title: Neutral endopeptidase (EC 3.4.24.11) in cirrhotic liver: a new target to treat portal hypertension?
abstract: 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.
authors.affiliation: Gastroenterology Unit, Gradenigo Hospital, Turin, Italy. giovannisan@iol.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sansoè
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mastrocola
authors.forename: Francesca
authors.initials: F
authors.lastname: Restivo
authors.forename: Giulio
authors.initials: G
authors.lastname: Mengozzi
authors.forename: Antonina
authors.initials: A
authors.lastname: Smedile
authors.forename: Floriano
authors.initials: F
authors.lastname: Rosina
authors.forename: Oliviero
authors.initials: O
authors.lastname: Danni
authors.forename: Maurizio
authors.initials: M
authors.lastname: Parola
authors.forename: Mario
authors.initials: M
authors.lastname: Rizzetto
mesh_terms: 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*
chemical_list: 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