Neutral endopeptidase (EC in cirrhotic liver: a new target to treat portal hypertension?

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Sansoe G, Aragno M, Mastrocola R, Restivo F, Mengozzi G, Smedile A, Rosina F, Danni O, Parola M, Rizzetto M

Neutral endopeptidase (EC in cirrhotic liver: a new target to treat portal hypertension?

J Hepatol. 2005 Nov;43(5):791-8. Epub 2005 Jun 20.

PubMed ID
16085334 [ View in PubMed

BACKGROUND/AIMS: In liver cirrhosis atrial natriuretic peptide (ANP) decreases portal vascular resistance and tributary flow. The enzyme neutral endopeptidase (NEP) degrades ANP and bradykinin and generates endothelin-1 from big-endothelin. We determined the effects of NEP inhibition by candoxatrilat on hormonal status, liver function and arterial and portal pressures in rats with CCl4-induced cirrhosis. METHODS: Two groups of seven control rats received 1 ml 5% glucose solution alone or containing 10 mg/kg candoxatrilat; three groups of 10 ascitic cirrhotic rats received placebo, 5 or 10 mg/kg candoxatrilat. NEP protein concentration and immunostaining were analyzed in normal and cirrhotic livers. RESULTS: In cirrhotic rats 10 mg/kg candoxatrilat significantly increased steady-state indocyanine green clearance (a parameter reflecting liver plasma flow) (P<0.01), decreased portal pressure (P<0.01), had no effect on arterial pressure and plasma renin activity but increased ANP plasma levels (P<0.05) and urinary excretions (P<0.01) of ANP and cGMP. In the cytosol fraction of rat cirrhotic livers a 280% increase in NEP content was found (P<0.01), chiefly localized in desmin-positive myofibroblast-like cells of fibrous septa. CONCLUSIONS: Candoxatrilat has few effects on systemic hemodynamics and hormonal status; its portal hypotensive action depends on effects exerted on intrahepatic vascular resistance.

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