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Article in Chinese | WPRIM | ID: wpr-921570


Olmesartan,an angiotensin Ⅱ receptor blocker,is a commonly used antihypertensive drug.Several case reports and cohort studies in recent years have described a severe gastrointestinal adverse event with chronic diarrhea,intestinal malabsorption,and weight loss after the administration of olmesartan.In such cases,the patients recovered after discontinuing olmesartan.This adverse effect is called olmesartan-associated enteropathy(OAE).This article reviews the potential pathogenesis and clinical characteristics of OAE,which broadens the disease spectrum for the differential diagnosis of chronic diarrhea and intestinal malabsorption.

Angiotensin Receptor Antagonists , Humans , Imidazoles , Intestinal Diseases/diagnosis , Tetrazoles/adverse effects
Arq. bras. cardiol ; 115(5): 821-827, nov. 2020. tab
Article in Portuguese | SES-SP, LILACS, SES-SP | ID: biblio-1142272


Resumo Fundamento O tratamento com sacubitril-valsartana teve seu benefício prognóstico confirmado no ensaio PARADIGM-HF. No entanto, dados sobre alterações no teste de esforço cardiopulmonar (TECP) com o uso de sacubitril-valsartana são escassos. Objetivo O objetivo deste estudo foi comparar os parâmetros do TECP antes e depois do tratamento com sacubitril-valsartana. Métodos Avaliação prospectiva de pacientes com insuficiência cardíaca (IC) crônica e fração de ejeção do ventrículo esquerdo ≤40%, mesmo sob terapia padrão otimizada, que iniciaram tratamento com sacubitril-valsartana, sem expectativa de tratamentos adicionais para a IC. Os dados do TECP foram coletados na semana anterior e 6 meses depois do tratamento com sacubitril-valsartana. Diferenças estatísticas com valor p <0,05 foram consideradas significativas. Resultados De 42 pacientes, 35 (83,3%) completaram o seguimento de 6 meses, uma vez que 2 (4,8%) morreram e 5 (11,9%) interromperam o tratamento devido a eventos adversos. A média de idade foi de 58,6±11,1 anos. A classe NYHA (classificação da New York Heart Association) melhorou em 26 (74,3%) pacientes. O consumo máximo de oxigênio (VO2max) (14,4 vs. 18,3 ml/kg/min, p<0,001), a inclinação VE/VCO2 (36,7 vs. 31,1, p<0,001) e a duração do exercício (487,8 vs. 640,3 s, p<0,001) também melhoraram com o uso de sacubitril-valsartana. O benefício foi mantido mesmo com a dose de 24/26 mg (13,5 vs. 19,2 ml/kg/min, p=0,018) de sacubitril-valsartana, desde que esta tenha sido a maior dose tolerada. Conclusões O tratamento com sacubitril-valsartana está associado a uma melhora acentuada do VO2max, da inclinação VE/VCO2 e da duração do exercício no TECP. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

Abstract Background Sacubitril/valsartan had its prognosis benefit confirmed in the PARADIGM-HF trial. However, data on cardiopulmonary exercise testing (CPET) changes with sacubitril-valsartan therapy are scarce. Objective This study aimed to compare CPET parameters before and after sacubitril-valsartan therapy. Methods Prospective evaluation of chronic heart failure (HF) patients with left ventricular ejection fraction ≤40% despite optimized standard of care therapy, who started sacubitril-valsartan therapy, expecting no additional HF treatment. CPET data were gathered in the week before and 6 months after sacubitril-valsartan therapy. Statistical differences with a p-value <0.05 were considered significant. Results Out of 42 patients, 35 (83.3%) completed the 6-month follow-up, since 2 (4.8%) patients died and 5 (11.9%) discontinued treatment for adverse events. Mean age was 58.6±11.1 years. New York Heart Association class improved in 26 (74.3%) patients. Maximal oxygen uptake (VO2max) (14.4 vs. 18.3 ml/kg/min, p<0.001), VE/VCO2slope (36.7 vs. 31.1, p<0.001), and exercise duration (487.8 vs. 640.3 sec, p<0.001) also improved with sacubitril-valsartan. Benefit was maintained even with the 24/26 mg dose (13.5 vs. 19.2 ml/kg/min, p=0.018) of sacubitril-valsartan, as long as this was the highest tolerated dose. Conclusions Sacubitril-valsartan therapy is associated with marked CPET improvement in VO2max, VE/VCO2slope, and exercise duration. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0)

Humans , Middle Aged , Aged , Ventricular Function, Left , Heart Failure/drug therapy , Oxygen , Stroke Volume , Tetrazoles , Prospective Studies , Treatment Outcome , Drug Combinations , Angiotensin Receptor Antagonists , Aminobutyrates
Article in Chinese | WPRIM | ID: wpr-828100


