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J Mol Cell Cardiol ; 52(3): 660-6, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22155238

RESUMEN

The study addressed the hypothesis that soluble epoxide hydrolase (sEH) inhibition, which increases cardiovascular protective epoxyeicosatrienoic acids (EETs), exerts beneficial effects in an established chronic heart failure (CHF) model. In CHF rats, left ventricular (LV) function, perfusion and remodeling were assessed using MRI and invasive hemodynamics after 42-day (starting 8 days after coronary ligation) and delayed 3-day (starting 47 days after coronary ligation) treatments with the sEH inhibitor AUDA (twice 0.25 mg/day). Delayed 3-day and 42-day AUDA increased plasma EETs demonstrating the effective inhibition of sEH. Delayed 3-day and 42-day AUDA enhanced cardiac output without change in arterial pressure, thus reducing total peripheral resistance. Both treatment periods increased the slope of the LV end-systolic pressure-volume relation, but only 42-day AUDA decreased LV end-diastolic pressure, relaxation constant Tau and the slope of the LV end-diastolic pressure-volume relation, associated with a reduced LV diastolic volume and collagen density. Delayed 3-day and, to a larger extent, 42-day AUDA increased LV perfusion associated with a decreased LV hypoxia-inducible factor-1alpha. Both treatment periods decreased reactive oxygen species level and increased reduced-oxidized glutathione ratio. Finally, MSPPOH, an inhibitor of the EET-synthesizing enzyme cytochrome epoxygenases, abolished the beneficial effects of 3-day AUDA on LV function and perfusion. Augmentation of EET availability by pharmacological inhibition of sEH increases LV diastolic and systolic functions in established CHF. This notably results from short-term processes, i.e. increased LV perfusion, reduced LV oxidative stress and peripheral vasodilatation, but also from long-term effects, i.e. reduced LV remodeling.


Asunto(s)
Circulación Coronaria , Epóxido Hidrolasas/antagonistas & inhibidores , Insuficiencia Cardíaca/enzimología , Insuficiencia Cardíaca/fisiopatología , Miocardio/enzimología , Adamantano/administración & dosificación , Adamantano/análogos & derivados , Adamantano/farmacología , Animales , Circulación Coronaria/efectos de los fármacos , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Epóxido Hidrolasas/metabolismo , Insuficiencia Cardíaca/tratamiento farmacológico , Hemodinámica/efectos de los fármacos , Ácidos Láuricos/administración & dosificación , Ácidos Láuricos/farmacología , Masculino , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/enzimología , Infarto del Miocardio/fisiopatología , Óxido Nítrico/metabolismo , Estrés Oxidativo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Transducción de Señal , Función Ventricular Izquierda/efectos de los fármacos , Remodelación Ventricular/efectos de los fármacos
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