Antioxidant effect of endothelin-1 receptor antagonist protects the rat kidney against chronic injury induced by hypertension and hyperglycemia.

Hypertension and Diabetes mellitus are the two main causes of chronic kidney disease that culminate in the final stage of kidney disease. Since these two risk factors are common and can overlap, new approaches to prevent or treat them are needed. Macitentan (MAC) is a new non-selective antagonist of the endothelin-1 (ET-1) receptor. This study aimed to evaluate the effect of chronic blockade of ET-1 receptor with MAC on the alteration of renal function observed in hypertensive and hyperglycemic animals. Genetically hypertensive rats were divided into control hypertensive (HT-CTL) group, hypertensive and hyperglycemic (HT+DIAB) group, and hypertensive and hyperglycemic group that received 25 mg/kg macitentan (HT-DIAB+MAC25) via gavage for 60 days. Kidney function and parameters associated with oxidative and nitrosative stress were evaluated. Immunohistochemistry for neutrophil gelatinase-associated lipocalin (NGAL), ET-1, and catalase in the renal cortex was performed. The HT+DIAB group showed a decrease in kidney function and an increase in NGAL expression in the renal cortex, as well as an increase in oxidative stress. MAC treatment was associated with attenuated ET-1 and NGAL production and increases in antioxidant defense (catalase expression) and nitric oxide production. In addition, MAC prevented an increase in oxidant injury (as measured by urinary hydroperoxide and lipid peroxidation), thus improving renal function. Our results suggest that the antioxidant effect of the ET-1 receptor antagonist MAC is involved in the improvement of kidney function observed in hypertensive and hyperglycemic rats.

Endothelin-1 receptor antagonists protect the kidney against the nephrotoxicity induced by cyclosporine-A in normotensive and hypertensive rats.

Cyclosporin-A (CsA) is an immunosuppressant associated with acute kidney injury and chronic kidney disease. Nephrotoxicity associated with CsA involves the increase in afferent and efferent arteriole resistance, decreased renal blood flow (RBF) and glomerular filtration. The aim of this study was to evaluate the effect of Endothelin-1 (ET-1) receptor blockade with bosentan (BOS) and macitentan (MAC) antagonists on altered renal function induced by CsA in normotensive and hypertensive animals. Wistar and genetically hypertensive rats (SHR) were separated into control group, CsA group that received intraperitoneal injections of CsA (40 mg/kg) for 15 days, CsA+BOS and CsA+MAC that received CsA and BOS (5 mg/kg) or MAC (25 mg/kg) by gavage for 15 days. Plasma creatinine and urea, mean arterial pressure (MAP), RBF and renal vascular resistance (RVR), and immunohistochemistry for ET-1 in the kidney cortex were measured. CsA decreased renal function, as shown by increased creatinine and urea. There was a decrease in RBF and an increase in MAP and RVR in normotensive and hypertensive animals. These effects were partially reversed by ET-1 antagonists, especially in SHR where increased ET-1 production was observed in the kidney. Most MAC effects were similar to BOS, but BOS seemed to be better at reversing cyclosporine-induced changes in renal function in hypertensive animals. The results of this work suggested the direct participation of ET-1 in renal hemodynamics changes induced by cyclosporin in normotensive and hypertensive rats. The antagonists of ET-1 MAC and BOS reversed part of these effects.

Potential role for ET-2 acting through ETA receptors in experimental colitis in mice.