OBJECTIVE@#To explore the effects of olmesartan on age-associated migration and invasion capacities and microRNA (miRAN) axis in human aortic vascular smooth muscle cells (HA-VSMCs).@*METHODS@#Cultured HA-VSMCs were divided into control group, bleomycin-mediated senescence (BLM) group and bleomycin + olmesartan treatment group. Wound-healing assay and Boyden chambers invasion assay were used to assess the changes in migration and invasion of the cells, gelatin zymography was used to analyze matrix metalloproteinase-2 (MMP-2) activation in the cells. The differentially expressed miRNAs were identified by miRNA microarray assay and validated by quantitative real-time PCR. MiR-3133 inhibitor was used to examine the effects of molecular manipulation of olmesartan on age-associated migration and invasion and MMP-2 activation in the cells.@*RESULTS@#Compared with those of the control group, the percentage of the repopulated cells and the number of cells crossing the basement membrane increased significantly in BLM group [(78.43±12.76)% (42.47±7.22)%, < 0.05; 33.33±5.51 13.00±4.36, < 0.05]. A significant increase of MMP-2 activation was found in BLM group as compared with the control group (1.66 ± 0.27 0.87 ± 0.13, < 0.05). Olmesartan significantly inhibited BLM-induced enhancement of cell migration and invasion and MMP-2 secretion in the cells. MiR-3133 was significantly downregulated in BLM group and upregulated in olmesartan group. Transfection with miR-3133 inhibitor significantly reversed the effects of olmesartan on age-associated migration and invasion of the cells [(85.87±7.39)% (49.77±3.05)%; 34.67±2.31 20.00±4.58, < 0.05] and MMP-2 activation in the cells (1.76±0.19 0.94±0.10, < 0.05).@*CONCLUSIONS@#Olmesartan inhibits the migration and invasion of ageassociated HA-VSMCs probably by upregulating of the miR-3133 axis.

Cell Movement , Cell Proliferation , Cells, Cultured , Humans , Imidazoles , Matrix Metalloproteinase 2 , MicroRNAs , Genetics , Muscle, Smooth, Vascular , Myocytes, Smooth Muscle , Tetrazoles
Int. j. morphol ; 37(2): 515-521, June 2019. tab, graf
Article in English | LILACS | ID: biblio-1002253


SUMMARY: Reproductive dysfunction is a complication for many diseases and toxins. Its early diagnosis and treatment are immensely important. Here the morphological histoarchitecture changes in early testicular and cauda toxicity before and after treatment with angiotensin receptor blockers were evaluated. Low-grade testicular damage was induced using thioacetamide (TAA, 50 mg/kg/day) intraperitoneally for two weeks in rats. The rats were randomly divided into four groups (n = 8) treated daily orally for three weeks as follows: Normal control (distilled water), TAA (positive control), TAA+candesartan (0.2 mg/kg) and TAA+losartan (7.5 mg/kg). Serum testosterone and testicular malondialdehyde and glutathione were measured. The changes in histoarchitecture of testis and cauda epididymis were evaluated by hematoxylin and eosin for general structure, Masson's trichrome for collagen, periodic acid Schiff for basement membrane, and caspase-3 and proliferating cell nuclear antigen (PCNA) for immunohistochemical analysis. The TAA-rats showed decreases of serum testosterone and testicular glutathione, increases in testicular malondialdehyde, degenerative changes and apoptosis in germ cells, thickening of tubular basal lamina and increases in expression of caspase 3, and decreases in expression of PCNA. The ARBs (candesartan and losartan) significantly reversed these changes with non-significant differences in-between. Treatment with ARBs (candesartan and losartan) significantly reversed TAA-induced low-grade testicular and cauda toxicity in rats. This could be potentially useful for early treatment of male patients with occupational toxicant-induced reproductive dysfunction especially if they are using ARBs for other comorbidities.

RESUMEN: La disfunción reproductiva es una complicación por muchas enfermedades y toxinas. Su diagnóstico y tratamiento tempranos son inmensamente importantes. Aquí se evaluaron los cambios morfológicos en la histoarquitectura en la toxicidad precoz testicular y cauda antes y después del tratamiento con bloqueadores de receptores de angiotensina. Se indujo daño testicular de bajo grado usando tioacetamida (TAA, 50 mg / kg / día) por vía intraperitoneal durante dos semanas en ratas. Las ratas se dividieron aleatoriamente en cuatro grupos (n = 8) tratados diariamente por vía oral durante tres semanas de la siguiente manera: control normal (agua destilada), TAA (control positivo), TAA + candesartan (0,2 mg / kg) y TAA + losartán (7,5 mg / kg). Se midieron la testosterona sérica, el malondialdehído testicular y el glutatión. Los cambios en la histoarquitectura de los testículos y la epidermis de la cauda se evaluaron mediante Hematoxilina y Eosina para determinar la estructura general, con tricrómicro de Masson para el colágeno, ácido periódico de Schiff para la membrana basal y la caspasa-3 y el antígeno nuclear de células proliferantes (PCNA) para análisis inmunohistoquímico. Las ratas TAA mostraron disminución de la testosterona sérica y glutatión testicular, aumentos en el malondialdehído testicular, cambios degenerativos y apoptosis en células germinales, engrosamiento de la lámina basal tubular y aumentos en la expresión de la caspasa 3, y disminución en la expresión de PCNA. Los ARB (candesartán y losartán) revirtieron significativamente estos cambios con diferencias no significativas en el medio. El tratamiento con BRA (candesartán y losartán) revirtió significativamente la toxicidad testicular y cauda inducida por TAA en ratas. Esto podría ser potencialmente útil para el tratamiento temprano de pacientes con disfunción reproductiva inducida por tóxicos ocupacionales, especialmente si están usando BRA para otras comorbilidades.

