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This Article Full Text Full Text (PDF) All Versions of this Article: 288/2/H722    most recent 00737.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Abassi, Z. A. Articles by Hoffman, A. Search for Related Content PubMed PubMed Citation Articles by Abassi, Z. A. Articles by Hoffman, A.

Cardiac and renal effects of omapatrilat, a vasopeptidase inhibitor, in rats with experimental congestive heart failure

¹Department of Physiology and Biophysics, Rappaport Family Institute for Research in the Medical Sciences, Bruce Rappaport Faculty of Medicine, Technion; Departments of ²Vascular Surgery and ³Internal Medicine E, Rambam Medical Center, Haifa; and ⁴Department of Pathology, Shaare Zedek Medical Center, Jerusalem, Israel

Submitted 22 July 2004 ; accepted in final form 5 October 2004

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 (U_NaV) > 1,200 µeq/day] and decompensated (U_NaV < 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 [U_NaV increased from 0.67 ± 0.19 to 3.27 ± 1.35 µeq/min, P < 0.05; fractional sodium excretion (FE_Na) 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 (FE_Na 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 U_NaV 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 0.41–0.43% (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.

cardiac hypertrophy; renal function; rat; angiotensin-converting enzyme inhibitor; neutral endopeptide inhibitor