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The purpose of this study was the assessment of kidney neutral endopeptidase expression and responses to candoxatrilat (a specific inhibitor of this enzyme) in rats with CCl<jats:sub>4<\/jats:sub>-induced cirrhosis. Two groups of control rats ( n = 5) were injected with vehicle or 3 mg\/kg candoxatrilat. Three groups of cirrhotic rats with ascites ( n = 10) received vehicle alone or 3 or 10 mg\/kg candoxatrilat. In cirrhotic rats, Western blot analysis revealed a 170% increase in renal neutral endopeptidase protein content ( P &lt; 0.03), mainly in the proximal nephron and macula densa, and both candoxatrilat dosages increased plasma ANP levels, urinary volume, and urinary excretion of sodium, ANP, and cGMP compared with vehicle alone (all P &lt; 0.03). Candoxatrilat (10 mg\/kg) also reduced tubular solute-free water reabsorption ( P &lt; 0.03) in cirrhotic rats, but renal blood flow, arterial pressure, and plasma renin activity were unaffected. 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