Animals , Male , Rats , Testis/drug effects , Thioacetamide/toxicity , Benzimidazoles/pharmacology , Losartan/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Testis/pathology , Testosterone/analysis , Tetrazoles/pharmacology , Immunohistochemistry , Rats, Sprague-Dawley , Proliferating Cell Nuclear Antigen/metabolism , Caspase 3/metabolism , Glutathione/analysis , Malondialdehyde/analysis
Rev. méd. Chile ; 147(3): 330-333, mar. 2019. tab
Article in Spanish | LILACS | ID: biblio-1043154


Background: Pharmacological treatment improves survival in patients with heart failure with reduced ejection fraction. The use of sacubutril/valsartan and ivabradine has been recently approved and incorporated in the latest guidelines. Aim: To identify candidates eligible for these therapies among patients treated in a heart failure clinic, considering the inclusion criteria for the PARADIGM-HF and SHIFT trials. Material and Methods: Cross-sectional study on 158 patients aged 62 ± 11 years (67% male) with heart failure and reduced ejection fraction, with at least three months of follow-up and without decompensation. The percentage of patients complying for the inclusion criteria for the PARADIGM-HF y SHIFT trials was determined. Results: In 37%, the etiology of heart failure was ischemic, 49% were in functional class I, their ejection fraction was 33 ± 11% and their median Pro-brain natriuretic peptide was 800 pg/mL. Ninety five percent were treated with vasodilators, 97% with beta-blockers and 82% with aldosterone antagonists. Using PARADIGM-HF and SHIFT criteria, 11 patients (7%) were eligible for sacubitril / valsartan and 21 patients (13.3%) for ivabradine. Among the main causes of non-eligibility for sacubitril / valsartan were being functional class I (48.7%) and not achieving a stable dose of enalapril ≥ 20 mg / day or losartan ≥ 100 mg / day (24.7%). In the case of ivabradine, apart from those in functional class I, the absence of sinus rhythm and a heart rate < 70 / min when receiving a maximal tolerated dose of beta-blockers, were present in 22%. Conclusions: A low percentage of our patients were eligible for these therapies. Among the causes that explain these results were clinical stability, a high percentage of patients in functional class I and being in a disease modifying treatment.

Humans , Male , Female , Middle Aged , Aged , Tetrazoles/administration & dosage , Cardiovascular Agents/administration & dosage , Angiotensin Receptor Antagonists/administration & dosage , Ivabradine/administration & dosage , Aminobutyrates/administration & dosage , Heart Failure/drug therapy , Cross-Sectional Studies , Patient Selection , Dose-Response Relationship, Drug , Drug Combinations , Heart Failure/physiopathology
Arch. cardiol. Méx ; 88(4): 287-297, oct.-dic. 2018. tab, graf
Article in Spanish | LILACS | ID: biblio-1124150


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)

Humans , Tetrazoles/therapeutic use , Enalapril/therapeutic use , Aminobutyrates/therapeutic use , Heart Failure/drug therapy , Quality of Life , Systole , Tetrazoles/pharmacology , Biphenyl Compounds , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Enalapril/pharmacology , Drug Combinations , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin Receptor Antagonists/pharmacology , Valsartan , Aminobutyrates/pharmacology , Heart Failure/physiopathology , Hospitalization/statistics & numerical data
Acta cir. bras ; 33(4): 296-305, Apr. 2018. tab, graf
Article in English | LILACS | ID: biblio-886282


Abstract Purpose: To evaluate the effect of the cilostazol on the evolution of partially avulsed flaps, using experimental model of cutaneous degloving in rat limbs. Methods: A controlled and randomized experimental study was carried out in which the blood flow and the percentage of flap necrosis were evaluated. We compared the study group, which received cilostazol, and the control group, which received enteral saline solution in the postoperative period. The blood flow in the flap was evaluated through Laser Doppler flowmetry, and a planimetry using the IMAGE J® software was employed for the calculation of the area of necrosis. Results: Enteral administration of cilostazol was associated with a higher mean blood flow in all regions of the flap, with a statistically significant difference in the proximal and middle regions (p<0.001) and a lower percentage of necrotic area in the flap (p<0.001). Conclusion: Postoperative enteral administration of cilostazol increased blood flow and decreased the total area of necrosis of avulsed cutaneous flaps of rat limbs.

