Publication: Vasodilatadores en la hipertensión pulmonar: selectividad por el territorio vascular, por oxígeno y efectos antiproliferativos
Loading...
Files
Official URL
Full text at PDC
Publication Date
2017-08-30
Authors
Advisors (or tutors)
Editors
Journal Title
Journal ISSN
Volume Title
Publisher
Universidad Complutense de Madrid
Citations
Exportar
Abstract
La Hipertensión Pulmonar (HP) es una enfermedad crónica y progresiva. La HP presenta una compleja fisiopatología caracterizada por vasoconstricción, remodelado vascular y trombosis. Las terapias actuales muestran efectos beneficiosos, sin embargo presentan también importantes limitaciones: 1) pobre selectividad pulmonar, 2) modesta eficacia vasodilatadora, 3) desacoplamiento de la ventilación/perfusión (V/Q) e 4) incapacidad para prevenir la progresión de la enfermedad. La quercetina es un flavonoide natural que se consume en la dieta. Ejerce efectos in vitro como vasodilatador, antiagregante y antiproliferativo. Además, reduce la presión arterial, la hipertrofia cardíaca y el remodelado vascular en modelos animales de hipertensión arterial. Hipótesis y objetivos La hipótesis general de esta tesis es que los fármacos vasodilatadores sensibles al oxígeno con selectividad pulmonar son eficaces para reducir la presión arterial pulmonar (PAP) y para preservar o mejorar la oxigenación arterial. El objetivo general de esta tesis es analizar los efectos vasodilatadores y antiproliferativos de una amplia gama de fármacos con el fin de identificar aquellos que potencialmente presenten una mejor eficacia y menos efectos secundarios, basado en su capacidad para: 1) combinar los efectos como vasodilatador y antiproliferativo, 2) ejercer efectos vasodilatadores selectivos en la circulación pulmonar, evitando la hipotensión sistémica, 3) inducir vasodilatación selectiva en zonas bien oxigenadas (preservando la vasoconstricción pulmonar hipóxica‐VPH) y 4) ejercer vasodilatación eficaz en condiciones de sensibilización al calcio. Material y métodos La selectividad pulmonar y por oxígeno se evaluaron utilizando arterias mesentérica y pulmonares (AP) de ratas y AP humanas bajo diferentes condiciones de oxigenación en un miógrafo isométrico. Las preparaciones se estimularon con una mezcla de serotonina, U46619 y endotelina‐1 antes de realizar curvas concentración‐respuesta a diferentes fármacos...
Pulmonary hypertension (PH) is a life‐threatening chronic and progressive disease. PH exhibits a complex pathophysiology characterized by vasoconstriction, vascular remodeling and micro‐thrombosis. Current therapies exert some beneficial effects; however they have a number of important limitations: 1) poor pulmonary selectivity 2) modest vasodilator efficacy, 3) ventilation/perfusion (V/Q) mismatch and 4) unability to prevent the progression of the disease. Quercetin is a natural flavonoid consumed in the diet that exerts vasodilator, antiagregant and antiproliferative effects in vitro, and reduces blood pressure, cardiac hypertrophy and vascular remodelling in animal models of arterial hypertension. Hypothesis and aim The general hypothesis of this thesis is that oxygen‐sensitive vasodilators with pulmonary selectivity are effective in lowering pulmonary arterial pressure (PAP) and preserve or improve arterial oxygenation. The general aim of this thesis is to analyze the vasodilator and antiproliferative effects of a wide range of drugs in order to identify those with potentially better efficacy and fewer side effects, based on their ability to: 1) combine both vasodilator and antiproliferative effects, 2) exert selective vasodilator effects in the pulmonary circulation, avoiding systemic hypotension, 3) induce selective vasodilator effects in the oxygenated lung areas (preserving hypoxic pulmonary vasoconstriction‐HPV) and 4) exert effective vasodilator effects under calcium‐sensitizing conditions. Matherial and methods Pulmonary and oxygen selectivity were assessed using mesenteric and pulmonary arteries (PA) from rats and human PA under different conditions of oxygenation. The preparations were stimulated with a mixture of serotonin, U46619 and endothelin‐1 before the concentration‐response curves to different drugs. In other set of experiments, HPV was recorded in rat PA. Vasodilator responses were evaluated in a wire myograph...
Pulmonary hypertension (PH) is a life‐threatening chronic and progressive disease. PH exhibits a complex pathophysiology characterized by vasoconstriction, vascular remodeling and micro‐thrombosis. Current therapies exert some beneficial effects; however they have a number of important limitations: 1) poor pulmonary selectivity 2) modest vasodilator efficacy, 3) ventilation/perfusion (V/Q) mismatch and 4) unability to prevent the progression of the disease. Quercetin is a natural flavonoid consumed in the diet that exerts vasodilator, antiagregant and antiproliferative effects in vitro, and reduces blood pressure, cardiac hypertrophy and vascular remodelling in animal models of arterial hypertension. Hypothesis and aim The general hypothesis of this thesis is that oxygen‐sensitive vasodilators with pulmonary selectivity are effective in lowering pulmonary arterial pressure (PAP) and preserve or improve arterial oxygenation. The general aim of this thesis is to analyze the vasodilator and antiproliferative effects of a wide range of drugs in order to identify those with potentially better efficacy and fewer side effects, based on their ability to: 1) combine both vasodilator and antiproliferative effects, 2) exert selective vasodilator effects in the pulmonary circulation, avoiding systemic hypotension, 3) induce selective vasodilator effects in the oxygenated lung areas (preserving hypoxic pulmonary vasoconstriction‐HPV) and 4) exert effective vasodilator effects under calcium‐sensitizing conditions. Matherial and methods Pulmonary and oxygen selectivity were assessed using mesenteric and pulmonary arteries (PA) from rats and human PA under different conditions of oxygenation. The preparations were stimulated with a mixture of serotonin, U46619 and endothelin‐1 before the concentration‐response curves to different drugs. In other set of experiments, HPV was recorded in rat PA. Vasodilator responses were evaluated in a wire myograph...
Description
Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Farmacología, leída el 22-12-2016