Neutral endopeptidase (EC 3.4.24.11) in cirrhotic liver: a new target to treat portal hypertension?
OBJECTIVE
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.
Sansoè
Giovanni
G
Gastroenterology Unit, Gradenigo Hospital, Turin, Italy. giovannisan@iol.it
Aragno
Manuela
M
Mastrocola
Raffaella
R
Restivo
Francesca
F
Mengozzi
Giulio
G
Smedile
Antonina
A
Rosina
Floriano
F
Danni
Oliviero
O
Parola
Maurizio
M
Rizzetto
Mario
M
D000818:Animals; D001127:Arginine Vasopressin / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002251:Carbon Tetrachloride / Q000633:toxicity; D006152:Cyclic GMP / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy*; D008099:Liver / Q000166:cytology / Q000201:enzymology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000201:enzymology*; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology; D011480:Protease Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*
D003509:Cyclohexanecarboxylic Acids; D016207:Cytokines; D019332:Endothelin-1; D011480:Protease Inhibitors; D001127:Arginine Vasopressin; C060942:candoxatrilat; D009320:Atrial Natriuretic Factor; D002251:Carbon Tetrachloride; D015260:Neprilysin; D006152:Cyclic GMP