Humans , Animals , Male , Tetrazoles/therapeutic use , Disease Models, Animal , Phosphodiesterase 3 Inhibitors/therapeutic use , Degloving Injuries/drug therapy , Reference Values , Regional Blood Flow/drug effects , Surgical Flaps , Tetrazoles/pharmacology , Time Factors , Random Allocation , Reproducibility of Results , Treatment Outcome , Rats, Wistar , Laser-Doppler Flowmetry , Lower Extremity/blood supply , Lower Extremity/injuries , Lower Extremity/pathology , Phosphodiesterase 3 Inhibitors/pharmacology , Degloving Injuries/surgery , Degloving Injuries/pathology , Necrosis/drug therapy
Arch. cardiol. Méx ; 87(4): 316-325, oct.-dic. 2017. tab, graf
Article in English | LILACS | ID: biblio-887542


Abstract: Objective: To evaluate efficacy and safety of 60 mg and 120 mg Fimasartan (FMS) alone or combined with 12.5 mg hydrochlorothiazide (HCTZ) in a Mexican population. Methods: A six month, treat-to-target, open study was conducted on subjects with grade 1-2 hypertension. The subjects were initially treated with 60 mg FMS once daily. In week 8, those with Diastolic Blood Pressure (DBP) <90 mmHg continued on the same FMS dose during the rest of the study, while those with DBP ≥90 mmHg were randomised to either 120 mg FMS or 60 mg FMS + 12.5 mg HCTZ once daily. In week 12, randomised subjects with DBP ≥90 mmHg received 120 mg FMS + 12.5 mg HCTZ, while those achieving target continued with their assigned treatment until the end of the study. Results: FMS 60 mg (n = 272) decreased both DBP and Systolic Blood Pressure (SBP) by 11.3 ± 8.9 (p<.0001) and 16.0 ± 14.1 (p<.0001) mmHg, respectively, with 75.4% of subjects reaching the treatment target. Subjects assigned to FMS 120 mg, FMS 60 mg + HCTZ 12.5 mg, or FMS 120 mg + HCTZ 12.5 mg once daily, showed significant reductions in DBP and SBP with their assigned treatment. At the end of the study, 237/272 subjects (87.1%) achieved a DBP < 90 mmHg and an SBP<140 mmHg. The most frequently reported adverse reactions included headache (3.7%), dry mouth (1.1%), transient liver enzyme increase (1.1%), and dizziness (0.7%). Conclusion: Fimasartan is safe and effective in Mexican subjects with grade 1-2 essential hypertension.

Resumen: Objetivo: Evaluar la eficacia y la seguridad de 60 y 120 mg de fimasartán (FMS) solo o combinado con 12.5 mg de hidroclorotiazida (HCTZ) en población mexicana. Métodos: Estudio abierto, de 24 semanas, con tratamiento escalado hasta el objetivo terapéutico en sujetos hipertensos grados 1-2. Tratamiento inicial: FMS 60 mg una vez al día; en la semana 8, los sujetos con presión arterial diastólica (PAD) <90 mmHg mantuvieron su tratamiento inicial durante el estudio, mientras que los sujetos con PAD ≥90 mmHg fueron aleatorizados a 120 mg de FMS o a 60 mg de FMS + 12.5 mg de HCTZ. En la semana 12, los sujetos aleatorizados con PAD ≥90 mmHg recibieron 120 mg de FMS + 12.5 mg de HCTZ; quienes alcanzaron el objetivo terapéutico mantuvieron su tratamiento asignado hasta finalizar el estudio. Resultados: FMS 60 mg (n = 272) disminuyó la PAD y la presión arterial sistólica (PAS) en 11.3 ± 8.9 (p < 0.0001) y 16.0 ± 14.1 (p < 0.0001) mmHg, respectivamente, con logro del objetivo de tratamiento en el 75.4% de los sujetos. Los sujetos asignados a 120 mg de FMS, a 60 mg de FMS + 12.5 mg de HCTZ 12.5 y a 120 mg de FMS + 12.5 mg de HCTZ mostraron reducciones significativas de PAD y PAS; al final del estudio, 237/272 sujetos (87.1%) lograron PAD <90 y PAS <140 mmHg. Las reacciones adversas más frecuentemente reportadas fueron: cefalea (3.7%), boca seca (1.1%), incremento de enzimas hepáticas (1.1%) y mareo (0.7%). Conclusión: FMS es seguro y eficaz en sujetos mexicanos con hipertensión esencial de grados 1-2.

Humans , Male , Female , Middle Aged , Pyrimidines/administration & dosage , Tetrazoles/administration & dosage , Biphenyl Compounds/administration & dosage , Essential Hypertension/drug therapy , Hydrochlorothiazide/administration & dosage , Antihypertensive Agents/administration & dosage , Pyrimidines/adverse effects , Tetrazoles/adverse effects , Biphenyl Compounds/adverse effects , Severity of Illness Index , Prospective Studies , Treatment Outcome , Drug Therapy, Combination , Mexico , Antihypertensive Agents/adverse effects
J. bras. nefrol ; 39(2): 108-118, Apr.-June 2017. tab, graf
Article in English | LILACS | ID: biblio-893744


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.

