title: Role of neutral endopeptidase 24.11 in AV fistular rat model of heart failure.
abstract: OBJECTIVE
  The aortovenocaval fistular (AVF) rat represents a model of heart failure caused by increased cardiac volume overload and reduced renal function. Both circulating vasoconstrictors like the renin-angiotensin-aldosterone system and vasodilators like atrial and brain natriuretic peptides (ANP and BNP) are activated in this animal model of heart failure. In addition, neutral endopeptidase 24.11 (NEP) in plasma and urine is elevated in AVF rats. In the present investigation we examined the renal and hormonal effects of the NEP inhibitor, ecadotril, in acute and chronic studies in rats with an aortovenocaval fistula (AVF).
  
  
  METHODS
  Sprague Dawley rats (350-430 g) were prepared by introducing a shunt between abdominal aorta and the vena cava.
  
  
  RESULTS
  Acute administration of the neutral endopeptidase inhibitor, ecadotril (30 mg/kg p.o.), significantly improved the reduced renal excretion of sodium in AVF rats (83 +/- 10 to 145 +/- 14 mumol/kg/h, P < 0.01) but had no significant effect in sham-operated rats. However, neutral endopeptidase activity in urine was significantly decreased after ecadotril in both groups. Plasma ANP was increased after ecadotril only in AVF rats (275 +/- 83 to 748 +/- 187 pg/ml, P < 0.05), whereas the increase in plasma BNP was not statistically significant. After 4 weeks of observation the ANP and BNP plasma levels, renin activity (PRA), angiotensin I, and neutral endopeptidase activity were significantly higher in AVF rats than in sham-operated rats. Four weeks on ecadotril (30 mg/kg p.o., b.i.d.) increased plasma ANP (245 +/- 48 as opposed to 450 +/- 77 pg/ml, P < 0.05) and decreased PRA (11.3 +/- 1.5 as opposed to 6.8 +/- 1.2 ng/ml/h, P < 0.005) in AVF rats. Plasma NEP activity was inhibited in both groups. Ventricle weight was significantly higher in AVF rats than in sham-operated controls, and ecadotril treatment over 4 weeks decreased ventricular hypertrophy to a slight extent.
  
  
  CONCLUSIONS
  These results indicate that in the AVF rat model of heart failure the neutral endopeptidase inhibitor, ecadotril, improves the reduced kidney function in AVF rats by raising natriuretic peptides in plasma and probably in urine. NEP inhibition with ecadotril could therefore offer useful therapeutic possibilities in the treatment of heart failure.
authors: Bayer AG, Wuppertal, Germany.
authors: M
authors: M
authors: Wegner
authors: C
authors: C
authors: Hirth-Dietrich
authors: J P
authors: JP
authors: Stasch
mesh_terms: D000803:Angiotensin I / Q000097:blood; D000818:Animals; D001011:Aorta; D001164:Arteriovenous Fistula / Q000097:blood / Q000201:enzymology* / Q000652:urine; D009320:Atrial Natriuretic Factor / Q000097:blood; D004195:Disease Models, Animal; D006333:Heart Failure / Q000097:blood / Q000201:enzymology* / Q000652:urine; D020097:Natriuretic Peptide, Brain; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000502:physiology* / Q000652:urine; D009419:Nerve Tissue Proteins / Q000097:blood; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D012964:Sodium / Q000652:urine; D015244:Thiorphan / Q000031:analogs & derivatives / Q000494:pharmacology; D014684:Venae Cavae
chemical_list: D009419:Nerve Tissue Proteins; D011480:Protease Inhibitors; D020097:Natriuretic Peptide, Brain; C049331:racecadotril; D009320:Atrial Natriuretic Factor; D000803:Angiotensin I; D012964:Sodium; D015244:Thiorphan; D012083:Renin; D015260:Neprilysin