PULMONARY AND RENAL NEUTRAL ENDOPEPTIDASE EC-3.4.24.11 IN RATS WITH EXPERIMENTAL HEART-FAILURE

Congestive heart failure is characterized by avid sodium retention and a blunted renal response to exogenous and endogenous atrial natriuret ic peptide. Inhibition of neutral endopeptidase EC 3.4.24.11, the main enzyme that degrades natriuretic peptides, produces a natriuretic res ponse in different models of congestive heart failure. This raises the possibility that an increase in either the expression or activity of neutral endopeptidase is responsible for these phenomena. In the prese nt study, we examined (1) the renal effects of SQ-28,603, a neutral en dopeptidase inhibitor, in rats with moderate and severe congestive hea rt failure induced by an aortocaval fistula compared with sham control s, and (2) neutral endopeptidase expression and activity in the lungs and kidneys of these rats. Infusion of SQ-28,603 (40 mg/kg IV) induced a significant natriuretic response in normal rats and rats with moder ate congestive heart failure. This response was blunted in rats with s evere congestive heart failure. Surprisingly, renal neutral endopeptid ase mRNA levels, assessed by quantitative reverse transcriptase-polyme rase chain reaction; protein levels, assessed by Western blotting; and activity, assessed by gelatin gels, were comparable in all groups. Pu lmonary neutral endopeptidase mRNA levels decreased by 45% in rats wit h severe congestive heart failure but not in rats with mild congestive heart failure. In addition, pulmonary neutral endopeptidase immunorea ctivity levels and activity were significantly decreased in congestive heart failure in correlation with the severity of the disorder. We co nclude that an increase in neutral endopeptidase expression or activit y does not occur in rats with congestive heart failure, and therefore, an upregulation of neutral endopeptidase is unlikely to account for t he blunted natriuretic response to the atrial natriuretic peptide and the positive sodium balance in congestive heart failure.