Animals , Male , Rats , Benzimidazoles/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Enalapril/pharmacology , Cytokines/urine , Angiotensin II Type 1 Receptor Blockers/pharmacology , Amides/pharmacology , Renin-Angiotensin System/drug effects , Tetrazoles/pharmacology , Random Allocation , Rats, Wistar , Fumarates/pharmacology , Nephrectomy
Braz. j. med. biol. res ; 50(11): e6665, 2017. tab, graf
Article in English | LILACS | ID: biblio-888944


Minimal hepatic encephalopathy is more common than the acute syndrome. Losartan, the first angiotensin-II receptor blocker (ARB), and candesartan, another widely-used ARB, have protected against developing fibrogenesis, but there is no clear data about their curative antifibrotic effects. The current study was designed to examine their effects in an already-established model of hepatic fibrosis and also their effects on the associated motor dysfunction. Low-grade chronic liver failure (CLF) was induced in 3-month old Sprague-Dawley male rats using thioacetamide (TAA, 50 mg·kg−1·day−1) intraperitoneally for 2 weeks. The TAA-CLF rats were randomly divided into five groups (n=8) treated orally for 14 days (mg·kg−1·day−1) as follows: TAA (distilled water), losartan (5 and 10 mg/kg), and candesartan (0.1 and 0.3 mg/kg). Rats were tested for rotarod and open-field tests. Serum and hepatic biochemical markers, and hepatic histopathological changes were evaluated by H&E and Masson's staining. The TAA-CLF rats showed significant increases of hepatic malondialdehyde, hepatic expression of tumor necrosis factor-α (TNF-α), and serum ammonia, alanine aminotransferase, γ-glutamyl transferase, TNF-α, and malondialdehyde levels as well as significant decreases of hepatic and serum glutathione levels. All treatments significantly reversed these changes. The histopathological changes were moderate in losartan-5 and candesartan-0.1 groups and mild in losartan-10 and candesartan-0.3 groups. Only candesartan significantly improved TAA-induced motor dysfunction. In conclusion, therapeutic antifibrotic effects of losartan and candesartan in thioacetamide-induced hepatic fibrosis in rats are possibly through angiotensin-II receptor blocking, antioxidant, and anti-inflammatory activities. Improved motor dysfunction by candesartan could be attributed to better brain penetration and slower "off-rate" from angiotensin-II receptors. Clinical trials are recommended.

Animals , Male , Angiotensin II Type 1 Receptor Blockers/therapeutic use , Benzimidazoles/therapeutic use , End Stage Liver Disease/complications , Losartan/therapeutic use , Motor Disorders/drug therapy , Tetrazoles/therapeutic use , Alanine Transaminase/blood , Ammonia/blood , Angiotensin II Type 1 Receptor Blockers/pharmacology , Benzimidazoles/pharmacology , Disease Models, Animal , End Stage Liver Disease/pathology , End Stage Liver Disease/physiopathology , Enzyme-Linked Immunosorbent Assay , gamma-Glutamyltransferase/blood , Glutathione/analysis , Liver Cirrhosis/complications , Liver Cirrhosis/pathology , Liver Cirrhosis/physiopathology , Liver/drug effects , Liver/pathology , Locomotion/physiology , Losartan/pharmacology , Malondialdehyde/analysis , Motor Disorders/etiology , Motor Disorders/physiopathology , Random Allocation , Rats, Sprague-Dawley , Reproducibility of Results , Reverse Transcriptase Polymerase Chain Reaction , Tetrazoles/pharmacology , Thioacetamide , Treatment Outcome , Tumor Necrosis Factor-alpha/blood
Rev. bras. cir. cardiovasc ; 31(4): 291-299, July-Sept. 2016. tab, graf
Article in English | LILACS | ID: biblio-829740


Abstract Objective: Intimal hyperplasia is associated with graft failure and vascular sutures in the first year after surgery and in postangioplasty restenosis. Allium sativum (common garlic) lowers cholesterol and has antioxidant effects; it also has antiplatelet and antitumor properties and, therefore, has great potential to reduce or inhibit intimal hyperplasia of the arteries. Our objective is to determine if the garlic has an efficacy to inhibit myointimal hyperplasia compared to cilostazol. Methods: Female New Zealand rabbits were divided into the following groups (n=10 each) according to treatment: group A, garlic, 800 µg×kg-1×day-1, orally; group C, cilostazol, 50, orally; group PS, 10 ml of 0.9% physiological saline solution, orally. Our primary is the difference of the mean of myointimal hyperplasia. Statistical analysis was performed by using ANOVA and Tukey tests, as well as the Chi-square test. We calculated the 95% confidence interval for each point estimate, and the P value was set as < 0.05. Results: Group PS had a mean hyperplasia rate of 35.74% (95% CI, 31.76–39.71%); group C, 16.21% (95% CI, 13.36–19.05%); and group A, 21.12% (95% CI, 17.26–25.01%); P<0.0001. Conclusion: We conclude that Allium sativum had the same efficacy in inhibiting myointimal hyperplasia when compared to the positive control, cilostazol.

