Acute hemodynamic, hormonal, and renal effects of neutral endopeptidase inhibition in ovine heart failure.
The effects of neutral endopeptidase inhibition (NEP-I) were studied in 6 conscious sheep with heart failure (HF) induced by rapid ventricular pacing for 7 days. Measurements were performed 1 h before and for 6 h after intravenous (i.v.) bolus administration of vehicle and SCH 39370 (1.25 and 5 mg/kg) on separate days. After the higher dose, an index of serum NEP activity decreased from 0.83 +/- 0.05 to 0.13 +/- 0.07 nmol/ml/min (p less than 0.001) at 1 h and then returned to control levels at 6 h. Plasma atrial natriuretic peptide (ANP) and cyclic GMP rose from 328 +/- 28 and 20.2 +/- 4.3 to a peak of 570 +/- 65 pmol/L (p less than 0.001) and 28.7 +/- 6.3 nmol/L (p less than 0.05) respectively. Natriuresis and diuresis were significant and left atrial pressure (LAP) decreased from 21.9 +/- 1.1 to 20.1 +/- 0.8 mm Hg (p less than 0.05). Despite high endogenous ANP levels in HF, NEP-I further increases both ANP and its "second messenger." Its natriuretic and hemodynamic effects are consistent with enhanced ANP activity in renal and vascular tissues, suggesting that NEP-I may be useful for treating HF.
Fitzpatrick
M A
MA
Department of Cardiology, Princess Margaret Hospital, Christchurch, New Zealand.
Rademaker
M T
MT
Charles
C J
CJ
Yandle
T G
TG
Espiner
E A
EA
Ikram
H
H
Sybertz
E
E
D000704:Analysis of Variance; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood*; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D006152:Cyclic GMP / Q000097:blood; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects*; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D009318:Natriuresis / Q000187:drug effects; D015260:Neprilysin / Q000037:antagonists & inhibitors*
D004151:Dipeptides; C060631:Sch 39370; D005665:Furosemide; D009320:Atrial Natriuretic Factor; D015260:Neprilysin; D006152:Cyclic GMP