OBJECTIVE AND DESIGN: This study attempted to clarify the roles of endothelins and mechanisms associated with ETA/ETB receptors in mouse models of colitis. MATERIALS AND METHODS: Colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS, 1.5 mg/animal) or dextran sulfate sodium (DSS, 3%). After colitis establishment, mice received Atrasentan (ETA receptor antagonist, 10 mg/kg), A-192621 (ETB receptor antagonist, 20 mg/kg) or Dexamethasone (1 mg/kg) and several inflammatory parameters were assessed, as well as mRNA levels for ET-1, ET-2 and ET receptors. RESULTS: Atrasentan treatment ameliorates TNBS- and DSS-induced colitis. In the TNBS model was observed reduction in macroscopic and microscopic score, colon weight, neutrophil influx, IL-1ß, MIP-2 and keratinocyte chemoattractant (KC) levels, inhibition of adhesion molecules expression and restoration of IL-10 levels. However, A192621 treatment did not modify any parameter. ET-1 and ET-2 mRNA was decreased 24 h, but ET-2 mRNA was markedly increased at 48 h after TNBS. ET-2 was able to potentiate LPS-induced KC production in vitro. ETA and ETB receptors mRNA were increased at 24, 48 and 72 h after colitis induction. CONCLUSIONS: Atrasentan treatment was effective in reducing the severity of colitis in DSS- and TNBS-treated mice, suggesting that ETA receptors might be a potential target for inflammatory bowel diseases.

Efectividad y seguridad del ambrisentan en pacientes con hipertensión pulmonar grupo 1 / Effectiveness and safety of ambrisentan in patients with pulmonary hypertension group 1

Introducción: la Hipertensión pulmonar (HTP) es una enfermedad progresiva caracterizada por el aumento de la presión arterial pulmonar (por encima de 25 mm HG) debido al aumento de la resistencia vascular pulmonar. La enfermedad lleva a falla cardíaca ventricular derecha y muerte prematura. Actualmente es causante de alta morbilidad y mortalidad entre los pacientes que la sufren, presentando una tasa de supervivencia media una vez diagnosticada la enfermedad de alrededor de 3,6 años. Esta evaluación tecnológica se desarrolló en el marco de la actualización integral del Plan Obligatorio de Salud para el año 2015. Objetivo: evaluar la efectividad y seguridad del uso de ambrisentan para el tratamiento de pacientes con hipertensión arterial pulmonar idiopática y asociada. Metodología: la evaluación fue realizada de acuerdo con un protocolo definido a priori. Se realizó una búsqueda sistemática hasta noviembre de 2014 en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects y LILACS, sin restricciones de idioma ni fecha de publicación. Se identificaron las RSL y ECA que cumplieran los criterios de elegibilidad. La calidad de los estudios fue valorada con la herramienta AMSTAR. Las características de los estudios fueron extraídas a partir de las publicaciones originales.Se actualizó la búsqueda de la RSL para identificar nuevos ECA. Los resultados se presentan de acuerdo al reporte de la RSL. Se realizó un meta-análisis de novo con los ECA que compararon solo ambrisentan. Resultados: se identificó una RSL de calidad alta por AMSTAR y moderada por GRADE que incluye dos ECA (393 pacientes). El ambrisentan disminuye el riesgo de muerte (OR=0,24 (IC 95% 0,06-0,99)) comparado contra placebo. No existe evidencia a favor para la mejoría de clase funcional (OR=1,08 (IC 95%0,72-1,62)). La mejoría en la prueba de la caminata de 6 minutos, fue en promedio de 43,02 metros (IC95% 25,68 a 60,36) en comparación con el placebo. La calidad de vida, mejoró estadísticamente significativa en la función física del SF-36 (3.41,+/-6.96) comparada con placebo (-0.20, +/-7.14). La hospitalización fue menor en el grupo de ambrisentan (OR=0,39 (IC95% 0,16-0,97)) comparado contra placebo. Conclusiones: de acuerdo con los hallazgos de una RSL de alta calidad el ambrisentan es una tecnología segura, con efectos a favor, ya que disminuye la mortalidad de los pacientes con HTP, mejora la distancia recorrida en la prueba de 6 minutos, mejora la prueba de disnea de Borg, disminuye la hospitalización y mejora la CVRS en el constructo de función física. No se encontró evidencia para el desenlace de atrioseptostomía. En general el ambrisentan es bien tolerado, comparado con el placebo, el perfil de seguridad de la tecnología en cuanto a hepatoxicidad es a favor del ambrisentan. Los eventos adversos más frecuentes reportados en el grupo de ambrisentan fueron edema periférico, cefalea, sinusitis, flushing y congestión nasal comparados contra el placebo.