Animals , Female , Rabbits , Arteriosclerosis/prevention & control , Tetrazoles/pharmacology , Tunica Intima/pathology , Garlic/chemistry , Arteriosclerosis/pathology , Immunohistochemistry , Platelet Aggregation Inhibitors , Cilostazol , Hyperplasia/prevention & control
Article in Chinese | WPRIM | ID: wpr-273734


<p><b>OBJECTIVE</b>To investigate the protective effects of irbesartan against cardiac inflammation associated with diabetes and obesity in the db/db mouse model of type 2 diabetes and explore the underlying mechanisms.</p><p><b>METHODS</b>Twenty- four 10-week-old diabetic db/db mice were equally randomized into irbesartan treatment (50 mg/kg per day) group and model group, using 12 nondiabetic littermates (db/+) as the controls, The mice were treated with irbesartan or saline vehicle for 16 consecutive weeks, after which the heart pathology was observed and the heart weight, body weight, and serum levels of fasting blood glucose (FBG), total cholesterol(TC), and triglycerides(TG) were measured. The expression of nuclear factor-kappaB (NF-κB) p65 in the myocardium was assessed with immunohistochemistry, the protein levels of P-IκBα ,IκBα and β-actin were analyzed with Western blotting, and the pro-inflammatory cytokines IL-6 and TNF-α mRNA were detected using quantitative real-time PCR (qPCR).</p><p><b>RESULTS</b>Compared with db/+ mice, the saline-treated db/db mice developed obesity, hyperglycemia and hyperlipidemia (P<0.01). Histopathological examination of the heart tissue revealed inflammatory cell infiltration, increased myocardial interstitium and disorders of myocardial fiber arrangement. The diabetic mice showed increased P-IαBα and decreased IκBα protein levels, enhanced activity and expression of NF-κB in the hearts, and increased mRNA expression of IL-6 and TNF-α in the myocardium. These abnormalities were all associated with increased inflammatory response. Treatment with irbesartan improved the heart architecture and attenuated high glucose-induced inflammation in the diabetic mice.</p><p><b>CONCLUSION</b>Treatment with irbesartan attenuates cardiac inflammation in type 2 diabetic db/db mice, and this effect was probably associated with the suppression of cardiac angiotensin II and NF-κB signaling pathway.</p>

Actins , Metabolism , Angiotensin II , Metabolism , Animals , Biphenyl Compounds , Pharmacology , Cardiovascular Diseases , Drug Therapy , Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Inflammation , Drug Therapy , Interleukin-6 , Metabolism , Mice , Obesity , Random Allocation , Real-Time Polymerase Chain Reaction , Signal Transduction , Tetrazoles , Pharmacology , Transcription Factor RelA , Metabolism , Tumor Necrosis Factor-alpha , Metabolism
Chinese Medical Journal ; (24): 2143-2148, 2016.
Article in English | WPRIM | ID: wpr-307451


<p><b>BACKGROUND</b>Atrial fibrillation (AF) is the most frequent tachyarrhythmia in patients with a permanent pacemaker. Angiotensin II receptor antagonists have a protective effect against the occurrence of AF in patients with heart diseases. This study aimed to assess the effectiveness of olmesartan in the prevention of new-onset AF and AF burden in atrioventricular block (AVB) patients with dual-chamber (DDD) pacemaker implantation.</p><p><b>METHODS</b>This was a single-center, prospective, randomized, single-blind, controlled clinical study. A total of 116 AVB patients, who received DDD pacemakers implantation with the percentage of ventricular pacing (VP%) ≥40% from April 22, 2011 to December 24, 2012, were prospectively randomized to olmesartan group (20 mg per day; n = 57) or control group (n = 59). Patients were followed up using pacemaker programming, 12-lead electrocardiography in the intrinsic sinus rhythm, laboratory examinations, and transthoracic echocardiography at 24 months. Atrial high rate events (AHREs) were defined as 180 beats/min over a minimum of 5 min. AF burden was calculated by the number of hours with AHREs divided by the number of measurement hours.</p><p><b>RESULTS</b>Ten (17.5%) patients in the olmesartan group and 24 patients (40.7%) in the control group occurred new-onset AF, and the difference between two groups was statistically significant (P = 0.04). AF burden was lower in olmesartan group than that in control group (8.02 ± 3.10% vs. 13.66 ± 6.14%, P = 0.04). There were no significant differences in mean days to the first occurrence of AHREs and mean cumulative numbers of AHREs between two groups (P = 0.89 and P = 0.42, respectively). Moreover, olmesartan group had smaller values of maximal P-wave durations and P-wave dispersion (PD) after 24 months follow-up compared with the control group (109.5 ± 7.4 ms vs. 113.4 ± 7.1 ms, P = 0.00; and 40.6 ± 4.5 ms vs. 43.3 ± 4.4 ms, P = 0.02, respectively). Left ventricular end-diastolic diameter and left ventricular ejection fraction were not significantly different between two groups (both P > 0.05).</p><p><b>CONCLUSION</b>This study suggested that 24-month of olmesartan therapy could reduce new-onset AF and AF burden in patients with DDD pacemakers.</p><p><b>CLINICAL TRIAL REGISTRATION</b>ChiCTR-TRC-12004443;</p>

