a eficácia, tolerabilidade e os efeitos metabólicos em médio e longo prazo (um ano) da combinação fixa de anlodipino e losartana versus anlodipino e losartana isoladamente. MÉTODOS: Estudo multicêntrico brasileiro, randomizado, duplo-cego e comparativo realizado com 198 pacientes com hipertensão arterial primária em estágios 1 e 2. RESULTADOS: A combinação fixa apresenta alta eficácia anti-hipertensiva que se mantém em longo prazo com percentual reduzido de escape do controle pressórico, inferior a dos dois regimes monoterápicos de comparação. Em longo prazo, mais de 60 por cento dos pacientes tratados com a combinação fixa permaneceram com níveis da PAD < 85 mmHg e o efeito anti-hipertensivo quando avaliado pela MAPA persistiu nas 24 horas com relação vale-pico de 76,7 por cento. A freqüência de eventos adversos foi bastante reduzida neste grupo sendo a incidência em longo prazo de edema de membros inferiores cerca de quatro vezes menor que a observada com o anlodipino isolado. A combinação fixa não alterou os metabolismos da glicose e dos lípides tanto em médio quanto em longo prazos. CONCLUSAO: Estes resultados nos permitem afirmar que a combinação de anlodipino e losartana, a primeira combinação fixa de um antagonista dos canais de cálcio e um bloqueador do receptor da angiotensina II disponível no mercado farmacêutico constitui-se em excelente opção para o tratamento da hipertensão arterial em larga gama de pacientes hipertensos.