Neutral endopeptidase (EC 3.4.24.11) in cirrhotic liver: a new target to treat portal hypertension?

Abstract

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.

• Authors: Giovanni Sansoè, Manuela Aragno, Raffaella Mastrocola, Francesca Restivo, Giulio Mengozzi, Antonina Smedile, Floriano Rosina, Oliviero Danni, Maurizio Parola, Mario Rizzetto
• Journal: Journal of hepatology (J Hepatol) Vol. 43 Issue 5 Pg. 791-8 (Nov 2005) ISSN: 0168-8278 [Print] Netherlands
• PMID: 16085334 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclohexanecarboxylic Acids
• Cytokines
• Endothelin-1
• Protease Inhibitors
• Arginine Vasopressin
• candoxatrilat
• Atrial Natriuretic Factor
• Carbon Tetrachloride
• Neprilysin
• Cyclic GMP

Topics

• Animals
• Arginine Vasopressin (metabolism)
• Atrial Natriuretic Factor (metabolism)
• Blood Pressure (drug effects, physiology)
• Carbon Tetrachloride (toxicity)
• Cyclic GMP (metabolism)
• Cyclohexanecarboxylic Acids (metabolism, pharmacology, therapeutic use)
• Cytokines (metabolism)
• Endothelin-1 (metabolism)
• Humans
• Hypertension, Portal (drug therapy)
• Liver (cytology, enzymology)
• Liver Cirrhosis, Experimental (chemically induced, enzymology)
• Male
• Neprilysin (antagonists & inhibitors, metabolism)
• Portal Vein (drug effects, physiology)
• Protease Inhibitors (metabolism, therapeutic use)
• Rats
• Rats, Wistar
• Vascular Resistance (drug effects, physiology)