Aged , Angiotensin Receptor Antagonists , Therapeutic Uses , Atrial Fibrillation , Drug Therapy , Atrioventricular Block , Drug Therapy , Female , Humans , Imidazoles , Therapeutic Uses , Male , Middle Aged , Single-Blind Method , Tetrazoles , Therapeutic Uses
Clinics ; 70(7): 500-507, 2015. tab, graf
Article in English | LILACS | ID: lil-752399


OBJECTIVES: Remote ischemic perconditioning is the newest technique used to lessen ischemia/reperfusion injury. However, its effect in hypertensive animals has not been investigated. This study aimed to examine the effect of remote ischemic perconditioning in spontaneously hypertensive rats and determine whether chronic treatment with Olmesartan could influence the effect of remote ischemic perconditioning. METHODS: Sixty rats were randomly divided into six groups: vehicle-sham, vehicle-ischemia/reperfusion injury, vehicle-remote ischemic perconditioning, olmesartan-sham, olmesartan-ischemia/reperfusion and olmesartan-remote ischemic perconditioning. The left ventricular mass index, creatine kinase concentration, infarct size, arrhythmia scores, HIF-1α mRNA expression, miR-21 expression and miR-210 expression were measured. RESULTS: Olmesartan significantly reduced the left ventricular mass index, decreased the creatine kinase concentration, limited the infarct size and reduced the arrhythmia score. The infarct size, creatine kinase concentration and arrhythmia score during reperfusion were similar for the vehicle-ischemia/reperfusion group and vehicle-remote ischemic perconditioning group. However, these values were significantly decreased in the olmesartan-remote ischemic perconditioning group compared to the olmesartan-ischemia/reperfusion injury group. HIF-1α, miR-21 and miR-210 expression were markedly down-regulated in the Olmesartan-sham group compared to the vehicle-sham group and significantly up-regulated in the olmesartan-remote ischemic perconditioning group compared to the olmesartan-ischemia/reperfusion injury group. CONCLUSION: The results indicate that (1) the protective effect of remote ischemic perconditioning is lost in vehicle-treated rats and that chronic treatment with Olmesartan restores the protective effect of remote ischemic perconditioning; (2) chronic treatment with Olmesartan down-regulates HIF-1α, ...

Animals , Rats , Angiotensin II Type 1 Receptor Blockers/pharmacology , Imidazoles/pharmacology , Myocardial Reperfusion Injury/prevention & control , Tetrazoles/pharmacology , Disease Models, Animal , Ischemic Preconditioning, Myocardial , Random Allocation , Rats, Inbred SHR
Article in Chinese | WPRIM | ID: wpr-239149


<p><b>OBJECTIVE</b>To observe the effect of Tripterygium glycosides (TG) on the expression of hypoxia-inducible factor-1α and endothelin-1 in the kidney of diabetic rats and explore the possible mechanism underlying the protective effect of TG against diabetic nephropathy.</p><p><b>METHODS</b>Sixty 8-week-old male SD rats were randomly divided into normal control group (n=10) and streptozotocin-induced diabetes mellitus (DM) model group (n=50). The diabetic model rats were then randomly divided into DM group, low-dose (8 mg/kg) and high-dose (16 mg/kg) TG treatment groups, and Irbesartan (50 mg/kg) treatment group. After 8 weeks, the levels of blood glucose (BG), 24-h urine protein (24 h Upro), serum creatinine (Scr) and blood urea nitrogen (BUN) were measured. The pathological changes in the renal tissues were examined by optical microscopy, and the mean glomerular area (MGA) and mean glomerular volume (MGV) were measured with pathological image analysis. Immunohistochemical and Western blotting were used to detect the expression of HIF-1α and ET-1 protein in the renal tissue, and their mRNA expressions were detected using real-time fluorescence quantitative PCR.</p><p><b>RESULTS</b>HIF-1α and ET-1 expression increased in the kidney of diabetic rats. Compared with the diabetic model rats, the rats receiving TG and Irbesartan treatment showed decreased levels of Scr, BUN, 24h Upro, MGA and MGV, improved renal histopathology, and reduced expression of HIF-1α and ET-1 mRNA and protein in the renal tissue. These changes were more obvious in high-dose TG treatment group. Correlation analysis showed that the expression of HIF-1α was positively correlated with that of ET-1, and they were both positively correlated with kidney weight index (KW/BW), 24 h Upro, MGA, and MGV.</p><p><b>CONCLUSION</b>HIF-1α and ET-1 are overexpressed in the kidney of diabetic rats. TG can improve kidney damage in diabetic rats and delay the development of diabetic nephropathy by inhibiting the HIF-1α and ET-1 expression.</p>

