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Omapatrilat (OMP) is a novel mixed inhibitor of angiotensin-converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), the enzyme that metabolizes natriuretic peptides. Congestive heart failure (CHF) is characterized by excessive sodium retention, attributed to both an excessive effect of angiotensin II and diminished responsiveness to natriuretic peptides. In this study, we examined the acute and chronic renal and cardiac effects of OMP in rats with compensated [urinary sodium excretion (UNaV) > 1,200 µeq/day] and decompensated (UNaV < 100 µeq/day) CHF, induced by a surgical aortocaval fistula (ACF). Bolus injection of OMP (10 mg/kg) to sham controls produced significant diuretic and natriuretic responses [UNaV increased from 0.67 ± 0.19 to 3.27 ± 1.35 µeq/min, P < 0.05; fractional sodium excretion (FENa) increased from 0.23 ± 0.06 to 0.95 ± 0.34%, P < 0.01] despite a significant decline in blood pressure (BP). Rats with compensated CHF displayed blunted diuresis and natriuresis to this dose of OMP but a significant decrease in BP. However, in rats with decompensated CHF, OMP induced significant natriuresis (FENa increased from 0.18 ± 0.15 to 0.82 ± 0.26%, P < 0.05) despite a further decrease in BP (from 90 ± 9 to 71 ± 6 mmHg, P < 0.01). Two weeks after ACF, the heart/body weight ratio was significantly greater in rats with CHF than controls (0.51 ± 0.026 vs. 0.30 ± 0.004%, P < 0.0001), and UNaV was significantly lower. Immediate or late (1 or 6 days after ACF) OMP treatment in the drinking water (140 mg/l) reduced cardiac hypertrophy to 0.410.43% (P < 0.01) and induced natriuresis. These results suggest that OMP improves both sodium balance and cardiac remodeling and might be advantageous to ACE inhibitors for the treatment of decompensated CHF. [ABSTRACT FROM AUTHOR]