Neutral endopeptidase degrades
atrial natriuretic peptide (
ANP) and
bradykinin and may generate
endothelin-1 from
big-endothelin. In advanced
cirrhosis,
sodium retention is accompanied by elevated plasma
ANP levels, and infusion of
ANP causes
hypotension, but in normal humans increasing the concentration of
ANP through the inhibition of
neutral endopeptidase, localized in renal proximal tubule cells, causes natriuresis without any arterial pressure drop. 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 CCl4-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 < 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 < 0.03).
Candoxatrilat (10 mg/kg) also reduced tubular solute-free water reabsorption (P < 0.03) in cirrhotic rats, but renal blood flow, arterial pressure, and plasma
renin activity were unaffected.
Neutral endopeptidase inhibition has natriuretic and aquaretic actions in
cirrhosis without any effect on blood pressure and kidney perfusion due to a significant overexpression of this
enzyme in renal cortex.