Animals , Biphenyl Compounds , Pharmacology , Blood Glucose , Blood Urea Nitrogen , Creatinine , Blood , Diabetes Mellitus, Experimental , Metabolism , Endothelin-1 , Metabolism , Glycosides , Pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit , Metabolism , Kidney , Metabolism , Male , Rats , Rats, Sprague-Dawley , Tetrazoles , Pharmacology , Tripterygium , Chemistry
Chinese Medical Journal ; (24): 153-158, 2015.
Article in English | WPRIM | ID: wpr-268347


<p><b>BACKGROUND</b>Angiotensin type 1 receptor (AT 1 R) antagonists are extensively used for blood pressure control in elderly patients with hypertension. This study aimed to investigate the inhibitory effects of AT 1 R antagonist valsartan on platelet aggregation and the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.</p><p><b>METHODS</b>Two-hundred and ten patients with hypertension and aged > 60 years were randomized to valsartan (n = 140) or amlodipine (n = 70) on admission. The primary endpoint was platelet aggregation rate (PAR) induced by arachidonic acid at discharge, and the secondary endpoint was the rate of thrombotic events including brain infarction and myocardial infarction during follow-up. Human aortic endothelial cells (HAECs) were stimulated by angiotensin II (Ang II, 100 nmol/L) with or without pretreatment of valsartan (100 nmol/L), and relative expression of cyclooxygenase-2 (COX-2) and thromboxane B 2 (TXB 2 ) and both p38 mitogen-activated protein kinase (p38MAPK) and nuclear factor-kB (NF-kB) activities were assessed. Statistical analyses were performed by GraphPad Prism 5.0 software (GraphPad Software, Inc., California, USA).</p><p><b>RESULTS</b>PAR was lower after treatment with valsartan (11.49 ± 0.69% vs. 18.71 ± 2.47%, P < 0.001), associated with more reduced plasma levels of COX-2 (76.94 ± 7.07 U/L vs. 116.4 ± 15.89 U/L, P < 0.001) and TXB 2 (1667 ± 56.50 pg/ml vs. 2207 ± 180.20 pg/ml) (all P < 0.001). Plasma COX-2 and TXB 2 levels correlated significantly with PAR in overall patients (r = 0.109, P < 0.001). During follow-up (median, 18 months), there was a significantly lower thrombotic event rate in patients treated with valsartan (14.3% vs. 32.8%, P = 0.002). Relative expression of COX-2 and secretion of TXB 2 with concordant phosphorylation of p38MAPK and NF-kB were increased in HAECs when stimulated by Ang II (100 nmol/L) but were significantly decreased by valsartan pretreatment (100 nmol/L).</p><p><b>CONCLUSIONS</b>AT 1 R antagonist valsartan decreases platelet activity by attenuating COX-2/TXA 2 expression through p38MAPK and NF-kB pathways and reduces the occurrence of cardio-cerebral thrombotic events in elderly patients with hypertension.</p>

Aged , Aged, 80 and over , Angiotensin Receptor Antagonists , Therapeutic Uses , Blood Platelets , Blotting, Western , Cell Line , Cyclooxygenase 2 , Blood , Female , Humans , Hypertension , Drug Therapy , Male , Platelet Aggregation , Real-Time Polymerase Chain Reaction , Tetrazoles , Therapeutic Uses , Thrombosis , Blood , Drug Therapy , Thromboxane B2 , Blood , Valine , Therapeutic Uses , Valsartan
Article in English | WPRIM | ID: wpr-99852


Angiotensin receptor blockers (ARBs) have organ-protective effects in heart failure and may be also effective in doxorubicin-induced cardiomyopathy (DOX-CMP); however, the efficacy of ARBs on the prevention of DOX-CMP have not been investigated. We performed a preclinical experiment to evaluate the preventive effect of a novel ARB, fimasartan, in DOX-CMP. All animals underwent echocardiography and were randomly assigned into three groups: treated daily with vehicle (DOX-only group, n=22), 5 mg/kg of fimasartan (Low-fima group, n=22), and 10 mg/kg of fimasartan (High-fima group, n=19). DOX was injected once a week for six weeks. Echocardiography and hemodynamic assessment was performed at the 8th week using a miniaturized conductance catheter. Survival rate of the High-fima group was greater (100%) than that of the Low-fima (75%) and DOX-only groups (50%). Echocardiography showed preserved left ventricular (LV) ejection fraction in the High-fima group, but not in the DOX-only group (P=0.002). LV dimensions increased in the DOX-only group; however, remodeling was attenuated in the Low-fima and High-fima groups. Hemodynamic assessment showed higher dP/dt in the High-fima group compared with the DOX-only group. A novel ARB, fimasartan, may prevent DOX-CMP and improve survival rate in a dose-dependent manner in a rat model of DOX-CMP and could be a treatment option for the prevention of DOX-CMP.

Angiotensin Receptor Antagonists/therapeutic use , Animals , Biphenyl Compounds/therapeutic use , Cardiomyopathies/chemically induced , Doxorubicin/toxicity , Echocardiography , Hemodynamics , Pyrimidines/therapeutic use , Rats , Rats, Sprague-Dawley , Receptor, Angiotensin, Type 1/chemistry , Survival Rate , Tetrazoles/therapeutic use , Ventricular Function, Left/physiology