Submitted on July 22, 2004
Accepted on October 5, 2004
Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart Failure
Zaid A. Abassi1*, Ali Yahia1, Samar Zeid1, Tony Karram1, Eliahu Golomb1, Joseph Winaver1, and Aaron Hoffman1
1 Department of Physiology and Biophysics, Rappaport Family Institute for Research in the Medical Sciences, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
* To whom correspondence should be addressed. E-mail: abassi{at}tx.technion.ac.il.
Omapatrilat (OMP) is a novel mixed inhibitor of angiotensin converting enzyme (ACE) and neutral endopeptidase 24.11 (NEP), the enzyme which metabolizes natriuretic peptides. Congestive heart failure (CHF) is characterized by excessive sodium retention, attributed to both excessive effect of angiotensin-II and diminished responsiveness to natriuretic peptides. In this study, we examined the acute and chronic renal effects of OMP in rats with compensated (Urinary sodium excretion (UNaV) >1200 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)- 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±6 to 71± 6 mmHg, p<0.01). Two weeks following ACF, 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 urinary Na+ excretion (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 0.41% (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.
